A new general three component solution-phase synthesis of 2-amino-1,3-thiazole and 2,4-diamino-1,3-thiazole combinatorial libraries

Article abstract of DOI:10.1016/S0040-4020(00)01003-6

A general procedure for the solution-phase synthesis of amino-1,3-thiazole libraries 9 and 10 is described. Their preparation is based on the condensation of amidines 1 and thiouronium salts 2 with isothiocyanates 3, affording amidino-thioureas and thiour

Full text of DOI:10.1016/S0040-4020(00)01003-6

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 153±156
A new general three component solution-phase synthesis of
2-amino-1,3-thiazole and 2,4-diamino-1,3-thiazole combinatorial
libraries
b
Thierry Masquelina, and Daniel Obrecht
*
aF. Hoffmann-La Roche AG, Pharma Research, CH-4070 Basel, Switzerland
bPolyphor AG, Gewerbestrasse 14, CH-4123 Allschwil, Switzerland
Received 11 February 2000; revised 23 October 2000; accepted 24 October 2000
AbstractÐA general procedure for the solution-phase synthesis of amino-1,3-thiazole libraries 9 and 10 is described. Their preparation is
based on the condensation of amidines 1 and thiouronium salts 2 with isothiocyanates 3, affording amidino±thioureas and thioureido-
thioureas of types 4 and 5. Subsequent treatment with a-bromo ketones 6 led to the S-alkylated intermediate, which yielded 1,3-thiazoles of
types 9 and 10 via a base-catalysed ring closure process (Scheme 1). In addition, this methodology tolerates a diverse range of functionality
without recourse to protection. q 2000 Elsevier Science Ltd. All rights reserved.
The richness of the pharmacopeia in compounds containing
heterocyclic systems is the basis of a continuing search for
versatile processes towards these key structural elements.
The 1,3-thiazole ring has been identi®ed as a central struc-
tural element of a number of biological active natural
products1±3 and of pharmacological active substances.4,5
Preparation of 1,3-thiazoles can be readily accomplished
using both classical and nonclassical approaches, for
example: (a) the Hantzsch synthesis,6,7 (b) via thiazolines
by condensation of aldehydes with a cysteine derivative
followed by oxidation,8 (c) reaction of 1-amidinothiourea
with a-bromo ketones,9 (d) condensation of a-halomethyl
ketimines with thioamides.10 and (e) reaction of ethyl diazo-
pyruvate with thioamides.11
isothiocyanates 3 in the presence of a base such as
1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or N,N-diiso-
propylethyl amine (DIPEA) to give amidino±thioureas
and thioureido-thioureas of type 4 and 5, followed by treat-
ment with a-bromo ketones 6 leading to the S-alkylated
intermediates 7 and 8, which underwent base-catalysed
intramolecular Knoevenagel-type condensation to furnish
1,3-thiazoles of type 9 and 10. Thereby, intermediates of
type 7 (R1ˆalkyl, aryl) and 8 (R1ˆSCH2Ar) yield, respec-
tively by elimination of ammonia, the 1,3-thiazoles 9, and
by elimination of the corresponding thiols, the 1,3-thiazoles
10 (Scheme 1).
Preliminary studies on the synthesis of the 1,3-thiazoles
using amidines 1 in dry DMF with isothiocyanates 3 in
the presence of DBU or DIPEA afforded the corresponding
amidino±thiourea derivatives 4 in good yields (Table 1;
Method A). Subsequent S-alkylation with a-bromo ketones
6, followed by base-catalysed ring closure with elimination
of NH3 gave 2-aminothiazoles 9 in excellent yields (Table 2;
Scheme 1; Method B). It is useful to note that this reaction
sequence was conveniently performed in one-pot reaction
without isolation of the intermediates 4 and 5.
Despite the existing approaches to 1,3-thiazoles, there is still
need for new general procedures, especially considering the
potential opportunities in parallel and combinatorial chem-
istry.12,13 Thus, in the course of our investigations towards
the development of potentially valuable strategies for the
combinatorial production of versatile heterocycles,14±18 we
report herein a general, rapid, and effective procedure for
the solution-phase synthesis of 2-amino- and 2,4-diamino-
1,3-thiazole libraries of types 9 and 10.
