Gold(I)-catalyzed intermolecular hydroarylation of alkenes with indoles under thermal and microwave-assisted conditions

Article abstract of DOI:10.1002/chem.200800040

An efficient method for intermolecular hydroarylation of aryl and aliphatic alkenes with indoles using a combination of [(PR₃)AuCl]/AgOTf as catalyst under thermal and microwave-assisted conditions has been developed. The gold(I)-catalyzed reactions of indoles with aryl alkenes were achieved in toluene at 85°C over a reaction time of 1-3 h with 2 mol% of [(PR ₃)AuCl]/ AgOTf as catalyst. This method works for a variety of styrenes bearing electron-deficient, electron-rich, and sterically bulky substituents to give the corresponding products in good to high yields (60-95%). Under microwave irradiation, coupling of unactivated aliphatic alkenes with indoles gave the corresponding adducts in up to 90% yield. Selective hydroarylation of terminal C=C bond of conjugated dienes with indoles gave good product yields (62-81 %). On the basis of deuteriumlabeling experiments, a reaction mechanism involving nucleophilic attack of Au(I)-coordinated alkenes by indoles is proposed.

Full text of DOI:10.1002/chem.200800040

FULL PAPER
DOI: 10.1002/chem.200800040
Gold(I)-Catalyzed Intermolecular Hydroarylation of Alkenes with Indoles
under Thermal and Microwave-Assisted Conditions
Ming-Zhong Wang, Man-Kin Wong,* and Chi-Ming Che*[a]
Abstract: An efficient method for in-
termolecular hydroarylation of aryl and
aliphatic alkenes with indoles using a
combination of [(PR3)AuCl]/AgOTf as
catalyst under thermal and microwave-
assisted conditions has been developed.
The gold(I)-catalyzed reactions of in-
doles with aryl alkenes were achieved
in toluene at 858C over a reaction time
of 1–3 h with 2 mol% of [(PR3)AuCl]/
AgOTf as catalyst. This method works
for a variety of styrenes bearing elec-
tron-deficient, electron-rich, and steri-
cally bulky substituents to give the cor-
responding products in good to high
yields (60–95%). Under microwave ir-
radiation, coupling of unactivated ali-
phatic alkenes with indoles gave the
corresponding adducts in up to 90%
yield. Selective hydroarylation of ter-
minal C=C bond of conjugated dienes
with indoles gave good product yields
(62–81%). On the basis of deuterium-
labeling experiments, a reaction mech-
anism involving nucleophilic attack of
Au(I)-coordinated alkenes by indoles is
proposed.
À
Keywords: C C coupling · gold ·
homogeneous catalysis
·
hydro-
AHCTREaGNU rylation · synthetic methods
Introduction
sized by carbon–carbon bond-forming reactions such as
acid- or base-promoted alkylation.[5] However, these litera-
ture methods require the use of stoichiometric or excess
amounts of strong acids/bases and air-sensitive/moisture-sen-
sitive organometallic reagents. Also, halide salts are ob-
tained as byproducts. Palladium,[6] platinum,[7] ruthenium,[8a]
nickel,[8b] and indium[8c] complexes have been employed as
catalysts for the functionalization of indoles through
carbon–carbon bond formation. Recently, Widenhoefer and
co-workers reported platinum(II)-catalyzed intermolecular
hydroarylation of unactivated alkenes with indoles in high
product yields. Hydroarylation of styrenes gave mixtures of
Markovnikov and anti-Markovnikov adducts.[7c]
Gold-catalyzed organic transformations have become of
considerable interest in organic synthesis in recent years.[9,10]
Gold(I) catalysts are soft and carbophilic Lewis acids that
have been used to activate alkenes towards nucleophilic
attack by oxygen,[11] nitrogen,[12] and carbon nucleophiles.[13]
Indeed, gold(I)-catalyzed coupling of indoles with al-
Intermolecular hydroarylation of alkenes is an efficient ap-
proach for functionalization of arenes through carbon–
carbon bond formation.[1] Transition-metal-catalyzed hydro-
arylation of alkenes is of particular importance due to its
high selectivity, synthetic efficiency, and environmental
friendliness. Ruthenium(II) and rhodium(I) complexes are
effective catalysts for intermolecular hydroarylation of unac-
tivated alkenes with arenes possessing directing groups such
as ketones[2a,b] and imines.[2c] Recently, Bi(OTf)3-catalyzed[3a]
ACHTREUNG
and FeCl3-catalyzed[3b] hydroarylation of styrenes was re-
ported for the synthesis of a variety of 1,1-diaryl alkanes in
good yields.
Alkylated indoles are important structural motifs com-
monly found in many bioactive natural products and drug
candidates.[4] Conventionally, alkylated indoles are synthe-
[a] M.-Z. Wang, Dr. M.-K. Wong, Prof. Dr. C.-M. Che
Department of Chemistry and Open Laboratory of Chemical Biology
of the Institute of Molecular Technology for Drug Discovery and
Synthesis
AHCTREUNG
AHCTREUNG
ported. Gold-catalyzed functionalization of dienes[11b,12b] has
also been developed. During the preparation of this manu-
script, Liu and co-workers[13c] reported the use of AuCl3/
AgOTf or triflic acid (HOTf) as a catalyst for hydroaryla-
tion of alkenes. Nevertheless, this reported hydroarylation
reaction was limited to N-phenylsulfonyl-protected indole.
As part of our ongoing effort to develop gold-catalyzed
The University of Hong Kong
Pokfulam Road, Hong Kong (China)
Fax : (+852)2857-1586
E-mail: cmche@hku.hk
mkwong@hkusua.hku.hk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800040 or from the author.
Chem. Eur. J. 2008, 14, 8353 – 8364
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8353

[15]
À
À
À
C O, C N, and C C bond-formation reactions, we here
report an efficient gold(I)-catalyzed intermolecular hydroar-
ylation of unactivated alkenes with indoles and extension of
the substrate scope to include indoles with different elec-
tronic properties and various cycloalkenes and conjugated
dienes. We demonstrate that microwave irradiation[16] is an
effective means to promote indole coupling with unactivated
aliphatic alkenes, which could not be achieved under ther-
mal reaction conditions.
catalyst was used. With 2/20% of [(PPh3)AuMe]/H2SO4 as
catalyst, 1a reacted with 2d in toluene at 858C over 4 h to
give 3d in 77% yield (Table 1, entry 10).[11f–g,12h]
To determine the substrate scope, we extended our study
to different indoles 1 and aryl alkenes 2 using 2 mol% of
[(PPh3)AuCl]/AgOTf as catalyst (Table 2). Coupling of N-
methylindole (1a) with styrenes 2a–e bearing electron-do-
nating substituents (p-MeO, p-dimethylamino, p-tert-butyl,
and p-Me) or an electron-withdrawing p-Cl substituent gave
the corresponding products in high substrate conversions
and product yields (Table 2, entries 1–5).
Results
The coupling reaction worked for bulky 1,1-diphenylethy-
lene (2 f) and indene (2g; Table 2, entries 6–7), and N-aryl
indoles 1b,c (Table 2, entries 8–10). The present protocol
also allows direct coupling of NH indoles 1d–g with styrenes
2a and 2c to give 3-alkylated indoles 3k–o without forma-
tion of N-alkylated indoles (Table 2, entries 11–15).
Gold(I)-catalyzed coupling of indoles with aryl alkenes:
First, we examined the coupling reaction between N-methyl-
indole (1a) and p-methylstyrene (2d; see Table 1). In the
By using 2 mol% of [(PPh3)AuCl]/AgOTf as catalyst, a
gram-scale coupling of 1a (10 g) with 2a (11.25 g) can be
conducted as a one-pot reaction to give 17.1 g of 3a in 85%
yield over a reaction time of 6 h.
Table 1. Effect of temperature and catalyst screening.[a]
For the reaction of 1a with styrene in toluene at 858C for
1.25 h (2 mol% of [(PPh3)AuCl]/AgOTf), only a trace
1
T [8C] Conversion [%][b] Yield [%][c]
amount of coupling product could be detected by H NMR
Entry PR3
analysis of the crude reaction mixture, and extensive styrene
1
2
3
PPh3
PPh3
PPh3
PPh3
85
65
R
85
85
85
85
85
85
95 85
<5 trace
T
100 75
99 87
95 82
95 80
70 52
50 40
86 77
polymerization was detected;[3a,b] the latter accounted for
0
–
the low product yield.
