Microwave-assisted synthesis of 1,3-dihydro-[1,2,5]thiadiazolo[3,4-b]pyrazine-2,2-dioxides

Article abstract of DOI:10.1016/j.tetlet.2006.09.097

1,3-Dihydro[1,2,5]thiadiazolo[3,4-b]pyrazine-2,2-dioxides are obtained in a good yield from the reaction of 2,3-diamino pyrazines with sulfamide under microwave conditions.

Full text of DOI:10.1016/j.tetlet.2006.09.097

Tetrahedron Letters 47 (2006) 8603–8606
Microwave-assisted synthesis of
1,3-dihydro-[1,2,5]thiadiazolo[3,4-b]pyrazine-2,2-dioxides
a
a
Sara Sevilla,a Pilar Forns,a, Joan-Carles Fernandez, Natalia de la Figuera,
*
`
Paul Eastwoodb and Fernando Albericioc
aAlmirall Prodesfarma-Barcelona Science Park Unit, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain
bMedicinal Chemistry Department, Almirall Prodesfarma, 08960 Sant Just Desvern, Barcelona, Spain
cInstitute of Research in Biomedicals, Barcelona Science Park, Josep Samitier 1, 08028 Barcelona, Spain
Received 4 August 2006; revised 18 September 2006; accepted 20 September 2006
Abstract—1,3-Dihydro[1,2,5]thiadiazolo[3,4-b]pyrazine-2,2-dioxides are obtained in a good yield from the reaction of 2,3-diamino
pyrazines with sulfamide under microwave conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
To attenuate toxicity and/or improve the pharmaco-
kinetic profile of biologically active molecules, the medi-
cinal chemist frequently utilizes a variety of bioisosteric
replacements.1 One such bioisostere, the sulfonylurea
group, has been used as a surrogate for amides, ureas,
thioureas, nitrosoureas, carbamates, and sulfonamides.2
However, the limitations of the chemical methods avail-
able for the preparation of this unit have probably con-
tributed to its limited use in medicinal chemistry.
Our interest in the use of this functional group in our
own research programs prompted us to search for a con-
venient method for the preparation of cyclic sulfonyl-
ureas. In particular we were interested in pyrazine
derivatives of type 1 (see Scheme 1). To the best of
our knowledge such structures have not been described
previously in the literature. Similar bicyclic ring systems
in which the pyrazine ring of 1 is replaced by a pyri-
dine10 or a benzene2b,11 ring have been documented.
Sulfonylureas are commonly prepared from the reaction
of an amine with sulfamide2b,3 or, alternatively, they can
be obtained using sulfuryl chloride.4 Other milder meth-
odologies described in the literature involve the use a
catecholsulfate,5 the displacement by an amine of the
N-oxazolidinone group from a sulfamoyl N-oxazolidi-
none,6 or by sequential activation of the imidazole
group in N,N0-sulfuryldiimidazoles using methyl triflate
followed by nucleophilic displacement with a variety of
amines and anilines.7 Unsymmetrical sulfonylureas
can also be prepared from the reaction of an amine with
a sulfamoyl chloride. In turn, sulfamoyl chlorides can be
obtained from the corresponding sulfamic acid by a
reaction with phosphorus pentachloride8 or by treat-
ment of an amine with sulfuryl chloride.2c,9
It was envisaged that derivatives of type 1 could be pre-
pared from the corresponding diamines 5 using method-
ologies such as described above. The synthesis of the
requisite diamine precursors is outlined in Scheme 2.
The key steps in the synthesis of the required intermedi-
ates 5 involve a regioselective nucleophilic aromatic
substitution of the 3-bromo moiety of 2-amino-3,5-dib-
romopyrazine 3 (obtained by bromination of commer-
cially available 2-aminopyrazine 2 with bromine in
chloroform in the presence of pyridine12) with an
R1
N
N
R2
N
O
S
N
H
O
Keywords: Microwave; Sulfonylureas; Suzuki reaction; Nucleophilic
aromatic substitution.
1
*
Corresponding author. Tel.: +34 93 403 4705; fax: +34 93 403
7109; e-mail: pforns@pcb.ub.es
Scheme 1. Target pyrazine derivatives.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.097

