Tetrahedron Letters 56 (2015) 89–94

Contents lists available at ScienceDirect

Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Novel synthesis of benzofuran- and indol-2-yl-methanamine

derivatives
Joachim Schlosser, Eugen Johannes, Melanie Zindler, Jan Lemmerhirt, Benjamin Sommer, Martin Schütt,
Christian Peifer ⇑
Institute of Pharmacy, University of Kiel, Gutenbergstr. 76, D-24118 Kiel, Germany

a r t i c l e i n f o a b s t r a c t

Article history: We report on a novel synthesis towards benzofuran-2-yl-methanamine and indol-2-yl-methanamine

Received 20 May 2014 derivatives by using ortho-methoxy and ortho-nitro substituted phenylacetic acids as starting material,
Revised 30 October 2014 respectively. For each compound series, a key intermediate bearing the oxazole-4-carboxylic acid meth-
Accepted 4 November 2014
ylester moiety was produced. Refluxing the ortho-methoxy series in HBr/HAc produced the desired ben-
Available online 13 November 2014
zofuran-2-yl-methanamines. Accordingly, for the synthesis of indoles the nitro-group was first reduced
and refluxing these intermediates in HCl gave the corresponding indol-2-yl-methanamines. The method
Keywords:
worked well with electron donating substituents. Limitations regarding electron withdrawing substitu-
Benzofuran-2-yl-methanamines
Indol-2-yl-methanamines
ents are discussed. This straightforward synthetic procedure can be a useful approach to generate a vari-
Phenyl acetic acid derivatives ety of substituted benzofuran-2-yl-methanamine and indol-2-yl-methanamine compounds by starting
Methyl-2-isocyanoacetate from readily available phenylacetic acid derivatives.
Oxazole-4-carboxylates Ó 2014 Elsevier Ltd. All rights reserved.

Benzofurane and indole scaffolds are present in a huge number
of chemical entities including compounds showing interesting bio-
logical activities, among them are compounds of natural origin.1–3
In line with this notion, chemical components or building blocks
bearing the benzofurane and indole moiety are of significant
importance in synthetic strategies leading to the desired
structures.
In the present Letter we report on the discovery of a novel
straightforward synthesis towards benzofuran-2-yl-methanam-
ines and indol-2-yl-methanamines, respectively. These products
were coincidentally obtained in our recent medicinal chemistry
project towards the preparation of (1H)-pyrazin-2-ones.4 Herein,
the original synthetic approach involved 1-amino-3-(aryl)propan-
2-ones (a-aminoketones, e.g., 1, Scheme 1 A) as key intermediates.
These a-aminoketones were typically produced from phenylacetic
acid derivatives (1a) by reaction with methyl-2-isocyanoacetate to
build their corresponding oxazole-4-carboxylic acid methylesters
1b.5 Subsequently, the acidic cleavage of the oxazole moiety
was used as a suitable method to avoid dimerization of the (non-
protonated) a-aminoketones.4 However, by refluxing methyl
5[(2-methoxyphenyl)methyl]oxazole-4-carboxylate 2b in HBr we
obtained benzofuran-2-yl-methanamine 2 in good yield and high
⇑ Corresponding author. Tel.: +49 431 880 1137; fax: +49 431 880 1352.
E-mail address: cpeifer@pharmazie.uni-kiel.de (C. Peifer).
purity instead of the expected 1-amino-3-(o-methoxyphenyl)
propan-2-one (Scheme 1 B).6 In line with this notion, comparable
procedures involving HBr via cleavage of ortho-methoxy groups
were employed for the synthesis of other benzofurane deriva-
tives.7–12
Consequently, the observation that 2 could be produced from
2a prompted us to also investigate the method for the synthesis
of some analogue indole derivatives. In fact, when o-nitrophenyl-
acetic acid 7a was employed as starting material, indol-2-yl-meth-
anamine 7 could be produced accordingly (upon reduction of the
nitro to the aniline moiety, Scheme 1C).13
A large variety of methods is available for the synthesis of ben-
zofurane- and indole derivatives in general (for recent reviews see
literature14,15). However, only a few methods have been reported
for the preparation of heteroaryl-2-yl-methanamines.3,16,17 While
most of the relevant publications regarding the preparation and
applications of heteroaryl-2-yl-methanamines (mostly for drug
discovery projects) can be found in patent literature from commer-
cial entities,18 some have been published by academic researchers.
For instance, Russo et al.16 developed a Sonogashira–Linstrumelle
reaction starting from 2-iodophenol leading to benzofuran-2-yl-
methanamines. Recently, a chemoenzymatic preparation of benzo-
furan-2-yl-ethanamines was published.3 Likewise, only a few
methods are available for the synthesis of indol-2-yl-methanam-
ines.16 However, these methods often involve drawbacks such as

