Parallel synthesis of 1,2,3-thiadiazoles employing a 'catch and release' strategy

Full text of DOI:10.1021/jo981874v

J . Org. Chem. 1999, 64, 1049-1051
1049
Ta ble 1. Syn th esis of 1,2,3-Th ia d ia zoles Usin g
Com m er cia lly Ava ila ble Keton es
P a r a llel Syn th esis of 1,2,3-Th ia d ia zoles
Em p loyin g a “Ca tch a n d Relea se” Str a tegy
Yonghan Hu,† Sylvie Baudart, and J ohn A. Porco, J r.*
Argonaut Technologies, 887 G Industrial Road,
San Carlos, California 94070
Received September 15, 1998
Combinatorial solid-1 and solution-phase2 methods
have been frequently employed in the synthesis of
compound libraries of potential biological and therapeutic
significance. Many novel methodologies have been de-
veloped, including “catch and release” and “resin capture”
strategies for the expedited workup and purification of
compounds synthesized in solution.3,4 In this paper, we
report a parallel synthesis of 1,2,3-thiadiazoles employing
a “catch and release” strategy wherein ketones may be
prepared in solution and captured to the solid support
via sulfonylhydrazone formation. 1,2,3-Thiadiazoles are
an important class of biologically active compounds5 as
well as useful intermediates in organic synthesis.6 For
example, 4,5-bis(4′-methoxyphenyl)-1,2,3-thiadiazole was
found to be an active inhibitor of collagen-induced platelet
aggregation in vitro.5a Many methods have been devel-
oped for the synthesis of 1,2,3-thiadiazoles,5d,e of which
the Hurd-Mori cyclization of R-methylene ketones is the
most convenient methodology.7,8 Further transformation
of support-bound sulfonylhydrazones (Stille coupling)
before final cyclative release of 1,2,3-thiadiazoles from
the resin is also described.
a
Purity measured by HPLC (Area %).
solid-phase synthesis. In our hands, sulfonylhydrazone
formation was found to be complete in 2-4 h at 50 °C in
the presence of acetic acid using 2.5 equiv of ketone. The
large number of commercially available ketones provides
access to a variety of support-bound sulfonylhydrazones
which may be subject to cleavage using thionyl chloride
(dichloroethane (DCE), 60 °C, 5 h) to afford 1,2,3-
thiadiazoles. Seven ketones were selected and sulfonyl-
hydrazone formation/Hurd-Mori cleavage conducted in
parallel using the Quest 210 organic synthesizer. Al-
though the regioselectivity of the Hurd-Mori reaction
has been studied,8a only aromatic or symmetrical ali-
phatic ketones were employed herein to avoid the forma-
tion of regioisomeric products. Purification of the cleavage
solution was performed in parallel using saturated
Na2CO3 preloaded onto liquid-liquid extraction car-
tridges.11 All thiadiazoles were obtained in high chemical
yield and purity (Scheme 1, Table 1).
Recently we prepared a gel-type polystyrene-sulfonyl-
hydrazide resin (PS-Ts-NHNH2) for carbonyl scavenging
applications.9,10 We felt that the sulfonylhydrazide resin
could also serve as a linker for carbonyl compounds in
† Current address: Genetics Institute, 85 Bolton St., Cambridge,
MA 02140.
(1) (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J .; Fodor, S. P. A.;
Gordon, E. M. J . Med. Chem. 1994, 37, 1233. For a recent review, see:
(b) Thompson, M. A.; Ellman, J . A. Chem. Rev. 1996, 96, 555.
(2) (a) Coffen, D. L., Ed.; Solution Phase Combinatorial Chemistry;
Tetrahedron 1998, 54. (b) Kaldor, S. W.; Siegel, M. W. Curr. Opin.
Chem. Biol. 1997, 1, 101.
(3) For “catch and release” of amines, see: (a) Siegel, M. G.; Hahn,
P. J .; Dressman, B. A.; Fritz, J . E.; Grunwell, J . R.; Kaldor, S. W.
Tetrahedron Lett. 1997, 38, 3357. (b) Shuker, A. J .; Siegel, M. G.;
Matthews, D. P.; Weigel, L. O. Tetrahedron Lett. 1997, 38, 6149. (c)
Liu, Y.; Zhao, C.; Bergbreiter, D. E.; Romo, D. J . Org. Chem. 1998, 63,
3471.