4[d]
5
PACHTREUNG(tBu)2(o-biphenyl)
P(4-C6H4OMe)3
PCy3
Microwave-assisted gold(I)-catalyzed coupling of indoles
with aliphatic alkenes: No product was found when unacti-
vated aliphatic alkenes such as allylbenzene (4a) were treat-
ed with indole 1b under the reaction conditions described
above. When the reaction between 1b and 4a was conduct-
ed in dichloroethane at 1208C for 16 h, a trace amount of
6
7
8
PACHTREUNG
9
10[e]
ACHTREUNG[(PPh3)AuMe]/H2SO4 85
[a] Reactions were conducted with 1a (0.3 mmol), 2d (0.33 mmol), and
[(PPh3)AuCl]/AgOTf (2 mol%) in toluene (1 mL) for 1.25 h. [b] Deter-
mined by H NMRanalysis of crude reaction mixture. [c] Yield of isolat-
1
product 5a could be detected on the basis of the H NMR
1
spectrum of the crude reaction mixture. However, we found
that product formation was accompanied by subsequent de-
composition of 5a. The reaction between 1h and 4j gave
5m in 21% yield based on 38% substrate conversion in di-
chloroethane at 1208C over 36 h. Our recent work revealed
that microwave radiation is an effective means to accelerate
gold(I)-catalyzed hydroamination of alkenes.[15c,e] The accel-
erating effects of microwave irradiation on organic syntheses
can not be easily achieved by conventional heating.[16c] In
this work, we employed microwave radiation to assist the
gold(I)-catalyzed intermolecular hydroarylation of aliphatic
alkenes with indoles (Table 3).
Under microwave irradiation (43 W, 7 min), coupling of
N-p-tolylindole (1b) and allylbenzene 4a with 5 mol% of
[(PPh3)AuCl]/AgOTf as catalyst in dichloroethane at 1308C
gave alkylated indole 5a in 81% yield (Table 3, entry 1).
Yet, 5a is not the expected product resulting from hydroary-
lation of the terminal C=C bond of 4a with 1b. Likely, mi-
gration of the C=C bond of 4a occurred and generated
trans-b-methylstyrene in situ under the reaction conditions
(see below). Similar gold-catalyzed migration of C=C bonds
has been reported.[11a,15c] Without microwave irradiation,
ed product. [d] 0.45 mmol of 2d was used. [e] 2 mol% of [(PPh3)AuMe]
and 20 mol% of H2SO4 for 4 h.
presence of [(PPh3)AuCl] (2 mol%) and AgOTf (2 mol%),
1a (0.3 mmol) reacted with 2d (0.33 mmol) in toluene at
858C over 1.25 h to give 3-alkylated indole 3d (Markovni-
kov product) in 85% yield based on 95% substrate conver-
sion (Table 1, entry 1). When either [(PPh3)AuCl] or AgOTf
was used, less than 10% substrate conversion was observed.
At 658C, less than 5% substrate conversion was found
(Table 1, entry 2). No reaction was observed at room tem-
perature (Table 1, entry 3). With 1.5 equivalents of 2d, 3d
was obtained in 75% yield and with complete substrate con-
version (Table 1, entry 4). A number of gold(I) catalysts
having different phosphine ligands were screened (Table 1,
entries 5–9), of which those with a PACHTRE(UNG tBu)2(o-biphenyl), P(4-
C6H4OMe)3, or PCy3 ligand were most effective. The reac-
tion between 1a and 2d to give 3d in 72% yield could be
achieved by using 5 mol% of triflic acid as catalyst, but the
reaction time was 12 h instead of the 1.25 h when a gold(I)
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Chem. Eur. J. 2008, 14, 8353 – 8364

Hydroarylation of Alkenes with Indoles
FULL PAPER
Table 2. Gold(I)-catalyzed coupling of indoles with aryl alkenes.[a]
coupling of 1b with trans-b-
methylstyrene gave 5a in
lower yield (67%) over 2 h at
858C.
Entry
Indole
Alkene
Product
Conversion [%][b]/yield [%][c]
100/95
1
Similarly, alkylated indoles
5b–e were obtained by cou-
pling of N-aryl indoles 1b,c
and NH indole 1 f with allyl-
benzenes 4a,b under micro-
wave irradiation (Table 3, en-
tries 2–5).
2
3
4
1a
1a
1a
92/86
90/82
95/85
When unactivated 3,3-di-
methyl-1-butene
(4c)
was
treated with 4-tolylindole (1b)
under microwave irradiation,
alkylated indole 5 f was ob-
tained (Table 3, entry 6). Note
that 5 f could also be obtained
by direct coupling of 2,3-di-
methyl-2-butene (4d) with 1b
(Table 3, entry 7); no reaction
was observed without micro-
wave irradiation. This suggests
that 4c may be converted to
4d by gold-catalyzed methyl-
group migration,[17] and the 4d
generated in situ coupled with
1b to give 5 f. Furthermore,
NH indole 1 f coupled with
4c,d to afford 5g (Table 3, en-
tries 8 and 9).
Under microwave irradia-
tion, gold-catalyzed coupling
of a series of unactivated ali-
phatic cycloalkenes 4e–i with
indoles 1 f,h were accom-
plished (Table 3, entries 10–
14). No reaction was observed
between 1 f and 1-hexene or
trans-5-decene.
5[d]
6[e]
7
1a
1a
1a
74/65
75/60
82/78
8
9
2a
2c
100/90
95/93
10
1c
2d
95/90
11
12
13
2a
2c
2a
95/85
95/82
95/90
Microwave-assisted gold-cat-
alyzed coupling of indoles with
unactivated aliphatic alkenes
1d
bearing remote
functional
groups such as ester, ether, and
amide were also examined.
Direct coupling of 6-nitroin-
dole (1h) with alkenes 4j,k
gave products 5m,n with the
ester and ether groups remain-
ing intact (Table 3, entries 15
and 16). For the reaction be-
tween 1h and amide-contain-
ing alkene 4l, less than 5%
conversion of 1h was found by
1H NMRanalysis of the crude
14
15
2a
2a
95/89
95/86
[a] Reactions were conducted with 1 (0.3 mmol), 2 (0.33 mmol) and 2 mol% of [(PPh3)AuCl]/AgOTf in tolu-
ene (1 mL) at 858C for 1.25 h. [b] Determined by H NMRanalysis of the crude reaction mixture. [c] Yield of
1
isolated product. [d] Reaction time was 3 h. [e] 0.6 mmol of 2 were used.
reaction
mixture
(Table 3,
Chem. Eur. J. 2008, 14, 8353 – 8364
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8355

M.-Z. Wang, M.-K. Wong, and C.-M. Che
Table 3. Microwave-assisted gold(I)-catalyzed coupling of substituted indoles with aliphatic alkenes.[a]
entry 17). Coupling of N-phe-
nylindole (1i) with ester- and
ether-containing alkenes 4j,k
was also achieved (Table 3, en-
tries 18 and 19).
Microwave-assisted gold-cat-
alyzed coupling of 1h and 4j
gave 5m in 85% yield based
on 92% substrate conversion
at 1408C over 5 min (Table 3,
entry 15). By using 5 mol% of
triflic acid as catalyst, 5m
could also be obtained in 32%
yield based on 45% conversion
at 508C, but the reaction time
was 16 h.
Entry
Indole
Alkene
Product
Conversion [%][b]
yield [%][c]
/
1
89/81
92/86
2
3
1b
4a
90/82
In view of the exceptional
accelerating effect of micro-
wave irradiation, we decided
to study microwave-assisted
coupling of aryl alkenes with
indoles. Notably, under micro-
wave irradiation, gold-cata-
lyzed coupling of indole 1a
with aryl alkenes 2a, 2e, and
2g afforded the corresponding
adducts 3a (93% yield), 3e
(68% yield), and 3g (62%
yield) at 1208C in just 1 min.
These findings could provide a
useful basis for further devel-
opment of high-throughput
gold(I) organic catalysis.
4
5
4a
4b
90/80
95/90
1 f
6
95/75
7
8
1b
1 f
5 f
100/85
50/45
4c
4d
Gold(I)-catalyzed coupling of
9
1 f
1 f
5g
95/84
51/42
indoles
with
conjugated
dienes: We performed hydroar-
ylation of conjugated diene 6a
(E/Z=1.4/1) with N-methylin-
dole (1a) using 5 mol% of
[(PPh3)AuCl]/AgOTf at 708C
to give adduct 7a in 81% yield
(Table 4, entry 1). The C=C
bond of 7a obtained is of E
configuration. Of particular in-
terest is that the configuration
of diene 6a recovered is pre-
dominantly Z (E/Z=1/10; see
below for a more detailed dis-
cussion). This coupling reac-
tion also worked well for in-
doles having different electron-
ic properties (Table 4, en-
tries 2–10), and the C=C bonds
of all products are E-config-
ured. For the reaction of elec-
tron-deficient conjugated diene
10
11
12
13
14
15
1 f
1 f
1 f
65/60
95/83
80/65
75/62
92/85
1h
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Hydroarylation of Alkenes with Indoles
Table 3. (Continued)
FULL PAPER
It has been reported that al-
kylated indoles 3 can be syn-
thesized by three methods:
substitution of benzotriazole-
containing anilines by in-
Entry
Indole
Alkene
Product
Conversion [%][b]
yield [%][c]
/
16
1h
89/80
AHCTREUNG
doles,[18a] Friedel–Crafts reac-
tion of indoles with a-amido
sulfones in the presence of
promoters,[18b]
and
17
18
1h
<5%/nd
acidic
Brønsted acid-catalyzed dehy-
drative nucleophilic substitu-
tion of benzyl alcohols by in-
doles.[18c] However, these meth-
ods require the use of air-sensi-
tive/moisture-sensitive organo-
metallic reagents and/or acids.
