One-pot synthesis of bis(amino)-1,2,4-thiadiazoles via direct S NAr

Article abstract of DOI:10.1016/j.tetlet.2012.11.107

The synthesis of bis(amino)-1,2,4-thiadiazoles usually relies on a four step sequence. Herein, we communicate to our knowledge the first one-pot synthesis of bis(amino)-1,2,4-thiadiazoles via a double S_NAr approach.

Full text of DOI:10.1016/j.tetlet.2012.11.107

Accepted Manuscript
One-pot synthesis of bis(amino)-1,2,4-thiadiazoles via direct S Ar
N
Howard A. Beeley, Sébastien Degorce, Craig S. Harris, Jonathan Lecoq, Rémy
Morgentin, David Perkins
PII:
S0040-4039(12)02070-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2012.11.107
TETL 42203
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
10 October 2012
10 November 2012
12 November 2012
Please cite this article as: Beeley, H.A., Degorce, S., Harris, C.S., Lecoq, J., Morgentin, R., Perkins, D., One-pot
synthesis of bis(amino)-1,2,4-thiadiazoles via direct S Ar, Tetrahedron Letters (2012), doi: http://dx.doi.org/
N
10.1016/j.tetlet.2012.11.107
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One-pot synthesis of bis(amino)-1,2,4-
thiadiazoles via direct SNAr
Howard A. Beeley, Sébastien Degorce, Craig S. Harris, Jonathan Lecoq, Rémy Morgentin and David Perkins
The synthesis of bis(amino)-1,2,4-thiadiazoles usually relies on a four step sequence. Herein, we communicate to our
knowledge the first one-pot synthesis of bis(amino)-1,2,4-thiadiazoles via a double SNAr approach.
R2
One-pot
R1NH2
DIPEA
Cl
NH
cyclohexanol,
r.t. to 80 °C
N
N
R1
N
N
R2NH2
Cl
ZnCl2
90-120 °C
N
H
S
S

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
One-pot synthesis of bis(amino)-1,2,4-thiadiazoles via direct SNAr
Howard A. Beeley,a Sébastien Degorce,a Craig S. Harris*,b Jonathan Lecoq,b Rémy
Morgentinb and David Perkinsa
aOncology iMed, AstraZeneca, Alderley Park, Cheshire SK10 4TG, U.K.
bOncology iMed, AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France
Abstract— The synthesis of bis(amino)-1,2,4-thiadiazoles usually relies on a four step sequence. Herein, we communicate to our
knowledge the first one-pot synthesis of bis(amino)-1,2,4-thiadiazoles via a double SNAr approach. © 2012 Elsevier Science. All rights
reserved
Protein kinases play a vital role in many cell processes including regulation of cell growth and survival.1 With over 500
protein kinases known, the human kinome represents a very important druggable target for the pharmaceutical industry.
Indeed, during the last three decades, there has been intensive research into looking for small molecule ATP-competitive
kinase inhibitors for the treatment of cancer.2 This research has been very successful with 11 compounds already on the
market for the treatment of various cancers and many more currently in late stage clinical trials.2 Some molecular scaffolds,
for example quinazolines whose core template is present for 4 marketed cancer treatments,2d-g have been exhaustively
exploited in just about ever vector searching for novelty and selectivity in a crowded chemical space.3 Therefore, the search
for novel small molecule templates has become very important for the drug industry.4 We turned our attention to the
exploitation of the 3,5-bis(amino)-1,2,4-thiadiazole or BAT motif as potential ATP-competitive inhibitors, where we
speculated that these class of compounds should fit nicely into the hinge-binding domain5 and we could potentially pick up an
extra electrostatic interaction between the S atom of the thiadiazole ring and the carbonyl of the hinge backbone (Figure 1).6
Figure 1. Proposed binding mode of the BAT motif in the hinge region according to the Traxler model (ATP in grey; hinge backbone in blue; gatekeeper
gatekeeper residue in red; key donor and acceptor interactions in magenta; conserved lysine residue in green).
———
* Craig Harris. Tel.: +33 (0)3 26 61 5912; fax: +33 (0)3 26 61 6842; e-mail: craig.harris2@astrazeneca.com
Keywords: SNAr; one-pot; Lewis acid-catalysed

