Facile synthesis of substituted 5-amino- And 3-amino-1,2,4-thiadiazoles from a common precursor

Article abstract of DOI:10.1021/ol902371y

[Chemical Equation Presented] A novel approach to the synthesis of substituted 5-amino- and 3-amino-1,2,4-thiadiazoles beginning from a common precursor has been achieved. Derivatization by palladium-catalyzed Suzuki-Miyaura coupling enables the rapid pre

Full text of DOI:10.1021/ol902371y

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5666-5669
Facile Synthesis of Substituted
5-Amino- and 3-Amino-1,2,4-Thiadiazoles
from a Common Precursor
Paul M. Wehn,*,† Paul E. Harrington,‡ and John E. Eksterowicz§
Department of Medicinal Chemistry, Amgen Inc., 1120 Veterans BouleVard,
South San Francisco, California 94080, Department of Medicinal Chemistry, Amgen Inc.,
One Amgen Center DriVe, Thousand Oaks, California 91320, and Department of Molecular
Structure, Amgen Inc., 1120 Veterans BouleVard, South San Francisco, California 94080
pwehn@amgen.com
Received October 14, 2009
ABSTRACT
A novel approach to the synthesis of substituted 5-amino- and 3-amino-1,2,4-thiadiazoles beginning from a common precursor has been
achieved. Derivatization by palladium-catalyzed Suzuki-Miyaura coupling enables the rapid preparation of analogs around this pharmaceutically
relevant core. FMO calculations rationalize the observed chemoselectivity for coupling at chlorine.
As part of a program aimed at the identification of allosteric
modulators of the calcium sensing receptor, we became
interested in the preparation of 3-aryl-5-amino-1,2,4-thia-
diazoles as metabolically stable replacements of a 2-amino-
4-aryl-thiazole moiety (eq 1). 2-Amino-thiazoles without
blocking substituents at C-5 can undergo oxidation in ViVo
to generate potentially toxic reactive epoxide metabolites.1
thiadiazole in potential pharmaceuticals2 and cytotoxic
natural products3 (Figure 1), there is a dearth of methods
available for the rapid synthesis of analogs.4 The most
efficient of these methods requires the use of amidine and
isothiocyanate intermediates (eq 2).5,6 For our purposes,
access to the unfunctionalized 3-aryl-5-amino-1,2,4-thiadia-
zoles was required (R ) H, eq 2). We envisaged a
complementary method that would obviate the need for
(1) Kalgutkar, A. S.; Gardner, I.; Obach, R. S.; Shaffer, C. L.; Callegari,
E.; Henne, K. R.; Mutlib, A. E.; Dalvie, D. K.; Lee, J. S.; Nakai, Y.;
O’Donnell, J. P.; Boer, J.; Harriman, S. P. Curr. Drug Metab. 2005, 6,
161–225.
(2) (a) Sutton, J. C.; Pi, Z.; Ruel, R.; L’Heureux, A.; Thibeault, C.; Lam,
P. Y. S. U.S. Patent US20060173002A1, 2006. (b) MacNeil, D. J.; McIntyre,
J. H.; van der Ploeg, L. H. T.; Ishihara, A. World Intellectual Property
Organization Patent WO04009015A2, 2004.
Despite the presence of the 5-amino-3-substituted-1,2,4-
thiadiazole and the isomeric 3-amino-5-substituted-1,2,4-
(3) Heitz, S.; Durgeat, M.; Guyot, M. Tetrahedron Lett. 1980, 21, 1457–
1458.
(4) Wilkins, D. J.; Bradley, P. A. ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New
York, NY, 1996; Vol. 4, Chapter 10, pp 307-354.
† Dept. of Medicinal Chemistry, So. San Francisco.
‡ Dept. of Medicinal Chemistry, Thousand Oaks.
§ Dept. of Molecular Structure, So. San Francisco.
(5) Wu, Y.-J.; Zhang, Y. Tetrahedron Lett. 2008, 49, 2869–2871
.
10.1021/ol902371y  2009 American Chemical Society
Published on Web 11/11/2009