We extended our process to thiouronium salts of type 2,
which were easily accessible by literature methods from
thiourea and a large variety of alkyl halides in excellent
yields.14,15,17
This versatile solution-phase procedure to 2-amino- and
2,4-diamino-1,3-thiazole libraries is based on the con-
densation of amidines 1 and thiouronium salts 2 with
Pleasingly, these compounds gave on reaction with isothio-
cyanates 3 in the presence of DBU or DIPEA the corre-
sponding thiourea derivatives 5 in good yield (Method C),
which upon subsequent treatment with a-bromo ketones 6
Keywords: amidines and thiouronium salts; isothiocyanates; ring closure
process.
* Corresponding author. Tel.: 141-61-688-74-60; fax: 141-61-688-17-45;
e-mail: thierry.masquelin@roche.com
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01003-6

154
T. Masquelin, D. Obrecht / Tetrahedron 57 (2001) 153±156
Scheme 1.
Table 1. Amidino- and thioureido-thiourea derivatives of type 4 and 5
2, isothiocyanates 3 and a-bromo ketones 6 in combination
with elimination of the thiol part after S-alkylation and base-
catalysed ring closure of the thiouera derivative 5. Finally,
this reaction sequence could conveniently be performed in
one-pot without isolation of the intermediates, allowing the
development of a straightforward, simple and ef®cient
procedure for the generation of libraries. Applications of
this sulfur linkage strategy to new heterocyclic systems
are under investigation, as well as an extension of the
present process to solid-support, and will be published in
due course.
Compounds
R1
R2
Products Yields [%]
1a
1b
2a
2a
2b
C6H5
2-thienyl
3-NC±C6H4±CH2S 2-Cl±C6H4
3-NC±C6H4±CH2S C6H5
C6H5
C6H5
4a
4b
5a
5b
5c
91
61
70
86
84
4-Cl±C6H4±CH2S
C6H5
led to the desired 2,4-diamino-1,3-thiazoles 10 in good
yields (Table 2; Method D). We assume that this approach
involves initial S-alkylation of the thiourea moiety,
followed by base-catalysed ring closure and elimination of
the corresponding thiol group (ArCH2SH) instead of NH3
(Scheme 1). Isolation of the corresponding disul®des or
thiomethylketones (obtained by reaction of thiols with
excess of a-bromo ketones) supported this prediction.
1. Experimental
All reactions which require air- or moisture-sensitive reac-
tants and solvents were carried out in oven- or ¯ame-dried
glassware under a positive pressure of dry argon. Reaction
solvents and liquid reagents were puri®ed before use or
purchased in abs. quality. Anal. TLC: 2.5£10 cm precoated
TLC plates, SiO2 60F-254, layer thickness 0.25 mm (E.
This approach constitutes a novel and ef®cient synthesis
towards 2,4-diamino-1,3-thiazoles using a three component
reaction between highly versatile thiouronium salts of type
Table 2. 2-Amino- and 2,4-diamino-1,3-thiazoles of type 9 and 10
Compounds
R1
R2
R3
Products
Yields [%]
4a
4a
4b
4b
5b
5c
5c
5c
C6H5
C6H5
2-thienyl
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeO±C6H4
4-Br±C6H4
C6H5
4-Br-C6H4
C6H11
4-MeO±C6H4
4-Br±C6H4
4-F±C6H4
9a
9b
9c
9d
10a
10b
10c
10d
70
94
73
74
65
90
84
99
2-thienyl
3-NC±C6H4±CH2S
4-Cl±C6H4±CH2S
4-Cl±C6H4±CH2S
4-Cl±C6H4-CH2S

T. Masquelin, D. Obrecht / Tetrahedron 57 (2001) 153±156
155
Merck & Co., Darmstadt, Germany). Flash chromatography
(FC):19 E. Merck SiO2 60 (70±230 Mesh ASTM). ATR/FT-
IR: Nicolet-7199 FT-IR spectrometer; solids in KBr pellets,
liquids as thin ®lms; characteristic bands in cm21. 1H NMR
and 13C NMR spectra: Bruker-AC-250 apparatus, at
250 MHz; in d6-DMSO or CDCl3; TMS as internal standard;
chemical shift of signal centres and ranges in ppm (d), J in
Hz. EI-MS: Finnigan MS9-AEI or Mat90; m/z (rel.).
