An efficient one-pot synthesis of 2-bromo-6-aryl[5H]pyrrolo[2,3-b]pyrazines

Article abstract of DOI:10.1016/j.tetlet.2015.02.005

We report a two step one-pot method for the synthesis of 2-bromo-6-aryl[5H]pyrrolo[2,3-b]pyrazines. The process makes use of a cleaner copper-free Sonogashira coupling and an improved base-mediated 5-exo-dig cyclisation to afford the products in good yields. This method expands the scope to structures that are poorly represented in the literature and incorporates a halide for further synthetic elaboration.

Full text of DOI:10.1016/j.tetlet.2015.02.005

Accepted Manuscript
An efficient one-pot synthesis of 2-bromo-6-aryl[5H]pyrrolo[2,3-b]pyrazines
Iain Simpson, Steve A. St-Gallay, Stephen Stokes, David T.E. Whittaker, Rafal
Wiewiora
PII:
S0040-4039(15)00248-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.005
TETL 45868
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 November 2014
12 January 2015
1 February 2015
Please cite this article as: Simpson, I., St-Gallay, S.A., Stokes, S., Whittaker, D.T.E., Wiewiora, R., An efficient
one-pot synthesis of 2-bromo-6-aryl[5H]pyrrolo[2,3-b]pyrazines, Tetrahedron Letters (2015), doi:http://dx.doi.org/
10.1016/j.tetlet.2015.02.005
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An efficient one-pot synthesis of 2-bromo-6-aryl[5H]pyrrolo[2,3-b]pyrazines
Iain Simpson, Steve A. St-Gallay, Stephen Stokes, David T. E. Whittaker*, Rafal Wiewiora
Oncology Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG
Fax: +44 (0) 1625 231453
E-mail: david.whittaker@astrazeneca.com
Abstract
We report a two step one-pot method for the synthesis of 2-bromo-6-aryl[5H]pyrrolo[2,3-
b]pyrazines. The process makes use of a cleaner copper-free Sonogashira coupling and an
improved base-mediated 5-exo-dig cyclisation to afford the products in good yields. This
method expands the scope to structures that are poorly represented in literature and
incorporates a halide for further synthetic elaboration.
Key Words
Sonogashira
Cyclisation
Kinase

Corresponding author:
David Whittaker
david.whittaker@astrazeneca.com
Tel: +441625233295
Fax: +441625513253
Leave this area blank for abstract info.
An efficient one-pot synthesis of 2-bromo-6-
aryl[5H]pyrrolo[2,3-b]pyrazines
Iain Simpson, Steve A. St-Gallay, Stephen Stokes, David T. E. Whittaker*, Rafal Wiewiora
Ar
Ar
Br
N
N
Br
N
N
Br
1 eq
1.5 eq NaH
Br
N
N
Ar
THF (0.024 M), 60 oC, 18 h
N
H
4% PdCl2(PPh3)2, 10 eq Et3N
THF (0.15 M), 60 oC, 3 h
NH2
NH2
Abstract
We report a two step, one-pot method for the synthesis of 2-bromo-6-aryl[5H]pyrrolo[2,3-
b]pyrazines. The process makes use of a copper-free Sonogashira coupling and an
improved base-mediated 5-exo-dig cyclisation to afford the products in good yields. This
method expands the scope to structures that are of importance in both synthetic and
medicinal chemistry and incorporates a halide for further synthetic elaboration.
Key Words
Sonogashira
Cyclisation
Kinase

