Efficient and simple zinc-mediated synthesis of 3-amidoindoles

Article abstract of DOI:10.1039/c1ob05576c

A general synthesis of 3-amidoindoles from easily available arylhydrazines and acylated propargylamines is described. In the presence of inexpensive Zn salts, alkyne amination and subsequent Fischer indole-cyclization took place in good yields with excell

Full text of DOI:10.1039/c1ob05576c

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Efficient and simple zinc-mediated synthesis of 3-amidoindoles†
Anahit Pews-Davtyan and Matthias Beller*
Received 12th April 2011, Accepted 20th June 2011
DOI: 10.1039/c1ob05576c
A general synthesis of 3-amidoindoles from easily available arylhydrazines and acylated
propargylamines is described. In the presence of inexpensive Zn salts, alkyne amination and subsequent
Fischer indole-cyclization took place in good yields with excellent regioselectivity providing an
interesting scaffold for potentially bio-active compounds.
The indole ring is a privileged structural motif present in a
variety of natural and synthetic therapeutic products.1,2 Among
the various indole derivatives 3-amino- and 3-amido-substituted
indoles have been scarcely investigated, except of d-carbolines and
their derivatives,3 which show a wide range of biological activities
(Fig. 1).4
marked in Fig. 1. To the best of our knowledge such compounds
have not been synthesized before. Except for our recent work,14 3-
amidoindoles have been prepared via multistep processes,15 which
often include protection and deprotection steps of the indole
nitrogen. Clearly, such syntheses possess several drawbacks and
a more general and concise synthesis of 3-amidoindole derivatives
would be a valuable tool for the further exploration of their
chemistry and biology.
In 2008, we developed a simple and general zinc-mediated
intermolecular hydroamination reaction of alkynes with phenylhy-
drazines (hydrohydrazination) to give 2,3-disubstituted indoles.16
The concept of this domino alkyne-amination-Fischer-indole-
sequence was first demonstrated by Bergman et al. on a stoichio-
metric basis17 and further improved by Odom and co-workers us-
ing titanium-based catalysts.18,19 Unfortunately, both the titanium-
mediated and -catalyzed reactions showed only limited functional
group tolerance and did not allow for the preparation of free
indoles.
On the other hand, we have recently shown that the zinc-
promoted intermolecular hydroamination of alkynes with arylhy-
drazines has a broad substrate scope. Hence, protected propargyl
alcohols and amines as well as other sensitive alkynes can be used
as substrates.16a,b,20,21
Fig. 1 d-Carbolines, marine alkaloids hymenialdisine and latonduines A
and B.
Furthermore, synthetic derivatives of 3-aminoindoles are
known to be valuable kinase inhibitors and are useful for
treating hyperproliferative disorders, diseases associated with
angiogenesis,5 inflammation and neurodegeneration,6 depressive
disorders, and anxiety.
Other biologically and synthetically interesting marine sponge
alkaloids are hymenialdisine,7 and recently isolated latonduines8
A and B (Fig. 1). Hymenialdisine derivatives are known to inhibit
various protein kinases,9 whereas latonduine related molecules
are useful for treatment of cystic fibrosis.10 Notably, also indole-
based natural11 and synthetic12 analogues bearing the highlighted
structural motives (Fig. 1) as well as related sulfur and oxygen
heterocycles show significant biological activity.12c,13
Advantageously, our protocol can be performed on air and
all starting materials are commercially available or can be easily
prepared by one step multigramm synthesis. For the performance
of domino sequence it was proved that ZnCl2 and ZnBr2 are the
best Zn-sources using aprotic solvents at 110 ◦C.
For the further exploration of our methodology, initially
we choose commercially available unprotected electron-rich and
electron-poor phenylhydrazines along with protected phenylhy-
drazines 1a–i to investigate their impact on the reaction outcome
(Fig. 2).
The applied propargylamides 2a–l (except 2c, which is
commercially available) were synthesized straightforward from
the propargyl amine and the corresponding acyl chloride
(Fig. 3).22
In agreement with previous investigations the hydroamination
reaction of the alkyne proceeds with excellent Markovnikov selec-
tivity (>99%) to give 2,3-disubstituted indoles in good yields.23
Based on our continuing interest in novel syntheses of biologi-
cally active indoles, we had the idea to prepare potentially bioactive
3-amidoindoles bearing biogenic heterocyclic amide fragments,
Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Albert-
Einstein-Str., 29a, D-18059, Rostock, Germany. E-mail: matthias.beller@
catalysis.de; Fax: +49 381 1281 51113; Tel: +49 381 1281 113
† Electronic supplementary information (ESI) available: Procedures and
characterisation data for all new compounds, scans of NMR spectra. See
DOI: 10.1039/c1ob05576c
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Table 1 Hydrohydrazination of acylated propargylamines with different
