A flexible and catalytic one-pot procedure for the synthesis of indoles

Article abstract of DOI:10.1002/anie.200351345

One pot, two bonds, three rings: A clever combination of a [Cp₂TiMe₂]-catalyzed hydroamination of alkynes with a Pd-catalyzed N-arylation of imines results in a new and general method for the synthesis of indoles. Impressively, two n

Full text of DOI:10.1002/anie.200351345

Communications
have repeatedly shown that the titanium-catalyzed hydro-
amination of alkynes[1] is a versatile tool for the highly flexible
synthesis of biologically interesting compounds.[2] Expanding
these studies, we now present a highly flexible and catalytic
one-pot procedure for the synthesis of indoles[3] employing
ortho-chloro-substituted 1-phenyl-2-alkyl alkynes or phenyl-
(aminoalkyl)alkynes as starting materials.
The general principle of the one-pot procedure is shown in
Scheme 1. The major expectation is that under basic con-
ditions, the imines, which are regioselectively formed during
Scheme 1. Outline of a flexible and catalytic one-pot procedure for the
synthesis of indoles.
the hydroamination in the presence of the Ti catalyst
[Cp2TiMe2] (Cp = C5H5)[4], will be in equilibrium with the
corresponding enamines. In addition, an ortho-chloro-sub-
stituent in the benzene ring, should offer the possibility to
convert the enamines into indoles by a Pd-catalyzed N-
arylation/cyclization (Buchwald–Hartwig reaction).[5] Since
the enamines are removed from the equilibrium during this
cyclization step it should be possible to convert the imines
completely into indoles. However, to our knowledge, corre-
sponding N-arylations of N-substituted imines under basic
conditions in the presence of Pd-catalysts have not been
reported.[6]
Catalytic Indol Synthesis
A Flexible and Catalytic One-Pot Procedure for
the Synthesis of Indoles**
To investigate the scope of the suggested synthetic
Holger Siebeneicher, Igor Bytschkov, and Sven Doye*
À
strategy, which includes two C N bond-forming steps, we
synthesized a number of ortho-chloro-substituted 1-phenyl-2-
alkyl alkynes (1–10, Table 1) by Sonogashira couplings[7]
starting from simple 1-chloro-2-iodobenzenes and terminal
alkynes.[2c] The alkynes 1–10, which could be isolated in high
yields, were then used for the one-pot procedure. For this
purpose, the alkynes were first hydroaminated with an
arbitrary primary amine in the presence of 5 mol%
[Cp2TiMe2]. Subsequently, 5 mol% [Pd2(dba)3] (dba = diben-
zylideneacetone, 10 mol% 1,3-bis(2,4,6-trimethylphenyl)imi-
dazolium chloride, and KOtBu were added directly to the
reaction mixture. After heating the resulting mixture to
1108C, most of the 1,2-, 1,2,5-, and 1,2,6-substituted indoles
11–20 could be isolated in good yields [Eq. (1), Table 1].
However, the reaction of 4 and tert-butylamine gave the
corresponding indole 14 in only 39% yield. This modest result
is because the regioselectivity of the [Cp2TiMe2]-catalyzed
hydroamination of 1-phenyl-2-alkenyl alkynes is worse than
that of 1-phenyl-2-alkyl alkynes.[2b]
Initiated by improved screening methods, a steadily increas-
ing demand for highly flexible synthetic procedures has
evolved during the last couple of years. The major purpose of
these synthetic methods is the fast generation of various
derivatives of a certain class of substances. In the past, we
[*] Dr. S. Doye, Dipl.-Chem. H. Siebeneicher, Dr. I. Bytschkov
Institut für Organische Chemie
Universität Hannover
Schneiderberg 1B, 30167 Hannover (Germany)
Fax: (+49)511-762-30-11
E-mail: sven.doye@oci.uni-hannover.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft,
the Fonds der Chemischen Industrie, and the Dr. Otto Röhm
Gedächtnisstiftung, Darmstadt. We further thank Professor E.
Winterfeldt for his generous support of our research.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
3042
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200351345
Angew. Chem. Int. Ed. 2003, 42, 3042 – 3044