(4) For examples of “resin capture”, see: (a) Keating, T. A.; Arm-
strong, R. W. J . Am. Chem. Soc. 1996, 118, 2574. (b) Brown, S. D.;
Armstrong, R. W. J . Am. Chem. Soc. 1996, 118, 6331. (c) Brown, S.
D.; Armstrong, R. W. J . Org. Chem. 1997, 62, 7076. (c) Chen, C.;
McDonald, I. A.; Munoz, B. Tetrahedron Lett. 1998, 39, 217.
(5) (a) Thomas, E. W.; Nishizawa, E. E.; Zimmermann, D. C.,
Williams, D. J . J . Med. Chem. 1985, 28, 442. (b) Lewis, G. S.; Nelson,
P. H. J . Med. Chem. 1979, 22, 1214. (c) Britton, T. C.; Lobl, T. J .;
Chidester, C. G. J . Org. Chem. 1984, 49, 4773. For reviews on the
chemistry of 1,2,3-thiadiazoles, see: (d) Thomas, E. W. In Compre-
hensive Heterocyclic Chemistry; Potts, K. T., Vol Ed.; Katritzky, A. R.,
Rees, C. W., Series Eds.; Pergamon Press: London, 1984; Vol. 6, Part
The formation of support-bound sulfonylhydrazones
from noncommercially available ketones may be facili-
tated by use of a “resin capture strategy”4 (Scheme 2,
Table 2). Six p-bromophenyl ketones were prepared in
parallel on the Quest 210 organic synthesizer by reacting
N-methoxy-N-methyl-p-bromobenzamide (8)12 with a va-
riety of Grignard reagents (THF, 0 °C). The reaction
(9) PS-TsNHNH2 resin (1.8-2.5 mmol/g, 1% cross-linked polystyrene-
co-divinylbenzene) is commercially available from Argonaut Technolo-
gies.
(10) For reports on the preparation and use of sulfonylhydrazide
resins, see: (a) Galioglu, O.; Akar, A. Eur. Polym. J . 1989, 25, 313. (b)
Emerson, D. W.; Emerson, R. R.; J oshi, S. C.; Sorensen, E. M.; Turek,
J . M. J . Org. Chem. 1979, 44, 4634. (c) Kamogawa, H.; Kanzawa, A.;
Kadoya, M.; Naito, T.; Nanasawa, M. Bull. Chem. Soc. J pn. 1983, 56,
762.
4B, Chapter 4.24,
p 447. (e) Thomas, E. W. In Comprehensive
Heterocyclic Chemistry; Storr, R. C., Vol Ed.; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Series Eds.; Pergamon Press: London, 1996;
Vol. 4, Chapter 4.07, p 289.
(6) Rovira, C.; Veciana, J .; Santalo, N.; Tarres, J .; Cirujeda, J .;
Molins, E.; Llorca, J .; Espinosa, E. J . Org. Chem. 1994, 59, 3307.
(7) Hurd, C. D.; Mori, R. I. J . Am. Chem. Soc. 1955, 77, 5359.
(8) (a) Fujita, M.; Kobori, T.; Hiyama, T.; Kondo, K. Heterocycles
1993, 36, 33. (b) Stanetty, P.; Kremslehner, M.; Mullner, M. J .
Heterocycl. Chem. 1996, 33, 1759.
(11) For examples of parallel workups employing liquid-liquid
extraction cartridges, see: (a) J ohnson, C. R.; Zhang, B.; Fantauzzi,
P.; Hocker, M.; Yager, K. M. Tetrahedron 1998, 54, 4097. (b) Breiten-
bucher, J . G.; J ohnson, C. R.; Haight, M.; Phelan, J . C. Tetrahedron
Lett. 1998, 39, 1295.