2
Tetrahedron Letters
The preferred synthesis of BATs (1) usually relies on a four-step sequence (Scheme 1, Route A).7 The synthesis starts from
amines 5 and 6 and relies on the individual preparation of the corresponding isothiocyanates (3) and guanidines (4).
Nucleophilic addition of the guanidine onto the isothiocyanate affords 2 that undergoes ring closure to 1 usually in the
presence of strong electrophiles such as bromine,8 iodine,9 diethyl azodicarboxylate (DEAD)10 and H2O2.11 While there was
sufficient literature precedent supporting Route A, the route was not appropriate for the rapid synthesis of BATs in a library
manner as it required 4 linear steps with purifications after each stage. Moreover, there was a strong question mark
surrounding the compatibility of the ring-closing conditions with some of our designs having electron-rich aryl moieties at R1
and R2. We anticipated that the aryl moieties themselves would undergo electrophilic substitution during the cyclisation
conditions leading to impurities. Therefore, we turned our attention to Route B involving the possibility of selectively
substituting commercially-available 3,5-dichloro-1,2,4-thiadiazole (7) either under SNAr or under Buchwald-Hartwig
conditions.
Route A
R1
N
H
N
H
N
R1
R1
R1
NH2
H
N
N
3
S
5
R2
R2
S
S
N
H
N
H
H2N
N
HN
R2
R2
1
2
H2N
N
H
HN
6
4
Route B
H
Cl
R1
N
R1
NH2
R2
N
5
N
?
R2
+
S
S
Cl
N
H
N
N
H2N
7
6
1
Scheme 1. Two possbile routes that we considered to synthesise our 3,5-bis(amino)-1,2,4-thiadiazole library
Initially, we set about trying to effect the first substitution using our preferred in-house Buchwald-Hartwig library conditions
but achieved very little conversion (Table 1, entry 1) presumably due to catalyst poisoning from the S atom of the thiadiazole
ring. Therefore, instead of dedicating resource to a large catalyst screen, we accepted that perhaps a PGM (platinum-metal
group)-catalysed approach was not the answer and we turned our attention to screening direct SNAr conditions.12 Under
aprotic conditions (entry 2), we achieved very little conversion at elevated temperatures but the displacement did take place
very smoothly with a range of amine nucleophiles (entries 3-7) in protic solvents (eg., cyclohexanol) using DIPEA as the
base. Under these optimised conditions, all the displacements were 100% regioselective at C-5 with total conversion using a
slight excess of the amine nucleophile and DIPEA.
Table 1. A selection of the results obtained after optimisation of the first SNAr step.
Cl
Cl
R1NH2
N
N
R1
N
N
Cl
N
H
conditions
S
S
Entry
R1
Conditions
%Yield
Pd(OAc)2, xantphos,
Cs2CO3, 1,4-
dioxane, 80-140 °C
1
2
3
traces
*
*
*
DMF, K2CO3, r.t. to
120 °C
traces
100
Cyclohexanol,
DIPEA, r.t.-80 °C

