A general and mild domino approach to substituted 1-aminoindoles

Article abstract of DOI:10.1039/c0cc03584j

A versatile and efficient palladium catalyzed domino reaction leading to a broad range of substituted 1-aminoindoles has been developed. The title compounds were prepared from 2-halo-phenylacetylenes and simple hydrazines in good to excellent yields in ju

Full text of DOI:10.1039/c0cc03584j

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A general and mild domino approach to substituted 1-aminoindolesw
´
Nis Halland,* Marc Nazare, Jorge Alonso, Omar R’kyek and Andreas Lindenschmidt*
Received 31st August 2010, Accepted 25th October 2010
DOI: 10.1039/c0cc03584j
A versatile and efficient palladium catalyzed domino reaction
leading to a broad range of substituted 1-aminoindoles has been
developed. The title compounds were prepared from 2-halo-
phenylacetylenes and simple hydrazines in good to excellent
yields in just a few hours under mild conditions.
Scheme 1 Proposed 1-aminoindole formation.
conversion and identical yields were obtained as with 5 mol%
catalyst although the reaction time was slightly prolonged.10
It should be noted that dried glassware was not employed
and as both catalyst precursors are airstable no special
handling precautions such as e.g. a glovebox or special
glassware are required.11 We then submitted several
substituted (2-halophenyl)-acetylenes 1 to the reaction with
N-Boc-N-phenylhydrazine 2a and from Table 1 it is clear that
both electron-donating and withdrawing substituents are
tolerated in the reaction providing 1-aminoindoles 3b–d
in excellent yields (entries 3–5). Furthermore, a pyridyl
The indole nucleus is without doubt a privileged structure in
medicinal chemistry and also very abundant in nature.1
Therefore, for more than a century organic chemists have
devoted their attention and synthetic efforts to the
development of novel approaches to this important scaffold.2
Although numerous indole syntheses have been described over
the years, a convenient access to 1-aminoindoles still needs to
be developed as very few syntheses have been reported.
Unsubstituted 1-aminoindoles have traditionally been
prepared using diazonium salts,3 hydroxylamines4 or
monochloramine5 usually under highly basic conditions,
whereas N-substituted 1-aminoindoles have only been
prepared by electrolysis6 or Pd catalyzed cyclization of N,N-
disubstituted o-chloroacetaldehyde hydrazones.7 Thus, to date
no direct, versatile and practical synthesis of substituted
1-aminoindoles from readily available precursors has been
developed preventing their potential use in e.g. the life sciences.
Here we report a straightforward one-pot domino reaction for
the synthesis of a wide variety of substituted 1-aminoindoles 3 from
readily available 2-halo-phenylacetylenes 1 and N,N-disubstituted
hydrazines 2 according to Scheme 1. The reaction was envisioned
to proceed through an initial palladium catalyzed coupling
between the 2-halo-phenylacetylene 1 and N,N-disubstituted
Table 1 Formation of N-Boc-N-phenyl-1-aminoindoles 3a–fa
Isolated
yieldb (%)
Entry
1
R1
H
Product
3a
86
2
3
87d
92
hydrazine
2 4
forming N0-aryl-N,N-disubstituted hydrazine
followed by an in situ 5-endo-dig cyclization to the desired N,N-
disubstituted-1-aminoindole 3. Having previously reported a
practical one-pot domino reaction for the synthesis of 2H-
6-F
3b
3c
3d
3e
3f
indazoles this presented
a good starting point for the
development of
a
1-aminoindole synthesis.8 We initially
4
5
6
5-CF3
6-MeO
5-N
90
99
89
87c
submitted N-Boc-N-phenylhydrazine 2a and 1-chloro-2-phenyl-
ethynylbenzene 1a to the PdCl2–tBu3P catalyst system employed
previously using Cs2CO3 as the base and DMF as the solvent and
to our delight we observed that the N-Boc-N-phenyl-1-
aminoindole 3a was formed in good yield in only a couple of
hours at 110 1C (Table 1, entry 1).9 Attempts to reduce catalyst
loading were only partly successful as only trace amounts of
aminoindole 3a were formed when 1 mol% catalyst was employed.
