Iridium-catalyzed C-3 allylation of indoles with allylic alcohols promoted by a bronsted acid

Article abstract of DOI:10.1055/s-0033-1341156

A highly regioselective method has been developed for the allylation of indoles with an iridium catalyst. This regioselective procedure uses allylic alcohols directly as allylating agents in the presence of a catalytic amount of sulfuric acid. A wide rang

Full text of DOI:10.1055/s-0033-1341156

PAPER
▌1717
paper
Iridium-Catalyzed C-3 Allylation of Indoles with Allylic Alcohols Promoted by
a Brønsted Acid
Allylation of Indoles with Allylic Alcohols
Shu-jie Chen, Guo-ping Lu, Chun Cai*
Chemical Engineering College, Nanjing University of Science & Technology, Nanjing, Jiangsu 210094, P. R. of China
E-mail: c.cai@mail.njust.edu.cn; Fax +86(25)84315030
Received: 12.01.2014; Accepted after revision: 17.03.2014
diates, because the allyl group is capable of undergoing a
Abstract: A highly regioselective method has been developed for
range of transformations, such as hydrogenation, haloge-
the allylation of indoles with an iridium catalyst. This regioselective
nation, or hydroformylation.5 These useful characteristics
have stimulated organic researchers to seek more efficient
procedure uses allylic alcohols directly as allylating agents in the
presence of a catalytic amount of sulfuric acid. A wide range of in-
doles reacted smoothly with asymmetrical allylic alcohols to give methods for the allylation of indoles.
the corresponding branched products in branched-to-linear ratios of
In 1999, Kočovský and co-workers described the first al-
up to 99:1 and yields as high as 92%. A series of inorganic and or-
ganic acids were tested in this approach, and it was shown that acids
with pKa values in acetonitrile of less than 15 are required in this
iridium-catalyzed system.
lylation of indole with allyl acetates in the presence of a
molybdenum(II) catalyst.6 Since then, the transition-
metal-catalyzed allylation of indoles has continued to at-
tract considerable interest, and a series of protocols have
been developed that use allyl carbonates or acetates in
conjunction with transition-metal catalysts.7 However,
these reactions often require large amounts of base (more
than one equivalent) and they involve wastage of the leav-
ing group, the addition of which to the corresponding al-
lylic alcohol entails an additional prior step. The direct use
of allylic alcohols as allylating agents is therefore both
more atom-economic and more environmentally friendly.
Key words: iridium, allylations, indoles, regioselectivity, homoge-
neous catalysis
The indole nucleus is a versatile building block for the
synthesis of a wide range of bioactive natural products
and pharmaceutical agents,1 such as the plant-growth hor-
mone indole-3-acetic acid2 and the nonsteroidal antiin-
flammatory drug indomethacin.3 As a result, significant
efforts have been devoted to the discovery of methods for
the preparation of functional indoles.4 Among these, allyl
indoles represent an important group of organic interme-
In 2005, Tamaru and co-workers described a palladi-
um(0)-catalyzed C-3-selective allylation of indoles with
allylic alcohols as allylating agents in the presence of tri-
Ph
previous work
[Mo3S4Pd(η3-allyl)]
OH
(1)
+
N
H
N
MeCN, reflux
H
Ph
*
[Ir(cod)Cl]2, L*
OCO2Me
+
(2)
Cs2CO3 (100 mol%)
dioxane, reflux
N
N
H
H
up to 92% ee
this work
Ph
OH
(3)
[Ir(cod)Cl]2
+
H2SO4 (5 mol%)
MeCN, 50 °C
N
H
N
H
Scheme 1 Regioselectivities of various transition-metal-catalyzed allylation reactions of indoles
SYNTHESIS 2014, 46, 1717–1724
Advanced online publication: 10.04.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1341156; Art ID: SS-2014-H0012-OP
© Georg Thieme Verlag Stuttgart · New York

1718
S.-j. Chen et al.
PAPER
Crafts-type allylic alkylation of indoles with allylic car-
bonates as the allylating agents and a chiral phosphorami-
dite as a ligand (Scheme 1, equation 2).13 This catalytic
system showed a high enantioselectivity (ee ≤ 92%) and a
different regioselectivity from that obtained by the palla-
dium-based approach (Scheme 1, equation 1).14 However,
there are few reports on iridium-catalyzed allylations of
indoles with allylic alcohols as allylating agents.15 In-
spired by the pioneering work of Carreira and co-workers
on iridium-catalyzed asymmetric allylic substitution reac-
tions with branched allylic alcohols as allylic precursors,16
we have developed a simple and highly regioselective
method for the allylation of indoles with allylic alcohols
in the presence of a catalytic amount of sulfuric acid
(Scheme 1, equation 3).
Table 1 Optimization of the Reaction Conditions
[Ir]
OH
+
+
N
acid
solvent
N
H
N
H
1a
2a
A
B
Entrya Catalyst
Acid
Solvent
Yieldb
Yieldb
(%) of A (%) of B
1
2
3
4
5
6
7
8e
9
[Ir(cod)Cl]2
BEt3
THF
n.d.d
41
35
5
n.d.