The gold-based protocol re-
ported here allows preparation
of indoles 3, 5, and 7 in good
yields under mild reaction con-
ditions.
85/75
26/20
19
1i
[a] Reactions were conducted with 1 (0.3 mmol), 4 (0.6 mmol), and 5 mol% of [(PPh3)AuCl]/AgOTf in
ClCH2CH2Cl (1 mL) with microwave irradiation (43 W, 5–30 min, 130–1408C). [b] Determined by 1H NMR
analysis of the crude reaction mixture. [c] Yield of isolated product.
A series of heterocyclic scaf-
folds featuring 3-cycloalkyl-
substituted indoles 5 as the
6d with N-methylindole (1a), only a trace amount of prod-
uct was identified by H NMRanalysis of the crude reaction
major structural elements have been found to exhibit potent
inhibitory effects on hepatitis C virus (HCV) NS5B poly-
merase.[18d] The preparation of these cycloalkyl-substituted
indoles required a two-step synthetic approach including
condensation of indoles with cyclic ketones under basic con-
ditions followed by palladium-catalyzed hydrogenation.[18d]
In this work, indoles 5 could be synthesized in good yields
by gold-catalyzed direct coupling of indoles with unactivated
aliphatic cycloalkenes in one step under microwave irradia-
tion.
1
mixture (Table 4, entry 11). Interestingly, when Z-configured
conjugated diene 8a was treated with 1a, adduct 7a of E
configuration was again obtained (Table 4, entry 12). When
5 mol% of triflic acid was used as a catalyst instead of
gold(I) catalysts in the coupling reaction of 1a with 6a, no
product was detected.
Discussion
Alkylated indoles 7 have been prepared by iodine-cataly-
zed[18e] and metal-catalyzed[18f–g] alkylation of indoles with al-
lylic alcohol derivatives. The gold-catalyzed direct coupling
of indoles with conjugated dienes described here offers a
simple, efficient, and one-step method to prepare this class
of compounds.
We have developed an efficient method using [(PR3)AuCl]/
AgOTf (2 mol%) as catalyst for direct coupling of indoles
with aryl and aliphatic alkenes to give C3-alkylated indoles
(Markovnikov adducts) in thermal and microwave-assisted
reactions. Unactivated aliphatic alkenes such as cyclohexene
do not readily react with indoles under thermal conditions
but smoothly react with indoles in the presence of 5 mol%
of [(PPh3)AuCl]/AgOTf as catalyst in dichloroethane at
1308C under microwave irradiation. This present protocol
provides a convenient way to synthesize the three classes of
C3-substituted indole derivatives 3, 5, and 7 depicted in
Scheme 1.
Gold-catalyzed migration of C=C bonds: As depicted in
Table 3, under microwave irradiation, gold-catalyzed cou-
pling of p-tolyl indole 1b with allylbenzene (4a) gave alky-
lated indole 5a, yet the latter is not the direct coupling
product coming from hydroarylation of the terminal C=C
bond of 4a with 1b. We propose that migration of the C=C
bond of 4a occurs to generate trans-b-methylstyrene in situ
under the current reaction con-
ditions. An independent ex-
periment in which 4a was
heated at 908C for 6 h in
[D8]toluene in the presence of
5 mol%
of
[(PPh3)AuCl]/
AgOTf was performed. On the
basis of 1H NMRanalysis of
the crude reaction mixture, a
Scheme 1. Three classes of C3-alkylated indoles synthesized in this work.
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8357

M.-Z. Wang, M.-K. Wong, and C.-M. Che
Table 4. Gold(I)-catalyzed coupling of indoles with conjugated dienes.[a]
4a to trans-b-methylstyrene
Entry
Indole
Diene
Product
Conversion [%][b]
yield [%][c]
/
and cis-b-methylstyrene by
heating in the presence of
the gold catalyst may ac-
count for the formation of
5a. We have attempted to
detect the conversion of 4a
to trans-b-methylstyrene in
the absence of indole 1b
under microwave irradia-
tion. However, intractable
mixtures of products were
obtained in several attempts,
which may result from
1
89/81
2
3
4
6a
6a
6a
82/76
80/72
85/75
alkene
polymerization.[19]
Zirconium,[20a] palladium,[20b]
and ruthenium[20c] complexes
were reported to be effec-
tive catalysts for the isomer-
ization of allylbenzene (4a)
to trans-b-methylstyrene and
cis-b-methylstyrene.
5
6
6a
82/70
85/80
1a
1d
Gold-catalyzed E/Z isomeri-
zation of the C=C bonds of
conjugated dienes: Predomi-
nately Z diene (E/Z=1/10)
was recovered in the cou-
pling reaction of conjugated
diene 6a (E/Z=1.4/1) with
1a. We propose that gold-
catalyzed isomerization of
mixtures of E/Z conjugated
7
8
9
6b
6b
86/75
87/74
83/65
1a
1d
dienes to
Z
conjugated
diene occurred (Scheme 3).
Treatment of E/Z diene
6a (0.3 mmol, E/Z=1.4/1)
10
6c
81/62
with
5 mol%
of
[(PPh3)AuCl]/AgOTf in tol-
uene at room temperature
for 24 h gave Z diene 8a
(100% Z configuration), as
11
12
1a
1a
trace
85/73
1
7a
confirmed by H NMRanal-
ysis of the crude reaction
mixture. In contrast, when
E/Z diene 6a was stirred at
room temperature or 708C
[a] Reactions were conducted with
[(PPh3)AuCl]/AgOTf in toluene (1 mL) at 708C for 16 h. [b] Determined by H NMRanalysis of the crude re-
action mixture. [c] Yield of isolated product.
1 (0.3 mmol), 6 (0.45 mmol) (E/Z=1.2/1–1.4/1), and 5 mol% of
1
for
24 h
without
mixture of 4a, trans-b-methylstyrene, and cis-b-methylstyr-
ene (4.5:6.3:1) was found (Scheme 2). Thus, conversion of
[(PPh3)AuCl]/AgOTf, no change in configuration was ob-
served. We also found that 5 mol% of triflic acid did not
change the configuration of E/Z-diene 6a. As depicted in
Scheme 3, this gold-catalyzed isomerization reaction works
well for dienes bearing electron-donating and electron-with-
drawing substituents. According to the literature,[21] Z aryl
dienes can be synthesized by Wittig reactions with bulky
phosphonium salts. Exclusive Z products could be prepared
in low yields at low temperature (À1008C) by using a strong
Scheme 2. Gold-catalyzed migration of C=C bonds.
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Hydroarylation of Alkenes with Indoles
FULL PAPER
Scheme 3. Gold-catalyzed isomerization of E/Z dienes to Z dienes.
Scheme 4. Proposed reaction pathway.
base such as butyllithium. The gold-catalyzed reaction de-
scribed here provides convenient and efficient access to Z
aryl dienes in good yields under mild reaction conditions.
Table 5. Competition experiment of gold(I)-catalyzed hydroarylation of
styrenes with 1a.[a]
Proposed reaction mechanism: A proposed reaction path-
way for the hydroarylation of styrenes with indoles is depict-
ed in Scheme 4. The C=C bond of an alkene coordinated to
cationic [AuPPh3]+ is attacked by nucleophilic indole to
give a gold complex intermediate that undergoes subsequent
À
protonolysis at the Au C bond to give the desired coupling
product. This proposed reaction pathway has support from
the following experiments.
3/3d
Product ratio[b]
A competition study was performed to examine the rela-
tive reaction rates of indole 1a with substituted styrenes 2a,
2c, 2d, and 2e. The relative reaction rates were calculated
3a/3d
3c/3d
3d/3d
3e/3d
15
1.03
1
1
by means of the integration ratio of the H NMRsignals of
0.42
the corresponding products in the crude reaction mixture.
The results are depicted in Table 5. Styrene 2a containing
an electron-rich p-methoxy substituent showed higher reac-
tivity than styrene 2e bearing an electron-withdrawing p-Cl
group. This result is consistent with the positively charged
transition state in gold(I)-catalyzed alkene functionalization
proposed in the literature.[11–13]
[a] Reactions were conducted with N-methylindole (1a, 0.3 mmol), 4-
methylstyrene (2d, 0.33 mmol), p-substituted styrene 2a, 2c, or 2e
(0.33 mmol), and 2 mol% of [(PPh3)AuCl]/AgOTf in toluene (1 mL) at
858C for 15 min. [b] Product ratio was determined by means of the inte-
gration ratios of their corresponding peak areas in the 1H NMRspec-
trum.