On the other hand, using 2.5 mol% catalyst gave complete
7
H
Sanofi-Aventis Deutschland GmbH, Industriepark Hochst Building
¨
a
All reactions were performed with 1 (0.5 mmol), 2a (1.4 equiv.), Pd
catalyst (5 mol%) and Cs2CO3 (1.4 equiv.) in DMF at 110 1C for
3–6 h. Yield of isolated product after flash chromatography on
G875, D-65926 Frankfurt am Main, Germany.
E-mail: nis.halland@sanofi-aventis.com; Fax: +49 69305 21618;
Tel: +49 69305 36193
w Electronic supplementary information (ESI) available: For
experimental procedures and spectroscopic data of all compounds.
See DOI: 10.1039/c0cc03584j
b
c
silica gel. Performed using N-phenyl-hydrazinecarboxylic acid ethyl
d
ester 2b. Performed using 1-bromo-2-phenyl-ethynylbenzene 1b.
c
1042 Chem. Commun., 2011, 47, 1042–1044
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substituted acetylene was employed in the reaction and found
to provide the corresponding 5-aza-1-aminoindole 3e in 89%
yield (entry 6).
desired 2-cyclopropyl, 2-pentyl and 2-tert-butyl substituted
1-aminoindoles 3j–l in excellent yields, although a significantly
longer reaction time was required for the very sterically
hindered 2-tert-butyl substituted 1-aminoindole 3l (entries
4–6). Also more functionalized acetylenes readily participated
in the reaction and e.g. a tert-butoxy-methylene, diethylamine-
methylene or tert-butyl ester substituted acetylene were found to
provide the corresponding 1-aminoindole 3m–o in reasonable
yields (entries 7–9). Having primarily used simple hydrazides
2a,b as coupling partners, we decided to further expand the
scope of the reaction by submitting a number of commercially
available hydrazines to the reaction with 1-halo-2-phenyl-
ethynylbenzenes 1. Thus, we found that when employing electron-
rich hydrazines such as N-methyl-N-phenyl-hydrazine 2c the
N-Phenyl-hydrazinecarboxylic acid ethyl ester 2b was also
employed in the reaction and was found to afford aminoindole
3f in similar yields as the Boc carbamate 2a afforded
aminoindole 3a (entries 1 and 7). We then turned our
attention to 1-chloro-2-ethynylbenzenes 1 having different
acetylene substituents and as expected arenes with
electronwithdrawing or donating groups as well as
a
2-pyridyl substituent provided the corresponding N-Boc-N-
phenyl-1-aminoindoles 3g–i in excellent 80% to 96% yield
(Table 2, entries 1–3). More surprising was the finding that
also alkyl substituted alkynes reacted well and formed the
Table 3 Formation of various 2-phenyl-1-aminoindoles 3p–wa
Table 2 Formation of N-Boc-N-phenyl-1-aminoindoles 3g–oa
Isolated
yieldb (%)
Isolated
yieldb (%)
Entry R1
Product
Entry
1
Hydrazine 2
X
Product
Cl
3p
3q
90
1
6-MeO-2-naphtyl
3g
96
2
3
Cl
Cl
96
81
2
3
4
5
6
7
8
4-CF3-Ph
2-pyridyl
CH(CH2)2
(CH2)4CH3
t-Bu
3h
3i
86
80
3r
3s
3j
87c
72d
82e
4
5
Cl
Br
87
74
3k
3l
3t
6
7
Br
Br
3u
3v
80c,d
CH2Ot-Bu
CO2t-Bu
CH2NEt2
3m 61
3n
3o
65
68
92
9
8
Br
3w
82c
a
All reactions were performed with 1 (0.5 mmol), 2a or 2b (1.4 equiv.),
Pd catalyst (5 mol%) and Cs2CO3 (1.4 equiv.) in DMF at 110 1C
for 3 h. Yield of isolated product after flash chromatography on
b
a
All reactions were performed with 1 (0.5 mmol), 2 (1.4 equiv.), Pd
catalyst (5 mol%) and Cs2CO3 (1.4 equiv.) in DMF at 110 1C for
3 h. Yield of isolated product after flash chromatography on
c
silica gel. Performed using 3-chloro-4-cyclopropylethynyl-benzoic
d
acid tert-butyl ester 1c. Performed using 1-bromo-2-hept-1-ynyl-
b
e
benzene. Reaction time 20 h.
c
silica gel. Reaction time 20 h. 2.4 equiv. Cs2CO3 was employed.
d
c
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desired N-methyl-N-phenyl-1-aminoindoles 3p,q were
obtained in almost quantitative yield (Table 3, entries 1 and 2).
