One-pot 2-aryl/vinylindole synthesis consisting of a ruthenium-catalyzed hydroamination and a palladium-catalyzed heck reaction using 2-chloroaniline

Article abstract of DOI:10.1055/s-2006-950440

A one-pot synthesis of 2-aryl- and 2-vinylindoles based on a ruthenium-catalyzed hydroamination and a palladium-catalyzed intramolecular Heck reaction is reported. The ruthenium-catalyzed addition reaction was applied to terminal as well as internal alkynes. Intramolecular Heck reactions of the resulting 2-chloroanilino enamines were achieved using an in situ generated palladium complex derived from an N-heterocyclic carbene. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950440

LETTER
3125
One-Pot 2-Aryl/Vinylindole Synthesis Consisting of a Ruthenium-Catalyzed
Hydroamination and a Palladium-Catalyzed Heck Reaction Using
2
-Chloroaniline
H
L
ydroamination
u
/Heck
R
eac
t
tion
S
eq
z
uence Employin
A
g2-Chloroanilinesckermann,* Andreas Althammer
Department Chemie und Biochemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Haus F, 81377 München,
Germany
Fax +49(89)218077425; E-mail: Lutz.Ackermann@cup.uni-muenchen.de
Received 24 April 2006
Dedicated to Professor Richard F. Heck in recognition of his seminal contributions to the development of palladium-catalyzed coupling
reactions
complements Larock’s annulation of alkynes by 2-halo-
Abstract: A one-pot synthesis of 2-aryl- and 2-vinylindoles based
aniline derivatives.1
7,18
on a ruthenium-catalyzed hydroamination and a palladium-cata-
lyzed intramolecular Heck reaction is reported. The ruthenium- As part of our program directed towards the development
catalyzed addition reaction was applied to terminal as well as in-
of protocols for efficient syntheses of selectively func-
ternal alkynes. Intramolecular Heck reactions of the resulting 2-
chloroanilino enamines were achieved using an in situ generated
palladium complex derived from an N-heterocyclic carbene.
19–24
tionalized heterocycles,
we became interested in
probing hydroamination methodologies based on late
transition-metal catalysts for novel one-pot indole syn-
Key words: aryl chlorides, Heck reaction, hydroamination, palladi-
um, ruthenium
25–30
31
theses. Ruthenium
and platinum
compounds
emerged as highly active catalysts for the intermolecular
3
2
10c
hydroamination of alkynes. However, Ru (CO) - and
3
12
PtBr -catalyzed intermolecular hydroamination reactions
2
The palladium-catalyzed coupling between an alkene and
33
were predominantly applied to addition reactions of ter-
1
,2
an aryl or a vinyl halide, often referred to as the Heck
reaction, is one of the most useful and versatile methodol-
ogies for the carbon–carbon bond formation involving
28,31
minal alkynes.
Herein, we report a one-pot synthesis
of 2-aryl- and 2-vinylindoles, which relies on a regio-
selective Ru (CO) -catalyzed hydroamination reaction
3
12
2
3
sp -hybridized carbons. Intramolecular Heck reactions
allowed for the development of protocols for the synthesis
and a palladium-catalyzed intramolecular Heck reaction
of the resulting 2-chloroanilino enamine.
4
of diversely substituted carbo- and heterocycles. Cycliza-
tion reactions of 2-haloanilino enamines proved valuable
tools for the synthesis of differently substituted indole
derivatives. A significant extension of this approach was
Ar
Cl
Cl
Ar
20 mol% TiCl4
5
R1
+
R1
t-BuNH2
R2
NH2
N
H
established through the in situ preparation of the corre-
R2
PhMe, 105 °C , 20 h
sponding enamines via condensation of 2-iodoanilines
3
with, preferably cyclic, ketones.6
1
2
Recently, we reported on a novel one-pot indole synthesis,
which relied on the in situ formation of 2-bromoanilino
1
0 mol% Pd(OAc)2
0 mol% 5, t-BuOK
PhMe, 105 °C , 20 h
Me
Me
1
Me
Me
7
–9
enamines via TiCl -catalyzed
hydroamination
4
1
0
11
reactions of alkynes with 2-bromoaniline. Aryl
chlorides are arguably the most useful single class of
electrophiles due to their lower cost and the significantly
Cl
Ar
N
N
R1
R2
Me
Me
Me
Me
1
2
N
wider diversity of available compounds. Therefore, we
developed a protocol for a one-pot indole synthesis
starting from more readily available 2-chloroaniline de-
5
H
4
Scheme 1 One-pot indole synthesis consisting of a titanium-cataly-
1
3–15
rivatives 1 (Scheme 1).