The coupling reaction of
deuterium-labeled
indole 1m[22] with 4-methoxy-
ACHTREUNGstyrene (2a) was attempted
N-methyl
(Scheme 5). Product 3a with
18% deuterium incorporation
was obtained in 91% yield
[Eq. (1)]. When [D8]toluene
was used as solvent, no deute-
rium-labeled product was ob-
served [Eq. (2)]. When cou-
pling of N-methylindole (1a)
with 2a was performed in tolu-
ene/D2O, 3a with 61% deuteri-
um incorporation was obtained
in 85% yield [Eq. (3)]. All
these findings revealed that D
(H) incorporated into the ter-
Scheme 5. Deuterium-labeling experiments.
Chem. Eur. J. 2008, 14, 8353 – 8364
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8359

M.-Z. Wang, M.-K. Wong, and C.-M. Che
127.8, 127.7, 125.8, 122.1, 121.2, 118.5, 114.3, 109.2, 47.5, 32.6, 29.5 ppm;
EIMS: m/z: 311 [M+]; HRMS (EI): m/z calcd for C23H21N: 311.1674;
found: 311.1676.
minal methyl group of 3a mainly comes from D2O
(H2O).[23–24]
3g: Yield: 78%; 1H NMR(CDCl 3, 300 MHz): d=7.40 (d, J=8.0 Hz,
1H), 7.24 (d, J=7.6 Hz, 2H), 7.05–7.21 (m, 4H), 6.97 (t, J=7.0 Hz, 1H),
6.66 (s, 1H), 4.59 (t, J=8.0 Hz, 1H), 3.70 (s, 3H), 2.92–2.98 (m, 2H),
2.50–2.54 (m, 1H), 2.12 ppm (m, 1H); 13C NMR(CDCl 3, 75.3 MHz): d=
147.5, 135.3, 130.7, 126.3, 126.2, 124.8, 124.4, 121.5, 119.5, 118.6, 115.7,
109.2, 42.3, 35.0, 32.6, 31.7 ppm; EIMS: m/z: 247 [M+]; HRMS (EI): m/z
calcd for C18H17N: 247.1361; found: 247.1358.
3h: Yield: 90%; 1H NMR(CDCl 3, 400 MHz): d=7.51 (d, J=7.9 Hz,
1H), 7.36–7.39 (m, 3H), 7.25–7.29 (m, 4H), 7.23 (t, J=4.0 Hz, 1H), 7.15
(s, 1H), 7.03 (t, J=4.0 Hz, 1H), 6.81 (d, J=8.7 Hz, 2H), 4.41 (q, J=
7.1 Hz, 1H), 3.77 (s, 3H), 2.42 (s, 3H), 1.71 ppm (d, J=7.1 Hz, 3H);
13C NMR(CDCl 3, 75.3 MHz): d=158.7, 138.7, 137.4, 136.5, 135.8, 130.1,
128.3, 125.0, 124.3, 124.1, 122.4, 122.2, 120.1, 119.9, 113.7, 110.4, 55.2,
36.1, 22.6, 21.0 ppm; EIMS: m/z: 341 [M+]; HRMS (EI): m/z calcd for
Conclusion
We have developed an efficient intermolecular coupling re-
action between indoles and aryl and aliphatic alkenes using
a combination of [(PPh3)AuCl]/AgOTf as catalyst under
thermal and microwave-assisted reaction conditions.
Experimental Section
C24H23NO: 341.1780; found: 341.1776.
General methods: The microwave-assisted reactions were conducted on a
CEM Focused instrument. NMRspectra were recorded on Bruker
AMX-300/400 spectrometer for 300/400 MHz 1H NMRand 75/100 MHz
1
3i: Yield: 93%; H NMR(CDCl , 300 MHz): d=7.48 (d, J=7.9 Hz, 1H),
3
7.37–7.40 (m, 3H), 7.25–7.31 (m, 4H), 7.22 (t, J=7.1 Hz, 1H), 7.18 (s,
1H), 6.95–7.05 (m, 3H), 4.43 (q, J=7.0 Hz, 1H), 3.81 (s, 3H), 2.42 (s,
13C NMRin CDCl . Mass spectra and HRmass spectra were obtained on
3
3H), 1.74 (d, J=7.1 Hz, 3H), 1.35 ppm (s, 9H); 13C NMR(CDCl
,
Finnigan GC-MS 4021 and Finnigan MAT-8430 instruments, respectively,
by using the electron-impact ionization technique (70 eV).
3
75.3 MHz): d=158.9, 148.7, 143.7, 137.2, 135.1, 133.2, 129.1, 126.9, 125.8,
125.2, 125.1, 122.1, 119.9, 119.4, 114.8, 110.5, 55.6, 36.5, 31.6, 22.6 ppm;
EIMS: m/z: 383 [M+]; HRMS (EI): m/z calcd for C27H29NO: 383.2249;
found: 383.2245.
General procedure for gold(I)-catalyzed hydroarylation of alkenes with
indoles: Indole 1 (0.3 mmol) and styrene 2 (0.33 mmol) were added to a
mixture of chloro(triphenylphosphine)gold(I) (3 mg, 0.006 mmol) and
silver triflate (1.8 mg, 0.006 mmol) in toluene (1.0 mL). After heating at
858C for 1.25–3 h, the reaction mixture was purified by flash column
chromatography (hexane/ethyl acetate 50/1 to 30/1) to afford alkylated
indole 3.
3a: Yield: 95%; 1H NMR(CDCl 3, 300 MHz): d=7.33 (d, J=7.9 Hz,
1H), 7.12–7.25 (m, 4H), 6.99 (t, J=7.0 Hz, 1H), 6.77–6.80 (m, 3H), 4.29
(q, J=7.1 Hz, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 1.65 ppm (d, J=7.1 Hz,
3H); 13C NMR(CDCl 3, 75.3 MHz): d=157.8, 139.2, 137.4, 128.2, 127.2,
125.9, 121.2, 120.3, 119.4, 118.3, 113.7, 109.1, 55.2, 36.0, 32.6, 22.6 ppm;
EIMS: m/z: 265 [M+]; HRMS (EI): m/z calcd for C18H19NO: 265.1467;
found: 265.1465.
3j: Yield: 90%; 1H NMR(CDCl 3, 300 MHz): d=7.38–7.43 (m, 4H),
7.24–7.25 (m, 2H), 7.00–7.21 (m, 7H), 4.39 (q, J=7.2 Hz, 1H), 3.87 (s,
3H), 2.30 (s, 3H), 1.72 ppm (t, J=7.2 Hz, 3H); 13C NMR(CDCl
,
3
75.3 MHz): d157.9, 144.3, 136.7, 135.6, 129.2, 127.5, 126.0, 125.4, 123.2,
122.3, 120.1, 119.6, 118.3, 117.5, 114.8, 110.4, 55.8, 36.7, 22.6, 21.2 ppm;
EIMS: m/z: 341 [M+]; HRMS (EI): m/z calcd for C24H23NO: 341.1780;
found: 341.1782.
3k: Yield: 85%; 1H NMR(CDCl 3, 300 MHz): d=7.95 (brs, NH, 1H),
7.34 (dd, J1 =7.9 Hz, J2 =0.5 Hz, 2H), 7.20 (d, J=6.2 Hz, 2H), 7.18 (t, J=
1.5 Hz, 1H), 6.96–6.99 (m, 2H), 6.79 (d, J=6.9 Hz, 2H), 4.32 (q, J=
7.1 Hz, 1H), 3.77 (s, 3H), 1.67 ppm (d, J=7.1 Hz, 3H); 13C NMR
(CDCl3, 75.3 MHz): d157.7, 138.9, 136.6, 128.3, 126.8, 121.9, 121.8, 120.9,
120.0, 118.9, 113.9, 110.9, 55.2, 36.0, 22.5 ppm; EIMS: m/z: 251 [M+];
HRMS (EI): m/z calcd for C17H17NO: 251.1310; found: 251.1315.
3l: Yield: 82%; 1H NMR(CDCl 3, 300 MHz): d=7.96 (brs, NH, 1H),
7.44 (d, J=7.8 Hz, 1H), 7.22–7.31 (m, 3H), 7.17–7.21 (m, 2H), 7.16 (t,
J=4.0 Hz, 1H), 7.00–7.04 (m, 2H), 4.38 (q, J=7.1 Hz, 1H), 1.72 (d, J=
7.16 Hz, 3H), 1.31 ppm (s, 9H); 13C NMR(CDCl 3, 75.3 MHz): d=148.5,
143.5, 136.6, 127.2, 126.9, 125.1, 124.1, 121.9, 120.9, 120.7, 119.7, 110.9,
36.3, 34.3, 31.4, 22.4 ppm; EIMS: m/z: 277 [M+]; HRMS (EI): m/z calcd
for C20H23N: 277.1830; found: 277.1832.
