Efficient synthesis of 3-(4,5-dihydro-1H-imidazole-2-yl)-1H-indoles

Article abstract of DOI:10.1016/S0040-4039(01)00960-1

A simple method for the synthesis of various 3-(4,5-dihydro-1H-imidazole-2-yl)-1H-indoles is described. Treatment of different substituted indoles with 1-acetyl-imidazolidin-2-one in the presence of phosphorus oxychloride afforded after hydrolysis in etha

Full text of DOI:10.1016/S0040-4039(01)00960-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5187–5189
Efficient synthesis of
3-(4,5-dihydro-1H-imidazole-2-yl)-1H-indoles
Ulrike Hary, Ulrike Roettig and Michael Paal*
Lilly Forschung GmbH, a Division of Eli Lilly Research Laboratories, Essener Straße 93, 22419 Hamburg, Germany
Received 31 May 2001; accepted 4 June 2001
Abstract—A simple method for the synthesis of various 3-(4,5-dihydro-1H-imidazole-2-yl)-1H-indoles is described. Treatment of
different substituted indoles with 1-acetyl-imidazolidin-2-one in the presence of phosphorus oxychloride afforded after hydrolysis
in ethanol the corresponding 3-(4,5-dihydro-1H-imidazole-2-yl)-1H-indoles in moderate to good yields. © 2001 Published by
Elsevier Science Ltd.
1. Introduction
Several methods for the formation of C-connected imi-
dazolines have been described in the literature, which
are mainly based on the reaction of compounds bearing
nitriles,4 esters5 or carboxylic acids6 with ethylenedi-
amine (or salts there of) under various conditions with
the corresponding imidazolines. However, the existing
methods for the synthesis of the desired 3-(4,5-dihydro-
1H-imidazole-2-yl)-1H-indoles with various sub-
stituents at the 2,4,5,6,7-position of the indole nucleus
were less satisfactory in terms of availability of starting
material, moderate yields, restricted generality and
harsh conditions. In order to design a versatile and
general approach, knowing that 1-acetyl-imidazolidin-
2-one is a useful reagent for the direct formation of
N-connected imidazolines by reaction with amines in
the presence of POCl3,7 we chose to use this method for
the synthesis of C-connected 3-(4,5-dihydro-1H-
imidazole-2-yl)-1H-indoles.
Over recent years a number of imidazoline containing
compounds have been identified that stimulate and
regulate insulin secretion in a glucose dependent man-
ner.1 However, despite their promise, no imidazoline
compound has yet come into clinical use as an effective
agent in treatment of type II diabetes due to several
side effects.
Our continuing interest in the search for new insulin
secretagogues with the desired profile led us to describe
the new imidazoline containing insulin secretagogue
5-chloro-2-methyl-3-(4,5-dihydro-1H-imidazole-2-yl)-
1H-indole 1.2 This compound belongs to a series of
various C-connected 3-(4,5-dihydro-1H-imidazole-
2-yl)-1H-indoles, which we have recently synthe-
sized.3
Table 1. Formation of 2-methyl-3-(4,5-dihydro-1H-imidazole-2-yl)-1H-indoles
Entry
Starting indole
R1
R2
Product
Yield (%)a
1
2
3
4
5
6
1a
2a
3a
4a
5a
6a
5-Cl
5-CF3
5-Br
5-CH3
5-OMe
H
CH3
CH3
CH3
CH3
CH3
CH3
1
2
3
4
5
6
62
52
80
51
64
44
a Yields are not optimized.
Keywords: 3-(4,5-dihydro-1H-imidazole-2-yl)-1H-indoles; insulin secretagogues.
* Corresponding author. Fax: +49-4052724-601; e-mail: paal michael@lilly.com
–
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00960-1