3050m, 2925m, 1678s, 1604s, 1593s, 1557s, 1497s, 753m,
703m. MS: 255 [M1] (40%), 135 (100%).
1.1.6. 1-(Imino-thiophen-2-yl-methyl)-3-phenyl-thiourea
(4b). According to Method A with 1 (0.2 g, 1.23 mmol), 3b
(0.150 ml, 1.29 mmol) and DBU (0.170 ml, 1.29 mmol):
0.195 g (61%) of 4b after FC puri®cation with AcOEt/
1
hexane [1:3±1:1]. Pale yellow solid. Mp 122±1278C. H
NMR (250 MHz, d6-DMSO): 10.49 (br.s, 2£NH); 9.28
(br.s, NH); 8.10±8.01 (m, 1H arom.); 7.86±7.82 (m. 1H
arom.); 7.70±7.50 (m, 2H arom.); 7.43±7.19 (m, 3H
arom.); 7.70±7.50 (m, 2H arom.); 7.10±7.02 (m, 1H
arom.). IR (KBr): 3350w, 3197w, 1600s, 1543s, 1176s,
758m, 690m. MS: 261 [M1] (30%), 135(100%).
1.1. General procedures
1.1.1. Amidino±thioureas 4. Method A: To a mixture of
amidine 1 (1.00 mmol) and isothiocyanate 3 (1.05 mmol) in
dry dimethylformamide (DMF; 5 ml) under argon at 08C, is
added DBU or DIPEA (1.05 mmol). The reaction mixture is
then stirred at rt until total consumption 1, quenched with a
1N aq. HCl solution and extracted with AcOEt. The
combined org. layers were washed with brine, dried
(Na2SO4) and evaporated. The residue was puri®ed by FC
(SiO2) as indicated in the corresponding description
yielding 4.
1.1.7. 1-[Imino-(3-cyanobenzylsul®nyl)-methyl]-3-(2-chloro-
phenyl)-thiourea (5a). According to Method B with 2 (3 g,
11 mmol), 3a (1.90 ml, 11.58 mmol) and DBU (1.73 ml,
11.58 mmol): 2.77 g (70%) of 5a after FC puri®cation
with AcOEt/hexane [1:3±1:1].White solid. Mp 114±
1
1158C. H NMR (250 MHz, d6-DMSO): 10.43 (s, NH);
9.43 (br.s, 2£NH); 7.70±7.05 (m, 8H arom.); 4.07 (s, 2H
aliph.).IR (KBr): 3350w, 3197w, 2250w, 1600s, 1543s,
1176s, 758m, 690m. MS: 361 [M1H]1 (20%), 169 (100%).
1.1.2. 2-Aminothiazoles 9. Method B: To a mixture of 4
(1.00 mmol) and a-bromoketone 6 (1.05 mmol) in DMF;
(5 ml) under argon at 08C, is added DBU (2.1 mmol). The
reaction mixture is then stirred at rt until total consumption
4, quenched with a 1N aq. HCl solution and extracted with
AcOEt. The combined org. layers were washed with brine,
dried (Na2SO4) and evaporated. The residue was puri®ed by
FC (SiO2) as indicated in the corresponding description
yielding 9.
1.1.8. 1-[Imino-(3-cyanobenzylsul®nyl)-methyl]-3-phenyl-
thiourea (5b). According to Method B with 2 (3 g,
11 mmol), 3b (1.38 ml, 11.58 mmol) and DBU (1.73 ml,
11.58 mmol): 3.09 g (86%) of 5b after FC puri®cation
with AcOEt/hexane [1:3±1:1].White solid. Mp 125±
1278C. 1H NMR (250 MHz, d6-DMSO): 10.49 (s, NH);
9.43 (br.s, 2£NH); 7.70±7.05 (m, 9H arom.); 4.07 (s, 2H
aliph.). IR (KBr): 3350w, 3197w, 2200w, 1595s, 1523s,
745m. MS: 336 [M1H]1 (100%).