3m: Yield: 90%; 1H NMR(CDCl 3, 400 MHz): d=7.98 (brs, NH, 1H),
7.30 (s, 1H), 7.16–7.22 (m, 3H), 7.14–7.16 (m, 1H), 7.07 (s, 1H), 6.79 (d,
J=6.6 Hz, 2H), 4.32 (q, J=7.1 Hz, 1H), 3.77 (s, 3H), 1.62 ppm (d, J=
7.1 Hz, 3H); 13C NMR(CDCl 3, 100 MHz): d=158.3, 139.0, 135.5, 128.8,
128.7, 125.4, 122.8, 122.1, 121.7, 119.7, 114.3, 112.5, 55.8, 36.4, 23.0 ppm;
EIMS: m/z: 285 [M+]; HRMS (EI): m/z calcd for C17H16ClNO: 285.0920;
found: 285.0923.
3b: Yield: 86%; 1H NMR(CDCl 3, 300 MHz): d=7.42 (d, J=7.9 Hz,
1H), 7.23 (d, J=9.4 Hz, 1H), 7.13–7.18 (m, 3H), 7.01 (t, J=7.9 Hz, 1H),
6.78 (s, 1H), 6.66 (d, J=8.7 Hz, 2H), 4.27 (q, J=7.1 Hz, 1H), 3.72 (s,
1H), 2.89 (s, 6H), 1.64 ppm (d, J=7.1 Hz, 3H); 13C NMR(CDCl
,
3
75.3 MHz): d=149.0, 135.2, 127.9, 125.8, 121.4, 120.8, 119.9, 118.5, 112.9,
109.0, 40.9, 35.8, 32.6, 22.6 ppm; EIMS: m/z: 278 [M+]; HRMS (EI): m/z
calcd for C19H22N2: 278.1783; found: 278.1782.
3c: Yield: 82%; 1H NMR(CDCl 3, 300 MHz): d=7.51 (d, J=7.9 Hz,
1H), 7.20–7.35 (m, 6H), 7.05 (t, J=7.1 Hz, 1H), 6.81 (s, 1H), 4.42 (q, J=
7.1 Hz, 1H), 3.75 (s, 3H), 1.72 (d, J=7.0 Hz, 3H), 1.51 ppm (s, 9H);
13C NMR(CDCl 3, 75.3 MHz): d=143.7, 138.2, 135.8, 127.5, 126.9, 125.8,
125.1, 121.4, 119.7, 118.5, 118.1, 109.0, 36.2, 32.6, 31.4, 29.7, 22.4 ppm;
EIMS: m/z: 291 [M+]; HRMS (EI): m/z calcd for C21H25N: 291.1987;
found: 291.1990.
3d: Yield: 85%; 1H NMR(CDCl 3, 400 MHz): d=7.56 (d, J=7.9 Hz,
1H), 7.06–7.38 (m, 6H), 6.96 (t, J=7.0 Hz, 1H), 6.82 (s, 1H), 4.34 (q, J=
7.0 Hz, 1H), 3.74 (s, 3H), 2.30 (s, 3H), 1.74 ppm (d, J=7.0 Hz, 3H);
13C NMR(CDCl 3, 100 MHz): d=142.5, 138.1, 135.7, 127.3, 126.3, 125.6,
125.0, 121.2, 119.2, 118.3, 117.8, 109.1, 32.5, 31.6, 27.8, 21.5 ppm; EIMS:
m/z: 249 [M+]; HRMS (EI): m/z calcd for C18H19N: 249.1517; found:
249.1515.
3e: Yield: 65%; 1H NMR(CDCl 3, 400 MHz): d=7.35 (d, J=8.9 Hz,
1H), 7.18–7.28 (m, 6H), 6.99 (t, J=6.9 Hz, 1H), 6.83 (s, 1H), 4.34 (q, J=
7.0 Hz, 1H), 3.75 (s, 3H), 1.66 ppm (d, J=7.0 Hz, 3H); 13C NMR
(CDCl3, 75.3 MHz): d=141.7, 134.6, 128.7, 128.4, 127.5, 125.9, 122.3,
121.6, 119.6, 118.7, 116.5, 109.1, 36.3, 32.6, 22.4 ppm; EIMS: m/z: 269
[M+]; HRMS (EI): m/z calcd for C17H16NCl: 269.0971; found: 269.0970.
3n: Yield: 89%; 1H NMR(CDCl 3, 400 MHz): d=9.78 (brs, NH, 1H),
8.05 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.13–7.19 (m, 3H), 7.03
(t, J=8.0 Hz, 1H), 6.79 (d, J=6.7 Hz, 2H), 4.31 (q, J=7.1 Hz, 1H), 3.76
(s, 3H), 1.67 ppm (d, J=7.1 Hz, 3H); 13C NMR(CDCl 3, 100 MHz): d=
158.5, 138.7, 131.3, 130.6, 128.7, 128.5, 123.9, 123.6, 119.7, 119.1, 114.4,
55.7, 36.4, 23.1 ppm; EIMS: m/z: 296 [M+]; HRMS (EI): m/z calcd for
C17H16N2O3: 296.1161; found: 296.1157.
3o: Yield: 86%; 1H NMR(CDCl 3, 400 MHz): d=7.71 (brs, NH, 1H),
7.36 (d, J=7.8 Hz, 1H), 7.23–7.25 (m, 3H), 7.06 (t, J=7.1 Hz, 1H), 6.96
(t, J=7.1 Hz, 1H), 6.80 (d, J=6.58 Hz, 2H), 4.37 (q, J=7.1 Hz, 1H), 3.76
3 f: Yield: 60%; 1H NMR(CDCl 3, 300 MHz): d=7.14–7.32 (m, 13H),
6.91 (t, J=7.0 Hz, 1H), 6.27 (s, 1H), 3.68 (s, 3H), 2.26 ppm (s, 3H);
13C NMR(CDCl 3, 75.3 MHz): d=146.6, 130.0, 128.4, 128.3, 128.2, 128.1,
(s, 3H), 2.32 (s, 3H), 1.74 ppm (d, J=7.1 Hz, 3H); 13C NMR(CDCl
,
3
75.3 MHz): d=158.6, 138.3, 135.1, 130.3, 128.2, 120.7, 119.3, 118.9, 118.1,
8360
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 8353 – 8364

Hydroarylation of Alkenes with Indoles
FULL PAPER
116.3, 113.4, 110.1, 55.2, 34.6, 20.7, 12.2 ppm; EIMS: m/z: 265 [M+];
HRMS (EI): m/z calcd for C18H19NO: 265.1467; found: 265.1463.
5h: Reaction was conducted at 1408C for 30 min. Yield: 42%; 1H NMR
(CDCl3, 300 MHz): d=9.72 (brs, NH, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.98
(d, J=7.7 Hz, 1H), 7.15–7.21 (m, 2H), 3.21 (m, 1H), 2.17–2.19 (m, 2H),
1.70–1.83 ppm (m, 6H); 13C NMR(CDCl 3, 75.3 MHz): d=127.7, 121.9,
119.2, 118.4, 118.2, 36.5, 33.3, 25.2 ppm.
General procedure for gold(I)-catalyzed hydroarylation of alkenes with
indoles under microwave-assisted conditions: Indole 1 (0.3 mmol) and
alkene 4 (0.6 mmol) were added to a mixture of chloro(triphenylphosph-
5i: Reaction was conducted at 1408C for 30 min. Yield: 60%; 1H NMR
(CDCl3, 300 MHz): d=9.70 (brs, NH, 1H), 8.16 (d, J=7.5 Hz, 1H), 7.97
(d, J=7.6 Hz, 1H), 7.11–7.19 (m, 2H), 2.85 (m, 1H), 2.08–2.09 (m, 4H),
1.77–1.89 ppm (m, 6H); 13C NMR(CDCl 3, 75.3 MHz): d=132.5, 128.7,
127.3, 121.9, 121.8, 119.1, 118.9, 118.3, 39.9, 34.1, 26.7, 26.3 ppm; EIMS:
m/z: 244 [M+]; HRMS (EI): m/z calcd for C14H16N2O2: 244.1212; found:
244.1209.
5j: Reaction was conducted at 1408C for 10 min. Yield: 83%; 1H NMR
(CDCl3, 300 MHz): d=9.78 (brs, NH, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.97
(d, J=8.1 Hz, 1H), 7.14–7.21 (m, 2H), 5.80 (m, 2H), 3.18–3.20 (m, 1H),
2.24–2.28 (m, 1H), 2.10–2.23 (m, 3H), 1.75–1.86 ppm (m, 2H); 13C NMR
(CDCl3, 75.3 MHz): d=133.2, 132.1, 131.9, 127.2, 127.1, 126.3, 124.8,
122.2, 119.1, 118.4, 32.5, 30.8, 29.4, 25.4 ppm; EIMS: m/z: 242 [M+];
HRMS (EI): m/z calcd for C14H14N2O2: 242.1055; found: 242.1057.