7
c
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
[Ir(cod)Cl]2
BF3·OEt2 THF
TFA
TFA
TFA
TFA
TFA
TFA
toluene
8
1,4-dioxane
THF
0
We began by studying the reaction of indole (1a; 0.2
mmol) with allylic alcohol (2a; 0.2 mmol), as model sub-
strates in tetrahydrofuran containing dichlorobis(cy-
clooctadiene)diiridium (2 mol%) and triethylborane (0.5
equiv) at 50 °C for 15 hours. Unfortunately, the triethyl-
borane failed to activate the allylic alcohol in this iridium-
catalyzed system, and no allylation product A or B was
obtained (Table 1, entry 1). In the presence of the stronger
Lewis acid boron trifluoride etherate (BF3·Et2O), the reac-
tion proceeded with a moderate yield (entry 2). When the
reaction was performed in the presence of trifluoroacetic
acid (0.5 equiv) in toluene at 50 °C for 15 hours, the al-
lylation products A and B were obtained as a 35:8 mixture
16
21
58
0
0
DMF
0
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
24
93
17
8
[Ir(cod)(OMe)]2 TFA
[Ir(cod)(OH)]2 TFA
53
32
n.d.
n.d.
7
10
11
12
13
14
15
16
IrCl3·H2O
TFA
TFA
TFA
H2SO4
–
n.d.
n.d.
0
f
[IrCp*Cl2]2
f
[Ir(coe)2Cl]2
g
[Ir(cod)2Cl]2
[Ir(cod)2Cl]2
–
60
n.d.
n.d.
21
n.d.
n.d.
Table 2 The Effect of the Acid on the Reaction
[Ir(cod)Cl]2
(2 mol%)
TFA
OH
+
+
acid
(0.5 equiv)
MeCN
a Reaction conditions: indole (1a; 0.2 mmol), allylic alcohol 2a (0.2
mmol), Ir catalyst (2 mol%), acid (0.5 equiv), solvent (1 mL), 50 °C,
N
N
N
H
H
1a
2a
A
B
50 °C
15 h.
b By GC.
Entrya Acid
pKab
Yieldc (%) A/B
of A + B
c 1 M solution in THF.
d n.d. = not detected.
e 3 equiv of 2a were used.
d
1
2
3
4
5
6
7
8
9
H2SO4
7.20
8.45
80
56:24
f Cp* = 1,2,3,4,5-pentamethylcyclopenta-1,3-diene; coe = cyclooc-
tene.
TsOH
HCld
78
55:23
52:30
59:18
58:23
57:14
19:0
–
g 5 mol% H2SO4 (1 M in H2O).
8.90
82
ethylborane (30 mol%).8 In this protocol, triethylborane
acts as a Lewis acid, coordinating to the hydroxy group to
activate the allylic alcohol. Pregosin and co-workers have
reported a series of ruthenium catalysts for the allylation
of indoles with allylic alcohols as allylating agents.9 In ad-
dition, enantioselective gold-catalyzed intramolecular al-
lylic alkylations of indoles with alcohols have been
reported by Bandini and co-workers.10 Recently, You and
co-workers developed a ruthenium-catalyzed intermolec-
ular dearomatization reaction of indoles with allylic alco-
hols in the presence of p-toluenesulfonic acid
monohydrate.11 Relevant researches have concentrated
mainly on the transition metals palladium, ruthenium, and
gold.12 In 2008, You and co-workers reported the first
iridium-catalyzed regio- and enantioselective Friedel–
MsOH
TFA
9.97
77
12.65
14.50
15.30
16.70
19.00
81
oxalic acid dihydrate
H2OCCH2CO2H
2-HOC6H4CO2H
2-ClC6H4CO2H
71
19
n.d.e
n.d.
-
a Reaction conditions: indole (1a; 0.2 mmol), allylic alcohol 2a (0.2
mmol), [Ir(cod)Cl]2 (2 mol%), acid (0.5 equiv), MeCN (1 mL), 50 °C,
5 h.
b In MeCN.17
c By GC.
d 1 M aq soln.
e n.d. = not detected.
Synthesis 2014, 46, 1717–1724
© Georg Thieme Verlag Stuttgart · New York

PAPER
Allylation of Indoles with Allylic Alcohols
1719
in a total yield of 43% (entry 3). Rapid screening of the action was related to the pKa of the acid in acetonitrile
solvent (entries 4–7) showed that acetonitrile was suitable (Table 2). When the pKa value was more than 15, the yield
for this reaction, giving the major product, the 3-substitut- decreased dramatically. In particular, the reaction pro-
ed allylic compound A, in 58% yield, together with a 24% ceeded smoothly and efficiently when an inorganic acid
yield of the double allylation product B as a minor product such as sulfuric acid or hydrochloric acid was used. We
(entry 7). By using an excess of the allylic alcohol 2a, the therefore inferred that the allylic alcohol is activated by
double allylation product B was obtained exclusively in protons dissociating from the Brønsted acid and subse-
93% yield (entry 8).
quently coordinates with the metal to form an iridium π-
allyl intermediate that participates in electrophilic substi-
tution of the indole to form the products.
The allylation of indole (1a) with bis(cyclooctadiene)di-
methoxyiridium as catalyst proceeded in a slightly low
yield of 70% (entry 9), and this yield decreased further To test the regioselectivity of the protocol, we examined
when bis(cyclooctadiene)dihydroxyiridium was used as the reaction of the asymmetric allylic alcohol 2b with in-
the catalyst (entry 10). Neither allylation product A or B dole (1a). The reaction regioselectively gave the branched
was formed when iridium(III) chloride monohydrate or products 3a and 4a in 90% yield and ratios as high as 99:1
tetrachlorobis(η5-1,2,3,4,5-pentamethylcyclopenta-1,3- (Table 3, entry 1). We then tested the generality of the re-
diene)diiridium was used as the catalyst (entries 11 and action by treating a series of substituted indoles 1b–l with
12). dichlorobis(cyclooctene)iridium also showed a low allylic alcohol 2b (entries 2–12). The protocol had a wide
catalytic activity in this reaction (entry 13). However, tolerance to various substituents; indoles carrying an elec-
when the strong Brønsted acid sulfuric acid was used as a tron-donating or electron-withdrawing substituent at the
1 M aqueous solution, a catalytic loading (5 mol%) was C-2, C-4, or C-5 position all reacted well with 2b (entries
sufficient to obtain a satisfactory result (entry14). The al- 2–8). It was noteworthy that the iridium-catalyzed system
lylation reaction failed to proceed in the absence of either was also active in allylation of the N-substituted indoles
the iridium catalyst or the acid (entries 15 and 16).