The intramolecular Heck zed hydroamination and a palladium-catalyzed Heck reaction
reactions of 2-chloroanilino enamines 3 were accom-
plished with the use of a palladium complex modified
On the outset of our studies we tested a variety of proto-
cols for intermolecular hydroamination reactions for a
regioselective one-pot indole synthesis. A potential addi-
tion of 2-chloroaniline (1a) onto either terminal alkyne 2a
1
6
with N-heterocyclic carbene precursor 5. The regio-
selective titanium-catalyzed hydroamination reaction of
alkyne 2 set the stage for the selective formation of 3-aryl-
substituted indole derivatives 4.1 This regioselectivity
3
34
or internal alkyne 2b employing FeCl (H O) was not
3
2
6
viable (Scheme 2, Table 1, entries 1, and 2). On the con-
trary, the platinum-catalyzed hydroamination31 with 2-
chloroaniline (1a) proved applicable to the functionaliza-
tion of terminal alkyne 2a (entry 3). However, a double
SYNLETT 2006, No. 18, pp 3125–3129
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-950440; Art ID: S09506ST
0
3
.1
1
.2
0
0
6
©
Georg Thieme Verlag Stuttgart · New York

3
126
L. Ackermann, A. Althammer
LETTER
Table 1 Evaluation of Late Transition-Metal-Catalyzed Hydroamination Protocols for a One-Pot Indole Synthesis (see Scheme 2)a
Entry
Hydroamination reaction conditions
FeCl ·6H O (5.0 mol%)
R
Isolated yield (%)
1
2
3
4
5
H (2a)
Ph (2b)
H (2a)
Ph (2b)
H (2a)
Ph (2b)
–b
3
2
FeCl ·6H O (5.0 mol%)
–b
3
2
PtCl (3.0 mol%)
–
2
PtCl (3.0 mol%)
24 (4b)
60 (4a)
89 (4b)
2
Ru (CO) (1.0 mol%), NH PF (3.0 mol%)
3
12
4
6
6
Ru (CO) (1.0 mol%), NH PF (3.0 mol%)
3 12 4 6
a
Reaction conditions: 1a (1.0 mmol), 2 (1.5 mmol), [M], additive, PhMe (1 mL), 105 °C, 18–22 h; Pd(OAc) (5.0 mol%), 5 (5.0 mol%),
2
t-BuOK (2.0 mmol), PhMe (2 mL), 24 h.
b
No conversion of 1a as judged by GC-MS analysis.
R
Table 2 Influence of Different Ligands on the One-Pot Indole Syn-
Cl
Cl
R
thesis (see Scheme 3)a
cat. [M], additive
+
PhMe, 105 °C , 18–22 h
NH2
N
H
Ph
Entry Ligand L
Isolated yield of 4b (%)
Ph
1
PPh3
6
7
24
1
a
R = H: 2a
R = Ph: 2b
3
Cl
Cl
5
.0 mol% Pd(OAc)2
.0 mol% 5, t-BuOK
PhMe, 105 °C , 24 h
2
15
19
Mes
Mes
Mes
N
N
N
5
3
4
8
9
Mes
R
N
Ph
Me
N
Me
Me
N
Me
H
Cl
R = H: 4a
R = Ph: 4b
31
89
N
Me
Me
Me
Me
Scheme 2
Me
N
Me
Me
Me
a) 1.0 mol% Ru3(CO)12
.0 mol% NH4PF6
PhMe, 105 °C , 18 h
Ph
Ph
Cl
3
Cl
5
5
N
+
Ph
b) 5.0 mol% Pd(OAc)2
N
NH2
Me
Me
Me
Me
H
Ph
5.0 mol% L, t-BuOK
105 °C , 24 h
1a
2b
4b
a
Reaction conditions: 1a (1.0 mmol), 2b (1.5 mmol), Ru (CO) (1.0
3
12
Scheme 3
mol%), NH PF (3.0 mol%), PhMe (1 mL), 105 °C, 18 h; Pd(OAc)
4
6
2
(
5.0 mol%), L (5.0 mol%), t-BuOK (2.0 mmol), PhMe (2 mL), 24 h.
3
6
Mes = 2,4,6-Me C H .