5k: Reaction was conducted at 1408C for 30 min. Yield: 65%; 1H NMR
(CDCl3, 400 MHz): d=9.81 (brs, NH, 1H), 8.12–8.17 (m, 2H), 7.12–7.25
(m, 2H), 3.08 (m, 0.12H), 2.06–2.17 (m, 3H), 1.62–1.76 (m, 4H), 1.53–
1.62 ppm (m, 6H); 13C NMR(CDCl 3, 100 MHz): d=129.4, 127.4, 122.8,
119.1, 118.7, 118.0, 38.3, 35.8, 34.9, 28.2, 27.8, 26.9, 26.4, 22.5 ppm; EIMS:
m/z: 258 [M+]; HRMS (EI): m/z calcd for C15H18N2O2: 258.1368; found:
258.1369.
ACHTREUNGine)gold(I) (7.4 mg, 0.015 mmol) and silver triflate (3.8 mg, 0.015 mmol)
in dichloroethane (1.0 mL) in a microwave reaction vessel. The reaction
vessel was sealed and subjected to microwave irradiation at a power of
43 W at 130–1408C for 5–30 min.
5a: Reaction was conducted at 1308C for 7 min. Yield: 81%; 1H NMR
(CDCl3, 300 MHz): d=7.47–7.50 (m, 2H), 7.25–7.47 (m, 8H), 7.04–7.16
(m, 4H), 4.10 (t, J=7.2 Hz, 1H), 2.42 (s, 3H), 2.24–2.29 (m, 1H), 2.05–
2.08 (m, 1H), 0.98 ppm (t, J=7.3 Hz, 3H); 13C NMR(CDCl , 75.3 MHz):
3
d=141.2, 139.7, 137.8, 134.9, 132.6, 130.1, 128.3, 128.1, 127.2, 125.9, 124.9,
124.1, 123.5, 122.2, 119.8, 119.6, 110.4, 44.8, 29.1, 21.0, 12.9 ppm; EIMS:
m/z: 325 [M+]; HRMS (EI): m/z calcd for C24H23N: 325.1830; found:
325.1833.
5b: Reaction was conducted at 1308C for 10 min. Yield: 86%; 1H NMR
(CDCl3, 300 MHz): d=7.49 (t, J=7.8 Hz, 1H), 7.35–7.37 (m, 3H), 7.25–
7.30 (m, 4H), 7.13–7.14 (m, 2H), 7.03 (t, J=7.1 Hz, 1H), 6.81 (m, 3H),
4.18 (t, J=7.1 Hz, 1H), 3.75 (s, 3H), 2.42 (s, 3H), 2.24–2.29 (m, 1H),
2.02–2.08 (m, 1H), 0.98 ppm (t, J=7.1 Hz, 3H); 13C NMR(CDCl
,
3
75.3 MHz): d=158.7, 137.2, 135.8, 130.1, 128.9, 128.7, 128.0, 124.8, 124.0,
122.2, 121.0, 120.2, 119.6, 118.1, 113.6, 110.4, 55.2, 43.9, 29.2, 20.9,
12.8 ppm; EIMS: m/z: 355 [M+]; HRMS (EI): m/z calcd for C25H25NO:
355.1936; found: 355.1932.
5l: Reaction was conducted at 1408C for 30 min. Yield: 62%; 1H NMR
(CDCl3, 400 MHz): d=8.48 (brs, NH, 1H), 8.32–8.33 (m, 1H), 7.95–7.98
(m, 1H), 7.82 (d, J=8.9 Hz, 0.73H); 7.65 (d, J=8.5 Hz, 0.27H), 3.12–3.16
(m, 0.27H), 2.15–2.64 (m, 2H), 1.91–1.98 (m, 0.73H), 1.83–1.87 (m, 3H),
1.52–1.83 ppm (m, 9H); 13C NMR(CDCl 3, 75.3 MHz): d=127.9, 126.0,
125.7, 121.3, 119.1, 114.5, 114.1, 108.0, 40.7, 38.3, 36.1, 34.9, 32.8, 30.1,
27.2, 26.2, 25.6, 23.2, 22.3 ppm; EIMS: m/z: 272 [M+]; HRMS (EI): m/z
calcd for C16H20N2O2: 272.1525; found: 272.1525.
5c: Reaction was conducted at 1308C for 7 min. Yield: 82%; 1H NMR
(CDCl3, 300 MHz): d=7.71 (d, J=7.2 Hz, 1H), 7.40–7.51 (m, 2H), 7.23–
7.49 (m, 6H), 7.15–7.21 (m, 2H), 7.05 (t, J=7.2 Hz, 1H), 6.83 (d, J=
7.0 Hz, 2H), 4.10 (t, J=7.0 Hz, 1H), 3.79 (s, 3H), 2.25–2.27 (m, 1H),
2.04–2.05 (m, 1H), 1.02 ppm (t, J=7.0 Hz, 3H); 13C NMR(CDCl
,
3
75.3 MHz): d=158.9, 137.4, 135.6, 130.2, 128.8, 128.6, 128.3, 124.5, 124.1,
122.6, 121.5, 120.4, 119.7, 119.2, 118.3, 114.2, 110.3, 55.1, 43.6, 29.5,
12.5 ppm; EIMS: m/z: 355 [M+]; HRMS (EI): m/z calcd for C25H25NO:
355.1936; found: 355.1932.
5d: Reaction was conducted at 1358C for 7 min. Yield: 80%; 1H NMR
(CDCl3, 300 MHz): d=9.75 (brs, NH, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.70
(d, J=8.1 Hz, 1H), 7.16–7.31 (m, 6H), 7.03 (t, J=7.9 Hz, 1H), 4.06 (t,
J=7.6 Hz, 1H), 2.18–2.25 (m, 1H), 2.03–2.10 (m, 1H), 0.97 ppm (t, J=
7.3 Hz, 3H); 13C NMR(CDCl 3, 75.3 MHz): d=144.4, 138.7, 131.2, 128.4,
127.8, 127.7, 126.3, 125.6, 123.2, 121.9, 119.2, 118.6, 44.5, 28.9, 12.6 ppm;
EIMS: m/z: 280 [M+]; HRMS (EI): m/z calcd for C17H16N2O2: 280.1212;
found: 280.1210.
5m: Reaction was conducted at 1408C for 5 min. Yield: 85%; 1H NMR
(CDCl3, 300 MHz): d=8.59 (brs, NH, 1H), 8.33 (s, 1H), 7.97 (d, J=
5.6 Hz, 1H), 7.79 (d, J=6.7 Hz, 1H), 7.22 (s, 1H), 4.09 (q, J=5.3 Hz,
2H), 2.16 (dd, J1 =6.5 Hz, J2 =4.4 Hz, 1H), 2.02 (dd, J1 =6.1 Hz, J2 =
6.1 Hz, 1H), 1.75–1.96 (m, 3H), 1.40 (s, 6H), 1.21 (t, J=5.3 Hz, 3H),
1.07–1.11 (m, 1H), 0.81 ppm (d, J=4.9 Hz, 3H); 13C NMR(CDCl
,
3
75.3 MHz): d=173.3, 142.6, 135.6, 130.5, 126.4, 120.7, 120.5, 118.1, 114.1,
108.1, 60.0, 42.5, 41.7, 37.1, 34.7, 36.0, 29.6, 28.6, 22.1, 19.5, 14.1 ppm;
EIMS: m/z: 360 [M+]; HRMS (EI): m/z calcd for C20H28N2O4: 360.2049;
found: 360.2047.
5e: Reaction was conducted at 1308C for 7 min. Yield: 90%; 1H NMR
(CDCl3, 300 MHz): d=9.73 (brs, NH, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.67
(d, J=8.1 Hz, 1H), 7.23 (s, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.06 (t, J=
7.8 Hz, 1H), 6.78 (d, J=8.5 Hz, 2H), 4.01 (t, J=7.9 Hz, 1H), 3.75 (s,
3H), 2.13–2.19 (m, 1H), 1.96–2.03 (m, 1H), 0.89 ppm (t, J=7.4 Hz, 3H);
13C NMR(CDCl 3, 75.3 MHz): d=158.7, 138.5, 136.5, 130.0, 128.7, 127.8,
123.1, 122.2, 119.2, 118.5, 118.1, 113.8, 55.2, 43.6, 29.0, 12.6 ppm; EIMS:
m/z: 310 [M+]; HRMS (EI): m/z calcd for C18H18N2O3: 310.1317; found:
310.1321.