Angewandte
Chemie
Table 1: One-pot procedure for the synthesis of indoles from ortho-
chloro-substituted 1-phenyl-2-alkyl alkynes and primary amines.
R2
1) 5.0 mol % [Cp2TiMe2]
Entry
Alkyne
Product
Yield [%][a]
110°C, 24 h
Cl
R2
(1)
R1
+
N
2) 5.0 mol % [Pd2(dba)3]
10.0 mol % L, KOtBu
1,4-dioxane, 110°C, 12 h
R1
N
R3
R3 NH2
1
65[b]
Cl
1
R
3 = tBu, p-Tol,
Cl
+
11
L:
4-MeOC6H4,
rac-CH(Ph)Me
N
N
N
2
78
Cl
As can be seen from Table 1, methyl and benzyl ethers
2
3
(entries 2, 5–7, 10), CF3 groups (entry 8), and diphenylimine
groups (entries 9, 10) are functional groups that are tolerated
under the reaction conditions. However, from a synthetic
point of view the successful transformations of the imine-
functionalized alkynes 9 and 10 into the indoles 19 and 20 are
especially interesting because these products can be easily
converted into the 6-aminoindoles 21 and 22 under acidic
conditions [Eq. (2)].[6a]
OMe
12
N
3
4
5
77
39
70
Cl
13
N
Cl
R1
R1
4
14
HCl, THF
30 min, 25°C
N
N
N
H2N
(2)
BnO
Ph
Ph
N
BnO
R2
R2
Cl
5
19 R1 = cPr
21 R1 = cPr
15
R2 = Me
R2 = Me (86%)
MeO
MeO
MeO
F3C
20 R1 = nBu
22 R1 = nBu
R2 = OMe
R2 = OMe (85%)
N
6
7
65
81
Cl
6
16
The products 11, 12, 17, and 20 have potentially remov-
able protecting groups at the indole N atom. In addition, the
O groups located in the side chains of 15 and 17 offer various
possibilities for further synthetic transformations (e.g. cycli-
zation to the carbazole skeleton).
BnO
MeO
N
BnO
Cl
7
For completeness, we also synthesized some ortho-chloro-
substituted 1-phenyl-2-(aminoalkyl)alkynes 23–30 by Sono-
gashira couplings[8] and used them as substrates for the
described one-pot procedure [Eq. (3), Table 2]. During this
study, we recognized that the hydroamination reactions
employing 23 and 25–30 went to completion within 4–6 h
while the sterically demanding d-aminoalkyne 24 needed 48 h
to reach 100% conversion. However, after the second part of
the one-pot procedure (the Pd-catalyzed cyclization reaction)
only the piperidine derivatives 31–34 could be obtained easily
and in reasonable yields (53–77%, entries 1–4). Starting from
the related g-aminoalkynes 27–30, only 28 could be converted
into the corresponding indole 36 (53% yield). Clearly,
OMe
17
F3C
N
8
9
68
75
Cl
8
18
N
N
Ph
Ph
N
Cl
Cl
Ph
Ph
Ph 9
19
N
N
10
64
N
Ph
Ph
Ph
10
OMe
20
[a] Reaction conditions: 1) alkyne (2.0 mmol), amine (2.0 mmol),
[Cp2TiMe2] (0.48 molLÀ1 in toluene, 0.1 mmol, 5.0 mol%), 1108C,
24 h; 2) [Pd2(dba)3] (0.1 mmol, 5.0 mol%), 1,3-bis(2,4,6-trimethyl-
phenyl)imidazolium chloride (0.2 mmol, 10.0 mol%), KOtBu
(3.0 mmol), 1,4-dioxane, 1108C, 12 h. [b] 10.0 mol% [Cp2TiMe2] and
amine (3.0 mmol) were used.
Angew. Chem. Int. Ed. 2003, 42, 3042 – 3044
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3043