1.1.3. Thioureido±thioureas 5. Method C: To a mixture of
thiouronium salts 2 (1.00 mmol) and isothiocyanate 3
(1.05 mmol) in dry dimethylformamide (DMF; 5 ml)
under argon at 08C, is added DBU or DIPEA (1.05 mmol).
The reaction mixture is then stirred at rt until total consump-
tion 2, quenched with a 1N aq. HCl solution and extracted
with AcOEt. The combined org. layers were washed with
brine, dried (Na2SO4) and evaporated. The residue was
puri®ed by FC (SiO2) as indicated in the corresponding
description yielding 5.
1.1.9. 1-[Imino-(4-chlorobenzylsul®nyl)-methyl]-3-phenyl-
thiourea (5c). According to Method B with 2 (4 g,
14.6 mmol), 3d (1.84 ml, 15.4 mmol): 4.13 g (84%) of 5c
after FC puri®cation with AcOEt/hexane [1:3±1:1]. White
1
solid. Mp 143±1458C. H NMR (250 MHz, d6-DMSO):
10.49 (s, NH); 9.43 (br.s, 2£NH); 7.70±7.05 (m, 9H
arom.); 4.07 (s, 2H aliph.). IR (KBr): 3350w, 3197w,
1595s, 1523s, 745m. MS: 336 [M1H]1 (100%).
1.1.4. 2,4-Diaminothiazoles 10. Method D: To a mixture of
5 (1.00 mmol) and a-bromoketone 6 (1.2 mmol) in dry
DMF (5 ml) under argon at 08C, is added DBU
(2.1 mmol). The reaction mixture is then stirred at rt until
total consumption 5, quenched with a 1N aq. HCl solution
and extracted with AcOEt. The combined org. layers were
washed with brine, dried (Na2SO4) and evaporated. The
residue was puri®ed as indicated by FC (SiO2) as indicated
in the corresponding description yielding 10.
1.1.10. 2-Phenylamino-4-phenyl-5-[(4-methoxyphenyl)car-
bonyl]carbonylthiazole (9a). According to Method C with
4a (0.20 g, 0.784 mmol), 6a (0.190 g, 0.822 mmol) and
DBU (0.245 ml, 1.64 mmol): 0.210 g (70%) of 9a. Yellow
1
solid. Mp 148±1528C. H NMR (250 MHz, d6-DMSO):
10.84 (s, NH); 7.70±7.67 (d, Jˆ7.70 Hz, 2H arom.);
7.52±7.49 (d, Jˆ8.78 Hz, 2H arom.); 7.24±7.19 (m, 3H
arom.); 7.08±7.02 (t, Jˆ7.32 Hz, 1H arom.); 6.76±6.72
(d, Jˆ7.70 Hz, 2H arom.); 3.72 (s, 3H aliph.). IR (KBr):
3162w, 2920w, 1594m, 1517s, 1254s, 1026m, 756m,
710m. MS: 386 [M1] (100%).
1.1.5. 1-(Imino-phenyl-methyl)-3-phenyl-thiourea (4a).