Pyrrolo[2,3-b]pyrazines are important molecular structures for drug discovery.
This is particularly relevant in the area of kinase inhibition, where they have been shown to
compete with ATP for binding to the kinase active site.1-5
During a recent medicinal chemistry program we became interested in the
synthesis of 2-bromo-6-phenyl[5H]pyrrolo[2,3-b]pyrazine (1) (Figure 1) as a key building
block for further elaboration. Whilst the synthesis of 6-phenyl[5H]pyrrolo[2,3-b]pyrazines has
been reported, this approach did not allow inclusion of the bromine atom that was required
for the convergent synthesis of our target molecules.
Previous in-house syntheses of pyrrolo[2,3-b]pyrazines have employed 5-
bromo-3-ethynylpyrazin-2-amines and their subsequent treatment with base to affect
cyclisation to form the desired bicycle (Scheme 1). This approach is well documented in the
literature for both pyrrolo[2,3-b]pyrazines and other related bicyclic structures,6-8 but does not
include any examples where the product pyrrolo[2,3-b]pyrazine has a phenyl ring at the 6-
position. The synthesis of 6-(3-indolynyl)[5H]pyrrolo[2,3-b]pyrazines has been reported,9
however, not only did we think that further work was warranted - as bourne out by our initial
results - on 6-phenyl systems, but it was thought that the 5-bromo substituent in our model
system would affect the cyclisation and require its own optimum conditions. Herein, we
report our attempts to develop a general method for the synthesis of 6-phenyl systems.
The initial strategy involved the synthesis of the required cyclisation precursor,
5-bromo-3-(phenylethynyl)pyrazin-2-amine 2, which was achieved through regioselective
Sonogashira coupling of readily available 2-amino-3,5-dibromopyrazine and ethynylbenzene
(Scheme 2). Later attempts at this reaction on both the parent compound and substituted
analogues were found to be successful in the absence of any copper catalyst (Table 1), and
this modification achieved higher isolated yields in most cases, through easier reaction work-
up and purification. Attempts were also made at reducing the equivalents of triethylamine,
but the inconsistent yields produced with fewer equivalents, along with the low cost and ease

of removal of the excess reagent, meant that 10 equivalents could be employed. The
reaction was also found to be tolerant of a range of solvents and temperatures, with the ideal
combination of THF and 60 °C allowing ease of work-up and an efficient reaction time
respectively, whilst minimising by-product formation.
Calculations show that the LUMO of 2-amino-3,5-dibromopyrazine is not
evenly distributed around the pyrazine ring and has a greater presence around the 3-position
(Figure 2). We postulate that this, along with potential pre-coordination of the palladium
catalyst to the amino group, gave rise to the high degree of selectivity observed for the
Sonogashira coupling. Reaction at C-5 of 2-amino-3,5-dibromopyrazine was only observed
with excess alkyne once the desired substitution at C-3 had taken place. This 3,5-
bis(phenylethynyl)pyrazin-2-amine impurity 3 could be effectively eliminated through careful
addition of the alkyne reagent, and any by-products that were formed could be easily
removed by standard chromatography techniques.
The initial attempt at cyclising 2 (entry 1, Table 2) employed standard
conditions for the reaction of 5-bromo-3-ethynylpyrazin-2-amines bearing a simple alkyl
group.9 Monitoring the reaction proved difficult due to the co-elution of the starting material
and the product in LCMS and TLC analyses, and the isolated sample contained an
inseparable mixture of these two components in low yield. Increasing the reaction time (entry
2, Table 2) gave complete conversion and also improved the yield modestly. Changing the
solvent from NMP to THF necessitated a slight lowering of the reaction temperature and was
intended to allow easier work-up of the reaction mixtures. This modification also resulted in a
higher yield (entry 3, Table 2). Employing the stronger base sodium hydride (entry 4, Table
2) also improved the reaction, presumably by achieving more complete and effective
deprotonation of the starting material, and also by ultimately giving a cleaner crude reaction
mixture.
Whilst these early improvements in yield were seen as encouraging, attempts
to obtain a product of higher yield and purity using a lower reaction temperature, the addition

