Mild Rh(III)-catalyzed C7-allylation of indolines with allylic carbonates

Article abstract of DOI:10.1021/jo502733q

The rhodium(III)-catalyzed direct allylation of indolines with allylic carbonates at room temperature is described. These transformations provide the facile and efficient construction of C7-allylated indolic scaffold.

Full text of DOI:10.1021/jo502733q

Article
pubs.acs.org/joc
Mild Rh(III)-Catalyzed C7-Allylation of Indolines with Allylic
Carbonates
Jihye Park,† Neeraj Kumar Mishra,† Satyasheel Sharma,† Sangil Han,† Youngmi Shin,† Taejoo Jeong,†
Joa Sub Oh,‡ Jong Hwan Kwak,† Young Hoon Jung,† and In Su Kim*,†
†School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
‡College of Pharmacy, Dankook University, Cheonan 330-714, Republic of Korea
S
* Supporting Information
ABSTRACT: The rhodium(III)-catalyzed direct allylation of indolines with allylic carbonates at room temperature is described.
These transformations provide the facile and efficient construction of C7-allylated indolic scaffold.
Aspergillus of ascomycota, and display broad structural
diversity.14 The prevalence of allylated indoles and indolines
in bioactive natural products and the versatility of olefin
transformations have led to the development of many useful
methods for their preparation.15,16 Notably, the C7-allylated
indoles and indolines are known as pivotal heterocyclic
compounds found in a number of bioactive synthetic molecules
and natural products, as shown in Figure 1.17
Recently, the directing group-assisted catalytic C7-function-
alizations of indolines with various coupling partners were
demonstrated (Scheme 1). For example, acylation,18 aryla-
tion,19 olefination,20 alkylation,21 and alkynylation22 of indo-
INTRODUCTION
■
Transition-metal-catalyzed C−H bond functionalization has
emerged as a powerful tool due to its remarkable potential for
step economy and environmental sustainability.1 With the
development of catalytic C−H bond functionalization, it has
become the most straightforward protocol leading to allylated
molecules. For example, Oi and Inoue first reported the
ruthenium-catalyzed direct allylation of 2-phenylpyridines with
allylic acetates affording a regioisomeric mixture of olefins.2
Bergman and Ellman described a single example for the
Rh(III)-catalyzed allylation of a ketoxime with allyl acetate in
the presence of copper oxidant to deliver a terminal alkene.3
Glorius disclosed a beautiful protocol on the Rh(III)-catalyzed
terminal allylation of benzamides and indoles with allylic
carbonates.4 In sharp contrast, Loh demonstrated the Rh(III)-
catalyzed internal allylation of benzamides with allylic acetates
to provide conjugated olefins.5 Friedel−Crafts-type C−H
allylations of aromatic compounds with allylic carbonates
under ruthenium catalysis were also demonstrated.6 Very
recently, direct C−H allylations of electron-deficient poly-
fluoroarenes and heterocycles under copper and palladium
catalysis were reported.7 Moreover, Krische,8 Ma,9 and
Cramer10 independently described the Ir- or Rh-catalyzed
allylation reactions of benzamides using allenes as allyl sources.
Interestingly, Glorius has recently reported the selective and
efficient Co(III)-catalyzed C−H allylation of indoles with allyl
carbonates.11 In addition, Wang demonstrated the Rh(III)-
catalyzed direct C−H allylation reaction with 4-vinyl-1,3-
dioxolan-2-ones to afford allylic alcohols.12
Figure 1. Selected examples for synthetic or natural C7-allylated
products.
The indoles and indolines are ubiquitous structural motifs
found in a large number of natural products with diverse and
important biological activities.13 In particular, the allylated
indole or indoline alkaloids are widely distributed in terrestrial
and marine organisms, especially in the genera Penicillium and
Received: December 3, 2014
Published: January 13, 2015
© 2015 American Chemical Society
1818
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827

The Journal of Organic Chemistry
Article
(Table 1, entry 3). Thus, we focused on the screening of other
carbamoyl directing groups. Interestingly, N-butylindoline-1-
carboxamide (1f), derived from indoline and n-butyl isocyanate,
was found to be far more effective in this coupling reaction to
afford our desired product 3f with high terminal selectivity
(9.5:1) in 80% yield (Table 1, entry 6).
Scheme 1. Catalytic C7-Functionalization of Indolines
With the optimal directing group of indolines in hand, we
further optimized the reaction conditions to afford increased
terminal selectivity (Table 2). Screening of solvents under
a
Table 2. Selected Optimization of the Reaction Conditions
b
c
entry
additive (mol %)
solvent
yield (%)
ratio (3f:4f)
lines at the C-7 position were described under ruthenium,
palladium, rhodium, iron, and iridium catalysis. In addition,
Ru(II)- or Ir(III)-catalyzed C7-aminations of indolines with
organic azides were reported by Zhu, Chang, and Zhou/Li,
respectively.23 Inspired by our recent study on the decarbox-
ylative acylation of indolines at the C7-position24 and in
continuation of the catalytic C−H allylation of aromatic and
α,β-unsaturated carboxamides,25 we herein disclose the
rhodium-catalyzed direct allylation and crotylation of indolines
with allylic carbonates via C−H bond activation.
1
2
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2·H2O (50)
PivOH (50)
DCE
80
39
29
5
9.5:1
5.7:1
7.5:1
1.0:1
8.9:1
>50:1
7.1:1
>50:1
6.3:1
>50:1
trace
0
DMF
3
toluene
MeCN
4
5
THF
74
84
66
5
6
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
7
8
9
AgOAc (50)
57
81
NR
NR
10
11
Cu(OAc)2 (30)
d
RESULTS AND DISCUSSION
12
Cu(OAc)2 (30)
■
a
Our study was initiated by examining the coupling of N-acetyl
indoline (1a) and allyl methyl carbonate (2a) under rhodium
catalysis (Table 1). To our delight, the cationic rhodium
Reaction conditions: 1f (0.3 mmol), 2a (0.6 mmol), [RhCp*Cl2]2
(2.5 mol %), AgSbF6 (10 mol %), additive (quantity noted), solvent (1
mL) under air at room temperature for 20 h in reaction tubes.
b
c
Isolated yield by flash column chromatography. Regioisomeric ratio
a
between terminal and internal olefins determined by 1H NMR analysis
Table 1. Screening of N-Protection Groups
d
of crude reaction mixture. In the absence of AgSbF6.
otherwise identical conditions revealed that tert-amyl alcohol (t-
AmOH) was found to be the most effective solvent in this
coupling reaction to afford terminal olefination product 3f in
high yield (84%) with excellent level of regioselectivity (>50:1),
whereas other solvents such as DCE, DMF, toluene, MeCN,
and THF were less effective (Table 2, entries 1−6). Further
study revealed that Cu(OAc)2 additive is unique in its ability to
facilitate high levels of conversion and selectivity (Table 2,
entries 7−9). In addition, decreasing amount of Cu(OAc)2 to
30 mol % provided a comparable yield (81%) and selectivity
(>50:1) (Table 2, entry 10), but no formation of 3f was
observed when either Cu(OAc)2 or AgSbF6 were excluded
(Table 2, entries 11 and 12).
To evaluate the scope and limitation of this process, the
optimal reaction conditions were applied to a range of N-butyl
carbamoyl indolines 1g−1t (Table 3). In all cases, good to
excellent yields and high terminal selectivity of the desired aryl
C−H allylation adducts were obtained. Exceptionally, indoline
1g with electron-rich moiety at the C4-position exhibited
slightly decreased reactivity. It should be noted that C6-
substituted indolines 1j and 1k were tolerated under current
reaction conditions to afford the corresponding products in
high yields and excellent level of regioselectivity. In addition,
this reaction was highly compatible with C2-substituted
indolines 1l, 1q, and 1r. To our surprise, this reaction is only
restricted to indolines. For example, N-methyl aniline 1s and
tetrahydroquinoline 1t containing a N-butylcarbamoyl directing
b
c
entry
R
substrate
yield (%)
ratio (3:4)
1
2
3
4
5
6
Me
1a
1b
1c
1d
1e
1f
55
37
35
12
19
80
1.9:1
1.4:1
6.9:1
3.5:1
10.9:1
9.5:1
t-Bu
NMe2
pyrrolidinyl
NHPh
NHnBu
a
Reaction conditions: 1a−1f (0.3 mmol), 2a (0.6 mmol),
[RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (50 mol
%), DCE (1 mL) under air at room temperature for 20 h in reaction
tubes. Isolated yield by flash column chromatography. Regioisomeric
ratio between terminal and internal olefins determined by H NMR
b
c
1
analysis of crude reaction mixture.
complex, derived from [Cp*RhCl2]2 and AgSbF6, was found to
catalyze the coupling of 1a and 2a in the presence of Cu(OAc)2
as an additive in dichloroethane (DCE) at room temperature
for 20 h to provide the C7-allylated product 3a with a
regioisomeric mixture of 1.9:1 ratio in 55% yield (Table 1, entry
1). Similarly, pivaloyl directing group 1b displayed low level of
both reactivity and selectivity (Table 1, entry 2). However,
N,N-dimethylcarbamoyl indoline (1c) gave terminal olefin 3c
with good level of regioselectivity (6.9:1), albeit in low yield
1819
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827

The Journal of Organic Chemistry
Article
a
Table 3. Scope of Indolines
a
Reaction conditions: 1f−1t (0.3 mmol), 2a (0.6 mmol), [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (30 mol %), t-AmOH (1 mL)
b
c
under air at room temperature for 20 h in reaction tubes. Isolated yield by flash column chromatography. Regioisomeric ratio between terminal
and internal olefins determined by H NMR analysis of crude reaction mixture. Scale-up experiment (1f, 3 mmol).
d
1
a
group failed to deliver the corresponding products under
standard reaction condtions.
Table 4. Scope of Allylic Carbonates
To further explore the scope and limitation of this
transformation, various allylic carbonates 2b−2f were screened
to couple with 1f, as shown in Table 4. The monosubstituted
allyl alkyl carbonates 2b−2d were smoothly coupled with 1f to
give the (Z)-crotylation products 5b−5d as major isomers in
high yields. In sharp contrast, α-phenyl-substituted allyl
carbonate 2e underwent completely trans-selectivity with 1f.
Notably, these reactions proceeded readily with complete γ-
selectivity in case of branched allylic carbonates, and no
migration of double bond on the products was observed.
However, linear crotyl carbonates and β-substituted allylic
carbonates did not deliver the corresponding coupling
products, presumably due to the increased steric hindrance of
electrophilic allylic carbonates, preventing formal SN-type
reactions with rhodacycle intermediate.26 In addition, α,α-
disubstituted allylic carbonate 2f was found to be unreactive
under the optimal reaction conditions.