According to Method A with 1 (0.20 g, 1.66 mmol), 3a
(0.205 ml, 1.75 mmol) and DBU (0.261 ml, 1.75 mmol):
0.386 g (91%) of 4a after FC puri®cation with AcOEt/hex-
ane [1:3±1:1]. Yellow solid. Mp 150±1548C. 1H NMR
(250 MHz, d6-DMSO): 10.49 (br.s, 2£NH); 9.28 (br.s,
NH); 8.10±8.01 (m, 1H arom.); 7.86±7.82 (m. 1H arom.);
7.70±7.50 (m, 2H arom.); 7.43±7.19 (m, 3H arom.); 7.70±
7.50 (m, 2H arom.); 7.10±7.02 (m, 1H arom.). IR (KBr):
1.1.11. 2-Phenylamino-4-phenyl-5-[(4-bromophenyl)-
carbonyl]thiazole (9b). According to Method C with 4a
(0.2 g, 0.784 mmol), 6b (0.228 g, 0.822 mmol) and DBU
(0.245 ml, 1.64 mmol): 0.320 g (94%) of 9b. Yellow
solid. Mp 18±1828C. 1H NMR (250 MHz, d6-DMSO):
10.95 (s, NH); 7.70±7.67 (d, Jˆ7.70 Hz, 2H arom.);
7.41±7.32 (m, 8H arom.); 7.25±7.04 (m, 4H arom.). 13C

156
T. Masquelin, D. Obrecht / Tetrahedron 57 (2001) 153±156
NMR (400 MHz, d6-DMSO): d 187.3 (s); 166.07 (s);
158.42 (s); 140.29 (s); 137.50 (s); 134.75 (s); 131.14
(2£d); 131.06 (2£d); 130.12 (2£d); 129.61 (2£d);
129.08 (d); 128.05 (2£d); 125.63 (s); 123.34 (d); 121.55
(s); 118.61 (2£d). IR (KBr): 3285w, 2924w, 1611m,
1507s, 1254s, 1119m, 747m. MS: 434 [M1] (100%).
7.63 (d, Jˆ8.75 Hz, 2H arom.); 7.63±7.60 (d, Jˆ7.77 Hz,
2H arom.); 7.39±7.33 (t, Jˆ7.52 Hz, 2H arom.); 7.09±7.04
(t, Jˆ7.52 Hz, 1H arom.). IR (KBr): 3414w, 3271w, 1592s,
1546s, 1431s, 755m, 695m. MS: 374 [M1H]1 (100%).
1.1.17. 2-Phenylamino-4-amino-5-[(4-¯uorophenyl)-
carbonyl]thiazole (10d). According to Method D with 5c
(0.4 g, 1.19 mmol), 6e (0.284 g, 1.43 mmol) and DBU
(0.372 ml, 2.50 mmol): 0.367 g (99%) of 10d. Yellow
1.1.12. 2-Phenylamino-4-(thiophen-2-yl)-5-phenylcarbonyl-
thiazole (9c). According to Method C with 4b (0.20 g,
0.765 mmol), 6c (0.160 g, 0.803 mmol) and DBU (0.239
ml, 1.606 mmol): 0.205 g (73%) of 9c. Yellow solid. Mp
135±1388C. 1H NMR (250 MHz, d6-DMSO): 10.89 (s, NH);
7.71±7.60 (m, 6H arom.); 7.59±7.36 (m, 5H arom.); 7.11±
7.04 (t, Jˆ7.35 Hz, 1H arom.); 6.97±6.94 (t, Jˆ4.45 Hz, 1H
arom.). IR (KBr): 3162w, 2924w, 1609m, 1495s, 1292s,
1119m, 858m, 767m, 693. MS: 362 [M1] (100%).
1
solid. Mp 190±1928C. H NMR (250 MHz, d6-DMSO):
10.82 (s, NH); 8.25 (br.s, NH2); 7.77±7.71 (dd, Jˆ14.32,
8.77 Hz, 2H arom.); 7.63±7.60 (d, Jˆ7.77 Hz, 2H arom.);
7.39±7.27 (m, 4H arom.); 7.09±7.04 (t, Jˆ7.52 Hz, 1H
arom.). IR (KBr): 3418w, 3197w, 1599s, 1550s, 1431m,
849m, 760m, 694m. MS: 314 [M1H]1 (100%).
Acknowledgements
1.1.13. 2-Phenylamino-4-(thiophen-2-yl)-5-[(4-bromo-
phenyl)carbonyl]thiazole (9d). According to Method C
with 4b (0.20 g, 0.765 mmol), 6b (0.223 g, 0.803 mmol)
and DBU (0.239 ml, 1.606 mmol): 0.23 g (74%) of 9d.
We gratefully thank our colleagues from F. HoffmannÐla
Roche AGÐfor analytical support.