1i–k, giving the corresponding C-3 allylation product
3i–k in 61–87% yield (entries 9–11). When the N-position
of the indole was locked by a strongly electron-withdraw-
ing tosyl substituent, the nucleophilic ability of the C-3
Next, we examined a series of acids to investigate their ef-
fect on the reaction, and we found that the yield of the re-
Table 3 Iridium-Catalyzed C-3 Allylation of Indoles 1a–l with Allylic Alcohol 2b
Ph
Ph
OH
[Ir(cod)Cl]2
R2
R2
+
R2
+
H2SO4, MeCN
50 °C, 5 h
N
N
R1
N
R1
R1
1a–l
2b
3
4
Entrya
R1
R2
Reactant
Product
Ratiob 3/4
Yieldc (%) of 3
1
2
H
H
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
99:1
98:2
99:1
99:1
97:3
98:2
97:3
99:1
99:1
97:3
98:2
–
90
87
84
92
85
86
83
86
87
61
89
n.d.
H
4-MeO
5-F
3
H
4
H
5-Br
5-MeO
5-Me
2-Me
2-Ph
H
5
H
6
H
7
H
1g
1h
1i
3g
3h
3i
8
H
9
Me
Ph
Bn
Ts
10
11
12
H
1j
3j
H
1k
1l
3k
3l
H
a Reaction conditions: indole 1 (0.2 mmol), allylic alcohol 2b (0.2 mmol), [Ir(cod)Cl]2 (2 mol%), 1 M aq H2SO4 (5 mol%), MeCN (1 mL), 50 °C,
5 h.
b By 1H NMR analysis of the crude mixture.
c Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1717–1724

1720
S.-j. Chen et al.
PAPER
position appeared to be seriously weakened, and none of
the desired product was formed (entry 12). These results
show that the mechanism of this iridium-catalyzed reac-
tion differs from that of many palladium/base-catalyzed
allylation reactions, which frequently required the pres-
ence of a base to deprotonate the nitrogen atom to form a
more nucleophilic anion.7a
Table 4 Scope of the Reaction With Respect to the Allylic Alcohol
Reactant
R
R
[Ir(cod)Cl]2
OH
+
+
H2SO4
MeCN
50 °C
N
N
N
R
H
H
H
Next, we conducted a series of experiments to investigate
the scope of the reaction in relation to the allylic alcohol
reactant (Table 4). The reactions of 1a with α-aryl allylic
alcohols bearing electron-donating or electron-withdraw-
ing substituents on the aromatic ring gave the correspond-
ing C-3 allylation indole products in moderate to good
yields and high regioselectivities (entries 1–5). The reac-
tions of allylic alcohols 2d and 2e required a higher cata-
lyst loading (4 mol%), but gave the corresponding
products 3n and 3o in 72% and 81% yield, respectively
(entries 2 and 3). The 4-methyl-substituted α-aryl allylic
alcohol 2g was less reactive than the 4-trifluoromethyl de-
rivative 2f, giving 3p in a moderate yield of 67% after a
slightly longer reaction time (entry 5). The 1-naphthyl al-
lylic alcohol 2h proved to be good substrate for the reac-
tion, giving the corresponding C-3 allylation indole 3r in
good yield and with excellent regioselectivity (entry 6).
Furthermore, the aliphatic allylic alcohol 2i was also tol-
erated by this system, and gave the corresponding product
3s in a moderate yield of 53% (entry 7).
1a
2c–i
3
4
Entrya Alcohol
Product Ratiob 3/4 Yieldc (%) of 3
1
2c
2d
2e
2f
2-BrC6H4
3m
3n
3o
3p
3q
3r
98:2
94:6
95:5
97:3
92:8
99:1
90:10
76
72
81
87
67
86
53
2d
3d
4
2-F3CC6H4
3-F3CC6H4
4-F3CC6H4
4-Tol
5e
6
2g
2h
2i
1-naphthyl
Ph(CH2)2
7
3s
a Reaction conditions: indole (1a; 0.2 mmol), allylic alcohol 2 (0.2
mmol), [Ir(cod)Cl]2 (2 mol%), 1 M aq H2SO4 (5 mol%), MeCN (1
mL), 50 °C, 5 h.
b By 1H NMR analysis of the crude mixture.
c Isolated yield.
d 4 mol% [Ir(cod)Cl]2 was used.
e Reaction time: 10 h.
We also examined the application of the method in the
asymmetric allylation of indole. We chose indole (1a; 0.2
mmol) and allylic alcohol 2b (0.2 mmol) as model sub-
strates. Initially, a chiral bisoxazoline ligand L* was added
to the catalytic system (Scheme 2). When 5 mol% sulfuric
acid was used as the additive, the alkylation product 3a
was obtained as a racemic mixture in 81% yield [Scheme
2 (a)]. Subsequently, we used the chiral Brønsted acid D-
camphorsulfonic acid as the activator. The reaction gave
the same product 3a in a slightly lower yield, but the prod-
uct was still racemic [Scheme 2 (b)]. These results showed
that the bisoxazoline ligand is not suitable for asymmetric
catalysis in this system. We are currently attempting to de-
velop more-efficient chiral ligands for the asymmetric al-
lylation of indoles.
agents, thereby avoiding the waste of a leaving group. The
method tolerates a wide range of substrates. For various
unsymmetrical allylic alcohols and substituted indoles,
the reaction proceeded smoothly in moderate to good
yields with excellent selectivity toward branched prod-
ucts. In addition, a series of inorganic and organic acids
was tested in this approach, and it was shown that an acid
with a pKa value in acetonitrile of less than 15 is required
in this iridium-catalyzed system.