To our delight, 2-vinyloxirane 2g was also coupled with
indoline 1f to afford a mixture of allylic alcohol 5g with 3:1 E/Z
ratio in 69% yield as a result of olefin insertion and epoxide
ring-opening, which is in agreement with the formal SN-type
reaction mechanism (Scheme 2).27
To demonstrate the synthetic utility of C7-allylated indo-
lines, various transformations of the allylated product 3f were
conducted (Scheme 3). Intermolecular olefin metathesis
between 3f and ethyl acrylate gave α,β-unsaturated ester 6a,
which subsequently underwent aza-Michael reaction to furnish
a
Reaction conditions: 1f (0.3 mmol), 2b−2f (0.6 mmol),
[RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (30 mol
%), t-AmOH (1 mL) under air at room temperature for 20 h in
reaction tubes. All cases provided the regioisomeric ratio of above 50:1
b
between terminal and internal olefins. Isolated yield by flash column
chromatography. Diastereomeric ratio between trans- and cis-olefins
determined by H NMR analysis. THF was used as a solvent. 40 h.
c
d
e
1
1820
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827

The Journal of Organic Chemistry
Article
Scheme 2. Indoline Allylation with 2-Vinyloxirane
Scheme 4. Mechanistic Investigations
tricyclic compound 6b in 45% yield. Interestingly, while
carrying out the deprotection of N-butylcarbamoyl group of
3f under standard basic conditions, we observed the
deprotection as well as olefin migration of 3f to provide free-
(NH)-indoline 6c in high yield. Subsequently this deprotected
product 6c under transfer hydrogenation conditions provided
smoothly C7-olefinated indole 6d in high yield.
To gain mechanistic insight, the following experiments were
performed (Scheme 4). A hydrogen−deuterium exchange using
MeOD indicated that the cleavage of the C−H bond at the
indoline C7-position was a reversible metalation−proto-
(deutero)demetalation process (Scheme 4a). In the presence
of allyl methyl carbonate (2a) and MeOD, no deuterium
incorporation of product 3a and significant deuteration (71%
D) of recovered starting material was observed (Scheme 4b).
Next, two parallel reactions of 1f and deuterio-1f with 2a under
standard reaction conditions resulted in the kinetic isotope
effect (kH/kD) of 2.89, thus indicating that C−H cleavage might
be involved in the rate-limiting step (Scheme 4c).28
Scheme 5. Proposed Reaction Mechanism
A proposed reaction mechanism was depicted in Scheme 5.
Coordination of the carbonyl group to cationic Rh(III) catalyst
and subsequent C−H cleavage delivers the cyclorhodated
species I, which on migratory insertion of a double bond into
Rh−C bond affords an eight-membered Rh(III) intermediate
II. Further, β-oxygen elimination provides the product 3f and
regenerates a Rh(III) catalyst. Alternatively, coordination of
allyl methyl carbonate to the cyclorhodated species I followed
by nucleophilic substitution can not be ruled out in the catalytic
cycle to afford 7-allylated product 3f.29
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of N-Acyl or N-
Carbamoyl Indolines (1a−1e). To a stirred solution of indoline
(1.00 g, 8.4 mmol) and triethylamine (3.5 mL, 25.2 mmol) in CH2Cl2
(10 mL) was added dropwise a solution of N-acyl or N-carbamoyl
chloride (12.6 mmol) in CH2Cl2 (7 mL) at 0 °C. The reaction mixture
was stirred at this temperature for 15 min and further stirred at room
temperature for 3 h. The resulting mixture was partitioned between
CH2Cl2 and H2O. The organic layer was dried over MgSO4 and
CONCLUSION
■
We have disclosed a highly selective C7-allylation of indolines
with allylic carbonates under rhodium catalysis. These trans-
formations have been applied to a wide range of substrates, and
typically proceed with excellent levels of chemoselectivity as
well as with high functional group tolerance.
Scheme 3. Synthetic Transformation of C7-Allylated Indolines
1821
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827

The Journal of Organic Chemistry
Article
concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, n-hexanes/EtOAc) to give the correspond-
ing products 1a−1e.
7.8 Hz, 2H), 3.33 (s, 2H), 3.17 (t, J = 7.9 Hz, 2H), 1.61−1.51 (m,
2H), 1.45−1.33 (m, 2H), 0.96 (t, J = 6.6 Hz, 3H); 13C NMR (175
MHz, CDCl3) δ 154.8, 143.0, 132.2, 130.4, 127.4, 116.1, 113.8, 47.0,
40.2, 32.2, 27.5, 20.1, 13.8; IR (KBr) υ 3343, 2956, 2928, 2871, 2176,
1645, 1519, 1468, 1327, 1298, 1253, 1154, 1090, 817, 734 cm−1;
HRMS (quadrupole, EI) calcd for C13H17BrN2O [M]+ 296.0524,
found 296.0522.
N-Butyl-5-chloroindoline-1-carboxamide (1i). 1.44 g (68%); light
yellow solid; mp = 87−91 °C; 1H NMR (300 MHz, CDCl3) δ 8.04 (d,
J = 8.1 Hz, 1H), 7.43 (s, 1H), 7.29−7.26 (m, 1H), 4.68 (br s, 1H),
4.07 (t, J = 8.9 Hz, 2H), 3.49−3.47 (m, 2H), 3.33 (t, J = 8.4 Hz, 2H),
1.77−1.68 (m, 2H), 1.62−1.50 (m, 2H), 1.15−1.10 (m, 3H); 13C
NMR (175 MHz, CDCl3) δ 154.9, 142.5, 131.8, 127.4, 126.4, 124.5,
115.6, 47.1, 40.2, 32.2, 27.6, 20.1, 13.8; IR (KBr) υ 3340, 2957, 2930,
2872, 1645, 1519, 1471, 1328, 1252, 1154, 1091, 874, 819, 733 cm−1;
HRMS (quadrupole, EI) calcd for C13H17ClN2O [M]+ 252.1029,
found 252.1034.
1-(Indolin-1-yl)ethanone (1a).20b 1.21 g (89%); white solid; mp =
102−104 °C; 1H NMR (700 MHz, CDCl3) δ 8.18 (d, J = 8.0 Hz, 1H),
7.18−7.14 (m, 2H), 6.98 (t, J = 7.4 Hz, 1H), 4.03 (t, J = 8.4 Hz, 2H),
3.18 (t, J = 8.4 Hz, 2H), 2.20 (s, 3H); 13C NMR (175 MHz, CDCl3) δ
168.7, 142.9, 131.0, 127.5, 124.5, 123.6, 117.0, 48.7, 28.0, 24.3.
1-(Indolin-1-yl)-2,2-dimethylpropan-1-one (1b).23a 1.33 g (78%);
1
light brown solid; mp = 54−58 °C; H NMR (500 MHz, CDCl3) δ
8.23 (d, J = 8.5 Hz, 1H), 7.19−7.17 (m, 2H), 7.02 (t, J = 7.0 Hz, 1H),
4.23 (t, J = 8.1 Hz, 2H), 3.14 (t, J = 8.1 Hz, 2H), 1.38 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 176.5, 144.7, 130.7, 127.3, 124.2, 123.6,
118.4, 49.4, 40.2, 29.3, 27.7.
N,N-Dimethylindoline-1-carboxamide (1c).20b 1.32 g (83%); light
brown solid; mp = 57−62 °C; 1H NMR (700 MHz, CDCl3) δ 7.13 (d,
J = 7.2 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.85
(t, J = 7.3 Hz, 1H), 3.87 (t, J = 8.2 Hz, 2H), 3.00 (t, J = 8.2 Hz, 2H),
2.91 (s, 6H); 13C NMR (175 MHz, CDCl3) δ 160.3, 144.3, 131.4,
120.7, 124.8, 121.3, 113.3, 50.3, 38.1, 28.1.
N-Butyl-6-fluoroindoline-1-carboxamide (1j). 1.29 g (65%); white
solid; mp = 114−116 °C; 1H NMR (300 MHz, CDCl3) δ 7.68 (d, J =
8.6 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.59−6.53 (m, 1H), 4.53 (br s,
1H), 3.91 (t, J = 9.0 Hz, 2H), 3.34−3.28 (m, 2H), 3.12 (t, J = 8.5 Hz,
2H), 1.59−1.50 (m, 2H), 1.44−1.32 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H);
13C NMR (175 MHz, CDCl3) δ 162.0 (d, JC−F = 239.5 Hz), 154.8,
Indolin-1-yl(pyrrolidin-1-yl)methanone (1d). 1.25 g (69%); light
1
yellow solid; mp = 76−85 °C; H NMR (700 MHz, CDCl3) δ 7.08−
7.03 (m, 3H), 6.79 (t, J = 7.2 Hz, 1H), 3.85 (t, J = 8.3 Hz, 2H), 3.39−
3.37 (m, 2H), 3.29−3.26 (m, 2H), 2.97 (t, J = 8.4 Hz, 2H), 1.82−1.80
(m, 2H), 1.75−1.72 (m, 2H); 13C NMR (175 MHz, CDCl3) δ 158.5,
144.3, 131.1, 126.9, 124.5, 121.3, 114.7, 49.9, 48.3, 47.8, 38.2, 28.5,
25.4; IR (KBr) υ 2969, 2873, 1637, 1600, 1478, 1384, 1259, 1204,
1017, 917, 871, 730 cm−1; HRMS (quadrupole, EI) calcd for
C13H16N2O [M]+ 216.1263, found 216.1262.
145.1 (d, JC−F = 12.0 Hz), 125.1 (d, JC−F = 2.5 Hz), 124.5 (d, JC−F
=
10.3 Hz), 107.8 (d, JC−F = 22.5 Hz), 103.0 (d, JC−F = 29.7 Hz), 47.8,
40.2, 32.2, 27.1, 20.1, 13.8; IR (KBr) υ 3338, 2954, 2931, 2870, 1643,
1530, 1490, 1390, 1300, 1263, 1160, 1079, 856, 786, 738 cm−1; HRMS
(quadrupole, EI) calcd for C13H17FN2O [M]+ 236.1325, found
236.1329.
N-Phenylindoline-1-carboxamide (1e). 1.40 g (70%); white solid;
mp = 109−111 °C; H NMR (700 MHz, CDCl3) δ 7.87 (d, J = 7.9
N-Butyl-6-chloroindoline-1-carboxamide (1k). 1.29 g (61%); light
yellow solid; mp = 83−85 °C; 1H NMR (700 MHz, CDCl3) δ 7.96 (s,
1H), 7.00 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 4.51 (br s,
1H), 3.89 (t, J = 8.4 Hz, 2H), 3.31 (t, J = 6.8 Hz, 2H), 3.12 (t, J = 8.4
Hz, 2H), 1.60−1.50 (m, 2H), 1.44−1.32 (m, 2H), 0.94 (t, J = 7.2 Hz,
3H); 13C NMR (175 MHz, CDCl3) δ 154.8, 145.0, 133.3, 124.9,
121.5, 115.2, 47.5, 40.3, 32.3, 27.4, 20.1, 13.8; IR (KBr) υ 3340, 2956,
2926, 2857, 1644, 1532, 1479, 1420, 1382, 1341, 1296, 1265, 1181,
1095, 988, 861, 789, 737 cm−1; HRMS (quadrupole, EI) calcd for
C13H17ClN2O [M]+ 252.1029, found 252.1030.
N-Butyl-2-methylindoline-1-carboxamide (1l). 1.46 g (75%);
white solid; mp = 105−108 °C; 1H NMR (300 MHz, CDCl3) δ
7.64 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.8 Hz, 2H), 6.91 (t, J = 7.2 Hz,
1H), 4.74 (br s, 1H), 4.44−4.34 (m, 1H), 3.42−3.33 (m, 3H), 2.60 (d,
J = 15.8 Hz, 1H), 1.61−1.51 (m, 2H), 1.45−1.33 (m, 2H), 1.30 (d, J =
6.3 Hz, 3H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ
154.7, 142.4, 129.9, 127.5, 125.2, 121.9, 114.7, 55.2, 40.2, 36.3, 32.3,
21.0, 20.2, 13.8; IR (KBr) υ 3310, 2960, 2927, 2859, 1633, 1517, 1477,
1456, 1371, 1289, 1220, 1152, 1085, 1022, 933, 858, 753 cm−1; HRMS
(quadrupole, EI) calcd for C14H20N2O [M]+ 232.1576, found
232.1574.