1
Yellow solid. Mp 132±1348C. H NMR (250 MHz, d6-
DMSO): 10.95 (s, NH); 7.68±7.58 (m, 8H arom.); 7.43±
7.36 (m, 2H arom.); 7.11±7.04 (t, Jˆ7.35 Hz, 1H arom.);
6.98±6.94 (m, 1H arom.). IR (KBr): 3276w, 2924w, 1614m,
1525s, 1290s, 1011m, 791m, 767m, 714. MS: 442 [M1H]1
(100%).
References
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1.1.14. 2-Phenylamino-4-amino-5-cyclohexylcarbonyl-
thiazole (10a). According to Method D with 5b (0.3 g,
0.919 mmol), 6d (0.188 ml, 1.10 mmol) and DBU
(0.288 ml, 1.93 mmol): 0.180 g (65%) of 10a after FC puri-
®cation with AcOEt/CH2Cl2 [1:4]. Yellow solid. Mp 211±
2138C. 1H NMR (250 MHz, d6-DMSO): 10.68 (s, NH); 7.95
(br.s, NH2); 7.62±7.59 (d, Jˆ7.65 Hz, 2H arom.); 7.39±
7.32 (t, Jˆ7.48 Hz, 2H arom.); 7.10±7.04 (t, Jˆ7.32 Hz,
1H arom.); 2.29±2.24 (t, Jˆ10.81 Hz, 1H aliph.); 1.75±
1.62 (m, 5H aliph.); 1.41±1.13 (m, 5H aliph.). 13C NMR
(400 MHz, d6-DMSO): d 191.9 (s); 165.66 (s); 164.16 (s);
140.22 (s); 129.56 (2£d); 123.61 (d); 119.31 (2£d); 50.71 (s);
29.31 (2£t); 26.01 (t); 25.80 (2£t). IR (KBr): 3418w, 2930w,
1611m, 1553s, 1451s, 783m, 700m. MS: 301 [M1] (100%).
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1.1.15. 2-Phenylamino-4-amino-5-[(4-methoxyphenyl)-
carbonyl]thiazole (10b). According to Method D with 5c
(0.4 g, 1.19 mmol), 6a (0.327 g, 1.43 mmol) and DBU
(0.372 ml, 2.50 mmol): 0.315 g (90%) of 10b after FC puri-
®cation with AcOEt/hexane [1:1]. Yellow solid. Mp 231±
2338C. 1H NMR (250 MHz, d6-DMSO): 10.76 (s, NH); 8.16
(br.s, NH2); 7.69±7.65 (d, Jˆ8.75 Hz, 2H arom.); 7.63±
7.60 (d, Jˆ7.77 Hz, 2H arom.); 7.39±7.33 (t, Jˆ7.52 Hz,
2H arom.); 7.09±7.04 (t, Jˆ7.52 Hz, 1H arom.); 7.03±6.99
(d, Jˆ8.75 Hz, 2H arom.); 3.81 (s, 3H aliph.). IR (KBr):
3413w, 3201w, 1587s, 1522s, 1251m, 761m, 694m. MS:
326 [M1H]1 (100%).
12. Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron
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13. Obrecht, D.; Villargordo, J. M. Solid-Supported Combinatorial
and Parallel Synthesis of Small-Molecular-Weight Compound
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J.; Villalgordo, J. M. Chimia 1996, 50, 525±530.
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1.1.16. 2-Phenylamino-4-amino-5-[(4-bromophenyl)-
carbonyl]thiazole (10c). According to Method D with 5c
(0.4 g, 1.19 mmol), 6b (0.397 g, 1.43 mmol) and DBU
(0.372 ml, 2.50 mmol): 0.373 g (84%) of 10c after FC puri-
®cation with AcOEt/Hexane [1:1]. Orange solid. Mp 205±
2078C. 1H NMR (250 MHz, d6-DMSO): 10.87 (s, NH); 8.25
(br.s, NH2); 7.70±7.67 (d, Jˆ8.75 Hz, 2H arom.); 7.67±
17. Masquelin, T.; Delgado, Y.; Baumle, V. Tetrahedron Lett.
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