(12) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
10.1021/jo981874v CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/15/1999

1050 J . Org. Chem., Vol. 64, No. 3, 1999
Ta ble 2. 1,2,3-Th ia d ia zoles P r ep a r ed via “Resin Ca p tu r e” of Keton es
Notes
Sch em e 1. Syn th esis of 1,2,3-Th ia d ia zoles Usin g Com m er cia lly Ava ila ble Keton es
Sch em e 2. 1,2,3-Th ia d ia zoles P r ep a r ed via “Resin
Ca p tu r e” of Keton es
Support-bound sulfonylhydrazones with aryl halide
substituents may be subjected to further transformations
such as the Stille reaction15,16 for the generation of more
highly diverse thiadiazole structures. Thus, a support-
bound sulfonylhydrazone generated from 4-bromoaceto-
phenone (Scheme 3, R1 ) Br) was reacted with aryl-
stannanes using either Pd(PPh3)2Cl2 or Pd(PPh3)4 as
catalyst (10 mol % in DMF). The reactions were found to
be complete in 24 h at 90 °C using either catalyst. After
thionyl chloride cleavage and cartridge-based purifica-
tion, the products were filtered through a small plug of
silica gel to remove baseline impurities. Table 3 shows
thiadiazole products generated from Stille coupling em-
ploying Pd(PPh3)2Cl2 as catalyst (Scheme 3, Table 3).
Entry 3 of Table 3 shows an example performed using
“resin capture” of an aryl ketone prepared in situ from
the Weinreb amide derivative.12
mixtures were then quenched with a macroporous poly-
styrene-sulfonic acid resin (MP-TsOH) to decompose the
tetrahedral intermediate.13 Acetic acid (10% v/v) was
added, and the ketone solutions were directly transferred
via cannula to reaction vessels containing PS-TsNHNH2
resin. After thionyl chloride cleavage and purification
(vide supra), a series of 1,2,3-thiadiazoles were prepared
with various substituents at 5 position. In the case of
entry 6 of Table 2, compound 14, resulting from the
further addition of HCl (from SOCl2) to the olefin, was
obtained. Compounds similar to 13 are of great interest
since antithrombotic compounds have been found to bear
aromatic substituents at both 4 and 5 positions of the
1,2,3-thiadiazole ring.5a Structurally similar compounds
may, in principle, be generated by resin capture of
ketones synthesized using other methods, e.g., aryl
Grignard addition to N-methoxy-N-methyl-2-arylacet-
amides or Friedel-Crafts reactions.14
In summary, we have developed a very efficient hybrid
solution-/solid-phase sequence for the synthesis of 1,2,3-
thiadiazoles employing “resin capture” of ketones without
the need for chromatography. Cyclative cleavage of resin-
bound sulfonylhydrazones was accomplished using thio-
nyl chloride to afford 1,2,3-thiadiazoles. Stille coupling
(C-C bond formation) of resin-bound intermediates was
also demonstrated. Additional diversification reactions
(15) Stille, J . K. Pure Appl. Chem. 1985, 57, 1771. For a recent
review on Stille coupling reactions, see: Farina, V.; Krishnamurthy,
V.; Scott, W. J . Org. React. 1997, 50, 1.
(16) For examples of Stille coupling on solid support, see: (a)
Blaskovich, M. A.; Kahn, M. J . Org. Chem. 1998, 63, 1119. (b) Chamoin,
S.; Houldsworth S.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4175. (c)
Forman, F. W.; Sucholeiki, I. J . Org. Chem. 1995, 60, 523. (d) Beaver,
K. A.; Siegmund, A. C.; Spear, K. L. Tetrahedron Lett. 1996, 37, 1145.
(e) Deshpande, M. S. Tetrahedron Lett. 1994, 35, 5613. (f) Plunkett,
M. J .; Ellman, J . A. J . Org. Chem. 1995, 60, 6006. (g) Plunkett, M. J .;
Ellman, J . A. J . Am. Chem. Soc. 1995, 117, 3306.
(13) MP-TsOH resin (1.4 mmol/g, macroporous polystyrene-co-divinyl-
benzene) is commercially available from Argonaut Technologies.
(14) Olah, G. A. Friedel-Crafts and Related Reactions; Interscience
Publishers: New York, 1963; Vol. 1.