N-Butyl-3-methylindoline-1-carboxamide (1m). 1.26 g (65%);
white solid; mp = 89−91 °C; 1H NMR (300 MHz, CDCl3) δ 7.85 (d,
J = 8.0 Hz, 1H), 7.19−7.10 (m, 2H), 6.19 (td, J = 7.8 Hz, 1H), 4.58
(br s, 1H), 4.05 (t, J = 8.2 Hz, 1H), 3.51−3.39 (m, 2H), 3.32 (t, J = 7.0
Hz, 2H), 1.60−1.51 (m, 2H), 1.54−1.32 (m, 5H), 0.94 (t, J = 7.3 Hz,
3H); 13C NMR (175 MHz, CDCl3) δ 155.1, 143.2, 135.4, 127.7,
123.4, 121.7, 114.5, 55.2, 40.2, 34.6, 32.3, 20.3, 20.1, 13.8; IR (KBr) υ
3338, 2957, 2927, 2870, 1643, 1520, 1478, 1461, 1342, 1288, 1153,
1090, 1022, 930, 747 cm−1; HRMS (quadrupole, EI) calcd for
C14H20N2O [M]+ 232.1576, found 232.1576.
1
Hz, 1H), 7.41 (d, J = 7.7 Hz, 2H), 7.28 (br s, 2H), 7.18−7.14 (m, 2H),
7.04 (br s, 1H), 6.93 (t, J = 6.9 Hz, 1H), 6.53 (br s, 1H), 4.01−3.94
(m, 2H), 3.16−3.13 (m, 2H); 13C NMR (175 MHz, CDCl3) δ 152.4,
144.2, 138.3, 130.7, 129.0, 127.7, 124.8, 123.6, 122.3, 120.3, 115.0,
47.5, 27.9; IR (KBr) υ 3316, 3048, 2884, 1652, 1523, 1478, 1438,
1342, 1237, 1171, 1141, 1024, 732 cm−1; HRMS (quadrupole, EI)
calcd for C15H14N2O [M]+ 238.1106, found 238.1107.
General Procedure for the Synthesis of N-Butylindoline-1-
carboxamides (1f−1r). To a stirred solution of indoline (1.00 g, 8.4
mmol) in CH2Cl2 (25 mL) were added triethylamine (3.5 mL, 25.2
mmol) and n-butyl isocyanate (1.25 g, 12.6 mmol) at 0 °C. The
reaction mixture was then stirred at room temperature for 3 h. The
reaction mixture was washed with H2O and extracted with EtOAc. The
organic layer was dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash column chromatography (silica gel, n-
hexanes/EtOAc) to give the corresponding products 1f−1r.
N-Butylindoline-1-carboxamide (1f). 1.48 g (81%); white solid;
mp = 72−74 °C; 1H NMR (700 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz,
1H), 7.13−7.09 (m, 2H), 6.86 (t, J = 7.4 Hz, 1H), 4.60 (br s, 1H),
3.85 (t, J = 8.4 Hz, 2H), 3.30−3.28 (m, 2H), 3.12 (t, J = 8.6 Hz, 2H),
1.54−1.50 (m, 2H), 1.38−1.33 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13C
NMR (175 MHz, CDCl3) δ 155.1, 143.8, 130.2, 127.6, 124.5, 121.6,
114.6, 47.0, 40.3, 32.3, 27.8, 20.1, 13.8; IR (KBr) υ 3344, 2956, 2928,
2861, 1643, 1520, 1480, 1461, 1386, 1339, 1292, 1264, 1153, 1088,
1022, 930, 748 cm−1; HRMS (quadrupole, EI) calcd for C13H18N2O
[M]+ 218.1419, found 218.1420.
N-Butyl-4-methylindoline-1-carboxamide (1g). 1.42 g (73%);
1
yellow sticky solid; H NMR (700 MHz, CDCl3) δ 7.68 (d, J = 8.8
Hz, 1H), 6.94−6.92 (m, 2H), 4.52 (br s, 1H), 3.85 (t, J = 8.3 Hz, 2H),
3.31−3.28 (m, 2H), 3.09 (t, J = 8.5 Hz, 2H), 2.25 (s, 3H), 1.54−1.50
(m, 2H), 1.39−1.33 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (175
MHz, CDCl3) δ 155.3, 141.5, 131.3, 130.6, 128.1, 125.5, 114.4, 47.3,
40.4, 32.5, 28.0, 21.0, 20.3, 14.0; IR (KBr) υ 3338, 2957, 2928, 2861,
1644, 1523, 1487, 1384, 1332, 1263, 1160, 1133, 817, 733 cm−1;
HRMS (quadrupole, EI) calcd for C14H20N2O [M]+ 232.1576, found
232.1577.
N-Butylspiro[cyclohexane-1,3′-indoline]-1′-carboxamide (1n).
1
1.68 g (70%); white solid; mp = 144−145 °C; H NMR (300 MHz,
CDCl3) δ 7.83 (d, J = 8.0 Hz, 1H), 7.19−7.08 (m, 2H), 6.92 (t, J = 8.2
Hz, 1H), 4.61 (br s, 1H), 3.69 (s, 2H), 3.34 (t, J = 7.1 Hz, 2H), 1.76−
1.53 (m, 8H), 1.44−1.33 (m, 6H), 0.96 (t, J = 7.0 Hz, 3H); 13C NMR
(175 MHz, CDCl3) δ 155.1, 142.6, 139.6, 127.9, 122.3, 121.7, 114.5,
57.5, 44.4, 40.3, 37.3, 32.3, 25.3, 23.0, 20.1, 13.8; IR (KBr) υ 3349,
2924, 2848, 1639, 1521, 1477, 1459, 1335, 1301, 1276, 1192, 1095,
1020, 936, 888, 750 cm−1; HRMS (quadrupole, EI) calcd for
C18H26N2O [M]+ 286.2045, found 286.2039.
5-Bromo-N-butylindoline-1-carboxamide (1h). 1.74 g (70%); light
yellow solid; mp = 159−162 °C; 1H NMR (300 MHz, CDCl3) δ 7.82
(d, J = 7.3 Hz, 1H), 7.27−7.24 (m, 2H), 4.52 (br s, 1H), 3.90 (t, J =
1822
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827

The Journal of Organic Chemistry
Article
tert-Butyl 1-(Butylcarbamoyl)spiro[indoline-3,4′-piperidine]-1′-
CDCl3) δ 178.2, 143.0, 136.7, 134.5, 131.6, 128.5, 125.2, 122.3, 116.1,
51.3, 40.1, 38.3, 31.3, 28.7; IR (KBr) υ 2963, 1967, 1648, 1587, 1430,
1347, 1322, 1265, 1183, 1149, 1088, 966, 903, 730 cm−1; HRMS
(quadrupole, EI) m/z calcd for C16H21NO [M]+ 243.1623, found
243.1622.
1
carboxylate (1o). 0.356 g (23%); light yellow sticky solid; H NMR
(300 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz, 1H), 7.19 (td, J = 8.6, 1.3
Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 6.94 (td, J = 7.8, 0.9 Hz, 1H), 4.68
(br s, 1H), 4.14−4.10 (m, 2H), 3.76 (s, 2H), 3.37−3.30 (m, 2H), 2.86
(t, J = 12.8 Hz, 2H), 1.88−1.78 (m, 2H), 1.66−1.36 (m, 15H), 0.96 (t,
J = 7.2 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 155.0, 154.8, 142.7,
137.8, 128.4, 122.5, 122.0, 114.4, 79.8, 56.6, 42.7, 40.3, 36.5, 32.3, 29.7,
28.4, 20.1, 13.8; IR (KBr) υ 3325, 2925, 2847, 1638, 1520, 1477, 1456,
1341, 1279, 1220, 1152, 1095, 933, 754 cm−1; HRMS (quadrupole,
EI) calcd for C22H33N3O3 [M]+ 387.2522, found 387.2521.
7-Allyl-N,N-dimethylindoline-1-carboxamide (3c). 24.2 mg (35%);
1
light brown sticky solid; H NMR (700 MHz, CDCl3) δ 7.02 (d, J =
7.2 Hz, 1H), 6.97 (d, J = 7.1 Hz, 1H), 6.93 (t, J = 7.4 Hz, 1H), 5.82
(ddt, J = 17.0, 10.0, 6.8 Hz, 1H), 5.08−5.00 (m, 2H), 3.88−3.84 (m,
2H), 3.27 (d, J = 6.8 Hz, 2H), 3.05 (t, J = 7.7 Hz, 2H), 2.95 (s, 6H);
13C NMR (175 MHz, CDCl3) δ 161.3, 143.6, 136.5, 133.6, 131.5,
128.3, 123.7, 122.4, 116.0, 52.9, 50.5, 38.3, 37.4, 30.6; IR (KBr) υ
2924, 2010, 1650, 1482, 1451, 1377, 1292, 1258, 1166, 1062, 1006,
911, 731 cm−1; HRMS (quadrupole, EI) m/z calcd for C14H18N2O
[M]+ 230.1419, found 230.1424.
(7-Allylindolin-1-yl)(pyrrolidin-1-yl)methanone (3d). 9.1 mg
(12%); light yellow sticky solid; 1H NMR (700 MHz, CDCl3) δ
6.98 (d, J = 6.9 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 6.87 (t, J = 7.4 Hz,
1H), 5.75 (ddt, J = 16.9, 10.0, 6.8 Hz, 1H), 5.02−4.92 (m, 2H), 3.87
(t, J = 8.2 Hz, 1H), 3.82 (t, J = 8.0 Hz, 1H), 3.39−3.36 (m, 4H), 3.27
(d, J = 6.7 Hz, 2H), 3.02−2.97 (m, 2H), 1.83−1.81 (m, 4H); 13C
NMR (175 MHz, CDCl3) δ 159.3, 143.5, 136.9, 131.4, 128.6, 123.6,
122.5, 115.8, 52.2, 50.2, 48.0, 37.8, 30.6, 28.7, 25.7; IR (KBr) υ 2874,
1966, 1644, 1592, 1452, 1383, 1285, 1254, 1196, 1124, 1048, 994, 912,
853, 753 cm−1; HRMS (quadrupole, EI) m/z calcd for C16H20N2O
[M]+ 256.1576, found 256.1573.
7-Allyl-N-phenylindoline-1-carboxamide (3e). 15.9 mg (19%);
light yellow solid; mp = 178−179 °C; 1H NMR (700 MHz, CDCl3) δ
7.35 (d, J = 8.6, 1.1 Hz, 2H), 7.28 (t, J = 7.4 Hz, 2H), 7.13−7.02 (m,
4H), 6.54 (s, 1H), 5.87 (ddt, J = 16.9, 10.2, 6.5 Hz, 1H), 5.08−5.04
(m, 2H), 4.16 (t, J = 7.2 Hz, 2H), 3.41 (d, J = 6.5 Hz, 2H), 3.03 (t, J =
7.6 Hz, 2H); 13C NMR (175 MHz, CDCl3) δ 154.3, 141.5, 138.5,
136.3, 135.6, 129.3, 129.2, 129.0, 125.2, 123.5, 123.3, 119.6, 116.8,
52.0, 36.9, 30.2; IR (KBr) υ 3263, 3051, 2926, 1998, 1650, 1594, 1525,
1479, 1439, 1343, 1315, 1240, 1141, 1025, 916, 734 cm−1; HRMS
(quadrupole, EI) m/z calcd for C18H18N2O [M]+ 278.1419, found
278.1422.