Tetrahedron Letters
3
Cyclohexanol,
DIPEA, r.t.-80 °C
4
80
Cl
*
Cyclohexanol,
DIPEA, r.t.-80 °C
O
5
6
91
98
S
*
H2N
O
Cyclohexanol,
DIPEA, r.t.-80 °C
*
According to the literature, we were not expecting to confront many obstacles for the first displacement.12 At the time of our
investigation, literature precedent for the second displacement was documented for nucleophilic aliphatic amines and
imidazole6, 13 but there were no references for aromatic amines, thus suggesting this would be the problematic step. Indeed,
this proved to be the case as most of our efforts were invested in trying to effect the second displacement under either
Buchwald-Hartwig12b or direct SNAr conditions. Table 2 shows a selection of results obtained from the optimisation of the
second displacement using the purified intermediate 8. As for the the displacement at C-5, attempts to carry out the
displacement in under Buchwald-Hartwig conditions resulted in very little conversion under a variety of conditions (e.g.,
entry 1). Direct SNAr under aprotic conditions (entry 2) also failed to give any conversion and after a period of prolonged
heating, the intermediate started to degrade. Therefore, we turned our attention to trying to employ similar optimised
conditions to those used for the displacement at C-5 but unfortunately only traces of substituted product were observed
(Table 2, entry 3).
Table 2. A selection of the results obtained from the optimisation of the second SNAr step.
H
N
Cl
OH
Conditions
N
N
N
NH
+
HO
N
N
N
H
N
H
OH
S
S
N
N
H
NH2
H2N
9
10
8
OH
Entry
Conditions
Pd(OAc)2, xantphos,
Cs2CO3, DMA, 80-160 °C
DMF, K2CO3,
r.t. to 120 °C
%Yield
1
2
traces
deg.
Cyclohexanol, DIPEA, r.t.-
140 °C
3
4
5
traces
43a
Neat aniline (3 eq), 140 °C
Cyclohexanol, cat. HCl,
r.t.-140 °C
deg.
Cyclohexanol, DIPEA,
ZnCl2, 120 °C
6
78
a The ring-opened product also formed in 18% yield; deg. = degradation.
In order to conclude whether direct SNAr at C-3 with weak nucleophiles, such as anilines, was possible under laboratory
conditions, we tried the reaction using a three-fold excess of aniline nucelophile (Table 2, entry 4). To our satisfaction, we
obtained the desired BAT (9) in 43% isolated yield with a significant close-running impurity that was isolated and
characterised as the ring-opened bis(guanidine) compound 10.14 Attempts to simplify the conditions by adding a catalytic
amount of dry HCl slowed down the reaction and led to degradation of the starting chloride (entry 5). While the melt
conditions afforded the first members of our library, the reaction mixtures were routinely contaminated with variable
quantities of the ring-opened bis(guanidine) impurity that was, in some cases, difficult to remove by standard
chromatographic techniques. Presumably, this impurity is formed by nucleophilic attack of another mole of aniline
nucleophile at the most electron-deficient C-5 position of the BAT with concomitant loss of a hydrogen sulfide (Scheme 2).
At present and to our knowledge, there are no preparatory procedures permitting the preparation of differentially-arylated
bis(guanidine) motifs.15

4
Tetrahedron Letters
R1
H
N
H
R2
R2
Cl
N
R2
N
H
H2N R2
140 °C
N
H
N
N
H+
N
R1
R1
R2
R1
N
N
NH
N
N
H
N
H
N
H
N
S
S
S
NH
R2
HCl
R2
N
H
SH
H2N
R1
R1
R1
R2
N
H
N
H
R2
N
H
N
H
R2
N
H
N
H+
R2
N
R2
SH
N
R2
N
+
H2S
N
H
N
H
N
H
N+ SH
N
NH2
H
Scheme 2. A possible mechanistic explanation of the ring-opened bis(guanidine) side-product obtained under solvent-free conditions.
H+
To avoid using harsh melt conditions, we postulated that we could employ a soft azaphilic Lewis acid that could coordinate to
either N2 or N4, thus, weakening the C-3-Cl bond and rendering it displaceable by weak nucleophiles such as anilines. After
a short Lewis acid screen, we identified that the use of stoichiometric ZnCl2 was sufficient to permit the second displacement
under much milder conditions in the presence of just 1.5 equivalents of the second nucleophile (Table 2, entry 6). Moreover,
as we could reduce the reaction temperature and number of equivalents of aniline, competing ring-opening of the 1,2,4-
thiazole ring was eliminated. As we managed to effect the second displacement in the same solvent as the first step and the
first step routinely gave very high conversions, we decided to combine both steps to see if we could synthesise the library in a
one-pot manner (Scheme 3).
R1
H
Cl
R2
N
NH2
N
a
b
N
R1
N
N
Cl
S
N
H
S
R2
NH2
Scheme 3. One-pot double substitution of 3,5-dichlorothiadiazole. Reagents and conditions: a) R1NH2 (1.1 eq), DIPEA (3 eq), cyclohexanol, 80 °C, 16
hours; b) R2NH2, (1.5 eq), ZnCl2(1.1 eq), 90-120 °C, 24 hours
Table 3. A small selection of the library compounds synthesised using this mild, two-step, one-pot approach
Entry
1
Compound
11
R1
R2
%Yield
*
56
N
Cl
Cl
*
*
O
O
2
12
40
S
*
H2N
O
3
4
13
14
45
37
HO
*
*
*
NC
*