Communications
Table 2: One-pot procedure for the synthesis of indoles from ortho-
chloro-substituted 1-phenyl-2-(aminoalkyl)alkynes.
Experimental Section
A Schlenk tube equipped with a Teflon stopcock and a magnetic
stirring bar was charged with amine (2.0 mmol), alkyne (2.0 mmol),
and a solution of [Cp2TiMe2] (0.21mL, 0.48 m in toluene, 0.1mmol,
5.0 mol%). The mixture was heated under argon to 1108C for 24 h
(thin-layer chromatography (TLC) monitoring). After the resulting
brown liquid had cooled to room temperature, [Pd2(dba)3] (92 mg,
0.1mmol, 5.0 mol%), 1,3-bis(2,4,6-trimethylphenyl)imidazolium
chloride (68 mg, 0.2 mmol, 10.0 mol%), KOtBu (337 mg, 3.0 mmol),
and 1,4-dioxane (5.0 mL) were added. The mixture was heated to
1108C for further 12 h (TLC monitoring) and then filtered through
SiO2. After the SiO2 had been washed with CH2Cl2, the organic layer
was concentrated under vacuum. The residue was purified by flash
chromatography (SiO2).
Entry
1
Aminoalkyne
Product
Yield [%][a]
N
68
31
2
53[b]
N
Cl
NH2
24
32
MeO
F3C
MeO
F3C
N
Received: March 6, 2003 [Z51345]
3
4
5
6
7
8
75
77
Cl NH2
33
25
Keywords: alkynes · homogeneous catalysis · hydroamination ·
.
palladium · titanium
N
Cl
NH2
34
26
[1] For reviews, see: a) F. Pohlki, S. Doye, Chem. Soc. Rev. 2003, 32,
104 – 114; b) I. Bytschkov, S. Doye, Eur. J. Org. Chem. 2003, 935 –
946.
H2N
[c]
N
–
[2] a) E. Haak, I. Bytschkov, S. Doye, Eur. J. Org. Chem. 2002, 457 –
463; b) H. Siebeneicher, S. Doye, Eur. J. Org. Chem. 2002, 1 21 3 –
1220; c) I. Bytschkov, H. Siebeneicher, S. Doye, Eur. J. Org.
Chem. 2003, in press.
[3] For a summary of recently published methods for the synthesis of
indoles, see: a) T. L. Gilchrist, J. Chem. Soc. Perkin Trans. 1 2001,
2491– 2515; a new method for the synthesis of highly substituted
indoles was published recently. This publication includes further
references for the synthesis of indoles: b) J. L. Rutherford, M. P.
Rainka, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 15168 –
15169.
[4] a) N. A. Petasis in Encyclopedia of Reagents for Organic Syn-
thesis, Vol. 1 (Ed.: L. A. Paquette), Wiley, New York, 1995,
pp. 470 – 473; b) H. Siebeneicher, S. Doye, J. Prakt. Chem. 2000,
342, 102 – 106.
[5] For reviews, see: a) J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L.
Buchwald, Acc. Chem. Res. 1998, 31, 805 – 818; b) B. H. Yang,
S. L. Buchwald, J. Organomet. Chem. 1999, 576, 125 – 146;
c) A. R. Muci, S. L. Buchwald, Top. Curr. Chem. 2002, 219,
131 – 209; d) J. F. Hartwig, Synlett 1997, 329 – 340; e) J. F. Hartwig,
Angew. Chem. 1998, 110, 2154 – 2177; Angew. Chem. Int. Ed. 1998,
37, 2046 – 2067.
[6] The Pd-catalyzed N-arylation of benzophenone imine has been
described: a) J. P. Wolfe, J. Šhman, J. P. Sadighi, R. A. Singer,
S. L. Buchwald, Tetrahedron Lett. 1997, 38, 6367 – 6370; The Pd-
catalyzed N-arylation of N,N-disubstituted hydrazones has been
described by: b) M. Watanabe, T. Yamamoto, M. Nishiyama,
Angew. Chem. 2000, 112, 2620 – 2623; Angew. Chem. Int. Ed.
2000, 39, 2501– 2504.
[7] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975,
16, 4467 – 4470; b) K. Sonogashira in Comprehensive Organic
Synthesis, Vol. 3 (Eds.: B. M. Trost, I. A. Fleming), Pergamon,
Oxford, 1991, pp. 521– 549.
Cl
35
27
H2N
53
N
Cl
28
36
MeO
F3C
MeO
F3C
H2N
[c]
N
–
Cl
37
29
H2N
[c]
N
–
Cl
38
30
[a] Reaction conditions: 1) aminoalkyne (1.0 mmol), [Cp2TiMe2]
(0.48 molLÀ1 in toluene, 0.05 mmol, 5.0 mol%), 1108C, 4–6 h;
2) [Pd2(dba)3] (0.05 mmol, 5.0 mol%), 1,3-bis(2,4,6-trimethylphenyl)-
imidazolium chloride (0.1 mmol, 10.0 mol%), KOtBu (1.5 mmol), 1,4-
dioxane, 1108C, 12 h. [b] The reaction time of the hydroamination step
was 48 h. [c] After a successful hydroamination reaction, no cyclization
product could be isolated.
cyclization reactions that result in the formation of two
annulated five-membered rings are disfavored by the
increased ring-strain. However, the reasonable results
obtained with substrates 24 and 28 prove that our one-pot
procedure can also be applied successfully for the synthesis of
4-substituted indoles (32, 36).
In summary, we have shown that a clever combination of a
[Cp2TiMe2]-catalyzed hydroamination of alkynes with a Pd-
catalyzed N-arylation of imines results in a new and general
[8] a) M. R. GagnØ, C. L. Stern, T. J. Marks, J. Am. Chem. Soc. 1992,
114, 275 – 294; b) I. Bytschkov, S. Doye, Tetrahedron Lett. 2002,
43, 3715 – 3718; c) I. Bytschkov, PhD thesis, University of Hann-
over, 2002.
À
method for the synthesis of indoles, in which two new C N
bonds are formed during the one-pot procedure. Since the
starting materials employed are easily accessible from
1-chloro-2-iodobenzenes and terminal alkynes by Sonoga-
shira coupling reactions this procedure offers a great deal of
synthetic flexibility.
3044
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 3042 – 3044