7-Allyl-N-butylindoline-1-carboxamide (3f). 65.0 mg (81%); light
brown solid; mp = 77−81 °C; 1H NMR (700 MHz, CDCl3) δ 7.06 (d,
J = 7.1 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 5.90
(ddt, J = 17.0, 10.1, 6.4 Hz, 1H), 5.10−5.06 (m, 2H), 4.70 (br s, 1H),
4.06 (t, J = 7.6 Hz, 2H), 3.37 (t, J = 6.4 Hz, 2H), 3.25−3.22 (m, 2H),
2.96 (t, J = 7.7 Hz, 2H), 1.49−1.45 (m, 2H), 1.34−1.29 (m, 2H), 0.89
(t, J = 7.3 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 157.3, 142.2,
136.8, 135.5, 129.1, 128.7, 124.6, 123.0, 116.3, 51.9, 40.7, 36.9, 32.4,
30.1, 20.3, 14.0; IR (KBr) υ 3313, 3051, 2929, 1993, 1642, 1522, 1482,
1450, 1311, 1248, 1187, 1152, 1086, 912, 734 cm−1; HRMS
(quadrupole, EI) m/z calcd for C16H22N2O [M]+ 258.1732, found
258.1735.
7-Allyl-N-butyl-4-methylindoline-1-carboxamide (3g). 41.3 mg
(44%); brown solid; mp = 89−92 °C; 1H NMR (700 MHz, CDCl3) δ
6.89 (s, 1H), 6.82 (s, 1H), 5.91 (ddt, J = 17.0, 10.1, 6.4 Hz, 1H), 5.10−
5.06 (m, 2H), 4.71 (br s, 1H), 4.05 (t, J = 7.6 Hz, 2H), 3.33 (d, J = 6.3
Hz, 2H), 3.23−3.20 (m, 2H), 2.90 (t, J = 7.6 Hz, 2H), 2.64 (s, 3H),
1.47−1.43 (m, 2H), 1.33−1.28 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C
NMR (175 MHz, CDCl3) δ 157.5, 139.9, 136.8, 135.8, 134.3, 129.4,
128.3, 123.9, 116.3, 52.0, 40.7, 36.7, 32.4, 30.1, 21.1, 20.2, 13.9; IR
(KBr) υ 3314, 3076, 2927, 1975, 1639, 1527, 1474, 1316, 1244, 1191,
1124, 1080, 994, 909, 854, 734 cm−1; HRMS (quadrupole, EI) m/z
calcd for C17H24N2O [M]+ 272.1889, found 272.1885.
7-Allyl-5-bromo-N-butylindoline-1-carboxamide (3h). 77.0 mg
(78%); brown solid; mp = 126−130 °C; 1H NMR (700 MHz,
CDCl3) δ 7.15 (s, 1H), 7.12 (s, 1H), 5.84 (ddt, J = 16.8, 10.2, 6.5 Hz,
1H), 5.10−5.07 (m, 2H), 4.68 (br s, 1H), 4.01 (t, J = 7.7 Hz, 2H),
3.31 (d, J = 6.5 Hz, 2H), 3.23−3.20 (m, 2H), 2.95 (t, J = 7.7 Hz, 2H),
1.48−1.44 (m, 2H), 1.34−1.28 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13C
NMR (175 MHz, CDCl3) δ 156.8, 141.4, 136.9, 135.8, 131.4, 130.7,
125.7, 116.9, 116.8, 51.7, 40.6, 36.7, 32.2, 29.7, 20.0, 13.8; IR (KBr) υ
3308, 3066, 2929, 1995, 1640, 1530, 1454, 1422, 1307, 1244, 1187,
N-Butyl-3-methyl-3-phenylindoline-1-carboxamide (1p). 1.68 g
1
(65%); light yellow solid; mp = 94−96 °C; H NMR (300 MHz,
CDCl3) δ 7.94 (d, J = 8.1 Hz, 1H), 7.32−7.19 (m, 6H), 6.94−6.93 (m,
2H), 4.51 (br s, 1H), 4.00 (d, J = 9.0 Hz, 1H), 3.88 (d, J = 9.1 Hz,
1H), 3.34−3.28 (m, 2H), 1.75 (s, 3H), 1.58−1.48 (m, 2H), 1.43−1.30
(m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ
154.9, 147.0, 143.1, 138.6, 128.4, 128.1, 126.6, 126.4, 123.9, 122.1,
114.7, 64.1, 47.8, 40.2, 32.2, 27.2, 20.1, 13.8; IR (KBr) υ 3338, 2958,
2929, 2871, 1644, 1520, 1478, 1337, 1264, 1154, 1023, 734 cm−1;
HRMS (quadrupole, EI) calcd for C20H24N2O [M]+ 308.1889, found
308.1902.
N-Butyl-4a-methyl-2,3,4,4a-tetrahydro-1H-carbazole-9(9aH)-car-
1
boxamide (1q). 1.32 g (55%); white solid; mp = 164−166 °C; H
NMR (300 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 1H), 7.17 (td, J = 8.1,
1.3 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.95 (td, J = 7.8, 0.8 Hz, 1H),
4.77 (br s, 1H), 3.81−3.76 (m, 1H), 3.34 (s, 2H), 2.24−2.18 (m, 1H),
2.11−2.06 (m, 1H), 1.61−1.50 (m, 5H), 1.45−1.33 (m, 2H), 1.25−
1.17 (m, 3H), 1.12 (s, 3H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (175
MHz, CDCl3) δ 155.1, 141.6, 138.6, 127.5, 122.2, 121.8, 115.2, 67.3,
43.6, 40.2, 32.4, 32.3, 31.0, 28.3, 22.3, 21.8, 20.2, 13.8; IR (KBr) υ
3323, 2925, 2854, 1634, 1532, 1473, 1387, 1285, 1197, 1119, 1022,
928, 844, 749 cm−1; HRMS (quadrupole, EI) calcd for C18H26N2O
[M]+ 286.2045, found 286.2041.
N-Butyl-3,3-dimethyl-2-phenylindoline-1-carboxamide (1r). 1.35
g (50%); white solid; mp = 137−139 °C; 1H NMR (300 MHz,
CDCl3) δ 8.05 (d, J = 8.0 Hz, 1H), 7.33−7.28 (m, 3H), 7.24−7.20 (m,
1H), 7.16−7.13 (m, 2H), 7.06−6.95 (m, 2H), 4.71 (s, 1H), 4.30 (br s,
1H), 3.24−3.00 (m, 2H), 1.43 (s, 3H), 1.29−1.19 (m, 2H), 1.06−0.93
(m, 2H), 0.85 (s, 3H), 0.75 (t, J = 7.1 Hz, 3H); 13C NMR (175 MHz,
CDCl3) δ 155.4, 143.1, 138.7, 138.2, 128.9, 128.3, 128.0, 126.6, 122.2,
122.1, 114.8, 45.4, 39.9, 32.6, 31.7, 24.2, 19.6, 13.6; IR (KBr) υ 3369,
2958, 2928, 2869, 1643, 1515, 1476, 1453, 1377, 1284, 1152, 1121,
1024, 939, 888, 826, 747 cm−1; HRMS (quadrupole, EI) calcd for
C21H26N2O [M]+ 322.2045, found 322.2039.
Typical Procedure for the C7-Allylation of N-Butylindoline-
1-carboxamides (3a−3t and 5b−5f). To an oven-dried sealed tube
charged with N-butylindoline-1-carboxamide (1f) (65.5 mg, 0.3 mmol,
100 mol %), [RhCp*Cl2]2 (4.6 mg, 2.5 mol %), AgSbF6 (10.3 mg, 10
mol %), and Cu(OAc)2 (16.3 mg, 30 mol %) in t-AmOH (1 mL) was
added allyl methyl carbonate (2a) (69.7 mg, 0.6 mmol, 200 mol %).
The reaction mixture was allowed to stir at room temperature for 20 h.
The reaction mixture was diluted with EtOAc (3 mL) and
concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, n-hexanes/EtOAc = 7:1) to afford 62.8 mg
of 3f in 81% yield.
1-(7-Allylindolin-1-yl)ethanone (3a). 33.0 mg (55%); light yellow
sticky solid; 1H NMR (700 MHz, CDCl3) δ 7.07−7.02 (m, 3H), 5.86
(ddt, J = 17.0, 10.1, 6.7 Hz, 1H), 5.07−5.01 (m, 2H), 4.03 (s, 2H),
3.42 (d, J = 6.3 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.24 (s, 3H); 13C
NMR (175 MHz, CDCl3) δ 168.6, 141.1, 136.8, 134.7, 129.0, 125.5,
125.0, 122.4, 116.0, 51.3, 38.4, 30.1, 23.9; IR (KBr) υ 2915, 1993,
1658, 1591, 1429, 1379, 1327, 1234, 1186, 1105, 968, 914, 847, 760,
730 cm−1; HRMS (quadrupole, EI) m/z calcd for C13H15NO [M]+
201.1154, found 201.1151.
1-(7-Allylindolin-1-yl)-2,2-dimethylpropan-1-one (3b). 26.7 mg
(37%); light yellow sticky solid; 1H NMR (700 MHz, CDCl3) δ 7.08−
7.07 (m, 1H), 7.04−7.01 (m, 2H), 5.82 (ddt, J = 17.0, 10.0, 6.7 Hz,
1H), 5.08−5.01 (m, 2H), 4.08 (t, J = 7.3 Hz, 2H), 3.28 (d, J = 6.7 Hz,
2H), 3.00 (t, J = 7.3 Hz, 2H), 1.36 (s, 9H); 13C NMR (175 MHz,
1823
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827

The Journal of Organic Chemistry
Article
1091, 993, 912, 853, 736 cm−1; HRMS (quadrupole, EI) m/z calcd for
C16H21BrN2O [M]+ 336.0837, found 336.0833.
1518, 1442, 1311, 1242, 1146, 1065, 994, 907, 735 cm−1; HRMS
(quadrupole, EI) m/z calcd for C21H30N2O [M]+ 326.2358, found
326.2359.
tert-Butyl 7-Allyl-1-(butylcarbamoyl)spiro[indoline-3,4′-piperi-
dine]-1′-carboxylate (3o). 79.9 mg (62%); light brown sticky solid;
1H NMR (700 MHz, CDCl3) δ 7.08−7.04 (m, 2H), 7.00−6.97 (m,
1H), 5.92 (ddt, J = 16.6, 10.2, 6.3 Hz, 1H), 5.11−5.09 (m, 2H), 4.77
(br s, 1H), 4.14−3.97 (m, 5H), 3.36 (d, J = 6.3 Hz, 2H), 3.24−3.21
(m, 2H), 2.88 (br s, 2H), 1.74 (br s, 2H), 1.54−1.46 (m, 3H), 1.45 (s,
9H), 1.32−1.25 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR (175
MHz, CDCl3) δ 157.4, 154.8, 142.7, 141.3, 136.3, 129.6, 128.7, 125.1,
120.7, 116.4, 79.7, 60.2, 44.4, 40.5, 36.2, 32.2, 28.4, 25.1, 20.0, 13.7; IR
(KBr) υ 3312, 2929, 1967, 1668, 1525, 1424, 1365, 1237, 1169, 1144,
1091, 969, 911, 862, 732 cm−1; HRMS (quadrupole, EI) m/z calcd for
C25H37N3O3 [M]+ 427.2835, found 427.2833.