8604
S. Sevilla et al. / Tetrahedron Letters 47 (2006) 8603–8606
N
N
Br
N
N
NHR1
NH2
N
N
NHR1
NH2
N
N
Br
Br
R2
b
c
a
NH2
NH2
2
3
4
5
Scheme 2. Synthesis of intermediates 5. (a) Br2, Pyr, CHCl3; (b) R1NH2, DIPEA, EtOH, MW, 140 °C, 35 min; (c) R2B(OH)2, Na2CO3 (2 M),
Pd(dppf)2Cl2ÆDCM, toluene/EtOH (2:1), 90 °C, 24 h.
appropriate amine, followed by a Suzuki reaction with
the corresponding boronic acid.13
conditions have been successfully used for reactions of
sulfamide with alkyl amines2a,3 and anilines.2b,d In our
hands, with 2,3-diaminopyrazines 5, none of the desired
sulfonylureas 1 were observed neither after 24 h nor
after three days reaction time. The poor nucleophilicity
of the heterocyclic amine is likely to be the main cause of
reaction failure. It is well known that the use of micro-
wave irradiation can facilitate reactions where pro-
longed heating is essential and can dramatically affect
both yields and the rate of the chemical reactions.16 In
the case of the cyclization with sulfamide as reagent it
was quickly ascertained that clean product formation
could be achieved under such conditions. After trying
different temperatures and times, we found that the best
conditions to effect cyclization were to heat reactions at
160 °C for 15 min at 200 W of power.17
The nucleophilic aromatic substitution of the 3-bromo
substituent of 3 by an amine was carried out in the
microwave in the presence of DIPEA in EtOH.13,14
Three different primary amines were used (Scheme 3)
and the yields ranged from 80% to 94% after the purifi-
cation by silica gel chromatography. The purities deter-
mined by HPLC were good and the structures were
assigned by NMR. Comparing 1H NMR spectra, an up-
field shift is seen for H-6 of the pyrazine, from 8.16 ppm
in compound 3 to approximately 7.45 ppm in the substi-
tution products 4.
The Suzuki reaction was carried out using three elec-
tronically different boronic acids to see if any differences
in the reactivity could be seen (Scheme 4).15 Yields of
coupled products 5 ranged from 66% to 100% with p-
methoxycarbonylphenylboronic acid giving the poorest
results. The crude reaction mixture was purified using
Dowex ion-exchange resin (H+ form). 1H NMR spectra
showed the characteristic aromatic protons of the
phenyl group and an upfield shift of the pyrazine H-5
ranging from 0.3 to 0.45 ppm depending upon the
compound.
Table 1 shows the yields and purities obtained with dif-
ferent R1 and R2 groups after purification of the crude
reaction mixtures with Bond Elut SAX cartridges (anion
exchange interaction). All the desired sulfonylureas 1
were obtained in good to excellent yields and purities,
the presence of electron-withdrawing or donating
groups in the para position of the R2 substituent did
not affect the sulfonylurea formation. All the com-
1
pounds were characterized by H NMR18 and ES-MS
to confirm their structural integrity.
With diamines 5 in hand we now turned our attention to
the preparation of the desired cyclic sulfonylureas.
Among the different synthetic methods available, we
tested those involving the use of sulfamide,3 sulfuryl
chloride,4 and catecholsulfate,5 as sources of the
synthon XSO2X (X being a leaving group). The use
of sulfuryl chloride4 or catecholsulfate5 under various
conditions did not give rise to the desired products.
Finally we tried to effect formation of the cyclic deriva-
tives using sulfamide under the reflux in pyridine as such
Table 2 shows the main differences found in the 1H
NMR spectra between diamines 5 and sulfonylureas 1.
It can be seen that there is a considerable upfield shift
Table 1. Yields and purities of sulfonylureas 1 after SAX purification
(all the products have been analyzed for structural integrity by 1H
NMR18
)
R1
N
S
N
H
N
N
N
N
NHR1
NH2
R2
R2
O
SO2(NH2)2, Pyr
°
MW, 160 , 15 min
O
O
O
NH2
NH2
5
1
NH2
O
O
Compound R1
R2
Yield Puritya
(%)
Scheme 3. Amines used in the SNAr reaction.
1a
CH3aO(CH2)2
CH3O(CH2)2
CH3O(CH2)2
2-THFCH2
2-THFCH2
2-THFCH2
3,4-(OCH2O)PhCH2 Ph
3,4-(OCH2O)PhCH2 pMeOPh
3,4-(OCH2O)PhCH2 p(MeOCO)Ph 77
Ph
pMeOPh
p(MeOCO)Ph 87
Ph
pMeOPh
90
74
93
73
88
99
99
89
99
99
95
1b
1c
1d
1e
1f
OH
OH
B
OH
B
90
84
B
H
H
H
p(MeOCO)Ph 79
O
1g
1h
1i
86
89
O
O
Scheme 4. Boronic acids used in the Suzuki reaction.
a By HPLC at 210 nm.