Tetrahedron Letters
5
O
*
5
6
15
16
70
48
N
*
H
*
*
O
S
*
H2N
O
*
7
8
9
17
18
19
54
56
71
N
N
N
O
*
*
*
O
O
*
*
N
N
10
11
20
21
71
31
*
O
*
*
O
*
12a
21
27
*
O
N
Ph
a Compound 21 was prepared in a two-step manner.
In conclusion, we have managed to use readily-available 3,5-dichloro-1,2,4-thiadiazole as a starting heterocyclic core in a
one-pot, double SNAr approach to synthesise large libraries of BATs, with satisfactory results and good functional group
tolerance (Table 3). In addition, we have also divulged, to our knowledge, a novel and convenient route to a differentially-
substituted bis(guanidine) motif that is under current investigation.
Acknowledgements
The authors would like to acknowledge Dr. Rob Bradbury for his valuable comments and Mr. Patrice Koza for his analytical
support.
Supplementary data
Full experimental procedures and supporting 1H and 13C NMR and HRMS characterisation data are available at no extra
charge via the on-line version.
References and notes

6
Tetrahedron Letters
1. a) Mannig, G.; Whyte, D. B.; Martinez, R.; Hunter, T.; Sudarsanam, S. Science 2002, 298, 1912–1934; b) Fabian,
A.; Biggs, H.; Treiber, D. K.; Atteridge, E.; Azimioara, M. D.; Benedetti, M. G.; Carter, T. A.; Ciceri, P.; Edeen, T.;
Floyd, M.; Ford, J. M.; Galvin, M.; Gerlach, J. L.; Grotzfeld, R. M.; Herrgard, S.; Insko, D. E.; Insko, M. A.; Lai, A.
G.; Lelias, J-M.; Mehta, S. A.; Milanov, Z. V.; Velasco, A. M.; Wodicka, L. M.; Patel, H. K.; Zarrinkar, P. P.;
Lockhart, D. J. Nature Biotech. 2005, 23, 329-336; c) Karaman, M. W.; Herrgard, S.; Treiber, D. K.; Gallant P.;
Atteridge, C. E.; Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.; Edeen, P. T.;, Faraoni, R.; Floyd, M.; Hunt,
J. P.; Lockhart, D. J.; Milanov, Z. V.; Morrison, M. J.; Pallares, G, Patel, H. K.; Pritchard, S.; Wodicka, L. M.;
Zarrinkar, P. P. Nature Biotech. 2008, 26, 127-132.
2. a) Bridges, A. J. Chem. Rev. 2001, 101, 2541-2571; b) Kebl, B. M.; Muller, G. Expert Opin. Ther. Targets 2005, 9,
975-993; c) Laird, A. D.; Cherrington, J. M. Expert Opin. Invest. Drugs 2003, 12, 51; d) Zhang, J.; Yang, P. L.;
Gray, N. S. Nat. Rev. Cancer 2009, 9, 28–39; d) Chahrour, O.; Cairns, D.; Omran, Z. Mini-Rev. Med. Chem. 2012,
12, 399-411; e) Traxler, P; Bold, G; Buchdunger, E; Caravatti, G; Furet, P; Manley, P; O'Reilly, T; Wood, J.;
Zimmermann, J. Med. Res. Rev. 2001, 21, 499-512; f) Zuccotto, F.; Ardini, E.; Casale, E.; Angiolini, M. J. Med.
Chem. 2010, 53, 2681–2694 and references cited therein; g) Morphy, R. J. Med. Chem. 2010, 53, 1413–1437.