catalysts under varying conditions gave uniformly disappointing
results (entries 2-5). Of these catalysts, Pd(PtBu3)2 stood out
as the best. Interestingly, the use of wet dioxane improved yields
slightly (entry 6). We suspected that the unprotected amino
group was responsible for the reduced yields10,11 and investi-
gated a strategy of temporarily protecting the amino group
as a t-butyl carbamate.12 Such protected thiadiazoles improved
reactivity (entry 7). A scan of basic additives indicated that reducing
the base strength also enhanced the yield slightly (entry 8). Finally,
the use of a phosphine analog of PtBu3 improved coupling to
synthetically useful levels (entry 9).13
With our optimized conditions in hand we explored coupling
with a variety of boronic acids and esters14 (Table 2). Results
demonstrate some dependence of reaction yield on the electron
richness of the boronic acid component (entries 1-3). Some
heteroaryl boronic esters are tolerated (entries 4, 9, and 10) and
mild steric crowding at the bononic acid is possible (entry 6).
3- and 4-Pyridylboronic acids, as well as 2,6-dimethylphenyl-
boronic acid, are not viable coupling partners, however.
Nonbasic N-H groups do not adversely impact yield (entries
1, 2, and 5). Alkenyl boronates work well (entries 7-8), but
aliphatic boronates do not.15 Deprotection of the t-butyl car-
bamate products is achieved under standard conditions (eq 4).
In the case of the N-t-butyl sulfonamide, it is possible to
selectively remove the Boc protecting group (eq 5).
Figure 1. Representative amino-1,2,4-thiadiazoles in natural prod-
ucts and potential pharmaceutical agents.
amidines and isothiocyanates by starting with the thiadiazole
intact and then functionalizing the nucleus as necessary (eq
3). By taking advantage of the broad functional group
tolerance of the Suzuki-Miyaura coupling,7 it would be
possible to efficiently prepare analogs.
A singular example from the patent literature suggested that
such an approach was feasible.8 The coupling of 5-amino-3-
bromo-1,2,4-thiadiazole9 to phenyl boronic acid using the
conditions reported gave only trace amounts of the desired
product, however (Table 1, entry 1). Examination of a suite of
Table 1. Optimization of Reaction Conditionsa
entry
-R
X mol % cat
5% Pd(PPh3)4
20% Pd(PPh3)4
20% Pd(PtBu3)2
base
solvent
yield
1b
2
3
4
5
6
7
8
9
-H
-H
-H
-H
-H
-H
K2CO3
Cs2CO3
Cs2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
CsF
aq. CH3CN 175 °C, µW
Dioxane 80 °C
Dioxane 80 °C
1-Butanol 100 °C
Dioxane 80 °C
aq. Dioxane 80 °C
aq. Dioxane 80 °C
aq. Dioxane 80 °C
aq. Dioxane 80 °C
tracec
tracec
8%d
4% Pd2(dba)3 8% XPhos
20% PdCl2(DPPF)
20% Pd(PtBu3)2
NDc
tracec
13%d
27%e
33%e
68%e
t
-CO2 Bu
5% Pd(PtBu3)2
-CO2 Bu
5% Pd(PtBu3)2
t
t
-CO2 Bu
5% PdCl2{PtBu2(p-NMe2-C6H4)}2
CsF
a Reaction time (8-16 h), aqueous solvent denotes 10% H2O. b Reaction time (15 min). c As determined by LCMS monitoring using UV detection at
e
254 nM. d Complete conversion, isolated yield, see footnote 11. Incomplete conversion, yield estimated by integration of H NMR from purified mixture
1
containing product and unreacted bromide.
Org. Lett., Vol. 11, No. 24, 2009
5667

