New use of bis(benzotriazolyl)-1,2-(dialkylamino)ethanes for the synthesis of 2-H-3-dialkylamino imidazo[1,2-a]pyrazine derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.12.077

First direct synthesis of 2-H-3-N-dialkyl-imidazo[1,2-a]pyrazines is described. This approach makes use of accessible substituted pyrazines and the assistance of benzotriazole. In such a manner we accomplished the introduction of cyclic amines at C-3 of the scaffold in a convenient formal cyclisation procedure. Detailed examples and utility of this approach are presented herein.

Full text of DOI:10.1016/j.tetlet.2011.12.077

Tetrahedron Letters 53 (2012) 1082–1084
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Tetrahedron Letters
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New use of bis(benzotriazolyl)-1,2-(dialkylamino)ethanes for the synthesis
of 2-H-3-dialkylamino imidazo[1,2-a]pyrazine derivatives
⇑
Joaquín Pastor , Sonsoles Rodríguez-Arístegui, Ana Isabel Hernández, Carmen Varela, Antonio Salgado,
Sonia Martínez
Medicinal Chemistry Department, Experimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, Madrid E-28029, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
First direct synthesis of 2-H-3-N-dialkyl-imidazo[1,2-a]pyrazines is described. This approach makes use
of accessible substituted pyrazines and the assistance of benzotriazole. In such a manner we accom-
plished the introduction of cyclic amines at C-3 of the scaffold in a convenient formal cyclisation proce-
dure. Detailed examples and utility of this approach are presented herein.
Received 22 November 2011
Revised 14 December 2011
Accepted 19 December 2011
Available online 30 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2-H-3-N-Dialkyl-imidazo[1,2-a]pyrazines
synthesis
One pot cyclisation
Benzotriazole
Imidazo[1,2-a]pyrazines are molecules with interesting biolog-
O
N
ical activities. More specifically they have been reported for the
treatment of degenerative, inflammatory,1 type
2 diabetes
diseases,2 as well as antiulcer3 and anticancer agents.4
8
N
6-Aryl/heteroaryl-8-morpholinyl-imidazo[1,2-a]pyrazines rep-
resent one of the most potent and drug-like chemical series of
PI3K (phosphatidylinositol 3-kinases) inhibitors within our drug
discovery project of new anticancer compounds.5 In order to ex-
plore the SAR (structure–activity relationship) around the central
imidazo[1,2-a]pyrazine core, we were very interested in the partic-
ular substitution of C-3 with secondary amines, 1. However, we
were limited by the poor reactivity of this position towards Buch-
wald type coupling of amines (Fig. 1).6 Thus, the initial attempts to
functionalise 3-Cl/Br/I-imidazo[1,2-a]pyrazines with piperidine
using different catalysts (Pd2(dba)3 or PdCl2(dppf)) and ligands
(XanPhos, DavePhos or BINAP), yielded unreacted starting material
together with the de-halogenated imidazo[1,2-a]pyrazine, and
only traces of the desired compound.
Although this type of heterocycles have significance in drug dis-
covery, there are few reported synthetic methods that enable the
preparation of 2-H-imidazo[1,2-a]pyrazine bearing amine substi-
tution at C-3. The literature describes mainly a variation of the
Ugi reaction involving three-component coupling (3-CC) with
isonitriles, aldehydes and the prerequisite 2-aminopyrazines,
2-aminopyrimidines or 2-aminopyridines.7 Further developments
of this procedure include microwave assisted protocols or polymer
N
2
N
3
Ar
6
5
N
1
Figure 1. 6-Aryl/heteroaryl-8-morpholinyl-imidazo[1,2-a]pyrazines.
supported chemistry applications.8,9 Among these reported meth-
odologies, only a few examples were found that leave the 2-
position unsubstituted. One method reported the nitration and
subsequent zinc/acetic acid reduction of the nitro intermediate at
C-3. Further reaction of the amino group, via reductive amination,
afforded a variety of mainly secondary amines.10 Following this
synthetic approach, a few 3-dialkylamino-imidazo[1,2-a]pyrazines
have been described recently.11 A second method was based on
the successful introduction of formaldehyde in the 3-CC
reaction, via glyoxylic acid, that leaves 2-unsubstituted-3-amino-
imidazoheterocycles.12 Nevertheless, all of these synthetic ap-
proaches suffer either from poor diversity in the accessible amine
synthons, or from the need of multi-step routes to build the sec-
ondary amines.
In 2003, Katritzky et al. developed an attractive methodology to
prepare 3-dialkylamino-imidazopyridines and pyrimidines. This
method relies on the preparation of 1,2-bis(benzotriazolyl)-1,2
⇑
Corresponding author. Tel.: +34 917328000; fax: +34 917328051.
E-mail address: jpastor@cnio.es (J. Pastor).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.077