3
6
2
alkenylation of aniline 1a led to the formation of numer-
ous products under the reaction conditions of the palla-
dium-catalyzed Heck cyclization. Interestingly, we Heck reaction of the resulting 2-chloroanilino enamine 3
observed an unprecedented platinum-catalyzed inter- in the same reaction flask, yielding indole 4a regioselec-
molecular hydroamination of an internal alkyne (entry 4). tively in good yield (entry 5). Additionally, the
Thus, the addition of aniline 1a onto tolan (2b) provided Ru (CO)12-based hydroamination protocol allowed for
3
the corresponding enamine 3, along with its tautomeric heterofunctionalization of internal alkyne 2b. Subsequent
imine, in high yield as determined by GC analysis. Un- palladium-catalyzed Heck reaction led to indole 4b in
fortunately, the isolated yield of product 4b was not satis- high yield of isolated product (entry 6).
factory (entry 4).
With an efficient protocol for a one-pot indole synthesis
2
6
The Ru (CO) -catalyzed hydroamination of terminal using 2-chloroaniline (1a) in hand, we probed the influ-
3
12
alkyne 2a with aniline 1a yielded selectively the formal ence of various stabilizing ligands on the palladium-cata-
Markovnikov addition product. It proved also viable to lyzed intramolecular Heck reaction of 2-chloroanilino
perform a subsequent intramolecular palladium-catalyzed enamine 3. Under otherwise identical reaction conditions,
Synlett 2006, No. 18, 3125–3129 © Thieme Stuttgart · New York

LETTER
Hydroamination/Heck Reaction Sequence Employing 2-Chloroanilines
3127
phosphine ligand 6 gave rise to lower yields of isolated
a) 1.0 mol% Ru3(CO)12,
3.0 mol% NH PF ,
PhMe, 105 °C , 18 h
R2
R2
3
5
product (Scheme 3, Table 2, entry 1). Among different
precursors for N-heterocyclic carbenes (entries 2–5),
sterically hindered imidazolium chloride 5 led to most
efficient catalysis (entry 5).
X
4
6
R1
R1
R3
+
b) 5.0 mol% Pd(OAc)2
5.0 mol% 5, t-BuOK
105 °C , 24 h
N
NH2
R3
H
1
2
4
Subsequently, the scope of the one-pot indole synthesis
was evaluated (Scheme 4, Table 3). Importantly, the
Scheme 4
Table 3 Scope of the One-Pot Synthesis of Substituted Indole Derivatives (Scheme 4)a
Entry Aniline
Alkyne
Indole
Isolated yield (%)
Cl
H
1
2
3
1a
1a
2a
2b
4a
<5b
60
Ph
H
H
Ph
NH2
N
H
Cl
Ph
4b
<5b
Ph
Ph
NH2
N
H
4
5
89
60c
Me
Cl
H
Me
6
1b
1a
1c
1a
1d
1d
1e
2a
2c
2c
2d
2a
2b
2a
4c
4d
4e
4f
75d
49e
35e
–
Ph
H
Ph
NH2
N
H
Cl
H
7
H
H
NH2
N
H
Cl
H
8
F3C
NH2
N
F3C
H
Cl
H
9
Ph
Ph
Ph
Ph
Et
H
Ph
NH2
Br
N
H
H
1
0
1
2
4a
4b
4g
78
73
87
Ph
NH2
N
H
Br
Ph
1
Ph
H
Ph
H
NH2
N
H
Cl
Br
Cl
1
Ph
NH2
N
H
a
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), Ru (CO) (1.0 mol%), NH PF (3.0 mol%), PhMe (1 mL), 105 °C, 18 h; Pd(OAc)
3
12
4
6
2
(
5.0 mol%), 5 (5.0 mol%), t-BuOK (2.0 mmol), PhMe (2 mL), 24 h.
b
Aniline 1 (1.0 mmol), 2 (1.5 mmol), Pd(OAc) (5.0 mol%), 5 (5.0 mol%), t-BuOK (2.0 mmol), PhMe (3 mL), 24 h.
2
c
d
e
Pd(OAc) (1.0 mol%), 5 (1.0 mol%).
2
Pd(OAc) (10.0 mol%), 5 (10.0 mol%).
2
Ru (CO) (3.0 mol%), NH PF (9.0 mol%), Pd(OAc) (10.0 mol%), 5 (10.0 mol%).
3
12
4
6
2
Synlett 2006, No. 18, 3125–3129 © Thieme Stuttgart · New York

3
128
L. Ackermann, A. Althammer
LETTER
(11) Ackermann, L. Organometallics 2003, 22, 4367.
loading of palladium catalyst for the intramolecular Heck
reaction could be significantly reduced (entry 5). The
methodology was also applicable to the synthesis of
regioselectively substituted 2-aryl- (entry 6) and 2-vi-
nylindoles (entries 7 and 8). Hydroamination of internal
alkyne 2d with 2-chloroaniline (1a) was not accomplished
with Ru (CO) as catalysts (entry 9). However, 2-bro-
(
(
(
12) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
176.
13) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem.
Commun. 2004, 6, 2824.
14) Recently, a palladium-catalyzed indole synthesis based on
an in situ condensation of 2-chloroanilines with ketones was
disclosed. See: Nazaré, M.; Schneider, C.; Lindenschmidt,
A.; Will, D. W. Angew. Chem. Int. Ed. 2004, 43, 4526.
15) See also: Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.;
Roschangar, F.; Farina, V.; Senanayake, C. H. Org. Lett.
4
3
12
moaniline (1d) gave rise to the corresponding indole de-
rivatives 4a and 4b in high yields of isolated product
(
(
entries 10 and 11). It is noteworthy that not only terminal
2004, 6, 4129.
alkyne 2a, but also internal alkyne 2b was efficiently con-
verted. Finally, dihaloaniline 1e was chemoselectively
transformed into chloro-substituted indole 4g (entry 12).
This chemoselectivity will allow for further functionaliza-
tion reactions of the resulting indole derivatives.
(
(
16) Herrmann, W. A. Angew. Chem. Int. Ed. 2002, 41, 1290.
17) Larock, R. C. J. Organomet. Chem. 1999, 576, 111.
(18) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem.
1998, 63, 7652.
(19) Ackermann, L.; Gschrei, C. J.; Althammer, A.; Riederer, M.
Chem. Commun. 2006, 1419.
In summary, we report on a one-pot synthesis of 2-aryl-
and 2-vinylindoles consisting of a Ru (CO) -catalyzed
(20) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem. Int.
Ed. 2006, 45, 2619.
3
12
hydroamination and an intramolecular palladium-cata-
lyzed Heck reaction employing 2-chloroaniline. Protocols
for Ru (CO) - and PtCl -catalyzed hydroamination
reactions were found applicable to addition reactions of
an internal alkyne. A bulky imidazolium salt preligand
enabled most efficient intramolecular palladium-cata-
lyzed Heck reactions of aryl chlorides.
(21) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew.
Chem. Int. Ed. 2005, 44, 7216.
(
(
22) Ackermann, L. Org. Lett. 2005, 7, 3123.
23) Ackermann, L.; Born, R. Angew. Chem. Int. Ed. 2005, 44,
3
12
2
2444.
(24) Ackermann, L. Org. Lett. 2005, 7, 439.
(25) Uchimaru, Y. Chem. Commun. 1999, 1133.
(26) Tokunaga, M.; Eckert, M.; Wakatsuki, Y. Angew. Chem. Int.
Ed. 1999, 38, 3222.
(27) Tokunaga, M.; Ota, M.; Haga, M.-a.; Wakatsuki, Y.
Tetrahedron Lett. 2001, 42, 3865.
Acknowledgment
(
28) (a) Wakatsuki, Y.; Hou, Z.; Tokunaga, M. Chem. Rec. 2003,
We thank the DFG for substantial financial support within the
Emmy Noether-Programm. Support by the Fonds der Chemischen
Industrie, the Ludwig-Maximilians-Universität, and Professor P.
Knochel is acknowledged. We are grateful to Saltigo (Leverkusen),
and Clariant (Frankfurt) for generous gifts of chemicals.
3, 144. (b) Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. In
Ruthenium in Organic Synthesis; Murahashi, S.-I., Ed.;
Wiley-VCH: Weinheim, 2004, 189.
(
(
29) Klein, D. P.; Ellern, A.; Angelici, R. J. Organometallics
2004, 23, 5662.
30) (a) Yi, C. S.; Yun, S. Y.; Guzei, I. A. J. Am. Chem. Soc.
2
2
005, 127, 5782. (b) Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc.
005, 127, 17000.
References and Notes
(
(
1) Heck, R. F.; Nolley, J. P. Jr. J. Org. Chem. 1972, 37, 2320.
2) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn.
(31) Brunet, J.-J.; Chu, N. C.; Diallo, O.; Vincendeau, S. J. Mol.
Catal. A: Chem. 2005, 240, 245.
1
971, 44, 581.
(32) Ruthenium-catalyzed hydroamidation reactions: (a) Kondo,
T.; Tanaka, A.; Kotachi, S.; Watanabe, Y. J. Chem. Soc.,
Chem. Commun. 1995, 413. (b) Gooßen, L. J.; Rauhaus, J.