Notes
J . Org. Chem., Vol. 64, No. 3, 1999 1051
Sch em e 3. 1,2,3-Th ia d ia zoles fr om Stille Cou p lin g Usin g P d (P P h 3)2Cl2 a s Ca ta lyst
Ta ble 3. 1,2,3-Th ia d ia zoles fr om Stille Cou p lin g
equiv: CH3MgCl (3.0 M, 465 µL), n-BuMgCl (2.0 M, 695 µL),
EtMgBr (3.14 M, 442 µL), i-BuMgCl (2.0 M, 695 µL), PhCH2-
MgCl (2.0 M, 695 µL), CH2dCHCH2 MgCl (2.0 M, 695 µL)) via
syringe. The reaction mixtures were allowed to agitate at 0 °C
for 3 h. To each reaction vessel was then added 1 g (1.45 mmol/
g, 1.45 mmol) of MP-TsOH. After agitation for 10 min at 0 °C
followed by addition of 0.3 mL of AcOH, the solutions were
transferred using a transfer cannula to the corresponding
reaction vessels containing PS-TsNHNH2 resin in bank A. The
reaction vessels in bank A were agitated at 50 °C for 4 h. The
reactions were cooled to room temperature, emptied, and washed
with THF (3 × 4 mL), hexane (2 × 4 mL), and dichloroethane
(3 × 4 mL). Then 2.3 mL dichloroethane and 700 µL of SOCl2
(9.6 mmol, 20 equiv) were added to each reaction vessel. After
agitating for 5 h at 60 °C, the reaction mixtures (and 3 × 4 mL
dichloroethane washes) were filtered through liquid-liquid
extraction cartridges (Extube Extraction Columns preloaded
with 3 mL of saturated Na2CO3 for 10 min) into scintillation
vials and concentrated to afford the 1,2,3-thiadiazole products.
a
Aryl ketone synthesized from the reaction of N-methoxy-N-
methyl-p-bromobenzamide (5) with n-BuMgCl.
1,2,3-Th ia d ia zole (9): 1H NMR (300 MHz, CDCl3) δ 8.65 (s,
1 H, dCH), 7.93 (d, 2 H, J ) 8.7 Hz, Ar-H), 7.65 (d, 2 H, J )
8.7 Hz, Ar-H) ppm; 13C NMR (75 MHz, CDCl3) δ 161.7, 132.2,
130.0, 129.6, 128.7, 123.5 ppm.
1,2,3-Th ia d ia zole (10): 1H NMR (300 MHz, CDCl3) δ 7.62
(m, 4 H, Ar-H), 3.02 (t, 2 H, J ) 7.7 Hz, -CH2-), 1.78 (m, 2 H,
-CH2-), 1.01 (t, 3 H, J ) 7.4 Hz, -CH3) ppm; 13C NMR (75 MHz,
CDCl3) δ 158.0, 153.1, 131.9, 130.3, 120.3, 123.0, 27.5, 25.0, 13.5
ppm; MS (APCI) calcd for C11H11N2SBr 282.1, found 283.0 [M
+ 1]+.
1,2,3-Th ia d ia zole (11): 1H NMR (300 MHz, CDCl3) δ 7.65
(m, 4 H, Ar-H), 2.71 (s, 3 H, -CH3) ppm; 13C NMR (75 MHz,
CDCl3) δ 158.5, 146.5, 132.8, 131.9, 130.1, 123.0, 10.1 ppm.
1,2,3-Th ia d ia zole (12): 1H NMR (300 MHz, CDCl3) δ 7.65
(d, 2 H, J ) 8.4 Hz, Ar-H), 7.56 (d, 2 H, J ) 8.4 Hz, Ar-H),
3.51 (septet, 1 H, J ) 6.6 Hz, -CH-), 1.39 (d, 6 H, J ) 6.6 Hz,
-(CH3)2) ppm; 13C NMR (75 MHz, CDCl3) δ 161.4, 157.7, 131.9,
130.5, 130.3, 123.1, 26.9, 25.6 ppm.