S. Sevilla et al. / Tetrahedron Letters 47 (2006) 8603–8606
Table 2. Relevant NMR data (ppm)a of diamines 5 and sulfonylureas 1
8605
R1
R1
N
N
N
N
NH
R2
R2
N
O
S
N
H
O
H6
H5
NH2
5
1
Compound H-5 C-5
NCH2 NCH2 Compound H-6 C-6
NCH2 NCH2 DH5–H6 DC5–C6 DCH
DCH
2ð4Þ–CH2ð5Þ
2ð4Þ–CH2ð5Þ
5a
5b
5c
5d
7.88 126.5 3.67
41.2
41.2
40.8
45.3
1a
1b
1c
1d
7.33 113.4 4.12
7.20 110 4.1
7.38 112.3 4.15
7.28 111.2 3.89
4.05
40.8
40.9
40.9
45.5
0.55
0.61
0.44
0.59
13.1
15.7
13.6
15.0
ꢀ0.45
0.4
7.81 125.7 3.67
7.82 125.9 3.71
7.87 126.2 3.43
3.86
7.71 124.3 3.40
3.88
7.92 126.4 3.41
3.88
7.79 125.3 4.63
7.71 124.2 4.62
7.82 126.5 4.55
ꢀ0.43
ꢀ0.44
ꢀ0.46
ꢀ0.19
ꢀ0.48
ꢀ0.16
ꢀ0.51
ꢀ0.18
ꢀ0.36
ꢀ0.36
ꢀ0.38
0.3
ꢀ0.1
ꢀ0.2
5e
5f
46.2
46.2
1e
1f
7.18 110
3.88
4.04
45.5
45.1
0.53
0.48
14.3
11.9
ꢀ0.5
7.44 114.5 3.92
4.06
7.34 113.0 4.9
7.19 111.6 4.9
7.38 114.8 5.00
1.1
5g
5h
5i
45.1
45.0
43.9
1g
1h
1i
44.2
44.1
44.2
0.45
0.52
0.44
12.3
12.6
11.7
0.9
0.9
ꢀ0.3
a 1H NMR spectroscopy was performed in CDCl3 with a few drops of added CD3OD (except 5a,b,d–f where only CDCl3 was used).
1
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(0.4–0.5 ppm) of H6 in the H spectra of 1 as compared
to compound 5. The same effect can be seen in the 13C
NMR spectra for C6 of compounds 1 and C5 of com-
pounds 5; in this case the upfield shifts range from 11
to 16 ppm.
It can be concluded that a simple microwave-assisted
methodology to obtain heterocyclic sulfonylureas has
been developed. The method is rapid, high-yielding
and involves the use of the inexpensive reagent sulf-
amide. Of particular note is that poor nucleophilic
amines react well. Studies involving the application of
the methodology to other heterocyclic diamines are
currently underway in our laboratories.
3. (a) Stetter, H.; Merten, R. Chem. Ber. 1957, 90, 868–874;
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Acknowledgements
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This work was supported by Almirall Prodesfarma
and the Barcelona Science Park. The authors thank
Dr. Victor Matassa and Dr. Hamish Ryder for their
encouragement.
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14. General procedure for SNAr reactions. A mixture of 2-
amino-3,5-dibromopyrazine 3 (1 equiv) a primary amine
(1.2 equiv) and DIPEA (1.2 equiv) in EtOH was placed in
the microwave (CEM Discover) and heated at 140 °C
(150 W) for 35 min. The solvent was removed under
reduced pressure and the residue was taken up with ethyl
acetate. The organic layer was washed with water and
brine, dried over MgSO4 and filtered. The filtrate was
concentrated under reduced pressure and the resulting
crude product was purified by column chromatography.
15. General procedure for Suzuki reactions. Bromo-pyrazine 4
(100 mg) was suspended in degassed toluene/EtOH (2:1,
1.2 mL). Pd(dppf)2Cl2ÆDCM (5 mol %), the appropriate
boronic acid (1.5 equiv) and Na2CO3 2 M (3 equiv) were
added and the mixture was degassed with nitrogen and
then shaken for 24 h at 90 °C. The solvent was removed
under reduced pressure in an EZ-2 apparatus and the
residue was purified using Dowex Resin. Samples were
dissolved in MeOH and approximately 1.5 g of Dowex
resin/mmol of the product was added and shaken for 18 h.
The solution was filtered and the resin washed with
MeOH, DCM and MeOH. Finally the compounds were
extracted from the resin with 2 mL of NH3 (7 N in
MeOH). After 2 h of shaking, the resins were filtered and
the filtrate collected and solvent removed in an EZ-2
apparatus.
16. (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–
6284; (b) Kappe, C. O.; Stadler, A. Microwaves Org. Med.
Chem. 2005; (c) Lidstro¨m, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225–9283.
17. General procedure for cyclization reactions: A mixture of
pyrazine 5 (1 equiv) and sulfamide (3.5 equiv) in pyridine
was placed in the microwave (CEM Discover) and heated
at 160 °C (200 W) for 15 min. The residues were purified
using Bond Elut SAX (Strong Anion Exchange) cartridges
(Varian) that were first soaked with ACN. The crude
samples were introduced in the cartridges, 7 mL of ACN
was then passed through in order to eliminate the pyridine
and excess of sulfamide. Finally compounds were eluted
with 5% HOAc in ACN and the solvent was removed in an
EZ-2 apparatus.
18. 1H NMR spectra of all compounds can be found in the
supporting information.