5n: Reaction was conducted at 1408C for 5 min. Yield: 80%; 1H NMR
(CDCl3, 300 MHz): d=8.41 (brs, NH, 1H), 8.30 (d, J=2.1 Hz, 1H), 7.95
(d, J=2.1 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H), 7.25–7.32 (m, 5H), 7.18 (d,
J=2.8 Hz, 1H), 4.45 (s, 2H), 3.38–3.45 (m, 2H), 1.74–1.77 (m, 2H), 1.34–
1.60 (m, 7H), 1.03–1.09 (m, 4H), 0.74 ppm (d, J=6.5 Hz, 3H); 13C NMR
(CDCl3, 75.3 MHz): d=142.4, 135.4, 130.6, 129.5, 128.3, 127.6, 127.5,
128.4, 120.8, 118.1, 114.2, 108.1, 72.9, 68.7, 42.9, 37.7, 36.6, 34.8, 29.6, 28.7,
22.2, 19.6 ppm; EIMS: m/z: 408 [M+]; HRMS (EI): m/z calcd for
C25H32N2O3: 408.2413; found: 408.2414.
5 f: Reaction was conducted at 1408C for 10 min. Yield: 75%; 1H NMR
(CDCl3, 300 MHz): d=7.83 (d, J=7.2 Hz, 1H), 7.53 (t, J=8.1 Hz, 1H),
7.36 (d, J=8.2 Hz, 2H), 7.28–7.30 (m, 3H), 7.03–7.25 (m, 2H), 6.90 (s,
3H), 2.42–2.46 (m, 4H), 1.45 (s, 6H), 0.85 ppm (d, J=7.0 Hz, 6H);
13C NMR(CDCl 3, 75.3 MHz): d=139.6, 135.7, 131.7, 129.9, 124.8, 124.2,
122.7, 122.5, 121.8, 121.5, 118.9, 110.5, 37.9, 35.5, 24.5, 20.9, 18.0 ppm;
EIMS: m/z: 291 [M+]; HRMS (EI): m/z calcd for C21H25N: 291.1987;
found: 291.1985
5g: Reaction was conducted at 1408C for 10 min. Yield: 45%; 1H NMR
(CDCl3, 300 MHz): d=9.78 (brs, NH, 1H), 8.12–8.16 (m, 2H), 7.10–7.17
(m, 2H), 2.30–2.32 (m, 3H), 1.36 (s, 6H), 0.83 ppm (d, J=6.8 Hz, 6H);
13C NMR(CDCl 3, 100 MHz): d=132.7, 131.5, 129.6, 129.1, 123.0, 122.8,
118.8, 118.1, 45.3, 37.8, 24.6, 17.9 ppm; EIMS: m/z: 246 [M+]; HRMS
(EI): m/z calcd for C14H18N2O2: 246.1368; found: 246.1370.
5p: Reaction was conducted at 1408C for 5 min. Yield: 75%; 1H NMR
(CDCl3, 300 MHz): d=7.86 (d, J=6.8 Hz, 1H), 7.58–7.61 (m, 2H), 7.53–
7.55 (m, 3H), 7.23–7.37 (m, 1H), 7.16–7.23 (m, 2H), 7.09 (s, 1H), 4.13 (t,
J=7.2 Hz, 2H), 2.22 (dd, J1 =5.7 Hz, J2 =2.0 Hz, 1H), 2.08 (dd, J1 =
8.2 Hz, J2 =3.0 Hz, 1H), 1.87–2.05 (m, 3H), 1.48 (s, 6H), 1.18–1.31 (m,
5H), 0.88 ppm (d, J=6.5 Hz, 3H); 13C NMR(CDCl 3, 75.3 MHz): d=
173.4, 139.9, 136.9, 129.5, 127.5, 126.0, 124.4, 124.3, 121.8, 121.5, 119.3,
110.6, 60.0, 42.6, 41.9, 37.4, 34.9, 30.2, 28.7, 22.2, 19.7, 14.3 ppm; EIMS:
m/z: 391 [M+]; HRMS (EI): m/z calcd for C26H33NO2: 391.2511; found:
391.2510.
5q: Reaction was conducted at 1408C for 5 min. Yield: 20%; 1H NMR
(CDCl3, 300 MHz): d=7.85 (d, J=6.8 Hz, 1H), 7.50–7.58 (m, 4H), 7.27–
7.50 (m, 7H), 7.06–7.21 (m, 3H), 4.55 (s, 3H), 3.41–3.47 (m, 2H), 1.82–
1.87 (m, 2H), 1.66 (s, 6H), 1.01–1.32 (m, 7H), 0.81 ppm (d, J=6.6 Hz,
Chem. Eur. J. 2008, 14, 8353 – 8364
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8361

M.-Z. Wang, M.-K. Wong, and C.-M. Che
3H); 13C NMR(CDCl 3, 75.3 MHz): d=139.8, 136.5, 129.5, 128.3, 127.6,
125.9, 124.4, 124.3, 121.8, 121.6, 119.3, 118.7, 110.6, 72.8, 68.8, 42.8, 37.8,
36.8, 34.9, 29.7, 28.7, 22.2, 19.7 ppm; EIMS: m/z: 439 [M+]; HRMS (EI):
m/z calcd for C31H37NO: 439.2875; found: 439.2876.
EIMS: m/z: 277 [M+]; HRMS (EI): m/z calcd for C19H19NO: 277.1467;
found: 277.1466.
7h: Yield: 74%; 1H NMR(CDCl 3, 300 MHz): d=7.69 (d, J=7.3 Hz,
1H), 7.28–7.33 (m, 3H), 7.26 (t, J=6.7 Hz, 1H), 7.06 (t, J=7.1 Hz, 1H),
6.93 (s, 1H), 6.81 (d, J=8.6 Hz, 2H), 6.44 (d, J=15.8 Hz, 1H), 6.34 (dd,
J1 =6.7 Hz, J2 =15.8 Hz, 1H), 4.15 (q, J=7.3 Hz, 2H), 3.79–3.93 (m, 4H),
General procedure for gold(I)-catalyzed coupling of indoles with dienes:
Indole 1 (0.3 mmol) and diene 6 (0.45 mmol) were added to a mixture of
chloro(triphenylphosphine)gold(I) (7.5 mg, 0.015 mmol) and silver triflate
(4.5 mg, 0.015 mmol) in toluene (1.0 mL). After heating at 708C for 16 h,
the reaction mixture was purified by flash column chromatography
(hexane/ethyl acetate 50/1 to 15/1) to afford allylated indole 7.
1.55 (d, J=7.0 Hz, 3H), 1.38 ppm (d, J=7.3 Hz, 3H); 13C NMR(CDCl
,
3
75.3 MHz): d=158.6, 136.4, 133.6, 130.5, 127.3, 127.2, 123.4, 121.3, 119.8,
118.5, 118.1, 113.8, 113.6, 109.2, 55.3, 40.8, 34.2, 20.9, 15.4 ppm; EIMS: m/
z: 305 [M+]; HRMS (EI): m/z calcd for C21H23NO: 305.1780; found:
305.1779.
7a: Yield: 81%; 1H NMR(CDCl 3, 500 MHz): d=7.66 (d, J=7.9 Hz,
1H), 7.27 (d, J=8.2 Hz, 1H), 7.21 (t, J=7.2 Hz, 1H), 7.08 (t, J=7.1 Hz,
1H), 6.86–6.90 (m, 2H), 6.76 (d, J=8.25 Hz, 1H), 6.45 (d, J=15.9 Hz,
1H), 6.30 (dd, J1 =7.9 Hz, J2 =15.8 Hz, 1H), 3.90–3.94 (m, 1H), 3.85 (s,
3H), 3.84 (s, 3H), 3.73 (s, 3H), 1.55 ppm (d, J=7.0 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): d=148.9, 148.3, 137.2, 133.8, 130.9, 127.5, 127.2,
125.3, 121.5, 119.7, 119.1, 118.7, 111.1, 109.2, 108.7, 55.9, 55.8, 34.1, 32.6,
20.9 ppm; EIMS: m/z: 321 [M+]; HRMS (EI): m/z calcd for C21H23NO2:
321.1729; found: 321.1728.
1
7i: Yield: 65%; H NMR(CDCl , 400 MHz): d=7.71 (d, J=7.2 Hz, 1H),
3
7.22–7.29 (m, 5H), 7.08 (d, J=8.0 Hz, 2H), 6.87 (s, 1H), 6.46 (d, J=
15.8 Hz, 1H), 6.35 (dd, J1 =6.7 Hz, J2 =15.8 Hz, 1H), 3.91–3.95 (m, 1H),
3.76 (s, 3H), 2.32 (s, 3H), 1.55 ppm (d, J=7.0 Hz, 3H); 13C NMR
(CDCl3, 100 MHz): d=137.8, 137.5, 135.2, 134.5, 129.1, 128.9, 127.8,
126.0, 125.2, 121.5, 119.7, 118.6, 109.1, 34.2, 32.6, 21.1, 20.9 ppm; EIMS:
m/z: 275 [M+]; HRMS (EI): m/z calcd for C20H21N: 275.1674; found:
275.1673.