Also N-amine heterocycles such as N-aminopiperidine, N-
aminomorpholine or 4-methyl-N-aminopiperazine provided
the corresponding piperidine, morpholine or 4-methyl-
piperazine substituted indoles 3r–t in 74–87% isolated yield
(entries 3–5). Hydrochloride salts also reacted well in the
reaction and N-aminopyrrolidone hydrochloride salt
afforded the pyrrolidone substituted indole 3u in 80% yield
when 2.4 equiv. base was employed (entry 6). Finally, the
heteroaromatic N-amines N-aminopyrrole and N-aminoindole
also provided good yields of the corresponding N-pyrrole and
N-indole substituted 2-phenylindoles 3v,w (entries 7 and 8).
In summary, we have developed a novel palladium catalysed
domino synthesis of substituted 1-aminoindoles from readily
available 2-halophenylacetylenes and N,N-disubstituted
hydrazines. The reaction affords the desired aminoindoles in
good to excellent yields in just a few hours and under mild
reaction conditions with high functional group tolerance. This
versatile reaction represents a previously unreported approach
to substituted 1-aminoindoles and thus closes a gap in current
synthetic methodology.
2 (a) G. R. Humprey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875,
for some recent approaches see: (b) J. L. Rutherford, M. P. Rainka
and S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 15168;
(c) H. Siebeneicher, I. Bytschkov and S. Doye, Angew. Chem.,
Int. Ed., 2003, 42, 3042; (d) L. Ackermann, Org. Lett., 2005, 7, 439;
(e) T. Konno, J. Chae, T. Ishihara and H. Yamanaka, J. Org.
Chem., 2004, 69, 8258.
3 (a) M. Satomura, J. Org. Chem., 1993, 58, 3757; (b) S. Khound and
P. J. Das, Tetrahedron, 1997, 53, 9749.
4 See e.g. (a) J. T. Klein, et al., J. Med. Chem., 1996,
39, 570; (b) T. B. Lee and K. E. Goehring, US pat., 5459274,
1995.
5 J. Hynes, Jr., W. D. Doubleday, A. J. Dyckman, J. D. Godfrey,
zJr., J. A. Grosso, S. Kiau and K. Leftheris, J. Org. Chem., 2004,
69, 1368.
6 B. A. Fontana-Uribe, C. Moinet and L. Toupet, Eur. J. Org.
Chem., 1999, 419.
7 M. Watanabe, T. Yamamoto and M. Nishiyama, Angew. Chem.,
Int. Ed., 2000, 39, 2501.
8 N. Halland, M. Nazare, O. R’kyek, J. Alonso, M. Urmann and
´
A. Lindenschmidt, Angew. Chem., Int. Ed., 2009, 48, 6879.
9 Part of this work has been disclosed in WO 2008/125207.
10 When employing 2.5 mol% catalyst in the reaction of 1-chloro-2-
phenyl-ethynylbenzene 1a with Boc carbamate 2a full conversion
was observed after 4 h compared to 3 h when using 5 mol%
catalyst.
11 General experimental procedure: To
a screw-cap test tube
were added PdCl2 (5 mol%), tBu3PHBF4 (10 mol%), Cs2CO3
(1.4 equiv.), a magnetic stirring bar and commercially available
anhydrous DMF (2.5 mL) and the mixture was stirred under argon
at ambient temperature for 15 min. Then the 2-
This work was supported by the European community
through a Marie Curie Host fellowship for the transfer of
knowledge (HCTMCR).
chlorophenylacetylene
1 (0.5 mmol) and the hydrazine (1.4
equiv.) were added and the mixture was heated to 110 1C for 3 h.
After cooling, the reaction mixture was diluted with NaHCO3 (aq,
sat) and extracted with EtOAc (ꢀ2) and the organic phase dried
over Na2SO4 and evaporated. The crude product was purified by
FC on silica gel using EtOAc/heptane as the eluent.
Notes and references
1 (a) J. A. Joule, in Science of Synthesis, Georg Thieme, Stuttgart,
´
2000, vol. 10, pp. 361; (b) F. R. de Sa Alves, E. J. Barreiro and C. A.
M. Fraga, Mini-Rev. Med. Chem., 2009, 9, 782.
c
1044 Chem. Commun., 2011, 47, 1042–1044
This journal is The Royal Society of Chemistry 2011