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U. Hary et al. / Tetrahedron Letters 42 (2001) 5187–5189
2. Chemistry
methyl-1H-indole and was separated from this mixture
by chromatography. Interestingly, the 2-unsubstituted
indole 10a gave according to the general procedure9 a
complex mixture of products and the desired product
could not be detected. In this case more work is needed
to optimize the reaction conditions in terms of tempera-
ture, dehydrating agent and using a different imida-
zolin-2-one derivative.
The preparation of the 3-(4,5-dihydro-1H-imidazole-2-
yl)-indoles 1–16 (Tables 1 and 2) starting from the
corresponding indoles with various substituents in dif-
ferent positions at the indole nucleus was carried out
following the general route shown in Scheme 1.
For the first series of compounds we chose to use
readily commercially available or synthesizable (via Fis-
cher indole synthesis8) 2-methyl-1H-indoles with differ-
ent substituents at the 5-position. Treatment of those
indoles with commercially available 1-acetyl-imidazo-
lidin-2-one in the presence of phosphorus oxychloride9
gave in moderate to good yields the desired products
(Table 1).
The starting indole 15a (entry 15) was prepared in two
steps (Scheme 2). The 5-chloro-1H-indole was treated
with diphenyl disulfide as described in the general pro-
cedure by Atkinson et al.10 and the resulting 5-chloro-3-
phenylthio-1H-indole was isomerized in polyphos-
phoric acid into the corresponding 5-chloro-2-phenyl-
thio-1H-indole as described by Hamel et al.11 for the
synthesis of 2-phenylthio-1H-indole in 67% yield.
To further extend the scope of this method we focused
on the synthesis of 3-(4,5-dihydro-1H-imidazole-2-yl)-
1H-indoles with different substitution at the indole
nucleus (Table 2).
Starting indole 16a was prepared in a similar fashion.
N-Benzylation of 5-chloro-1H-indole as described by
Santaniello et al. for the parent indole,12 followed by
thermal isomerization in polyphosphoric acid led to
2-benzyl-5-chloro-1H-indole as described for 2-benzyl-
1H-indole by Wiedenau et al.13 in 60% yield (Scheme
3).14
Starting indoles 7a–14a were made according to the
Fischer indol synthesis.8 It has to be noticed that the
6-chloro-2-methyl-1H-indole (entry 8) was obtained in
a 1:1 mixture with the corresponding 4-chloro-2-
Table 2. Formation of 3-(4,5-dihydro-1H-imidazole-2-yl)-1H-indoles
Entry
Starting indole
R1
R2
Product
Yield(%)a
7
8
9
10
11
12
13
14
15
16
7a
8a
9a
10a
11a
12a
13a
14a
15a
16a
4-Cl
6-Cl
7-Br
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
CH3
CH3
CH3
H
7
8
9
56
60
48
0
67
59
62
67
63
61
Et
11
12
13
14
15
16
Cyclohexyl
Phenyl
4-Me-Phenyl
Phenylthio
Benzyl
a Yields are not optimized.
Scheme 1.
Scheme 2.

U. Hary et al. / Tetrahedron Letters 42 (2001) 5187–5189
5189
Scheme 3.
3. Conclusion
5. Sperber, N.; Fricano, R. J. Am. Chem. Soc. 1953, 75,
2986–2988.
In summary we described a new method for the forma-
tion of at the indole nucleus substituted 3-(4,5-dihydro-
1H-imidazole-2-yl)-1H-indoles starting from various
1H-indoles in a one-pot reaction. This approach pro-
vides significant advantages over the existing methods
in terms of yields, reaction conditions and effectiveness,
especially if the target molecule is substituted in the 4-,
5-, 6- or 7-position.
6. Kuzmerkiewicz, W.; Saczewski, F.; Foks, H. Arch.
Pharm. 1986, 319, 830–834.
7. Chapleo, C. B.; Butler, C. M.; England, D. C.; Myers, P.
L.; Roach, A. G.; Smith, C. F. C.; Stillings, M. R.;
Tulloch, I. F. J. Med. Chem. 1989, 32, 1627–1630.
8. (a) Fischer, E.; Schmitt, T. Chem. Ber. 1888, 21, 1071 and
1811; (b) Hamel, P.; Zajac, N.; Atkinson, J. G.; Girard,
Y. J. Org. Chem. 1994, 59, 6372–6377 and references
cited therein.
9. General procedure for the synthesis of 3-(4,5-dihydro-
1H-imidazole-2-yl)-1H-indoles:
Acknowledgements
A mixture of indole (10 mmol) and 1-acetyl-imidazo-
lidine-2-one (11 mmol) was added to phosphorus oxy-
chloride (8 ml) and heated to 50°C. After 3–5 h,
phosphorus oxychloride was evaporated. The residue was
treated with ethanol (10 ml) cautiously and maintained at
reflux for 2–3 h. The mixture was concentrated under
reduced pressure to half of the volume to obtain a
precipitate, which was collected by filtration. The crys-
talline residue was treated with water, washed with ethyl
acetate and dried in vacuo.
The authors would like to thank Dr. Andreas Weichert
and Dr. Chuan Shih for helpful discussions.
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