phenylhydrazines to 3-amidoindolesa
Entry
1
Product (yieldb, %)
Entry
2
Product (yieldb, %)
Fig. 2 Used phenylhydrazines.
3 (91)14
5 (71)c
7 (94)14
9 (46)d
4 (89)14
6 (60)c,d
8 (48)c
3
5
7
9
4
6
8
10 (88)
10
Fig. 3 Used propargylamides.
We have already shown excellent yields and high selectivity in
the synthesis of compounds 3, 4 and 7 (Table 1, entries 1, 2 and
5). Further experiments demonstrated that other activated (Fig. 1,
compounds 1d and 1f) and deactivated (Fig. 1, compounds 1c
and 1i) phenylhydrazines or protected ones (Fig. 1, compounds
1g and 1h) gave the desired products in moderate to good yields
(Table 1, entries 6 and 7). Obviously substituents with a stronger
positive inductive effect at the indole nitrogen or aromatic ring are
not favourable for the construction of the 3-aminoindole moiety.
Apparently, such substrates are activated for the electrophilic
attack at different positions resulting in unwanted side reactions.
Interestingly, hydrohydrazination of N-propargylphthalimide (2c)
let not only to the expected minor anti-Markovnikov and main
Markovnikov products, but also to its structural isomer in minor
amounts (Table 1, entry 10).
11 (61)c
12 (83)d,e,f
11
12
13 (60)g
14 (64)g
a Reaction conditions: Alkyne 1 mmol, arylhydrazine 1.5 eq., ZnBr2 3 eq.,
solvent: DME 5 mL, 110 ◦C, 20–22 h, conventional heating in pressure
tube. b Yield of isolated product. c ZnCl2 was used. d Toluene was used.
e Zn–salt 5 eq. f Mixture of isomers (55% isolated product 12 along with
the 28% of unseparatble mixture of two other isomers). g Microwave
irradiation, 110 ◦C, 1 h.
Next, phenylhydrazines 1a, 1b and 1e were used for the hydro-
hydrazination of more challenging heterocyclic propargylamides
(Table 2). However, the previously optimized reaction conditions
were not easily transferable to these more demanding substrates
(Fig. 2, compounds 2f–2l). Using three equivalents of Lewis
acid gave detrimental results for nitrogen heterocycles because of
decomposition of the heterocycle. To our delight, decreasing the
catalyst amount ensured good yields with both electron-rich and
electron-poor phenylhydrazines (Table 2). Additionally, switching
from conventional heating to microwave irradiation, allowed us to
decrease the reaction time with improved selectivities.
Nitrogen- as well as sulfur- and oxygen-containing heterocycles
did not show significant differences in their reactivity towards
phenylhydrazines. Notably, at lower temperature than 100 ◦C
along with indole significant amounts of oxazole were formed by
a competetive Zn-catalyzed cyclization of the alkynes. At elevated
temperature indolization reaction is faster and only minor
amounts of corresponding oxazoline (or oxazole) were detected
by GC-MS. Further experiments showed that known cyclizations
of propargylamides22b to oxazolines (main product) and oxazoles
(minor product) are simply catalyzed by zinc triflate without any
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Table 2 Scope of hydrohydrazination of heterocyclic propargylamides
Table 2 (Contd.)
with different phenylhydrazinesa
Entry
13
Product (yieldb,%)
Entry
14
Product (yieldb,%)
Entry
1
Product (yieldb,%)
Entry
2
Product (yieldb,%)
27 (54)c,d
28 (61)
15 (59)
16 (60)
3
4
a Reaction conditions: Alkyne 1 mmol, arylhydrazine 1.5 eq., ZnBr2 2 eq.,
solvent: DME 2 mL, 120 ◦C, 1 h, microwave irradiation. b Yield of isolated
product. c ZnBr2 1 eq. d 130 ◦C. [e] 110 ◦C. e 100 ◦C.
noble metal catalysts at ambient temperature in good to
excellent yields.
17 (59)
18 (66)c,d
It is important to note that all new compounds are crystalline,
stable materials, which make their storage, handling, and further
transformations easy. In solution, the N-acylated 3-aminoindoles
exist as mixture of rotamers. In polar aprotic solvents, like DMSO
or acetone rotation is very fast and only minor signals of the
second rotamer in NMR were detectable (see ESI†).
5
6
In conclusion, we have developed a general, effective and one-
step approach to the synthesis of biogenic 3-amidoindoles. The
Zn-mediated synthesis starts from commercially available phenyl-
hydrazines and acylated propargylamines without the necessity of
indole protection. Advantageously, no expensive catalysts need
to be used and broad functional group tolerance is achieved.
Biological tests of new products are ongoing.
19 (46)c,e
20 (63)c,d
7
8
Acknowledgements
21 (51)
22 (58)c,e
This work has been supported by the BMBF (Bundesministerium
fu¨r Bildung und Forschung) and the Deutsche Forschungs-
gemeinschaft (Leibniz–price; GRK 1113). We also thank our
analytical department for their excellent support, Dr D. Michalik
and Dr M. Gruit for providing substrates 2h and 2i, 2j, and
S. Werkmeister, K. Volpert and J. Schranck for their support
during the synthesis of heterocyclic propargylamides and products
13–15.
9
10
23 (54)
24 (52)c,d
11
12
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6334 | Org. Biomol. Chem., 2011, 9, 6331–6334
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©