J. Pastor et al. / Tetrahedron Letters 53 (2012) 1082–1084
1083
Table 1
(dialkylamino)-ethanes that react with the required 2-aminopyri-
dine or 2-aminopyrimidine in a formal cyclisation.13
Synthesis of 2-unsubstituted-3-N-cyclic-amine-imidazo[1,2-a]pyrazines
In this communication we would like to report our work in the
application of this approach to prepare 2-H-3-N-dialkylamino-imi-
dazo[1,2-a]pyrazines. In order to facilitate a rapid exploration of C-
3 with secondary amines, we fixed substituents at C-6 and C-8 in
our target molecules, and therefore, in the key intermediates as
well. Phenol, indazole and 2-aminopyrimidine were chosen for
the C-6 aryl/heteroaryl substitution, and morpholine was selected
at C-8.
These fragments have been reported to provide key interactions
in the ATP binding pocket of PI3-kinase,14 and are introduced by a
classical sequence of steps (Scheme 1, 3a–c). On the other hand,
the bis(benzotriazole) intermediates 4a–k (Scheme 2) were readily
prepared under mild conditions via condensation of glyoxal, ben-
zotriazole and the corresponding amines in ethanol.15,16
The adducts 4a–k were used directly into next step. Both pyraz-
inyl intermediates (3a–c) and amine adducts (4a–k) were reacted
in a convergent manner through a formal cyclisation, by heating in
1,2-dichloroethane (DCE) to produce the corresponding 3-dialkyla-
mino-imidazo[1,2-a]pyrazines (Table 1, 5a–o).17,18
O
R1
O
Y
N
R2
N
N
Bt
N
(i)
N
NH2
N
N
Bt
N
Ar
+
N
N
Ar
Y
R2
4a-k
R1
Y
R1
R2
3a-c
5a-o
Compound
number
Ar/Het
Y
R1
R2
Yielda
(%)
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
3-Phenol
1H-Indazol-4-yl
3-Phenol
N
N
N
N
N
N
C
C
N
C
Me
Me
H
H
H
H
H
H
H
NH2
H
40
24
SO2Me
H
SO2Me
H
15
3-Phenol
15b
23
1H-Indazol-4-yl
1H-Indazol-4-yl
1H-Indazol-4-yl
1H-Indazol-4-yl
2-Aminopyrimidinyl
1H-Indazol-4-yl
1H-Indazol-4-yl
1H-Indazol-4-yl
1H-Indazol-4-yl
1H-Indazol-4-yl
1H-Indazol-4-yl
15b
30b,c
15b,c
18
The cyclisation reaction proved to be highly regioselective, as
reported previously by Katritzky et al. giving only C-3 substitution
also in our imidazo[1,2,-a]pyrazine scaffold. This result was con-
firmed by NOE experiments for selected compounds 5a, 5d and
5j. Irradiation of H-5 in the pyrazine ring gave positive NOE effect
with certain protons of piperazine and piperidine substituents,
according to required substitution pattern.
NH2
H
SO2Me
H
SO2Me
Phenyl
H
H
H
H
48c
30c
34c
C
C
C
C
Phenyl 68c
Me
H
H
27c
23c
C
CH2Ph
a
b
c
Isolated compounds with purity P95%.
Yield after Boc-group deprotection.
Racemic mixture of regioisomers.
O
N
O
N
Br
Despite the moderate yields obtained with this synthetic route,
NH2
NH2
(results summarised in Table 1), the short number of steps and the
readily available starting building blocks (secondary amines), al-
lowed us an immediate access to these specific imidazo[1,2-a]pyr-
azine derivatives. Such a straightforward and rapid synthetic
approach is very valuable in medicinal chemistry SAR explorations
in comparison with multi-step and more elaborate pathways.
In conclusion, we have demonstrated the application of the
methodology reported by Katritzky et al. to the first straightfor-
ward synthesis of complex 2-H-3-dialkylamino-6-aryl/heteroaryl-
8-morpholinyl imidazo[1,2-a]pyrazines. Further applications for
the preparation of bioactive compounds are in progress in our
medicinal chemistry projects.16
NH2
N
(i)
(ii)
N
N
N
N
N
Br
Br
Ar
2
3a-c
N
N
Ar=
HO
N
H2N
N
3c
3b
3a
Scheme 1. Reagents and conditions: (i) morpholine, 120 °C, 48 h, 96%; (ii)
arylboronic acid, K2CO3, PdCl2(dppf), DME, MW, 130 °C, 10 min (3a 49%, 3b 63%,
3c 90%).
R1
Y
Acknowledgment
R2
We thank the Ministry of Science and Innovation (MICINN) of
Spain for financial support (Project CIT-090100-2007-48).
H
N
O
N
N
Bt
(i)
N
+
+
N
R2
Y
O
Bt
N
References and notes
R1
Bt = benzotriazolyl
Y
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17. General procedure A. Preparation of Bis(benzotriazolyl) products (4b, 4c, 4f, 4g,
4h, 4i, 4j, 4k):
appropriate piperidine or piperazine (2.43 mmol) in EtOH (20 mL) was
stirred for 20 min. Glyoxal (0.160 mL of 40% solution in water,
A mixture of benzotriazole (300 mg, 2.43 mmol), the
a
w
1.2 mmol) was added, and the resultant mixture was stirred for 16 h. The
white solid formed was filtered off, washing with EtOH and diethylether to
yield required products that were used in the next reaction step without
further purification. General procedure B. Preparation of Bis(benzotriazolyl)
products (4a, 4d, 4e): A mixture of benzotriazole (300 mg, 2.43 mmol), the
appropriate piperidine or piperazine (2.43 mmol) in EtOH (20 mL) was stirred
for 20 min. Glyoxal (0.160 mL of a 40% w solution in water, 1.2 mmol) was
added, and the resultant mixture was stirred for 16 h. The solution was
concentrated under high vacuum leaving an oily residue. The cream/white
solid formed by the addition of diethyl ether was filtered off, rinsing with
diethyl ether and dried in vacuo. The product was used in the next reaction
step.
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18. General procedure C. Synthesis of 3-substituted-imidazo[1,2-a]pyridazines. (5a–
k): Required bis(benzotriazolyl) (0.44 mmol) and 5-aryl-3-morpholinopyrazin-
2-amine (0.44 mmol) were dissolved in DCE (7 ml) and refluxed until reaction
was completed as determined by LC–MS analysis (5–48 h). The reaction
mixture was cooled down to rt and then KOH (powder, 250 mg) was added.
The mixture was stirred for 20 min at rt, filtered off and washed with DCM.
Filtrate was concentrated and the residue obtained was purified by Biotage
flash column chromatography eluting with the adequate required solvent
system.