All chemicals were purchased from commercial suppliers and used
as received unless otherwise noted. TLC was performed on glass
plates coated with silica gel; visualization was performed by UV ir-
radiation (254 nm). Mass spectra were recorded on a Finnigan TSQ
Quantum-MS instrument operated in the electrospray ionization
(ESI) mode. IR spectra were recorded on a Thermo Scientific Nico-
let iS10 instrument. 1H NMR, 13C NMR, and 19F NMR spectra were
recorded in CDCl3 on a Bruker AVANCE 500 spectrometer operat-
In conclusion, we have developed a simple iridium-cata-
lyzed system for the allylation of indoles. Our new ap-
proach uses used allylic alcohols directly as allylating
Ph
OH
[Ir(cod)Cl]2 (2 mol%)
L* (4 mol%)
+
additive
MeCN, 50 °C
N
H
N
H
O
O
N
1a
2b
3a
N
N
additive
a) H2SO4 (5 mol%) (1 M in H2O), 81% yield, 0% ee
b) D-camphorsulfonic acid (50 mol%), 75% yield, 0% ee
L*
Scheme 2 Attempted asymmetric allylations of indole
Synthesis 2014, 46, 1717–1724
© Georg Thieme Verlag Stuttgart · New York

PAPER
Allylation of Indoles with Allylic Alcohols
1721
ed at 500, 125, or 470 MHz, respectively. Chemical shifts are re-
ported in ppm relative to TMS as an internal standard. Elemental
analyses were performed on a Yanagimoto MT3CHN instrument.
GC analysis were performed on an Agilent 7890A instrument (Col-
umn: Agilent 19091J-413, 30 m × 320 μm × 0.25 μm; carrier gas:
H2; FID detection).
1H NMR (500 MHz, CDCl3): δ = 7.97 (s, 1 H), 7.28 (t, J = 3.9 Hz,
4 H), 7.18 (dt, J = 5.5, 4.1 Hz, 1 H), 7.08 (t, J = 8.0 Hz, 1 H), 6.96
(d, J = 7.9 Hz, 1 H), 6.81 (d, J = 2.0 Hz, 1 H), 6.45 (d, J = 7.7 Hz, 1
H), 6.39 (ddd, J = 17.0, 10.1, 6.8 Hz, 1 H), 5.42 (d, J = 6.8 Hz, 1 H),
5.16 (d, J = 10.1 Hz, 1 H), 4.98 (d, J = 17.1 Hz, 1 H), 3.75 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 153.89, 143.56, 140.84, 137.13,
127.55, 126.95, 124.70, 121.92, 120.11, 118.12, 116.10, 113.73,
103.33, 98.98, 54.02, 46.16.
Allylic Alcohols 2b–i; General Procedure18
An oven-dried round-bottomed flask was charged with a solution of
the appropriate aldehyde (10 mmol, 1 equiv) in anhydrous THF (20
mL), and the mixture was stirred for 10 min under N2 at 0 °C. A 1
M solution of vinylmagnesium bromide in THF (12 mmol, 1.2
equiv) was added slowly. After 15 min, the mixture was allowed to
warm to r.t. and stirred for an additional 1–3 h. The reaction was
quenched with sat. aq NH4Cl, and the mixture was extracted with
Et2O (3 × 30 mL). The organic layers were combined, washed with
brine, dried (MgSO4), filtered, and concentrated to give the crude
allylic alcohol 2b–i, which was used in the next step without further
purification.
MS (ESI): m/z = 264 [M + H]+.
Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32. Found: C,
82.34; H, 6.39; N, 5.49.
5-Fluoro-3-(1-phenylprop-2-en-1-yl)-1H-indole (3c)
Pale-yellow oil; yield: 42.2 mg (84%).
IR (neat): 3427, 2980, 1483, 1452, 1166, 796, 698, 591 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.94 (s, 1 H), 7.31–7.17 (m, 6 H),
7.00 (dd, J = 9.8, 2.0 Hz, 1 H), 6.91–6.83 (m, 2 H), 6.29 (ddd, J =
17.1, 10.1, 7.1 Hz, 1 H), 5.17 (d, J = 10.1 Hz, 1 H), 5.04 (d, J = 17.1
Hz, 1 H), 4.85 (d, J = 7.1 Hz, 1 H).
Allylindoles A, B, and 3a–s; General Procedure
MeCN (1 mL), allylic alcohol 2 (0.200 mmol), and 1 M aq H2SO4
(0.010 mmol) were successively added from a syringe to a N2-
purged flame-dried Schlenk tube containing indole 1 (0.200 mmol)
and [Ir(cod)Cl]2 (0.004 mmol), and the mixture was stirred at 50 °C
for 5 h. When the reaction was complete, the solvent was removed
under reduced pressure. The branched/linear ratio of regioisomers
1
13C NMR (125 MHz, CDCl3): δ = 156.57 (d, JC,F = 233.4 Hz),
141.81, 139.11, 132.17, 127.44, 127.37, 126.18, 125.46, 123.25,
117.73, 114.71, 110.64 (d, JC,F = 9.0 Hz), 109.47 (d, JC,F = 26.4
3
2
Hz), 103.80 (d, 2JC,F = 23.5 Hz), 45.94.