of more base and the use of different purification techniques (entries 5-9, Table 2) gave
varying degrees of success with respect to the isolated yield. However, reducing the reaction
concentration (entry 10, Table 2) gave a significant and readily reproducible improvement.
Scheme 3 and Table 3 summarise the application of our optimised conditions
for both the Sonogashira and cyclisation reactions on a number of substituted phenyl and
heteroaryl analogues. Synthetically useful yields were obtained in most cases showing that
this method is of general use. The largest single contributing factor to the lowering of the
isolated yield was the solubility of the final compound and its behaviour during
chromatography. Certain analogues produced better results when purified by trituration
methods, but in order to obtain high purity samples for analysis and to provide a consistent
representative yield for comparison purposes, all yields quoted are for samples obtained
after silica gel column chromatography.
Notable results are those for the ortho-nitrophenyl and para-methyl benzoate
(entries 5 and 16, respectively), which gave poor results in both Sonogashira and cyclisation
reactions. Whilst the result for ortho-nitrophenyl is a puzzling discrepancy, particularly in
comparison to the other nitrated analogues (entries 10 and 15), the loss of desired product
from the methyl ester was found to be caused by hydrolysis to the corresponding carboxylic
acid.
The fact that both the Sonogashira and cyclisation reactions are performed in
the same solvent presented a potential useful opportunity for telescoping them together into
a convenient one-pot procedure. The only practical considerations to be addressed were the
differing concentrations of the two reactions and the need for anhydrous conditions for the
cyclisation. For development of this process we went back to the model system of reacting
2-amino-3,5-dibromopyrazine with ethynylbenzene, and subsequent cyclisation to form 1.
Our initial conditions involved performing the Sonogashira reaction at the lower
concentration required for optimum cyclisation, with the practical benefit that the reaction

mixture would only require cooling to ambient temperature and the addition of sodium
hydride as the manipulations between reactions. This resulted in an appreciably slower
Sonogashira reaction (~90% complete after 7 hours by LC-MS) and gave a slightly lower
yield of product 1 of 62%, partly due to the more difficult purification.
In an attempt to achieve the rapid and complete conversion seen in earlier
Sonogashira reactions, our second attempt involved carrying out this step at its original
concentration and then transfering the crude reaction mixture into a larger flask and
evaporating to dryness. This could then be redissolved in a larger volume of THF to give the
optimum concentration for the cyclisation step. This approach not only involved more
practical manipulation between stages, but also resulted in a significantly lower yield of 1 of
44%. This was most likely due to a failure to create optimum cyclisation conditions from the
mixture transfer.
Our third attempt also involved carrying out the Sonogashira reaction at its
original concentration, followed by simply adding more solvent to the same reaction vessel to
achieve the concentration required for the optimum cyclisation. This process gave an
improved yield of 1 of 64%. Whilst this one-pot procedure did not produce quite as high a
yield of cyclised product as the original two-step process (71% over two steps), there are
clear advantages to the synthetic chemist in terms of time saved and purification steps
avoided, which makes the one-pot procedure a preferable option.
The final column in Table 3 shows the yields for the one-pot procedure on all
the original analogues. Again, all the yields are quoted for material isolated after silica gel
column chromatography and are generally equal to, or higher than, the overall yield obtained
by performing the two steps separately. As poor reactants for this process, entries 5 and 16
still present discrepancies from the other analogues, the methyl ester proving to be
completely unstable to the reaction conditions for telescoping.
In conclusion, this methodology provides a facile and versatile one-pot
approach to 2-bromo-6-phenyl[5H]pyrrolo[2,3-b]pyrazines, for further elaboration into useful

drug-like molecules. The remaining bromine atom in the product provides a useful functional
group for subsequent synthetic manipulations and our method has been developed with this
in mind. Access to the corresponding des-bromo analogues would be desirable in certain
cases, but is not achieved readily from the logical 2-amino-3-bromopyrazine starting
material. This reagent is significantly more expensive and less readily available than the
dibromide used here. However, in order to demonstrate access to these moieties, we have
successfully carried out debromination10 of parent 1 (Scheme 4) in good yield.
Supplementary data
Supplementary data (general and optimised synthetic procedures, 1H and 13C NMR, IR and
mass spectrometry data) associated with this article can be found, in the online version, at
References
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Br
N
N
N
H
1
Figure 1. 2-Bromo-6-phenyl[5H]pyrrolo[2,3-b]pyrazine (1)
M+ B-
Scheme 1. Base-mediated cyclisation of 5-bromo-3-ethynylpyrazin-2-amine
Figure 2. The LUMO density map of 2-amino-3,5-dibromopyrazine