7-Allyl-N-butyl-5-chloroindoline-1-carboxamide (3i). 69.4 mg
1
(79%); light yellow solid; mp = 112−117 °C; H NMR (700 MHz,
CDCl3) δ 7.02 (s, 1H), 6.99 (s, 1H), 5.85 (ddt, J = 17.5, 10.3, 6.5 Hz,
1H), 5.11−5.08 (m, 2H), 4.62 (t, J = 5.1 Hz, 1H), 4.04 (t, J = 7.7 Hz,
2H), 3.32 (d, J = 6.5 Hz, 2H), 3.25−3.22 (m, 2H), 2.96 (t, J = 7.7 Hz,
2H), 1.49−1.45 (m, 2H), 1.35−1.29 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H);
13C NMR (175 MHz, CDCl3) δ 157.1, 141.0, 136.8, 136.0, 130.4,
129.5, 128.7, 123.0, 117.0, 52.0, 40.8, 36.9, 32.4, 30.0, 20.2, 13.9; IR
(KBr) υ 3297, 3065, 2928, 1991, 1639, 1531, 1456, 1424, 1308, 1254,
1188, 1145, 1092, 992, 913, 857, 736 cm−1; HRMS (quadrupole, EI)
m/z calcd for C16H21ClN2O [M]+ 292.1342, found 292.1335.
7-Allyl-N-butyl-6-fluoroindoline-1-carboxamide (3j). 68.7 mg
1
(83%); light yellow solid; mp = 76−81 °C; H NMR (700 MHz,
7-Allyl-N-butyl-3-methyl-3-phenylindoline-1-carboxamide (3p).
CDCl3) δ 6.97 (t, J = 7.2 Hz, 1H), 6.68 (t, J = 9.9 Hz, 1H), 5.90 (ddt, J
= 16.8, 10.2, 5.8 Hz, 1H), 4.99−4.96 (m, 2H), 4.83 (br s, 1H), 4.05 (t,
J = 7.7 Hz, 2H), 3.41 (d, J = 5.8 Hz, 2H), 3.21−3.18 (m, 2H), 2.89 (t,
J = 7.5 Hz, 2H), 1.47−1.42 (m, 2H), 1.32−1.26 (m, 2H), 0.87 (t, J =
7.2 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 160.6 (d, JC−F = 240.9
1
81.8 mg (78%); light brown solid; mp = 79−83 °C; H NMR (700
MHz, CDCl3) δ 7.27−7.22 (m, 4H), 7.18 (t, J = 8.4 Hz, 1H), 7.12 (d,
J = 7.6 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 5.98
(ddt, J = 17.0, 10.1, 6.4 Hz, 1H), 5.16−5.11 (m, 2H), 4.81 (br s, 1H),
4.30 (d, J = 10.8 Hz, 1H), 3.99 (d, J = 10.7 Hz, 1H), 3.43 (d, J = 6.5
Hz, 2H), 3.21−3.12 (m, 2H), 1.65 (s, 3H), 1.37−1.32 (m, 2H), 1.22−
1.17 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (175 MHz, CDCl3)
δ 157.3, 145.8, 143.4, 141.9, 136.5, 129.3, 129.0, 128.3, 126.6, 126.5,
125.1, 122.2, 116.3, 67.2, 49.8, 40.3, 36.5, 32.2, 25.5, 19.9, 13.8; IR
(KBr) υ 3312, 2958, 2929, 2010, 1644, 1524, 1441, 1317, 1263, 1068,
1029, 912, 758, 735 cm−1; HRMS (quadrupole, EI) m/z calcd for
C23H28N2O [M]+ 348.2202, found 348.2204.
Hz), 156.8, 143.6 (d, JC−F = 7.6 Hz), 135.3, 130.4, 123.0 (d, JC−F
=
10.2 Hz), 116.7 (d, JC−F = 20.1 Hz), 115.2, 110.5 (d, JC−F = 23.9 Hz),
52.5, 40.5, 32.1, 30.5, 30.4, 29.3, 20.0, 13.7; IR (KBr) υ 3310, 3071,
2930, 1967, 1644, 1525, 1470, 1309, 1240, 1215, 1139, 1113, 992, 910,
802, 735 cm−1; HRMS (quadrupole, EI) m/z calcd for C16H21FN2O
[M]+ 276.1638, found 276.1636.
7-Allyl-N-butyl-6-chloroindoline-1-carboxamide (3k). 77.0 mg
1
(82%); light yellow solid; mp = 87−93 °C; H NMR (700 MHz,
CDCl3) δ 7.05 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 5.87 (ddt,
J = 17.1, 10.1, 5.8 Hz, 1H), 5.01−4.99 (m, 1H), 4.96−4.93 (m, 1H),
4.78 (br s, 1H), 4.06 (t, J = 7.7 Hz, 2H), 3.55 (d, J = 7.4 Hz, 2H),
3.22−3.19 (m, 2H), 2.91 (t, J = 7.7 Hz, 2H), 1.47−1.43 (m, 2H),
1.32−1.27 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (175 MHz,
CDCl3) δ 157.1, 144.1, 134.8, 134.4, 134.0, 127.1, 125.7, 123.5, 115.5,
52.6, 40.6, 34.2, 32.1, 29.7, 20.0, 13.8; IR (KBr) υ 3313, 3055, 2956,
1963, 1647, 1527, 1445, 1427, 1331, 1303, 1265, 1190, 1087, 990, 912,
801, 733 cm−1; HRMS (quadrupole, EI) m/z calcd for C16H21ClN2O
[M]+ 292.1342, found 292.1344.
7-Allyl-N-butyl-2-methylindoline-1-carboxamide (3l). 68.1 mg
(83%); light yellow sticky solid; 1H NMR (700 MHz, CDCl3) δ
7.05 (d, J = 7.0 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 6.97 (t, J = 7.3 Hz,
1H), 5.91−5.85 (m, 1H), 5.06−5.03 (m, 2H), 4.70 (br s, 1H), 4.64−
4.60 (m, 1H), 3.43−3.40 (m, 1H), 3.36−3.28 (m, 2H), 3.27−3.17 (m,
2H), 2.36 (d, J = 6.6 Hz, 1H), 1.48−1.43 (m, 2H), 1.32−1.28 (m,
2H), 1.17 (d, J = 6.7 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (175
MHz, CDCl3) δ 156.7, 140.5, 136.6, 134.2, 129.1, 128.8, 124.4, 123.4,
115.9, 58.6, 40.4, 36.9, 36.7, 32.2, 21.7, 20.1, 13.8; IR (KBr) υ 3348,
2957, 1969, 1641, 1513, 1445, 1377, 1357, 1298, 1264, 1190, 1108,
1075, 994, 910, 735 cm−1; HRMS (quadrupole, EI) m/z calcd for
C17H24N2O [M]+ 272.1889, found 272.1885.
8-Allyl-N-butyl-4a-methyl-2,3,4,4a-tetrahydro-1H-carbazole-9-
(9aH)-carboxamide (3q). 76.1 mg (78%); light yellow solid; mp =
94−101 °C; 1H NMR (700 MHz, CDCl3) δ 7.05−7.02 (m, 2H), 6.94
(dd, J = 6.8, 1.6 Hz, 1H), 5.89 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.08−
5.05 (m, 2H), 4.70 (t, J = 5.3 Hz, 1H), 4.13−4.10 (m, 1H), 3.44−3.28
(m, 2H), 3.25−3.23 (m, 2H), 2.19−2.16 (m, 1H), 2.03−1.99 (m, 1H),
1.53−1.23 (m, 10H), 1.08 (s, 3H), 0.88 (t, J = 7.3 Hz, 3H); 13C NMR
(175 MHz, CDCl3) δ 157.5, 142.9, 140.9, 136.7, 130.0, 129.2, 125.2,
120.3, 116.1, 70.7, 45.6, 40.6, 36.4, 33.3, 32.5, 30.6, 30.0, 23.6, 22.2,
20.2, 13.9; IR (KBr) υ 3288, 2926, 1994, 1638, 1524, 1436, 1304,
1264, 1187, 1146, 1083, 993, 911, 757, 734 cm−1; HRMS (quadrupole,
EI) m/z calcd for C21H30N2O [M]+ 326.2358, found 326.2359.
7-Allyl-N-butyl-3,3-dimethyl-2-phenylindoline-1-carboxamide
(3r). 87.3 mg (80%); yellow sticky solid; 1H NMR (700 MHz, CDCl3)
δ 7.26−7.23 (m, 3H), 7.11 (d, J = 7.7 Hz, 1H), 7.06−7.03 (m, 3H),
6.91 (dd, J = 7.2, 1.1 Hz, 1H), 5.98 (ddt, J = 16.9, 10.0, 6.7 Hz, 1H),
5.17−5.08 (m, 2H), 4.94 (s, 1H), 4.54 (t, J = 5.3 Hz, 1H), 3.61 (dd, J
= 15.8, 6.6 Hz, 1H), 3.46 (dd, J = 15.8, 6.7 Hz, 1H), 3.30−3.26 (m,
1H), 3.21−3.16 (m, 1H), 1.48−1.43 (m, 2H), 1.42 (s, 3H), 1.31−1.25
(m, 2H), 0.89 (t, J = 7.3 Hz, 6H); 13C NMR (175 MHz, CDCl3) δ
157.0, 142.0, 141.2, 140.0, 136.8, 129.4, 128.4, 128.1, 127.7, 126.8,
124.5, 120.5, 116.2, 78.4, 46.3, 40.3, 37.4, 32.5, 32.1, 22.9, 19.9, 13.7;
IR (KBr) υ 3346, 2957, 2928, 2007, 1945, 1659, 1505, 1439, 1362,
1290, 1246, 1203, 1138, 1072, 994, 910, 751 cm−1; HRMS
(quadrupole, EI) m/z calcd for C24H30N2O [M]+ 362.2358, found
362.2368.