http://dx.doi.org/10.1016/j.tetlet.2014.11.015
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
90 J. Schlosser et al. / Tetrahedron Letters 56 (2015) 89–94

(A)
O O Cl
–
O
I N II +
H3 N
HO

1a O O 1b 1

(B)
O
O N
I III
HO –
H3 C O Br O
O O O CH3 +
C H3 H3N
2a 2b 2

(C)
O O
O N
I IV N V
HO –
H3 C NO2 H3 C NH2 Cl + N
NO2 O O O O H
H3 N
7a 7b 7c 7

Scheme 1. (A) Synthesis of a-aminoketones as key intermediates in our recent project towards the synthesis of (1H)-pyrazin-2-ones; (B) preparation of benzofuran-2-yl-
methanamine by using o-methoxyphenylacetic acid as starting material; (C) preparation of indol-2-yl-methanamine by using o-nitrophenylacetic acid as starting material.
Reactants and conditions I: 1. CDI, 2. methyl-2-isocyanoacetate; II: HCl, reflux; III: HBr, reflux; IV: Pd/C, cyclohexene, microwave heating; V: HCl, reflux.

expensive amounts of catalysts, prolonged reaction times, tedious
work-up procedures or limited availability of starting material
with the desired decoration.
Regarding the present method, the formation of heteroaryl-
2-yl-methanamines from the oxazole moiety is discussed in
Scheme 2 exemplified by the synthesis of compound 2 starting
from 2b (the mechanism for building the oxazole moiety from
arylacetic acid 2a by reaction with methyl-2-isocyanoacetate has
been published elsewhere5). We propose that the reaction towards
the formation of benzofuran-2-yl-methanamine starts by acid
mediated degradation of the oxazole ring in 2b (Scheme 2). Ester
cleavage and subsequent decarboxylation produce the protonated
a-aminoketone. When HBr is used a cleavage of the methoxy-ether
occurs to form the free phenol-function. Subsequently, the
benzofurane ring in 2 is build by means of a Knoevenagel-reaction.
In line with this notion, when HCl was employed (instead of HBr)
the reaction produces 1-amino-3-(2-methoxyphenyl)propan-2-
one-HCl (17, Scheme 2). This indicates that the methoxy moiety
remains stable under these conditions. In turn, refluxing a-ami-
noketone 17 in HBr yielded the respective benzofuran-2-yl-meth-
anamine 2 hence providing further evidence for the proposed
reaction mechanism.
Thus, we became interested in the question if this procedure
could lead to a general synthetic method towards substituted
benzofuran-2-yl-methanamines and indol-2-yl-methanamines,
respectively. Therefore, in order to characterize this reaction in
more detail for each series, we investigated the application for a
set of substituted phenylacetic acids as starting material. Accord-
ingly, the method was successfully applied to the synthesis of
the benzofuran-2-yl-methanamines 2–6 and indol-2-yl-methan-