19F NMR (470 MHz, CDCl3): δ = –124.47.
MS (ESI): m/z = 252 [M + H]+.
1
was then determined by H NMR spectroscopic analysis of the
crude reaction mixture. Finally, the crude residue was purified by
flash column chromatography [silica gel, PE–EtOAc (95:5 to
90:10)].
Anal. Calcd for C17H14FN: C, 81.25; H, 5.62; N, 5.57. Found: C,
81.04; H, 5.74; N, 5.70.
3-Allyl-1H-indole (A)19
Yellow oil; yield: 15.6 mg (50%).
5-Bromo-3-(1-phenylprop-2-en-1-yl)-1H-indole (3d)
Pale-yellow oil; yield: 57.2 mg (92%).
IR (neat): 3421, 2922, 1453, 794, 698, 579 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.62 (d, J = 7.9 Hz,
1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.24–7.18 (m, 1 H), 7.16–7.10 (m, 1
H), 6.99 (s, 1 H), 6.09 (ddt, J = 16.6, 10.0, 6.5 Hz, 1 H), 5.18 (dq,
J = 17.0, 1.7 Hz, 1 H), 5.09 (ddd, J = 10.0, 3.1, 1.4 Hz, 1 H), 3.54
(dd, J = 6.5, 1.1 Hz, 2 H).
1H NMR (500 MHz, CDCl3): δ = 8.04 (s, 1 H), 7.56–7.52 (m, 1 H),
7.32 (dd, J = 10.0, 4.7 Hz, 2 H), 7.29–7.26 (m, 3 H), 7.23 (dd, J =
10.2, 3.4 Hz, 2 H), 6.88 (d, J = 1.7 Hz, 1 H), 6.32 (ddd, J = 17.1,
10.1, 7.0 Hz, 1 H), 5.22 (d, J = 10.1 Hz, 1 H), 5.06 (d, J = 17.1 Hz,
1 H), 4.91 (d, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 136.31, 135.47, 126.47, 121.02,
13C NMR (125 MHz, CDCl3): δ = 141.68, 139.05, 134.26, 127.61,
127.45, 127.35, 125.49, 123.99, 122.73, 121.37, 117.33, 114.83,
111.69, 111.51, 45.69.
120.64, 118.27, 118.11, 114.19, 113.57, 110.08, 28.83.
1,3-Diallyl-1H-indole (B)19
Yellow oil; yield: 33.8 mg (86%).
MS (ESI): m/z = 312 [M + H]+.
1H NMR (500 MHz, CDCl3): δ = 7.64 (dd, J = 7.9, 3.2 Hz, 1 H),
7.37–7.29 (m, 1 H), 7.24 (ddd, J = 8.2, 3.1, 1.3 Hz, 1 H), 7.19–7.08
(m, 1 H), 6.99–6.86 (m, 1 H), 6.22–5.89 (m, 2 H), 5.31–5.00 (m, 4
H), 4.82–4.60 (m, 2 H), 3.68–3.42 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 136.46, 135.61, 132.70, 127.06,
124.46, 120.59, 118.26, 117.85, 116.16, 114.09, 112.39, 108.53,
47.69, 28.81.
Anal. Calcd for C17H14BrN: C, 65.40; H, 4.52; N, 4.49. Found: C,
65.56; H, 4.34; N, 4.38.
5-Methoxy-3-(1-phenylprop-2-en-1-yl)-1H-indole (3e)
Pale-yellow oil; yield: 44.7 mg (85%).
IR (neat): 3418, 2936, 1483, 1205, 1170, 915, 701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.90 (s, 1 H), 7.33 (d, J = 4.4 Hz,
4 H), 7.26 (t, J = 2.0 Hz, 1 H), 7.24 (t, J = 2.1 Hz, 1 H), 6.91–6.81
(m, 3 H), 6.37 (ddd, J = 17.1, 10.1, 7.1 Hz, 1 H), 5.27–5.20 (m, 1
H), 5.11 (dt, J = 17.1, 1.5 Hz, 1 H), 4.94 (dd, J = 7.1, 0.8 Hz, 1 H),
3.77 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 152.78, 142.13, 139.39, 130.83,
127.46, 127.36, 126.28, 125.31, 122.33, 117.22, 114.46, 111.11,
110.74, 100.89, 54.84, 46.02.
3-(1-Phenylprop-2-en-1-yl)-1H-indole (3a)13
Yellow oil; yield: 41.8 mg (90%).
IR (neat): 3414, 3059, 1457, 917, 736, 702 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.43 (d, J = 8.0 Hz,
1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.32 (d, J = 4.4 Hz, 4 H), 7.24 (dt,
J = 8.7, 4.2 Hz, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1
H), 6.91–6.88 (m, 1 H), 6.38 (ddd, J = 17.1, 10.1, 7.1 Hz, 1 H), 5.22
(d, J = 10.1 Hz, 1 H), 5.10 (d, J = 17.1 Hz, 1 H), 4.99 (d, J = 7.1 Hz,
1 H).
13C NMR (125 MHz, CDCl3): δ = 142.22, 139.50, 135.68, 127.45,
127.36, 125.85, 125.31, 121.49, 121.09, 118.87, 118.36, 117.56,
114.48, 110.09, 45.99.
MS (ESI): m/z = 264 [M + H]+.
Anal. Calcd for C18H17NO: C, 82.10; H, 6.51; N, 5.32. Found: C,
81.84; H, 6.37; N, 5.49.
5-Methyl-3-(1-phenylprop-2-en-1-yl)-1H-indole (3f)
Pale-yellow oil; yield: 42.5 mg (86%).