(E)-7-(But-2-enyl)-N-butylindoline-1-carboxamide and (Z)-7-
(But-2-enyl)-N-butylindoline-1-carboxamide (5b). 72.6 mg (89%);
brown solid; mp = 85−89 °C; E:Z ratio = 1:2.7; 1H NMR (700 MHz,
CDCl3) E-isomer, δ 7.05 (d, J = 7.0 Hz, 1H), 7.02 (t, J = 7.1 Hz, 1H),
6.99−6.96 (m, 1H), 5.60−5.45 (m, 2H), 4.70 (br s, 1H), 4.08−4.05
(m, 2H), 3.54 (d, J = 7.0 Hz, 2H), 3.26−3.21 (m, 2H), 2.96−2.93 (m,
2H), 1.67−1.66 (m, 3H), 1.50−1.43 (m, 2H), 1.35−1.28 (m, 2H),
0.90 (t, J = 7.3 Hz, 3H); Z-isomer, δ 7.05 (d, J = 7.0 Hz, 1H), 7.02 (t, J
= 7.1 Hz, 1H), 6.99−6.96 (m, 1H), 5.60−5.45 (m, 2H), 4.74 (br s,
1H), 4.08−4.05 (m, 2H), 3.28 (br s, 2H), 3.26−3.21 (m, 2H), 2.96−
2.93 (m, 2H), 1.67−1.66 (m, 3H), 1.50−1.43 (m, 2H), 1.35−1.28 (m,
2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (175 MHz, CDCl3) E-isomer,
δ 157.4, 142.2, 135.4, 129.5, 129.2, 128.4, 125.8, 124.8, 122.7, 51.9,
40.7, 35.5, 32.4, 30.2, 20.3, 18.1, 13.9; Z-isomer, δ 157.3, 142.1, 135.6,
130.2, 129.1, 128.6, 126.9, 124.6, 122.8, 51.9, 40.7, 35.5, 32.4, 30.1,
20.3, 18.1, 13.9; IR (KBr) υ 3312, 2956, 2928, 2011, 1641, 1525, 1449,
7-Allyl-N-butyl-3-methylindoline-1-carboxamide (3m). 62.6 mg
1
(77%); light yellow solid; mp = 72−76 °C; H NMR (700 MHz,
CDCl3) δ 7.02−6.98 (m, 3H), 5.90 (ddt, J = 16.8, 10.1, 6.3 Hz, 1H),
5.09−5.05 (m, 2H), 4.81 (br s, 1H), 4.22 (t, J = 8.8 Hz, 1H), 3.55−
3.52 (m, 1H), 3.36 (d, J = 6.3 Hz, 2H), 3.30−3.17 (m, 3H), 1.47−1.43
(m, 2H), 1.32−1.27 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.2
Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 157.3, 141.7, 140.4, 136.6,
128.9, 128.5, 124.6, 121.5, 116.1, 59.5, 40.5, 36.6, 36.5, 32.2, 20.0, 18.4,
13.8; IR (KBr) υ 3312, 2958, 1959, 1641, 1524, 1443, 1321, 1300,
1243, 1144, 1089, 1059, 993, 910, 735 cm−1; HRMS (quadrupole, EI)
m/z calcd for C17H24N2O [M]+ 272.1889, found 272.1886.
7′-Allyl-N-butylspiro[cyclohexane-1,3′-indoline]-1′-carboxamide
(3n). 77.0 mg (79%); light yellow solid; mp = 140−146 °C; 1H NMR
(700 MHz, CDCl3) δ 7.03−6.98 (m, 3H), 5.90 (ddt, J = 17.0, 10.1, 6.4
Hz, 1H), 5.11−5.06 (m, 2H), 4.79 (br s, 1H), 3.89 (s, 2H), 3.36 (d, J
= 6.4 Hz, 2H), 3.24−3.21 (m, 2H), 1.71−1.67 (m, 4H), 1.56−1.50 (m,
4H), 1.47−1.43 (m, 2H), 1.41−1.35 (m, 2H), 1.32−1.26 (m, 2H),
0.88 (t, J = 7.3 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 157.6, 144.4,
141.3, 136.5, 129.0, 128.5, 124.7, 120.5, 116.1, 61.3, 46.0, 40.5, 36.4,
35.6, 32.2, 25.6, 23.2, 20.2, 13.8; IR (KBr) υ 3349, 2927, 1994, 1642,
1824
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827

The Journal of Organic Chemistry
Article
1308, 1248, 1188, 1152, 1089, 966, 847, 757 cm−1; HRMS
(quadrupole, EI) m/z calcd for C17H24N2O [M]+ 272.1889, found
272.1884.
E-isomer, δ 7.07−7.00 (m, 2H), 6.97 (t, J = 7.3 Hz, 1H), 5.77−5.67
(m, 2H), 4.66 (br s, 1H), 4.08 (d, J = 5.6 Hz, 2H), 4.04 (t, J = 7.7 Hz,
2H), 3.38 (d, J = 6.1 Hz, 2H), 3.27−3.23 (m, 2H), 2.97 (t, J = 7.7 Hz,
2H), 1.65 (br s, 1H), 1.52−1.45 (m, 2H), 1.37−1.29 (m, 2H), 0.90 (t,
J = 7.3 Hz, 3H); Z-isomer, δ 7.07−7.00 (m, 2H), 6.97 (t, J = 7.3 Hz,
1H), 5.62−5.58 (m, 2H), 4.62 (br s, 1H), 4.17 (d, J = 7.0 Hz, 2H),
4.01 (t, J = 7.7 Hz, 2H), 3.43 (d, J = 7.1 Hz, 2H), 3.27−3.23 (m, 2H),
3.00 (t, J = 7.7 Hz, 2H), 1.65 (br s, 1H), 1.52−1.45 (m, 2H), 1.37−
1.29 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13C NMR (175 MHz, CDCl3)
E-isomer, δ 157.4, 142.1, 135.4, 130.7, 129.6, 129.1, 128.8, 124.6,
123.1, 63.7, 58.4, 51.9, 40.8, 35.7, 32.4, 30.1, 20.3, 14.0; Z-isomer, δ
157.6, 141.9, 134.8, 130.9, 129.6, 129.0, 128.8, 124.7, 122.8, 63.7, 58.4,
51.8, 40.8, 35.7, 32.4, 30.1, 20.3, 14.0; IR (KBr) υ 3313, 2929, 2870,
1946, 1642, 1523, 1450, 1314, 1249, 1187, 1091, 972, 905, 762, 731
cm−1; HRMS (quadrupole, EI) m/z calcd for C17H24N2O2 [M]+
288.1838, found 288.1837.
(E)-N-Butyl-7-(undec-2-enyl)indoline-1-carboxamide (5c). 93.7
mg (84%); orange sticky solid; E:Z ratio = 1:2.9; 1H NMR (700
MHz, CDCl3) E-isomer, δ 7.06−7.01 (m, 2H), 6.98−6.96 (m, 1H),
5.53−5.41 (m, 2H), 4.70 (br s, 1H), 4.07 (t, J = 7.6 Hz, 2H), 3.34 (d, J
= 7.0 Hz, 2H), 3.26−3.21 (m, 2H), 2.96−2.93 (m, 2H), 2.10−2.07 (m,
2H), 1.50−1.44 (m, 2H), 1.40−1.06 (m, 14H), 0.91 (t, J = 7.3 Hz,
3H), 0.85 (t, J = 7.0 Hz, 3H); Z-isomer, δ 7.06−7.01 (m, 2H), 6.98−
6.96 (m, 1H), 5.53−5.41 (m, 2H), 4.74 (br s, 1H), 4.07 (t, J = 7.6 Hz,
2H), 3.29 (d, J = 5.3 Hz, 2H), 3.26−3.21 (m, 2H), 2.96−2.93 (m,
2H), 2.00−1.98 (m, 2H), 1.50−1.44 (m, 2H), 1.40−1.06 (m, 14H),
0.89 (t, J = 7.3 Hz, 3H), 0.85 (t, J = 7.0 Hz, 3H); 13C NMR (175
MHz, CDCl3) E-isomer, δ 157.4, 142.1, 135.3, 132.0, 130.3, 128.6,
127.3, 124.7, 122.7, 51.9, 40.7, 35.5, 32.4, 32.0, 30.2, 29.8, 29.7, 29.5,
29.4, 27.5, 22.8, 20.3, 13.9; Z-isomer, δ 157.3, 142.1, 135.5, 132.7,
129.6, 129.0, 127.8, 124.6, 122.8, 51.9, 40.7, 35.5, 32.7, 32.0, 30.1, 29.8,
29.6, 29.5, 29.4, 27.5, 22.8, 20.3, 14.2; IR (KBr) υ 3313, 2923, 2853,
1966, 1644, 1527, 1450, 1313, 1249, 1188, 969, 850, 763, 735 cm−1;
HRMS (quadrupole, EI) m/z calcd for C24H38N2O [M]+ 370.2984,
found 370.2980.
Experimental Procedure and Characterization for Olefin
Metathesis of 3f. To an oven-dried sealed tube charged with 7-allyl-
N-butylindoline-1-carboxamide (3f) (51.6 mg, 0.2 mmol, 100 mol %)
in toluene (1 mL) were added Hoveyda−Grubbs second generation
catalyst (8.4 mg, 5 mol %) and ethyl acrylate (60.0 mg, 0.6 mmol, 300
mol %) at room temperature. The reaction mixture was allowed to stir
at 100 °C for 24 h, and cooled to room temperature. The reaction
mixture was diluted with EtOAc (3 mL) and concentrated in vacuo.
The residue was purified by flash column chromatography (silica gel,
n-hexanes/EtOAc = 5:1) to afford 40.0 mg of 6a in 60% yield.
(E)-Ethyl 4-(1-(Butylcarbamoyl)indolin-7-yl)but-2-enoate (6a).
(S,E)-N-Butyl-7-(5,9-dimethyldeca-2,8-dienyl)indoline-1-carboxa-
mide and (S,Z)-N-Butyl-7-(5,9-dimethyldeca-2,8-dienyl)indoline-1-
carboxamide (5d). 96.7 mg (84%); orange sticky solid; E:Z ratio =
1
1:2.8; H NMR (700 MHz, CDCl3) E-isomer, δ 7.06−7.02 (m, 2H),
6.97 (t, J = 7.4 Hz, 1H), 5.53−5.44 (m, 2H), 5.08−5.05 (m, 1H), 4.67
(t, J = 5.6 Hz, 1H), 4.08−4.05 (m, 2H), 3.34 (d, J = 5.8 Hz, 2H),
3.26−3.22 (m, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.11−1.82 (m, 4H), 1.66
(s, 3H), 1.57 (s, 3H), 1.50−1.44 (m, 3H), 1.37−1.29 (m, 3H), 1.16−
1.08 (m, 1H), 0.91−0.85 (m, 6H); Z-isomer, δ 7.06−7.02 (m, 2H),
6.97 (t, J = 7.4 Hz, 1H), 5.53−5.44 (m, 2H), 5.08−5.05 (m, 1H), 4.70
(t, J = 5.5 Hz, 1H), 4.08−4.05 (m, 2H), 3.31 (d, J = 4.6 Hz, 2H),
3.26−3.22 (m, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.11−1.82 (m, 4H), 1.66
(s, 3H), 1.57 (s, 3H), 1.50−1.44 (m, 3H), 1.37−1.29 (m, 3H), 1.16−
1.08 (m, 1H), 0.91−0.85 (m, 6H); 13C NMR (175 MHz, CDCl3) E-
isomer, δ 157.3, 142.1, 135.5, 131.3, 131.2, 130.5, 129.8, 129.1, 129.0,
128.6, 128.1, 125.1, 125.0, 124.8, 124.6, 122.8, 122.7, 51.9, 40.8, 36.9,
34.8, 33.2, 32.5, 30.4, 25.8, 20.3, 19.7, 17.8, 14.0; Z-isomer, δ 157.3,
142.1, 135.5, 131.2, 130.5, 129.8, 129.1, 128.6, 125.0, 124.6, 122.8,
51.9, 40.1, 36.8, 35.7, 34.8, 32.9, 32.5, 30.4, 30.1, 25.9, 25.7, 20.3, 19.6,
17.8, 14.0; IR (KBr) υ 3315, 2925, 1975, 1643, 1527, 1449, 1312,
1249, 1188, 1089, 970, 847, 762, 737 cm−1; HRMS (quadrupole, EI)
m/z calcd for C25H38N2O [M]+ 382.2984, found 382.2982.