O O O
N
(I) + (II) +
H3 N H3 N
- HCOOH - CO2
2b O O - MeOH
O
O O 17
O O
(III)
- MeBr

+ H
+ O
H3 N H3 N +
H3 N
- H2O HO O
O
O
H
2
Scheme 2. Proposed reaction mechanism exemplified for the formation of benzofuran-2-yl-methanamine 2 starting from key intermediate methyl-5-[(2-methoxy-
phenyl)methyl]oxazole-4-carboxylate (compound 2b). Reactants and conditions I/II: reflux, HCl, MeOH; III: reflux, HBr, HAc. A comparable mechanism is discussed for the
formation of the indol-2-yl-methanamines, for example, 7 by using the corresponding methyl-5-[(2-aminophenyl)methyl]oxazole-4-carboxylate 7c and HCl, not shown).
 J. Schlosser et al. / Tetrahedron Letters 56 (2015) 89–94 91

Table 1
Synthesis of benzofuran-2-yl-methanamine derivatives by using substituted o-methoxyphenylacetic acids as starting material via oxazole intermediates

Starting material Oxazole Product Yielda (%)

O O Br –
N
HO H3N+
O O 90
CH 3 O O CH 3 O

2a 2b 2
H 3C H 3C –
O O Br C H3
–
H3 N+
Cl
O
O
O +
H3 N
HO 61
O
O O
CH 3 CH 3

3a 3b b 3
H 3C H 3C –
O O Br

O O H3 N+ OH
N
HO O 23
O
O O O CH 3
CH 3
4
3a 4b
Cl Cl –
Br
O O H3 N + Cl
N
HO 88
O
O O
O O CH 3
CH 3
5
5a 5b
CH 3 CH 3 –
Br

O O H3 N+ CH 3
N
HO O 60
O
O O O CH 3
CH 3
6
6b
6a
b
Compound 3b was synthesized from oxazole 4b by refluxing in HCl. Compound 3 was prepared by using BBr3 and workup with MeOH gave the final compound.
a
Yield is given for final step (cleavage of the oxazole).

amines 7–13 (Tables 1 and 2). The structure of compound 3 could
be determined by X-ray analysis (Fig. 1).
Interestingly, the nature of these substituents is not signifi-
cantly influencing the yield of the terminal benzofurane/indole
ring closure. In contrast to these efficient examples (Tables 1 and
2) the p-acetyl moiety in 14 was found to strongly prevent the gen-
eration of the benzofurane product. This can be explained by the
present phenyloge carbonic acid: following the concurrent cleav-
age of the oxazole and the methylether in this intermediate a
phenyloge carbonic acid is produced in which the tautomerization
is killing the nucleophilicity of the phenol moiety (Scheme 3). This
restriction of the method should be also true for further electron
withdrawing moieties such as nitro and cyano substituents. As a
consequence the ring closure towards the benzofurane is inhibited
demonstrating a limitation of this method regarding the substitu-
tion pattern of the aryl system. Interestingly, when compound 14
was reacted in HCl we obtained the a-aminoketone 16 (also see
Scheme 1). Again, by refluxing 16 in HBr no product was produced.
As the presented method requires o-nitro/methoxy-substituted
phenylacetic acids as starting material we also focused on the
availability and preparation of those compounds. The o-nitrophe-
nylacetic acids 7a, 8a and 12a and the o-methoxyphenylacetic
acids 2a, 3a and 5a are commercially available. The synthesis of
o-methoxy-phenylacetic acid 6a was performed in five steps start-
ing from 2-methoxy-5-methylbenzaldehyde which was treated
with KCN and Na2S2O5 to achieve the cyanohydrin.19 The chlorina-
tion20 of cyanohydrin by SOCl2 was followed by reduction with Zn
and AcOH to build the 2-methoxy-5-methylphenylacetonitril.21
92 J. Schlosser et al. / Tetrahedron Letters 56 (2015) 89–94

Table 2
Synthesis of indol-2-yl-methanamine derivatives by using substituted o-nitrophenylacetic acids as starting material via oxazole intermediates

Starting material Oxazole Product Yielda (%)