5-chloro-1,2,4-thiadiazole. The sequential selective cross-
coupling of such polyhalogenated heterocycles has emerged
as an efficient strategy for the construction of polysubstituted
heterocycles.16 Our prediction was that reaction should occur
at the C-3 bromide exclusively. However, upon using the
optimized conditions developed previously, the product of
selectiVe coupling at the C-5 chloride was obserVed (Table
3, entry 1).17 Further investigation of the reaction with a
Table 2. Suzuki-Miyaura Couplings of tert-Butyl
3-Bromo-1,2,4-thiadiazol-5-ylcarbamatea
Table 3. Suzuki-Miyaura Couplings of 3-Bromo-5-chloro-
1,2,4-thiadiazolea
a Reaction conditions: thiadiazole bromide (1.0 equiv), boronic acid or
boronate (1.3 equiv), CsF (2.1 equiv), 10% aqueous 1,4-dioxane (3 mL/
mmol thiadiazole), scale (1-6 mmol thiadiazole), reaction time (6 h).
b Isolated yield based on an average of two runs. c Pd cat (8 mol %) was
used and reaction heated to 90 °C for 16 h.
a Reaction conditions: thiadiazole (1.0 equiv), boronic acid or boronate
(1.2 equiv), CsF (2.0 equiv), 10% aqueous 1,4-dioxane (5 mL/mmol
thiadiazole), scale (2 mmol thiadiazole), reaction time (16 h). b Isolated
yield based on an average of two runs. c Conditions changed: thiadiazole
(1.75 equiv), boronic acid (1.0 equiv), see ref 18.
As an alternative to coupling the problematic 3-bromo-
5-amino-1,2,4-thiadiazole, we explored the possibility of
performing a chemoselective coupling on the parent 3-bromo-
diverse set of boronic acids and esters confirmed this
selectivity.18 Coupling is possible with electron-rich and
-poor boronic acids (entry 2 vs 3). The presence of nonbasic
(6) Other efficient methods: (a) Martin, D.; Graubaum, H.; Kulpe, S. J.
Org. Chem. 1985, 50, 1295–1298. (b) Du¨ru¨st, Y.; Yildirim, M.; Aycan, A.
J. Chem. Res. 2008, 235–239.
(10) There are few reports of successful Suzuki-Miyaura reactions in
the presence of unprotected heteroaryl amines. For leading approaches see
the following and references therein: (a) Billingsley, K.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 3358–3366. (b) Guram, A. S.; Wang, X.;
Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J. J. Org. Chem.
2007, 72, 5104–5112. (c) Kudo, N.; Perseghini, M.; Fu, G. C. Angew. Chem.,
Int. Ed 2006, 45, 1282–1284. (d) Itoh, T.; Mase, T. Tetrahedron Lett. 2005,
46, 3573–3577.
(7) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419–2440.
(8) (a) No yield reported: Krenitsky, P.; Joshi, P.; Wilson, D. M.; Termin,
A. P.; Fanning, L. T. D. World Intellectual Property Organization Patent,
WO06130493A2, 2006. A patent claiming Suzuki coupling on a related
chloride derivative in a single example: (b) Apodaca, R.; Breitenbucher,
J.G.;Pattabiraman,K.;Seierstad,M.;Xiao,W.U.S.PatentUS20070004741A1,
2007.
(9) Prepared on multigram scale by reacting 3-bromo-5-chloro-1,2,4-
thiadiazole with ammonia in EtOH (see Supporting Information).
(11) Heating the unprotected 5-amino-3-bromo-1,2,4-thiadiazole in the
presence of carbonate base leads to decomposition.
5668
Org. Lett., Vol. 11, No. 24, 2009