3. Harris, C. S.; Hennequin, L. F. ; Morgentin, R.; Pasquet, G. Targets in Heterocyclic Systems 2010, 14, 315-350.
4. Dobson, C. M. Nature 2004, 432, 824–828.
5. To our knowledge there is just one reference proposing the 3,5-bis(amino)-1,2,4-thiadiazole motif as a potential
template for polo-like kinase inhibition that was published after our programme: Diebold, R. B.; Djuric, S. W.;
Giranda, V. L.; Hexamer, L.; Lin, N-H.; Miyashiro, J. M.; Penning, T. D.; Przytulinska, M.; Sowin, T.; Sullivan, G.;
Tao, Z-F.; Tong, Y.; Vasudevan, A.; Wang, L.; Woods, K. W.; Xia, Z.; Zhang, H. Q. PCT Int. Appl. 2007 WO
2007140233.
6. a) Hudson, R. F.;Wallis, J. D.; Hansel1, D. P. Heterocycles 1994, 37, 1933-1950; b) Martin Pomerantz, M.
Tetrahedron Lett. 2003, 44, 1563–1565; c) McKinnon, D. M.; Abouzeid, A. A. J. Het. Chem. 1991, 749-752.
7. Pandey, A. K.; Singh, R.; Verma, V. K. J. Ind. Chem. Soc. 1987, 64, 675-677.
8. a) Kurzer, F. J. Chem. Soc., Perkin Trans. 1 1985, 2, 311-314; b) Panpalia, R.; Bhagwatkar, R.; Tayade, D. Int. J.
Chem. Sci. 2010, 8, 676-680; c) Tayade, D. T.; Waghmare, J. S.; Patil, S. U. Indian. J. Heterocycl. Chem. 2006, 15,
379-382.
9. Gandhe, S. V.; Berad, B. N. Asian J. Chem. 2008, 20, 32-36.
10. Kihara, Y.; Kabashima, S.; Uno, K.; Okawara, T.; Yamasaki, T.; Furukawa, M. Synthesis 1990, 11, 1020-1023.
11. Azhakumoni, L.; Joshua, C. P.; Rajasekharan, K. N. Ind. J. Chem., Sect. B: Org. Chem. Inc. Med. Chem. 1977,
15B, 490-491; b) Gupta, A.; Mishra, P.; Pandeya, S. N.; Kashaw, S. K.; Kashaw, V.; Stables, J. P. Eur. J. Med.
Chem. 2009, 44, 1100-1105.
12. For direct SNAr with aromatic and heteroaromatic amines see: a) Smith, N. D.; Bonnefous, C.; Zhuang, H.; Chen,
X.; Duron, S.; Lindstrom, A. PCT Int. Appl. 2009, WO2009029617; b) Blurton, P.; Fletcher, S.; Teall, M.;
Harrison, T.; Munoz, B.; Rivkin, A.; Hamblett, C.; Siliphaivanh, P.; Otte, K. PCT Int. Appl. 2008, WO2008099210.
13. Gahman, T. C.; Herbert, M. R.; Lang, H.; Thayer, A.; Symons, K. T.; Nguyen, P. M.; Massari, M. E.; Dozier, S.;
Zhang, Y.; Sablad, M.; Rao, T. S.; Noble, S. A.; Shiau, A. K.; Hassig, C. A. Bioorg. Med. Chem. Lett. 2011, 21,
6888-6894.
14. a) Suyama, T.; Soga, T.; Miyauchi, K. Nippon Kagaku Kaishi 1989, 5, 884-887; b); Dahmen, S.; Braese, S. Org.
Lett. 2000, 2, 3563-3565; c) O'Connor, S. P.; Atwal, K.; Li, C.; Liu, E. C.-K.; Seiler, S. M.; Shi, M.; Shi, Y.; Stein,
P. D.; Wang, Y. Bioorg Med Chem. Lett. 2008, 18, 4696-4699.
15. Search carried out using Sci-Finder© on 5th October 2012.