1,2,3-Th ia d ia zole (13): 1H NMR (300 MHz, CDCl3) δ 7.51
(m, 5 H, Ph-H), 7.44-7.33 (m, 4 H, Ar-H) ppm; 13C NMR (75
MHz, CDCl3) δ 156.3, 151.1, 131.8, 131.6, 130.5, 129.8, 129.2,
129.1, 127.51, 123.2 ppm; MS (APCI) calcd for C14H9N2SBr 316.2,
found 317.2 [M + 1]+.
1,2,3-Th ia d ia zole (14): 1H NMR (300 MHz, CDCl3) δ 7.70
(m, 4 H, Ar-H), 5.39 (q, 1 H, J ) 6.8 Hz, -CClH-), 1.97 (d, 3
H, J ) 6.8 Hz, -CH3) ppm; 13C NMR (75 MHz, CDCl3) δ 157.6,
154.7, 132.3, 131.9, 130.4, 123.7, 48.0, 28.3 ppm; MS (EI) calcd
for C10H8N2SBrCl 303.9, found 304 (M+), 289, 276, 241, 236, 195
(base), 160, 149, 128, 116.
of resin-bound sulfonylhydrazones are possible, as well
as alternative cleavage protocols (e.g., Shapiro olefin
synthesis,17 reductive cleavage10c,18) to form additional
compound classes. Further studies along these lines are
in progress and will be reported in due course.
Exp er im en ta l Section
Gen er a l. Standard reagents were obtained from commercial
suppliers and used without further purification. Polystyrene-
sulfonylhydrazide resin (PS-Ts-NHNH2) and macroporous poly-
styrene-sulfonic acid resin (MP-TsOH) were obtained from
Argonaut Technologies (San Carlos, CA). N-Methoxy-N-methyl-
p-bromobenzamide was prepared according to the literature
procedure.12 All parallel synthesis transformations were per-
formed on the Quest 210 organic synthesizer (Argonaut Tech-
nologies, San Carlos, CA). Extube liquid-liquid extraction
cartridges (Chem Elut, Part no. 1219-8003) were purchased from
Varian Sample Preparation Products (Harbor City, CA). 1H and
13C NMR spectra were obtained on a Varian 300 MHz spectrom-
eter in CDCl3 and are reported in ppm. Mass spectroscopy was
performed at SynPep Corp. (Dublin, CA). GC analysis was
performed on a Hewlett-Packard 6890 GC with an HP-5 phenyl-
methylsilicone capillary column (30 m × 0.32 mm × 0.25 µm)
(GC method 175 °C (3 min), ramp up to 300 °C (20 °C/min), 300
°C for 5 min). HPLC analysis was performed on a Hewlett-
Packard 1050 HPLC with a Microsorb MV C18 column (HPLC
method 2-95% acetonitrile/water (8 min), 95-2% acetonitrile/
water (2 min)).
Exp er im en ta l P r oced u r e for th e Syn th esis of 1,2,3-
Th ia d ia zoles via “Resin Ca p tu r e” (Ta ble 2, En tr ies 1-6).
PS-TsNHNH2 resin (200 mg, 2.4 mmol/g, 0.48 mmol) was loaded
into six 5-mL Teflon reaction vessels on bank A of the Quest
210 synthesizer. Reaction vessels containing resin were then
purged with nitrogen for 2 min. On bank B of the Quest 210,
N-methoxy-N-methyl-p-bromobenzamide12 (215 µL, 1.25 mmol)
was added into six 5-mL Teflon reaction vessels with 3 mL of
dry THF, respectively. The reaction vessels were cooled to 0 °C
using a J ulabo recirculating chiller. To the reaction vessels were
then added the appropriate Grignard reagents (1.38 mmol, 1.1
Ack n ow led gm en t . We thank J eff W. Labadie,
Owen W. Gooding, and Sukanta Bhattacharyya (Argo-
naut Technologies) for helpful discussions and Alasdair
MacDonald and Reid Otto (Argonaut Technologies) for
experimental assistance.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for thiadiazoles 1-7 and
1
15-16 and representative H and 13C NMR spectra for 1,2,3-
thiadiazoles. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) For a review, see: Adlington, R. M.; Barrett, A. G. M. Acc.
Chem. Res. 1983, 16, 55.
(18) Caglioti, L. Org. Synth. 1972, 52, 122.
J O981874V