1
Light brown sticky solid; E:Z ratio = 50>:1; H NMR (700 MHz,
CDCl3) δ 7.07 (d, J = 6.7 Hz, 1H), 7.01−6.94 (m, 3H), 5.81 (d, J =
15.5 Hz, 1H), 4.59 (t, J = 5.3 Hz, 1H), 4.15−4.12 (m, 2H), 4.02 (t, J =
7.8 Hz, 2H), 3.56 (d, J = 6.7 Hz, 2H), 3.25−3.22 (m, 2H), 3.00 (t, J =
7.7 Hz, 2H), 1.49−1.45 (m, 2H), 1.35−1.30 (m, 2H), 1.25−1.22 (m,
3H), 0.90 (t, J = 7.3 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 166.7,
157.1, 147.1, 142.3, 135.0, 129.2, 127.1, 124.6, 123.3, 122.5, 60.3, 51.7,
40.8, 35.9, 32.4, 30.1, 29.8, 20.2, 14.4, 13.9; IR (KBr) υ 3328, 2927,
2975, 1715, 1646, 1523, 1459, 1306, 1263, 1187, 1154, 1042, 983, 905,
845, 734 cm−1; HRMS (quadrupole, EI) m/z calcd for C19H26N2O3
[M]+ 330.1943, found 330.1943.
Experimental Procedure and Characterization for the
Intramolecular Cyclization of 6a. To a stirred solution of (E)-
ethyl 4-(1-(butylcarbamoyl)indolin-7-yl)but-2-enoate (6a) (44.4 mg,
0.13 mmol, 100 mol %) in DMF (2 mL) was added NaH (7.8 mg, 0.19
mmol, 150 mol %, 60% dispersion in mineral oil) at 0 °C. The reaction
mixture was stirred for 1 h at 0 °C. The reaction mixture was
quenched and partitioned between EtOAc and H2O. The organic layer
was dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel, n-hexanes/EtOAc
= 6:1) to afford 18.6 mg of 6b in 45% yield.
Ethyl 3-Butyl-4-oxo-1,2,3,4,6,7-hexahydro-[1,3]diazepino[6,7,1-
hi]indole-2-carboxylate (6b). Light brown sticky solid; 1H NMR
(700 MHz, CDCl3) δ 7.02 (d, J = 7.0 Hz, 1H), 6.83−6.79 (m, 2H),
4.19 (q, J = 10.8 Hz, 1H), 4.17−4.11 (m, 1H), 4.09−4.05 (m, 2H),
3.74−3.70 (m, 1H), 3.29−3.25 (m, 1H), 3.10 (dd, J = 16.1, 2.5 Hz,
1H), 3.03−2.96 (m, 3H), 2.66−2.65 (m, 1H), 2.36−2.35 (m, 1H),
1.62−1.49 (m, 3H), 1.34−1.29 (m, 2H), 1.18 (t, J = 7.1 Hz, 3H), 0.91
(t, J = 7.3 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 171.6, 156.1,
140.3, 132.5, 129.3, 123.9, 121.8, 120.3, 61.0, 53.2, 51.9, 50.0, 38.1,
36.8, 30.6, 26.7, 20.4, 14.3; IR (KBr) υ 2925, 1730, 1628, 1460, 1423,
1366, 1351, 1307, 1239, 1176, 1106, 1029, 930, 853, 734 cm−1; HRMS
(quadrupole, EI) m/z calcd for C19H26N2O3 [M]+ 330.1943, found
330.1944.
General Procedure and Characterization for the Depro-
tection and Olefin Migration of 3f. To an oven-dried sealed tube
charged with 7-allyl-N-butylindoline-1-carboxamide (3f) (51.6 mg, 0.2
mmol, 100 mol %) in EtOH (2 mL) was added aqueous s-KOH
solution (1 mL) at room temperature. The reaction mixture was
stirred for 20 h at 100 °C and cooled to 0 °C. The reaction mixture
was neutralized with aqueous s-NH4Cl solution, and partitioned
between EtOAc and H2O. The organic layer was dried over MgSO4
and concentrated in vacuo. The residue was purified by flash column
N-Butyl-7-cinnamylindoline-1-carboxamide (5e). 85.3 mg (85%);
1
light yellow solid; mp = 121−123 °C; E:Z ratio = 50>:1; H NMR
(700 MHz, CDCl3) E-isomer, δ 7.32 (t, J = 8.4 Hz, 2H), 7.26 (t, J =
7.6 Hz, 2H), 7.19−7.16 (m, 1H), 7.09−7.08 (m, 2H), 6.99 (t, J = 7.5
Hz, 1H), 6.45 (d, J = 15.8 Hz, 1H), 6.28 (dt, J = 15.8, 6.7 Hz, 1H),
4.67 (br s, 1H), 4.07 (t, J = 7.8 Hz, 2H), 3.55 (dd, J = 6.7, 1.2 Hz, 2H),
3.25−3.22 (m, 2H), 2.99 (t, J = 7.7 Hz, 2H), 1.47−1.42 (m, 2H),
1.32−1.26 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (175 MHz,
CDCl3) E-isomer, δ 157.4, 142.3, 137.7, 135.4, 131.6, 129.3, 129.1,
128.7, 128.6, 127.3, 126.3, 124.7, 123.1, 51.9, 40.9, 36.3, 32.5, 30.2,
20.3, 14.0; IR (KBr) υ 3312, 2926, 1996, 1641, 1525, 1449, 1311,
1247, 1188, 963, 752, 734 cm−1; HRMS (quadrupole, EI) m/z calcd
for C22H26N2O [M]+ 334.2045, found 334.2039.
Experimental Procedure and Characterization for the C7-
Allylation of Indoline with 2-Vinyloxirane. To an oven-dried
sealed tube charged with N-butylindoline-1-carboxamide (1f) (65.5
mg, 0.3 mmol, 100 mol %), [RhCp*Cl2]2 (4.6 mg, 2.5 mol %), AgSbF6
(10.3 mg, 10 mol %), and Cu(OAc)2 (16.3 mg, 30 mol %) in t-AmOH
(1 mL) was added 2-vinyloxirane (2g) (42.1 mg, 0.6 mmol, 200 mol
%). The reaction mixture was allowed to stir at room temperature for
20 h. The reaction mixture was diluted with EtOAc (3 mL) and
concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, n-hexanes/EtOAc = 1:1) to afford 59.6 mg
of 5g in 69% yield.
N-Butyl-7-(4-hydroxybut-2-enyl)indoline-1-carboxamide (5g).
1
Brown sticky solid; E:Z ratio = 3:1; H NMR (700 MHz, CDCl3)
1825
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827

The Journal of Organic Chemistry
Article
chromatography (silica gel, n-hexanes/EtOAc = 15:1) to afford 22.3
mg of 6c in 70% yield.
ASSOCIATED CONTENT
* Supporting Information
Detailed kinetic isotope effect (KIE) experiment and H NMR
and 13C NMR copies of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(E)-7-(Prop-1-enyl)indoline (6c). Brown sticky solid; 1H NMR (700
MHz, CDCl3) δ 7.02 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H),
6.70 (t, J = 7.4 Hz, 1H), 6.34 (dd, J = 15.8, 1.6 Hz, 1H), 6.10 (dq, J =
15.7, 6.5 Hz, 1H), 3.57 (t, J = 8.4 Hz, 2H), 3.03 (t, J = 8.4 Hz, 1H),
1.86 (dd, J = 6.5, 1.7 Hz, 3H); 13C NMR (175 MHz, CDCl3) δ 147.7,
130.3, 127.6, 126.6, 125.2, 123.1, 121.2, 119.9, 47.3, 30.0, 19.1; IR
(KBr) υ 3363, 2921, 2850, 1731, 1647, 1590, 1433, 1373, 1333, 1248,
1056, 962, 749 cm−1; HRMS (quadrupole, EI) m/z calcd for C11H13N
[M]+ 159.1048, found 159.1046.
1
AUTHOR INFORMATION
Corresponding Author
*Tel.: +82-31-290-7788. Fax: +82-31-292-8800. E-mail:
insukim@skku.edu.
■
General Procedure and Characterization for Oxidation of 6c.
To an oven-dried sealed tube charged with 6c (47.8 mg, 0.3 mmol,
100 mol %) in acetone (1 mL) was added 10% Pd/C (8.8 mg) at
room temperature. The reaction mixture was stirred for 20 h at 80 °C
and concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, n-hexanes/EtOAc = 20:1) to afford 35.4
mg of 6d in 75% yield.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea Government
(MSIP) (no. 2013R1A2A2A01005249).
1
(E)-7-(Prop-1-enyl)-1H-indole (6d). Yellow sticky solid; H NMR
(700 MHz, CDCl3) δ 8.32 (br s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.22−
7.20 (m, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.68
(dd, J = 15.7, 6.6 Hz, 1H), 6.57−6.56 (m, 1H), 6.32−6.27 (m, 1H),
1.98 (dd, J = 8.4 Hz, 1H), 1.86 (dd, J = 6.6, 1.7 Hz, 3H); 13C NMR
(175 MHz, CDCl3) δ 133.5, 128.3, 127.5, 127.0, 124.0, 121.9, 120.1,
119.9, 119.5, 103.1, 18.9; IR (KBr) υ 3376, 2922, 2848, 1593, 1434,
1248, 1195, 1056, 961, 748 cm−1; HRMS (quadrupole, EI) m/z calcd
for C11H11N [M]+ 157.0891, found 157.0891.
REFERENCES
■
(1) For selected reviews on C−H functionalization, see:
(a) Ackermann, L. Chem. Rev. 2011, 111, 1315. (b) Cho, S. H.;
Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068.
(c) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
̈
2011, 40, 4740. (d) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902.
(e) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40,
1885. (f) Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111, 1170. (g) Kuhl,
N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem.,
Int. Ed. 2012, 51, 10236. (h) Mousseau, J. J.; Charette, A. B. Acc. Chem.
Res. 2013, 46, 412.
Experimental Procedure and Characterization of H/D
Exchange Experiment without 2a. To an oven-dried sealed tube
charged with N-butylindoline-1-carboxamide (1f) (65.5 mg, 0.3 mmol,
100 mol %), [RhCp*Cl2]2 (4.6 mg, 2.5 mol %), AgSbF6 (10.3 mg, 10
mol %), and Cu(OAc)2 (16.3 mg, 30 mol %) in THF (1 mL) was
added MeOD (20 equiv). The reaction mixture was allowed to stir at
room temperature for 20 h. The reaction mixture was diluted with
EtOAc (3 mL) and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, n-hexanes/EtOAc = 8:1) to
afford 64.8 mg of 1f/deuterio-1f (79% D incorporation) in 99% yield.
N-Butylindoline-1-carboxamide (1f) and N-Butyl-7-deuterioindo-
(2) Oi, S.; Tanaka, Y.; Inoue, Y. Organometallics 2006, 25, 4773.
(3) Tsai, A. S.; Brasse, M.; Bergman, R. G.; Ellman, J. A. Org. Lett.
2011, 13, 540.