IR (neat): 3410, 2918, 912, 791, 703, 586 cm–1.
4-Methoxy-3-(1-phenylprop-2-en-1-yl)-1H-indole (3b)
Pale-yellow oil; yield: 45.8 mg (87%).
© Georg Thieme Verlag Stuttgart · New York
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S.-j. Chen et al.
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1H NMR (500 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.33 (d, J = 4.6 Hz,
4 H), 7.28–7.22 (m, 3 H), 7.03 (dd, J = 8.2, 1.3 Hz, 1 H), 6.84 (d,
J = 1.8 Hz, 1 H), 6.38 (ddd, J = 17.1, 10.1, 7.1 Hz, 1 H), 5.25–5.20
(m, 1 H), 5.13–5.06 (m, 1 H), 4.97 (dd, J = 7.1, 0.7 Hz, 1 H), 2.42
(s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 142.29, 139.60, 133.99, 127.58,
127.46, 127.34, 126.10, 125.26, 122.73, 121.67, 118.37, 117.00,
114.41, 109.76, 45.88, 20.55.
10.1, 7.2 Hz, 1 H), 5.25 (d, J = 10.1 Hz, 1 H), 5.16 (d, J = 17.0 Hz,
1 H), 5.04 (d, J = 7.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 141.91, 139.31, 138.85, 135.47,
128.57, 127.47, 127.27, 125.42, 125.33, 125.19, 123.40, 123.20,
121.50, 119.19, 118.95, 118.52, 114.72, 109.55, 45.96.
MS (ESI): m/z = 310 [M + H]+.
Anal. Calcd for C23H19N: C, 89.28; H, 6.19; N, 4.53. Found: C,
89.46; H, 6.28; N, 4.38.
MS (ESI): m/z = 248 [M + H]+.
1-Benzyl-3-(1-phenylprop-2-en-1-yl)-1H-indole (3k)
Pale-yellow oil; yield: 57.4 mg (89%).
Anal. Calcd for C18H17N: C, 87.41; H, 6.93; N, 5.66. Found: C,
87.54; H, 6.76; N, 5.78.
1H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 7.9 Hz, 1 H), 7.33 (s,
2 H), 7.32 (s, 3 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.25 (dd, J = 8.4, 4.9
Hz, 2 H), 7.18–7.14 (m, 1 H), 7.12 (d, J = 6.9 Hz, 2 H), 7.06–7.02
(m, 1 H), 6.87 (s, 1 H), 6.38 (ddd, J = 17.1, 10.1, 7.1 Hz, 1 H), 5.31
(s, 2 H), 5.24–5.18 (m, 1 H), 5.10 (dt, J = 17.0, 1.5 Hz, 1 H), 5.01
(d, J = 7.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 142.26, 139.61, 136.75, 136.07,
127.74, 127.44, 127.35, 126.52, 125.73, 125.63, 125.27, 123.92,
120.82, 119.04, 118.06, 116.60, 114.41, 108.71, 49.01, 45.99.
2-Methyl-3-(1-phenylprop-2-en-1-yl)-1H-indole (3g)
Pale-yellow oil; yield: 41.1 mg (83%).
1H NMR (500 MHz, CDCl3): δ = 7.80 (s, 1 H), 7.36 (d, J = 7.9 Hz,
1 H), 7.30 (dt, J = 8.2, 5.7 Hz, 5 H), 7.20 (t, J = 7.1 Hz, 1 H), 7.10
(t, J = 7.6 Hz, 1 H), 6.99 (t, J = 7.5 Hz, 1 H), 6.47 (ddd, J = 17.1,
10.1, 7.0 Hz, 1 H), 5.22 (d, J = 10.1 Hz, 1 H), 5.08 (d, J = 17.1 Hz,
1 H), 5.00 (d, J = 7.0 Hz, 1 H), 2.35 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 142.19, 138.96, 134.35, 130.51,
127.22, 127.17, 127.01, 124.99, 119.89, 118.43, 118.15, 114.53,
111.76, 109.22, 44.85, 11.35.
MS (ESI): m/z = 324 [M + H]+.
Anal. Calcd for C24H21N: C, 89.12; H, 6.54; N, 4.33. Found: C,
89.01; H, 6.36; N, 4.50.
MS (ESI): m/z = 248 [M + H]+.
Anal. Calcd for C18H17N: C, 87.41; H, 6.93; N, 5.66. Found: C,
87.64; H, 6.77; N, 5.54.
3-[1-(2-Bromophenyl)prop-2-en-1-yl]-1H-indole (3m)
Yellow oil; yield: 47.3 mg (76%).
IR (neat): 3409, 2976, 915, 736 cm–1.
2-Phenyl-3-(1-phenylprop-2-en-1-yl)-1H-indole (3h)
Pale-yellow oil; yield: 53.1 mg (86%).
1H NMR (500 MHz, CDCl3): δ = 8.01 (s, 1 H), 7.66–7.59 (m, 1 H),
7.41 (d, J = 8.0 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.23–7.16 (m, 3
H), 7.13–7.03 (m, 2 H), 6.93 (d, J = 1.3 Hz, 1 H), 6.31 (ddd, J =
16.9, 10.2, 6.4 Hz, 1 H), 5.49 (dd, J = 6.3, 1.0 Hz, 1 H), 5.27 (d, J =
10.2 Hz, 1 H), 5.04 (d, J = 17.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 141.08, 137.87, 135.67, 131.91,
129.21, 126.93, 126.42, 125.83, 123.85, 121.79, 121.22, 118.76,
118.50, 116.67, 115.35, 110.09, 44.57.