N-H functionality is not deleterious (entries 4-5). Mono-
substitution ortho to the boronic acid is tolerated (entry 6)
and alkenyl boronic esters are viable coupling partners (entry
7). Lastly, weakly basic heterocyclic boronic acids may be
used, but the yield is reduced (entry 8). Coupling with
unsubstituted 3- or 4-pyridylboronic acids was ineffective.
The 3-bromo-5-substitued-1,2,4-thiadiazoles are versatile
intermediates readily affording access to other derivatives.19
For our purposes, however, preparation of the regioisomeric
3-amino-5-substituted-1,2,4-thiadiazoles20 would complete
the investigation. To this end, treatment of the 3-bromo-5-
substitued-1,2,4-thiadiazoles with LHMDS affords the ami-
nated derivatives (eq 6).
co-workers have invoked the analysis of the frontier mole-
cular orbitals (FMO) to explain chemoselectivity in the cross-
coupling of polyhalogenated heterocycles.22 The key interac-
tion determining selectivity is the magnitude of a stabilizing
π* LUMO - Pd dxy HOMO secondary orbital interaction.
Mapping of the LUMO for 3-bromo-5-chloro-1,2,4-thiadia-
zole identifies a π* LUMO at the 5-position (Figure 2), thus
validating the observed selectivity.23
Figure 2. High level ab initio calculations showing the π* LUMO
of 3-bromo-5-chloro-1,2,4-thiadiazole.
While chemoselectivity in cross-coupling reactions nor-
mally follows the pattern of C-I > C-Br > C-Cl, there
are rare examples when that trend is broken.21 Houk and
In summary, the serendipitous discovery of preferential
cross-coupling at the chloride of 3-bromo-5-chloro-1,2,4-
thiadiazole has enabled the delineation of a convenient
protocol for the expeditious synthesis of both 3-substituted-
5-amino- and 3-amino-5-substituted-1,2,4-thiadiazoles from
this common starting material. These intermediates should
find utility as synthons for the preparation of medicinally
relevant agents. In addition, the current methodology comple-
ments existing technologies for the construction of 3-sub-
stituted-5-amino-1,2,4-thiadiazoles. Finally, results from
these investigations reinforce the use of FMO analysis in
predicting chemo/regioselectivity for the cross-coupling of
polyhalogenated heterocycles.
(12) Caron, S.; Masset, S. S.; Bogle, D. E.; Castaldi, M. J.; Braish, T. F.
Org. Process Res. DeV. 2001, 5, 254–256.
(13) Shortly before submission of this manuscript, we discovered that
PdCl2(D-tBPF) (ref 10d) delivers slightly improved results relative to
PdCl2{PtBu2(p-NMe2-C6H4)}2 (ref 10b). For the reaction in Table 2,
complete conversion and 83% isolated yield are observed with 5 mol% of
PdCl2(D-tBPF). Both catalysts were ineffective when coupling was at-
tempted in the presence of the unprotected amino group.
(14) The use of boronic acids or esters reflects availability and not an
attempt to optimize yield.
(15) MeBF3K gives no product. The incompatibility of PdCl2{PtBu2(p-
NMe2-C6H4)}2 with aliphatic boronates has been observed previously, see
ref 10b.
(16) Schro¨ter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245–2267.
(17) Such reactivity has been observed before for 3-bromo-5-chloro-
1,2,4-thiadiazole. Single example of Stille coupling of a vinyl stannane,
see: (a) Dart, M. J.; Searle, X. B.; Tietje, K.; Toupence, R. B. U.S. Patent
US20040044029A1, 2004. Single example of Suzuki-Miyaura coupling,
see: (b) Sawyer, J. S.; Beight, D. W.; Smith, E. C. R.; McMillen, W. T.
U.S. Patent US6797723, 2004.
Acknowledgment. We thank Drs. Sarah E. Lively and
Oliver R. Thiel for helpful comments during manuscript
preparation.
(18) Yield is reduced by formation of small amounts of the bis-coupled
product. For non-polar products, the use of 1.75 equiv of thiadiazole
minimizes formation of the bis-coupled product that can complicate
purification of the mono-coupled product.
(19) Buchwald-Hartwig amination: Blurton, P.; Fletcher, S.; Teall,
M.; Harrison, T.; Munoz, B.; Rivkin, A.; Hamblett, C.; Siliphaivanh, P.;
Otte, K. World Intellectual Property Organization Patent, WO08099210A2,
2008.
Supporting Information Available: Experimental pro-
cedures, characterization data, and calculations. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL902371Y
(20) For a related approach to the synthesis of 3-amino-5-substituted-
1,2,4-thiadiazoles see: Reiter, L. A.; Subramanyam, C.; Mangual, E. J.;
Jones, C. S.; Smeets, M. I.; Brissette, W. H.; McCurdy, S. P.; Lira, P. D.;
Linde, R. G.; Li, Q.; Zhang, F.; Antipas, A. S.; Blumberg, L. C.; Doty,
J. L.; Driscoll, J. P.; Munchhof, M. J.; Ripp, S. L.; Shavnya, A.; Shepard,
R. M.; Sperger, D.; Thomasco, L. M.; Trevena, K. A.; Wolf-Gouveia, L. A.;
Zhang, L. Bioorg. Med. Chem. Lett. 2007, 17, 5447–5454.
(21) Mangalagiu, I.; Benneche, T.; Undheim, K. Acta Chem. Scand.
1996, 50, 914–917.
(22) Legault, C. Y.; Garcia, Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem.
Soc. 2007, 129, 12664–12665. (b) Garcia, Y.; Schoenebeck, F.; Legault,
C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632–
6639.
(23) The calculated bond dissociation energies for the C-Cl and C-Br
bonds are 88.2 and 80.4 kcal/mol, respectively. The bond dissociation
energies of the carbon-halogen bonds were calculated using B3LYP/6-
31G(d). These results strongly suggest control of chemoselectivity by FMO
interactions between the heterocycle and palladium catalyst.
Org. Lett., Vol. 11, No. 24, 2009
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