7j: Yield: 62%; 1H NMR(CDCl 3, 300 MHz): d=7.89 (brs, NH, 1H),
7.67 (d, J=7.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H),
7.17 (t, J=7.1 Hz, 1H), 7.06–7.08 (m, 3H), 6.98 (s, 1H), 6.45 (d, J=
15.8 Hz, 1H), 6.38 (dd, J1 =6.7 Hz, J2 =15.8 Hz, 1H), 3.87–3.95 (m, 1H),
2.30 (s, 3H), 1.53 ppm (d, J=7.0 Hz, 3H); 13C NMR(CDCl 3, 75.3 MHz):
d=136.6, 135.0, 134.4, 129.1, 129.0, 128.6, 128.0, 126.9, 126.1, 122.2, 121.9,
120.7, 120.4, 119.7, 119.2, 118.2, 110.1, 34.2, 21.0, 20.8 ppm; EIMS: m/z:
261 [M+]; HRMS (EI): m/z calcd for C19H19N: 261.1517; found:
261.1516.
7b: Yield: 76%; 1H NMR(CDCl 3, 300 MHz): d=8.03 (brs, NH, 1H),
7.68 (d, J=7.9 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.19 (t, J=7.2 Hz, 1H),
7.06 (t, J=7.2 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 6.88–6.92 (m, 2H), 6.81
(d, J=8.0 Hz, 1H), 6.43 (d, J=15.6 Hz, 1H), 6.35 (dd, J1 =6.7 Hz, J2 =
15.6 Hz, 1H), 3.91–3.96 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 1.59 ppm (d,
J=7.0 Hz, 3H); 13C NMR(CDCl 3, 75.3 MHz): d=148.8, 148.2, 136.6,
133.7, 130.9, 127.8, 126.9, 121.9, 120.6, 120.4, 119.6, 119.4, 119.1, 111.2,
111.1, 108.7, 55.9, 55.8, 34.2, 20.8 ppm; EIMS: m/z: 307 [M+]; HRMS
(EI): m/z calcd for C20H21NO2: 307.1572; found: 307.1574.
General procedure for competitive gold(I)-catalyzed hydroarylation of
styrenes with 1a: Compound 1a (0.3 mmol), 4-methyl styrene 2d
(0.33 mmol), and p-substituted styrene 2a, 2c, or 2e (0.33 mmol) were
7c: Yield: 72%; 1H NMR(CDCl 3, 300 MHz): d=8.09 (brs, NH, 1H),
7.71 (s, 1H), 7.24 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.04 (s, 1H), 6.91 (d,
J=8.9 Hz, 2H), 6.81 (d, J=8.0 Hz, 1H), 6.45 (d, J=15.8 Hz, 1H), 6.29
(dd, J1 =6.7 Hz, J2 =15.8 Hz, 1H), 3.82–4.01 (m, 1H), 1.53 ppm (d, J=
7.0 Hz, 3H); 13C NMR(CDCl 3, 75.3 MHz): d=148.9, 148.4, 134.9, 133.1,
130.8, 128.1, 127.9, 124.9, 122.3, 121.9, 120.4, 119.1, 119.4, 112.1, 111.2,
108.8, 55.9, 55.8, 34.0, 20.8 ppm; EIMS: m/z: 341 [M+]; HRMS (EI): m/z
calcd for C20H20ClNO2: 341.1183; found: 341.1182.
7d: Yield: 75%; 1H NMR(CDCl 3, 400 MHz): d=7.90 (brs, NH, 1H),
7.25 (d, J=4.8 Hz, 1H), 7.11 (s, 1H), 7.0 (s, 1H), 6.83–6.90 (m, 3H), 6.77
(d, J=8.2 Hz, 1H), 6.42 (d, J=15.8 Hz, 1H), 6.35 (dd, J1 =6.7 Hz, J2 =
15.8 Hz, 1H), 3.83–3.88 (m, 7H), 3.81 (s, 3H), 1.56 ppm (d, J=7.0 Hz,
3H); 13C NMR(CDCl 3, 75.3 MHz): d=153.7, 148.9, 148.2, 133.5, 131.7,
130.9, 127.8, 127.2, 121.3, 120.2, 119.0, 111.9, 111.7, 111.1, 108.6, 104.9,
101.7, 55.9, 55.8, 34.2, 20.8 ppm; EIMS: m/z: 337 [M+]; HRMS (EI): m/z
calcd for C21H23NO3: 337.1678; found: 337.1680.
added to
a
mixture of chloro(triphenylphosphine)gold(I) (3 mg,
0.006 mmol) and silver triflate (1.8 mg, 0.006 mmol) in toluene (1.0 mL).
After heating at 858C for 15 min, the solvent was removed under re-
duced pressure and the crude mixture was analyzed by 1H NMRspec-
troscopy. The ratios of indoles 3a, 3c, or 3e to 3d were determined by
means of the integration ratios of their corresponding peak areas in the
1H NMRspectra. Conversion based on styrene was determined by GC
analysis.
Conversion of 2a/2d (31/3.2%), 2c/2d (3.2/3.1%), 2e/2d (1.5/3.2%),
Chemical shift of CHCH3: 3a (4.29), 3c (4.42), 3d (4.34), and 3e
(4.34 ppm). Chemical shift of CHCH3: 3a (1.65), 3c (1.72), 3d (1.74), and
3e (1.66 ppm).
7e: Yield: 70%; 1H NMR(CDCl 3, 300 MHz): d=8.20 (brs, NH, 1H),
7.55 (d, J=7.9 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H),
7.04 (t, J=7.8 Hz, 1H), 6.90–6.96 (m, 2H), 6.77 (d, J=8.1 Hz, 1H), 6.39
(d, J=15.8 Hz, 1H), 6.27 (dd, J1 =6.7 Hz, J2 =15.8 Hz, 1H), 3.86–3.94 (m,
7H), 1.56 ppm (d, J=7.0 Hz, 3H); 13C NMR(CDCl 3, 100 MHz): d=
148.9, 148.3, 138.9, 133.1, 128.1, 121.3, 121.1, 120.0, 119.1, 118.3, 111.1,
101.6, 55.9, 55.8, 34.3, 20.7 ppm; EIMS: m/z: 341 [M+]; HRMS (EI): m/z
calcd for C20H20ClNO2: 341.1183; found: 341.1182.
7 f: Yield: 80%; 1H NMR(CDCl 3, 300 MHz): d=7.68 (d, J=7.3 Hz,
1H), 7.21–7.30 (m, 4H), 7.07 (t, J=6.9 Hz, 1H), 6.81–6.92 (m, 3H), 6.43
(d, J=15.8 Hz, 1H), 6.31 (dd, J1 =6.7 Hz, J2 =15.8 Hz, 1H), 3.91–3.97 (m,
1H), 3.88 (s, 3H), 3.75 (s, 3H), 1.53 ppm (d, J=7.0 Hz, 3H); 13C NMR
(CDCl3, 75.3 MHz): d=158.6, 136.5, 133.5, 130.8, 127.4, 127.2, 125.2,
121.5, 119.7, 118.6, 113.9, 109.2, 55.3, 34.2, 32.6, 20.9 ppm; EIMS: m/z:
291 [M+]; HRMS (EI): m/z calcd for C20H21NO: 291.1623; found:
291.1622.
7g: Yield: 75%; 1H NMR(CDCl 3, 400 MHz): d=7.91 (brs, 1H, NH),
7.66 (d, J=7.9 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.29 (d, J=8.6 Hz, 2H),
7.17 (t, J=6.1 Hz, 1H), 7.07 (t, J=7.0 Hz, 1H), 6.99 (s, 1H), 6.82 (d, J=
8.8 Hz, 2H), 6.42 (d, J=15.8 Hz, 1H), 6.30 (dd, J1 =6.7 Hz, J2 =15.8 Hz,
1H), 3.87–3.91 (m, 1H), 3.77 (s, 3H), 1.55 ppm (d, J=7.0 Hz, 3H);
13C NMR(CDCl 3, 75.3 MHz): d=158.7, 136.6, 133.4, 130.7, 127.6, 127.2,
126.9, 121.9, 120.8, 120.4, 119.7, 119.3, 113.9, 111.1, 55.3, 34.2, 20.8 ppm;
Acknowledgements
We are thankful for the financial support of The University of Hong
Kong (University Development Fund), Hong Kong Research Grant
Council (HKU 7052/07P), and the Areas of Excellence Scheme estab-
lished under the University Grants Committee of the Hong Kong Special
Administrative Region, China (AoE/P-10/01).
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Hydroarylation of Alkenes with Indoles
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8364
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Chem. Eur. J. 2008, 14, 8353 – 8364