E.; Deng, G. Angew. Chem. Int. Ed. 2005, 44, 4042.
(33) A ruthenium-catalyzed hydroamination of 1,3-diynes with
2-aminophenols: Shimada, T.; Yamamoto, Y. J. Am. Chem.
Soc. 2003, 125, 6646.
(34) For iron-catalyzed intramolecular hydroamidation reactions
of alkenes, see: Komeyama, K.; Morimoto, T.; Takaki, K.
Angew. Chem. Int. Ed. 2006, 45, 2938.
(
3) (a) Tsuji, J. Palladium Reagents and Catalysts, 2nd ed.;
Wiley: Chichester, 2004. (b) Bräse, S.; de Meijere, A. In
Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.;
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004, 217.
(
c) Beller, M.; Zapf, A.; Riermeier, T. H. In Transition
Metals for Organic Synthesis; Beller, M.; Bolm, C., Eds.;
Wiley-VCH: Weinheim, 2004, 271.
(
4) Link, J. T. In Organic Reactions, Vol. 60; Overman, L. E.,
Ed.; Wiley: Chichester, 2002, 160.
(
(
5) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
6) Chen, C.-y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676.
(35) The use of PCy or HP(t-Bu) BF led to inferior results under
3
3
4
otherwise identical reaction conditions. Versatile palladium-
catalyzed intermolecular Heck reactions of aryl chlorides
(7) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Org. Lett. 2004,
employing P(t-Bu) were reported. See: Littke, A. F.; Fu, G.
3
6
, 2515.
C. J. Am. Chem. Soc. 2001, 123, 6989.
(36) Representative Procedure: Synthesis of 2,3-Diphenyl-
indole (4b)
(
(
8) Ackermann, L.; Born, R. Tetrahedron Lett. 2004, 45, 9541.
9) Kaspar, L. T.; Fingerhut, B.; Ackermann, L. Angew. Chem.
Int. Ed. 2005, 44, 5972.
10) Reviews: (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem.
Rev. 2004, 104, 3079. (b) Beller, M.; Seayad, J.; Tillack, A.;
Jiao, H. Angew. Chem. Int. Ed. 2004, 43, 3368. (c) Pohlki,
F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104. (d) Brunet, J.
J.; Neibecker, D. In Catalytic Heterofunctionalization;
Togni, A.; Grützmacher, H., Eds.; Wiley-VCH: Weinheim,
2-Chloroaniline (1a; 133 mg, 1.04 mmol), and tolan (2b; 267
mg, 1.50 mmol) were added to a solution of Ru (CO) (6.4
(
3
12
mg, 0.01 mmol, 1 mol%) and NH PF (4.9 mg, 0.03 mmol,
4
6
3 mol%) in toluene (1 mL) and the resulting mixture was
stirred for 18 h at 105 °C. Thereafter, t-BuOK (224 mg, 2.00
mmol), Pd(OAc) (11.2 mg, 0.05 mmol, 5 mol%), 5 (21.3
2
mg, 0.05 mmol, 5 mol%), and toluene (2 mL) were added
2001, 91.
and the mixture was stirred at 105 °C for 24 h. Et O (50 mL)
2
Synlett 2006, No. 18, 3125–3129 © Thieme Stuttgart · New York

LETTER
Hydroamination/Heck Reaction Sequence Employing 2-Chloroanilines
3129
and brine (50 mL) were added to the cold suspension. The
13C NMR (100 MHz): d = 135.8, 135.0, 134.0, 132.7, 130.1,
128.7, 128.6, 128.5, 128.1, 127.7, 126.2, 122.7, 120.4,
119.7, 115.0, 110.8. IR (ATR): 3396, 3052, 1600, 1533,
1455, 1439, 1371, 1328, 1249, 1152, 1070, 1011, 965, 919,
separated aqueous phase was washed with Et O (2 × 50 mL).
2
Drying with MgSO and purification by column chromatog-
4
raphy (silica gel; n-pentane–Et O, 10:1 to 6:1) yielded
2
–
1
2
,3-diphenylindole (4b; 248 mg, 89%) as a yellow solid;
828, 763, 740, 693 cm . HRMS (EI): m/z calcd for C H N:
20 15
1
mp 129.8–130.0 °C. H NMR (400 MHz): d = 8.23 (s, 1 H),
.71 (d, J = 8.6 Hz, 1 H), 7.49–7.14 (m, 13 H).
269.1204; found: 269.1202.
7
Synlett 2006, No. 18, 3125–3129 © Thieme Stuttgart · New York