(4) Wang, H.; Schroder, N.; Glorius, F. Angew. Chem., Int. Ed. 2013,
̈
52, 5386.
(5) Feng, C.; Feng, D.; Loh, T.-P. Org. Lett. 2013, 15, 3670.
(6) Fernandez, I.; Hermatschweiler, R.; Breher, F.; Pregosin, P. S.;
́
1
line-1-carboxamide (deuterio-1f). H NMR (300 MHz, CDCl3) δ
Veiros, L. F.; Calhorda, M. J. Angew. Chem., Int. Ed. 2006, 45, 6386.
(7) (a) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int.
Ed. 2011, 50, 2990. (b) Makida, Y.; Ohmiya, H.; Sawamura, M. Angew.
Chem., Int. Ed. 2012, 51, 4122. (c) Fan, S.; Chen, F.; Zhang, X. Angew.
Chem., Int. Ed. 2011, 50, 5918. (d) Yu, Y. B.; Fan, S.; Zhang, X.
Chem.Eur. J. 2012, 18, 14643.
7.85 (d, J = 8.0 Hz, 0.21H), 7.12−7.07 (m, 2H), 6.85 (t, J = 7.3 Hz,
1H), 4.69 (br s, 1H), 3.83 (t, J = 8.5 Hz, 2H), 3.31−3.24 (m, 2H),
3.10 (t, J = 8.5 Hz, 2H), 1.56−1.47 (m, 2H), 1.40−1.28 (m, 2H), 0.92
(t, J = 7.2 Hz, 3H).
Experimental Procedure and Characterization of H/D
Exchange Experiment with 2a. To an oven-dried sealed tube
charged with N-butylindoline-1-carboxamide (1f) (65.5 mg, 0.3 mmol,
100 mol %), [RhCp*Cl2]2 (4.6 mg, 2.5 mol %), AgSbF6 (10.3 mg, 10
mol %), and Cu(OAc)2 (16.3 mg, 30 mol %) in THF (1 mL) were
added allyl methyl carbonate (2a) (69.7 mg, 0.6 mmol, 200 mol %)
and MeOD (20 equiv). The reaction mixture was allowed to stir at
room temperature for 3 h. The reaction mixture was diluted with
EtOAc (3 mL) and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, n-hexanes/EtOAc = 8:1 to
6:1) to afford 57.3 mg of 3f (74% yield) and 13.2 mg of 1f/deuterio-1f
(71% D incorporation, 20% yield), respectively.
Kinetic Isotope Effect (KIE) Experiment. To an oven-dried
sealed tube charged with 1f (32.8 mg, 0.15 mmol, 50 mol %),
[RhCp*Cl2]2 (4.6 mg, 2.5 mol %), AgSbF6 (10.3 mg, 10 mol %), and
Cu(OAc)2 (16.3 mg, 30 mol %) in t-AmOH (1 mL) were added allyl
methyl carbonate (2a) (69.7 mg, 0.6 mmol, 200 mol %) and
tetradecane (59.5 mg, 0.3 mmol) as an internal standard. In another
reaction tube, deuterio-1f (32.9 mg, 0.15 mmol, 50 mol %, >99% D)
was used instead of 1f. The two reactions were allowed to stir at room
temperature. An aliquot of each reaction mixture was taken at the time
of 10, 20, 30, 40, and 50 min. The relative yield of each product was
determined by GC−MS (tetradecane as an internal standard). A
kinetic isotope effect value (kH/kD) of 2.89 was observed (see the
Supporting Information for details).
(8) Zhang, Y. J.; Skucas, E.; Krische, M. J. Org. Lett. 2009, 11, 4248.
(9) Zeng, R.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2012, 134, 9597.
(10) Ye, B.; Cramer, N. J. Am. Chem. Soc. 2013, 135, 636.
(11) Yu, D.-G.; Gensch, T.; de Azambuja, F.; Vas
Glorius, F. J. Am. Chem. Soc. 2014, 136, 17722.
́ ́
quez-Cespedes, S.;
(12) Zhang, S.-S.; Wu, J.-Q.; Lao, Y.-X.; Liu, X.-G.; Liu, Y.; Lv, W.-X.;
Tan, D.-H.; Zeng, Y.-F.; Wang, H. Org. Lett. 2014, 16, 6412.
(13) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell
Science Ltd.: Oxford, 2000. (b) Boger, D. L.; Boyce, C. W.; Garbaccio,
R. M.; Goldberg, J. A. Chem. Rev. 1997, 97, 787. (c) Horton, D. A.;
Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893. (d) Chen, F.-
E.; Huang, J. Chem. Rev. 2005, 105, 4671. (e) Trost, B. M.; Brennan,
M. K. Synthesis 2009, 3003.
(14) Li, S.-M. Nat. Prod. Rep. 2010, 27, 57.
(15) For selected examples on C3-allylations of indoles, see:
(a) Butsugan, Y.; Nagai, K.; Nagaya, F.; Tabuchi, H.; Yamada, K.;
Araki, S. Bull. Chem. Soc. Jpn. 1988, 61, 1707. (b) Zhu, X.; Ganesan, A.
J. Org. Chem. 2002, 67, 2705. (c) McCubbin, J. A.; Hosseini, H.;
Krokhin, O. V. J. Org. Chem. 2010, 75, 959. (d) Kimura, M.; Futamata,
M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 4592. (e) Ma,
S.; Yu, S.; Peng, Z.; Guo, H. J. Org. Chem. 2006, 71, 9865. (f) Zaitsev,
A. B.; Gruber, S.; Pluss, P. A.; Pregosin, P. S.; Veiros, L. F.; Worle, M.
̈
̈
J. Am. Chem. Soc. 2008, 130, 11604. (g) Sundararaju, B.; Achard, M.;
Demerseman, B.; Toupet, L.; Sharma, G. V. M.; Bruneau, C. Angew.
1826
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827

The Journal of Organic Chemistry
Article
Chem., Int. Ed. 2010, 49, 2782. (h) Montgomery, T. D.; Zhu, Y.;
Kagawa, N.; Rawal, V. H. Org. Lett. 2013, 15, 1140.
(16) For selected examples on C2-allylations of indoles, see:
(a) Gagnon, D.; Spino, C. J. Org. Chem. 2009, 74, 6035. (b) Yamakawa,
T.; Ideue, E.; Shimokawa, J.; Fukuyama, T. Angew. Chem., Int. Ed.
2010, 49, 9262. (c) Auzzas, L.; Larsson, A.; Matera, R.; Baraldi, A.;
Deschen
G.; Ciacci, A.; Vesci, L.; Pisano, C.; Hanessian, S. J. Med. Chem. 2010,
53, 8387. (d) Bennasar, M.; Sole, D.; Zulaica, E.; Alonso, S. Org. Lett.
̂
es-Simard, B.; Giannini, G.; Cabri, W.; Battistuzzi, G.; Gallo,
́
2011, 13, 2042. (e) Li, B.; Ma, J.; Xie, W.; Song, H.; Xu, S.; Wang, B.
Chem.Eur. J. 2013, 19, 11863. (f) Kim, M.; Park, J.; Sharma, S.; Han,
S.; Han, S. H.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org. Biomol. Chem.
2013, 11, 7427.
(17) (a) Chakravarty, S.; Hart, B. P.; Jain, R. P. WO 2011103460 A1,
2011. (b) Kreft, A. F.; Caufield, C. E.; Failli, A. A.; Caggiano, T. J.;
Greenfield, A. A.; Kubrak, D. M. US 5776967 A, 1998. (c) Reisch, J.;
Adebajo, A. C.; Kumar, V.; Aladesanmi, A. J. Phytochemistry 1994, 36,
1073. (d) Meragelman, K. M.; McKee, T. C.; Boyd, M. R. J. Nat. Prod.
2000, 63, 427. (e) Wang, Y.; Gloer, J. B.; Scott, J. A.; Malloch, D. J.
Nat. Prod. 1995, 58, 93.
(18) Chatani, N.; Yorimitsu, S.; Asaumi, T.; Kakiuchi, F.; Murai, S. J.
Org. Chem. 2002, 67, 7557.
(19) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330. (b) Shi, Z.; Li, B.; Wan, X.; Cheng, J.;
Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem., Int. Ed. 2007, 46,
5554. (c) Nishikata, T.; Abela, A. R.; Huang, S.; Lipshutz, B. H. J. Am.
Chem. Soc. 2010, 132, 4978. (d) De, S.; Ghosh, S.; Bhunia, S.; Sheikh,
J. A.; Bisai, A. Org. Lett. 2012, 14, 4466. (e) Jiao, L.-Y.; Oestreich, M.
Chem.Eur. J. 2013, 19, 10845. (f) Jiao, L.-Y.; Smirnov, P.; Oestreich,
M. Org. Lett. 2014, 16, 6020.
́
(20) (a) Urones, B.; Arrayas, R. G.; Carretero, J. C. Org. Lett. 2013,
15, 1120. (b) Jiao, L.-Y.; Oestreich, M. Org. Lett. 2013, 15, 5374.
(c) Song, Z.; Samanta, R.; Antonchick, A. P. Org. Lett. 2013, 15, 5662.
(d) Pan, S.; Wakaki, T.; Ryu, N.; Shibata, T. Chem.Asian J. 2014, 9,
1257.
(21) (a) Pan, S.; Ryu, S.; Shibata, T. Adv. Synth. Catal. 2014, 356,
929. (b) Ai, W.; Yang, X.; Wu, Y.; Wang, X.; Li, Y.; Yang, Y.; Zhou, B.
Chem.Eur. J. 2014, 20, 17653.
(22) Yang, X.-F.; Hu, X.-H.; Feng, C.; Loh, T.-P. Chem. Commun.
2015, DOI: 10.1039/C4CC09330E.
(23) (a) Pan, C.; Abdukader, A.; Han, J.; Cheng, Y.; Zhu, C. Chem.
Eur. J. 2014, 20, 3606. (b) Shin, K.; Chang, S. J. Org. Chem. 2014, 79,
12197. (c) Hou, W.; Yang, Y.; Ai, W.; Wu, Y.; Wang, X.; Zhou, B.; Li,
Y. Eur. J. Org. Chem. 2015, DOI: 10.1002/ejoc.201403355.
(24) Kim, M.; Mishra, N. K.; Park, J.; Han, S.; Shin, Y.; Sharma, S.;
Lee, Y.; Lee, E.-K.; Kwak, J. H.; Kim, I. S. Chem. Commun. 2014, 50,
14249.
(25) Kim, M.; Sharma, S.; Mishra, N. K.; Han, S.; Park, J.; Kim, M.;
Shin, Y.; Kwak, J. H.; Han, S. H.; Kim, I. S. Chem. Commun. 2014, 50,
11303.
(26) For a recent review on formal SN-type reaction mechanism, see:
Kuhl, N.; Schroder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356, 1443.
̈
(27) For the Rh(III)-catalyzed allylation using 2-vinyloxiranes, see:
Yu, S.; Li, X. Org. Lett. 2014, 16, 1200.
(28) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
(29) For the nucleophilic substitution mechanism under Rh(III)
catalysis, see: (a) Yang, L.; Correia, C. A.; Li, C.-J. Adv. Synth. Catal.
2011, 353, 1269. (b) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett.
2012, 14, 656. (c) Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2012, 14,
272.
1827
DOI: 10.1021/jo502733q
J. Org. Chem. 2015, 80, 1818−1827