H
~
O
S
N
~
N
H
N
O
~
O
H
H
R
N
Gatekeeper
residue
H
H
N
N
O
N
N
N
H
H
R1
N
N
N
Hydrophobic
back pocket
N
R2
N
HO
HO
H
O
N+
H
H
O
O
O
P
O
O
P
O
O
O
P
O
O
Figure 1. Proposed binding mode of the BAT motif in the hinge region according to the Traxler model (ATP in grey; hinge backbone
in blue; gatekeeper gatekeeper residue in red; key donor and acceptor interactions in magneta; conserved lysine residue in green).

Table 1. A selection of the results obtained after optimisation of the first SNAr step.
Cl
Cl
R1NH2
N
N
R1
N
N
Cl
N
conditions
S
S
H
Entry
1
R1
Conditions
Pd(OAc)2, xantphos,
Cs2CO3, 1,4-
%Yield
traces
*
*
*
dioxane, 80-140 °C
DMF, K2CO3, r.t. to
120 °C
2
3
4
traces
100
80
Cyclohexanol,
DIPEA, r.t.-80 °C
Cyclohexanol,
DIPEA, r.t.-80 °C
Cl
O
*
Cyclohexanol,
DIPEA, r.t.-80 °C
5
6
91
98
S
*
H2N
O
Cyclohexanol,
DIPEA, r.t.-80 °C
*

Table 2. A selection of the results obtained from the optimisation of the second SNAr step.
H
Cl
N
OH
Conditions
N
N
N
+
HO
NH
N
N
N
N
OH
S
S
N
N
NH2
H
H
H2N
H
9
10
8
OH
Entry
1
Conditions
Pd(OAc)2, xantphos,
Cs2CO3, DMA, 80-160 °C
%Yield
traces
DMF, K2CO3,
r.t. to 120 °C
Cyclohexanol, DIPEA,
r.t.-140 °C
Neat aniline (3 eq), 140
°C
2
3
4
5
6
deg.
traces
43a
Cyclohexanol, cat. HCl,
r.t.-140 °C
deg.
78
Cyclohexanol, DIPEA,
ZnCl2, 120 °C
a The ring-opened product also formed in 18% yield; deg. = degradation.

Table 3. A small selection of the library compounds synthesised using this mild, two-step, one-pot approach
Entry
1
Compound
11
R1
R2
%Yield
*
56
N
Cl
Cl
*
*
O
O
2
12
40
S
*
H2N
O
3
4
13
14
45
37
HO
*
*
*
NC
*
O
*
5
6
15
16
70
48
N
*
H
*
*
O
S
*
H2N
O
*
7
8
9
17
18
19
54
56
71
N
N
N
O
*
*
*
O
O
*
*
N
N
10
11
20
21
71
31
*
O
*
*
O
*
12a
21
*
27
O
N
Ph
a Compound 21 was prepared in a two-step manner.

Graphical Abstract
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Fonts or abstract dimensions should not be changed or altered.
Leave this area blank for abstract info.
One-pot synthesis of bis(amino)-1,2,4-
thiadiazoles via direct SNAr
Howard A. Beeley, Sébastien Degorce, Craig S. Harris, Jonathan Lecoq, Rémy Morgentin and David Perkins
The synthesis of bis(amino)-1,2,4-thiadiazoles usually relies on a four step sequence. Herein, we communicate to our
knowledge the first one-pot synthesis of bis(amino)-1,2,4-thiadiazoles via a double SNAr approach.
One-pot
R2
R1NH2 DIPEA
Cl
NH
cyclohexanol,
r.t. to 80 °C
N
N
R1
N
N
Cl
R2NH2
ZnCl2
N
S
S
H
90-120 °C