–
O O Cl
H3N+
N
HO
NO2 N H2 63
O O N
H
7a 7c
7
F F –
Cl
O O H3 N+ F
N
HO
N 98
NO2 N H2 H
O O

8a 8c 8
Cl Cl –
Cl
O O H3 N+ Cl
N
HO 33
N H2
N
NO2 O O H

9a 9c 9
Br Br –
Cl
O O
H3 N+ Br
N
HO 53
N H2 N
NO2 O O H

10a 10c 10
H 3C H 3C –
O O Cl CH 3
H3 N+ O
O O
N
HO N 99
H
NO2 N H2
O O
11a 11
11c
H3C H3C
O CH 3 Cl – CH 3
O H3C
O O H3 N+ O
O O
N N CH 3
O 97
HO H
NO2 N H2
O O
12a 12
12c
O –
O Cl
N
H3N+
HO
N H2
NO2 O O N 81
H

13a 13c
13
a
Yield is given for the final step (cleavage of the oxazole moiety). For clarity, the corresponding methyl-5-(2-nitrobenzyl)oxazole-4-carboxylates 7b–13b are not presented
in Table 2. Analytical data for all compounds can be found in SI.
 J. Schlosser et al. / Tetrahedron Letters 56 (2015) 89–94
Figure 1. Molecular structure of compound 3 determined by X-ray crystallography
showing the atom numbering scheme (CCDC number 1002571 via http://
www.ccdc.cam.ac.uk).
The preparation of 6a was then achieved by hydrolysing the ace-
tonitrile moiety under basic conditions.
The synthesis of o-nitro-phenylacetic acids 9a, 10a, 11a and 13a
was performed in two steps starting from the respective aromatic
nitro compound via formation of the o-nitrile by vicarious nucleo-
philic substitution (VNS) reported by Makosza et al.22,23 The prep-
aration of the desired phenylacetic acids was then achieved by
hydrolysis of the nitrile moiety under acidic conditions24 (for syn-
thetic and analytical details also see SI).
When using the chloro and bromo analogues of oxazole 8b as
starting material, these halogen atoms undergo hydrogenolysis
during the reduction of the nitro moiety using standard methods
hence yielding compound 7 (see step IV, Scheme 1; additional
methods used: Pd/C, cyclohexene, microwave; Pd/C, H2 1 bar,
MeOH, rt; FeCl3*6  H2O, Zn, HAc, DMF/H2O (1:1), reflux). How-
ever, an alternative reduction method converting the nitro moiety
in 9b and 10b into the amine function using sodium dithionite25 let
to the respective chloro (9c) and bromo (10c) derivatives.
In summary we report on a novel method for the synthesis of
benzofuran-2-yl-methanamines and indol-2-yl-methanamines,
respectively, by using readily available or accessible ortho-methoxy
O CH3
O HBr
N
14 O OH
O O CH3
HCl
O CH3
–
Cl
+ O
H3N
16
Scheme 3. Phenyloge carbonic ester moiety in compound 14. We assume that after HBr-mediated oxazole and methoxyether cleavage the tautomerization of the potentially
resulting phenyloge carbonic acid in 15 (not isolated) strongly reduces the nucleophilic attack of the phenol to the ketone moiety thus preventing a Knoevenagel ring closure
towards the benzofurane. In contrast, by using HCl as reagent a-aminoketone 16 was obtained from 14. However, refluxing 16 in HBr gave no product but a complex mixture
of black tar.
93
or ortho-nitro phenylacetic acids as starting material. The reaction
provides the products in high yield and proceeds without tedious
workup. The method may also be useful for the preparation of
further substituted benzofuran-2-yl-methanamines and indol-2-
yl-methanamines. Moreover, it may also be interesting for the syn-
thesis of benzothiophen-2-yl-methanamines and for corresponding
heteroaryl-2-yl-methanamine derivatives.
Acknowledgments
The authors thank Dr. Ulrich Girreser for excellent technical
assistance during synthesis and analytical characterization at the
Institute of Pharmacy, Kiel. The help of Dr. Dieter Schollmeyer,
Institute of Organic Chemistry, University of Mainz, Germany for
X-ray structure determination is gratefully acknowledged. We also
acknowledge financial support by DFG grant PE 1605/2-1.
Supplementary data
Supplementary data (supplementary data including relevant
preparation procedures, 1H/13C NMR, and MS for all compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.11.015.
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