IR (neat): 3405, 3054, 1447, 1243, 736, 697 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.10 (s, 1 H), 7.57–7.53 (m, 2 H),
7.50–7.39 (m, 5 H), 7.36 (d, J = 7.4 Hz, 2 H), 7.29 (t, J = 7.6 Hz, 2
H), 7.21 (dd, J = 15.4, 7.6 Hz, 2 H), 7.03 (t, J = 7.6 Hz, 1 H), 6.56
(ddd, J = 17.1, 10.1, 7.0 Hz, 1 H), 5.27 (d, J = 10.1 Hz, 1 H), 5.17
(d, J = 6.9 Hz, 1 H), 5.11 (d, J = 17.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 142.20, 139.08, 135.29, 134.56,
132.03, 127.83, 127.59, 127.27, 127.23, 127.03, 126.92, 125.04,
121.12, 120.36, 118.58, 115.15, 112.78, 109.94, 44.92.
MS (ESI): m/z = 312 [M + H]+.
Anal. Calcd for C17H14BrN: C, 65.40; H, 4.52; N, 4.49. Found: C,
65.63; H, 4.66; N, 4.60.
MS (ESI): m/z = 310 [M + H]+.
Anal. Calcd for C23H19N: C, 89.28; H, 6.19; N, 4.53. Found: C,
89.06; H, 6.41; N, 4.37.
3-{1-[2-(Trifluoromethyl)phenyl]prop-2-en-1-yl}-1H-indole
(3n)
Pale-yellow oil; yield: 43.3 mg (72%).
1-Methyl-3-(1-phenylprop-2-en-1-yl)-1H-indole (3i)
Pale-yellow oil; yield: 42.8 mg (87%).
IR (neat): 2912, 1473, 1330, 1230, 913, 737, 698 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.91 (s, 1 H), 7.61 (d, J = 7.9 Hz,
1 H), 7.29 (dd, J = 14.1, 6.9 Hz, 2 H), 7.25–7.11 (m, 3 H), 7.10–7.02
(m, 1 H), 6.96–6.82 (m, 2 H), 6.21 (ddd, J = 16.9, 10.2, 6.6 Hz, 1
H), 5.31 (d, J = 6.5 Hz, 1 H), 5.13 (dd, J = 10.2, 1.2 Hz, 1 H), 4.86
(d, J = 17.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 140.98, 138.93, 135.72, 130.75,
129.74, 127.25 (q, 1JC,F = 29.3 Hz), 127.03, 125.56, 125.35, 124.84,
121.82, 121.22, 118.66, 118.54, 117.29, 115.14, 110.03, 41.16.
1H NMR (500 MHz, CDCl3): δ = 7.48 (d, J = 8.0 Hz, 1 H), 7.38–
7.33 (m, 5 H), 7.30–7.25 (m, 2 H), 7.09 (ddd, J = 8.0, 7.0, 1.0 Hz, 1
H), 6.78 (d, J = 0.5 Hz, 1 H), 6.42 (ddd, J = 17.1, 10.1, 7.1 Hz, 1 H),
5.28–5.23 (m, 1 H), 5.15 (dt, J = 17.0, 1.5 Hz, 1 H), 5.03 (dd, J =
7.1, 0.8 Hz, 1 H), 3.78 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 142.48, 139.75, 136.49, 127.50,
127.42, 126.32 (2 C), 125.34, 120.69, 118.99, 117.87, 116.00,
114.40, 108.25, 46.05, 31.72.
19F NMR (470 MHz, CDCl3): δ = –58.50.
MS (ESI): m/z = 302 [M + H]+.
MS (ESI): m/z = 248 [M + H]+.
Anal. Calcd for C18H14F3N: C, 71.75; H, 4.68; N, 4.65. Found: C,
71.91; H, 4.57; N, 4.74.
Anal. Calcd for C18H17N: C, 87.41; H, 6.93; N, 5.66. Found: C,
87.62; H, 7.07; N, 5.48.
3-{1-[3-(Trifluoromethyl)phenyl]prop-2-en-1-yl}-1H-indole
(3o)
1-Phenyl-3-(1-phenylprop-2-en-1-yl)-1H-indole (3j)
Yellow oil; yield: 37.7 mg (61%).
IR (neat): 3030, 1595, 1497, 1453, 1214, 737, 695 cm–1.
Colorless oil; yield: 48.7 mg (81%).
IR (neat): 3419, 2982, 1327, 1118, 1071, 740, 701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.61 (s, 1 H), 7.49
(dd, J = 14.7, 7.7 Hz, 2 H), 7.45–7.35 (m, 3 H), 7.25–7.18 (m, 1 H),
7.12–7.03 (m, 1 H), 6.90 (d, J = 1.7 Hz, 1 H), 6.36 (ddd, J = 17.1,
1H NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 8.3 Hz, 1 H), 7.52 (d,
J = 4.3 Hz, 4 H), 7.48 (d, J = 7.9 Hz, 1 H), 7.36 (ddd, J = 8.5, 5.4,
3.8 Hz, 5 H), 7.26–7.24 (m, 1 H), 7.22 (dd, J = 8.2, 1.1 Hz, 1 H),
7.13–7.09 (m, 1 H), 7.08 (d, J = 0.7 Hz, 1 H), 6.42 (ddd, J = 17.1,
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Allylation of Indoles with Allylic Alcohols
1723
10.1, 7.0 Hz, 1 H), 5.27 (d, J = 10.1 Hz, 1 H), 5.10 (d, J = 17.1 Hz,
1 H), 5.05 (d, J = 6.9 Hz, 1 H).
1 H), 2.76–2.61 (m, 2 H), 2.23 (ddt, J = 13.2, 9.8, 6.5 Hz, 1 H), 2.11
(dddd, J = 13.6, 9.8, 7.8, 6.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 143.20, 138.62, 135.69, 130.87,
129.66 (q, 1JC,F = 31.8 Hz), 127.79, 125.59, 124.40, 124.20, 122.28,
121.58, 121.33, 118.58 (2 C), 116.68, 115.33, 110.22, 45.69.