2
3
Scheme 2. Synthesis of 5-bromo-3-(arylethynyl)pyrazin-2-amines via Sonogashira coupling.
Reagents and conditions: PdCl2(PPh3)2 (0.04 equiv), Et3N (10 equiv).
i)
ii)
Scheme 3. Optimisied conditions for the Sonogashira coupling and cyclisation. Reagents
and conditions: (i) alkyne (1 equiv), PdCl2(PPh3)2 (0.04 equiv), Et3N (10 equiv), THF (0.15
M), 60 °C, 3 h; (ii) NaH (1.5 equiv), THF (0.024 M), 60 °C, 18 h.
1
Scheme 4. Silane-mediated hydrodehalogenation of 1. Reagents and conditions: Pd2(dba)3
(0.05 equiv), S-Phos (0.05 equiv), Et3SiH (5 equiv), Et3N (2 equiv), 1,4-dioxane, 89% yield.

Table 1. Optimising the Sonogashira reaction between 2-amino-3,5-dibromopyrazine and ethynylbenzene.
Alkyne
(equiv)
1.2
CuI
(equiv)
0.12
Conc
(M)
Temp
(°C)
120
100
60
Time
(h)
Yield of 2
Yield of 3
Entry
Solvent
(%)
52
67
69
82
(%)
-
1
2
3
4
0.22
0.22
0.15
0.15
DMF
DMF
THF
THF
0.17
0.17
2.00
2.00
1.2
0.12
29
0
1.0
0.10
1.0
0.00
60
0

Table 2. Optimising the cyclisation of 5-bromo-3-(phenylethynyl)pyrazin-2-amine 2.
Base
(equiv)
Conc
(M)
Temp
(°C)
Time
(h)
Quench
reagent
Entry
1
Solvent
NMP
Purification method
Yield (%)
6
KOtBu
(1.0)
aq work-up and silica
column
0.2
80
1.5
sat. NH4Cl
(1.8:1 mix of
2 and 1)
KOtBu
(1.0)
KOtBu
(1.0)
2
3
NMP
THF
THF
THF
THF
THF
THF
THF
THF
0.2
0.2
80
70
70
70
60
60
60
60
60
18
18
18
18
18
18
18
18
18
sat. NH4Cl
sat. NH4Cl
sat. NH4Cl
sat. NH4Cl
sat. NH4Cl
AcOH
aq work-up
aq work-up
aq work-up
26
40
55
37
45
63
17
80
86
NaH
(1.0)
4
0.2
NaH
(1.0)
aq work-up and
trituration in MeCN
5
0.2
NaH
(1.0)
aq work-up and
trituration in CH2Cl2
6
0.2
NaH
(1.0)
aq work-up and
trituration in CH2Cl2
7
0.2
NaH
(1.25)
aq work-up and silica
column
8
0.2
HCl
NaH
(1.25)
aq work-up and
trituration in CH2Cl2
9
0.2
-
NaH
(1.5)
10
0.024
H2O
silica column

Table 3. Main Results.
Combined yield of
the two-step
reaction (%)
Yield of Sonogashira
reaction (%)
Yield of cyclisation
reaction (%)
Yield of the one-pot
procedure (%)
Entry
1
Ara
82
80
40
86
77
63
71
62
25
64
67
42
2
3
O
Cl
42
14
48
68
0
29
0
55
0
4
5
6
33
16
55
N
89
80
74
61
66
49
54
56
7
8
O

89
75
81
49
72
37
46
30
9
Cl
10
N
62
81
32
82
20
66
59
74
11
12
O
75
68
51
48
13
Cl
73
47
54
48
39
23
61
33
14
15
O
O
53
44
34
40
18
18
0
16
17
N
22

54
92
83
98
45
90
79
80
18
19
S
S
a See Scheme 3.