13C NMR (125 MHz, CDCl3): δ = 141.54, 140.86, 135.58, 127.55,
127.33, 125.80, 124.72, 121.02, 119.76, 118.58, 118.22, 117.79,
113.19, 110.18, 39.71, 35.38, 32.91.
19F NMR (470 MHz, CDCl3): δ = –62.35.
MS (ESI): m/z = 302 [M + H]+.
MS (ESI): m/z = 262 [M + H]+.
Anal. Calcd for C19H19N: C, 87.31; H, 7.33; N, 5.36. Found: C,
87.57; H, 7.43; N, 5.19.
Anal. Calcd for C18H14F3N: C, 71.75; H, 4.68; N, 4.65, Found: C,
71.58; H, 4.89; N, 4.50.
Acknowledgment
3-{1-[4-(Trifluoromethyl)phenyl]prop-2-en-1-yl}-1H-indole
(3p)13
We are grateful for financial support from the Natural Science
Foundation of Jiangsu Province (BK20131346).
Yellow oil; yield: 52.4 mg (87%).
1H NMR (500 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.56 (d, J = 8.2 Hz,
2 H), 7.45–7.33 (m, 4 H), 7.24–7.17 (m, 1 H), 7.05 (t, J = 7.5 Hz, 1
H), 6.93 (s, 1 H), 6.35 (ddd, J = 17.1, 10.1, 7.1 Hz, 1 H), 5.25 (d, J =
10.1 Hz, 1 H), 5.09 (d, J = 17.1 Hz, 1 H), 5.04 (d, J = 7.0 Hz, 1 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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13C NMR (125 MHz, CDCl3): δ = 146.29, 138.60, 135.69, 127.73
(q, JC,F = 32.0 Hz), 127.77, 125.55, 124.30, 123.98, 122.26, 121.54,
121.32, 118.58, 116.60, 115.28, 110.22, 45.75.
References
19F NMR (470 MHz, CDCl3): δ = –62.27.
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3-[1-(4-Tolyl)prop-2-en-1-yl]-1H-indole (3q)
Yellow oil; yield: 33.0 mg (67%).
IR (neat): 3415, 2918, 1457, 737 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.87 (s, 1 H), 7.31 (d, J = 8.0 Hz,
1 H), 7.25 (d, J = 8.1 Hz, 1 H), 7.07 (ddd, J = 9.2, 6.2, 2.0 Hz, 3 H),
7.01 (d, J = 7.9 Hz, 2 H), 6.93 (dd, J = 11.1, 3.9 Hz, 1 H), 6.78 (d,
J = 1.4 Hz, 1 H), 6.24 (ddd, J = 17.1, 10.1, 7.2 Hz, 1 H), 5.08 (d, J =
10.1 Hz, 1 H), 4.97 (d, J = 17.0 Hz, 1 H), 4.83 (d, J = 7.1 Hz, 1 H),
2.23 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 139.68, 139.19, 135.67, 134.75,
128.05, 127.28, 125.87, 121.40, 121.04, 118.89, 118.31, 117.74,
114.24, 110.05, 45.59, 20.06.
MS (ESI): m/z = 248 [M + H]+.
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Anal. Calcd for C18H17N: C, 87.41; H, 6.93; N, 5.66. Found: C,
87.61; H, 6.77; N, 5.73.
3-[1-(1-Naphthyl)prop-2-en-1-yl]-1H-indole (3r)
Pale-yellow oil; yield: 48.7 mg (86%).
IR (neat): 3415, 2972, 781, 736 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.14 (d, J = 8.1 Hz, 1 H), 7.93 (s,
1 H), 7.91–7.88 (m, 1 H), 7.78 (dd, J = 6.7, 2.5 Hz, 1 H), 7.51–7.39
(m, 5 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.07 (t,
J = 7.5 Hz, 1 H), 6.75 (s, 1 H), 6.47 (ddd, J = 16.8, 10.1, 6.3 Hz, 1
H), 5.78 (d, J = 6.2 Hz, 1 H), 5.29 (d, J = 10.1 Hz, 1 H), 5.05 (d, J =
17.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 138.90, 137.92, 135.67, 133.04,
130.81, 127.75, 126.16, 126.00, 124.86 (2 C), 124.50, 124.39,
123.17, 122.38, 121.10, 118.71, 118.41, 117.29, 115.34, 110.12,
41.17.
MS (ESI): m/z = 284 [M + H]+.
Anal. Calcd for C21H17N: C, 89.01; H, 6.05; N, 4.94. Found: C,
89.15; H, 5.94; N, 5.13.
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3-[1-(2-Phenylethyl)prop-2-en-1-yl]-1H-indole (3s)
Pale-yellow oil; yield: 27.6 mg (53%).
IR (neat): 3419, 2918, 1475, 912, 732, 698 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.61 (d, J = 7.9 Hz,
1 H), 7.37 (d, J = 8.1 Hz, 1 H), 7.31–7.26 (m, 2 H), 7.22–7.16 (m, 4
H), 7.13–7.08 (m, 1 H), 7.00 (s, 1 H), 6.08–6.00 (m, 1 H), 5.20–5.12
(m, 1 H), 5.09 (ddd, J = 10.2, 1.7, 0.9 Hz, 1 H), 3.62 (q, J = 7.3 Hz,
© Georg Thieme Verlag Stuttgart · New York
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