A convenient synthesis of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-thiazole-4-carboxylic acid via N-Fmoc-thiourea

Article abstract of DOI:10.1081/SCC-120034173

2-(9H-Fluoren-9-ylmethoxycarbonylamino)-thiazole-4-carboxylic acid has been prepared in high yield from 3-bromopyruvic acid and (aminothioxomethyl)carbamic acid 9H-fluoren-9-ylmethyl ester (N-Fmoc-thiourea) that was obtained from potassium thiocyanate.

Full text of DOI:10.1081/SCC-120034173

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 10, pp. 1891–1895, 2004
A Convenient Synthesis of 2-(9H-Fluoren-9-
ylmethoxycarbonylamino)-thiazole-4-
carboxylic Acid via N-Fmoc-thiourea
*
Kang Le and Robert A. Goodnow Jr.
Roche Research Center, Hoffmann-La Roche Inc., Nutley,
New Jersey, USA
ABSTRACT
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-thiazole-4-carboxylic acid has
been prepared in high yield from 3-bromopyruvic acid and (aminothioxo-
methyl)carbamic acid 9H-fluoren-9-ylmethyl ester (N-Fmoc-thiourea) that
was obtained from potassium thiocyanate.
Key Words: 2-Aminothiazole-4-carboxylic acid; 2-(9H-Fluoren-9-
ylmethoxycarbonylamino)-thiazole-4-carboxylic acid; N-tert-butoxy-
carbonylthiourea.
*
Correspondence: Robert A. Goodnow, Jr., Roche Research Center, Hoffmann-La
Roche Inc., Nutley, New Jersey, USA; E-mail: robert.goodnow@roche.com.
1891
DOI: 10.1081/SCC-120034173
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Le and Goodnow
INTRODUCTION
2-Aminothiazoles have been used in varieties of applications, which
cover the fields of agriculture, pharmacy, photography, or related activities.[1]
They are also among one of the key building blocks in drug discovery. There
are more than 500 structures containing the 2-aminothiazole moiety reported
in the Derwent World Drug Index.[2] Therefore, it is of interest to include
2-aminothiazoles in compound library designs for lead generation. Solid
phase combinatorial chemistry is a powerful tool for generating novel
compounds for lead generation. However, the potential of solid phase com-
binatorial chemistry is limited by the availability in sufficient quantity of
appropriately protected reagents. As of this writing, 2-(9H-fluoren-9-
ylmethoxycarbonylamino)-thiazole-4-carboxylic acid is not commercially
available at reasonable cost in quantities sufficient for library synthesis.
To this end, we sought a convenient method for preparation of multi-gram
quantities of 2-(9H-fluoren-9-ylmethoxycarbonylamino)-thiazole-4-carboxylic
acid such that the acid component in the molecule could be used as a reactive
functionality for loading to solid phase linkers. Subsequent cleavage of
the Fmoc group could be easily performed according to standard conditions
(1 : 4 vol/vol piperidine/DMF) to expose the terminal amine group. The
resin-bound, free amine can then be subjected to a diversity of chemistries
generating many structurally diverse molecules.
Conceivably, title compound 5 could be obtained by the reaction of N-9-
fluorenylmethoxycarbonyl chloride (Fmoc-Cl) and ethyl 2-aminothiazole-4-
carboxylate, which is easily prepared from cyclization of ethyl bromopyruvate
and thiourea.[3] The ethyl ester could then be carefully hydrolyzed to give
the free acid. Although N-Boc protection of the ethyl 2-aminothiazole-4-
carboxylate has been reported,[4] our efforts to react 2-aminothiazole-4-
carboxylic acid with 9H-fluoren-9-ylmethyl chloroformate were not successful
(Fmoc-Cl, triethylamine, dimethylaminopyridine, THF, room temperature,
12 hr).
Alternatively, one envisions that compound 5 could be obtained by con-
densation of N-Fmoc-thiourea 3 with bromopyruvic acid 4. Previously, the
preparation of N-tert-butoxycarbonylthiourea[5] and N, N 0-bis-tert-butoxy-
carbonylthiourea[6] were reported by reaction of the sodium salt of thiourea
with di-tert-butyldicarbonate. A similar condition was employed to prepare
N-Fmoc-thiourea. In our hands, this reaction was found to result in a complex
mixture and thus was judged not to be a viable route.
In this report, N-Fmoc-thiourea 3 was obtained by reacting methanolic
and ethanolic ammonia with N-Fmoc-thiocyanate (carbon(isothiocyanatidic
acid 9H-fluoren-9-ylmethyl ester)) 2, which was conveniently prepared from
potassium thiocyanate and Fmoc-Cl 1 (Sch. 1). Thiourea 3 and bromoketone

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Le and Goodnow
4 were cyclized to afford 2-(9H-fluoren-9-ylmethoxycarbonylamino)-thia-
zole-4-carboxylic acid 5. This two-step sequence is easy, convenient, and
inexpensive. The overall yield is high. No flash chromatography is required.
Both intermediate 3 and the title product 5 were isolated by simple filtration;
further purification of product 5 was effected by re-crystallization from
methanol.
In practice, 2-(9H-Fluoren-9-ylmethoxycarbonylamino)-thiazole-4-
carboxylic acid generated with this method was later used in the solid phase
synthesis of several library designs from, which new lead structures have
been discovered.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a Varian Unity 400
NMR spectrometer. Infrared spectra were measured on a Perkin Elmer
Spectrum GX FT-IR spectrophotometer as KBr pellets. Mass spectra were
obtained on a Bruker Apex II FT-ICRmass spectrometer. Elemental analyses
were performed by Robertson Microlit Laboratories, Inc. of Madison,
NJ 07910.
N-9-Fluorenylmethoxycarbonyl thiourea (3). To a suspension of
potassium thiocyanate (8.55 g, 88 mmol) in ethyl acetate (100 mL) cooled to
08C was added dropwise a solution of Fmoc-Cl (20.7 g, 80 mmol) in ethyl
acetate (100 mL) over a period of 15 min. The resulting stirred suspension
was allowed to warm to ambient temperature overnight. The resultant salt
was filtered off and the remaining solution was concentrated in vacuo to afford
an orange oil. Without further purification, the oil was dissolved in absolute
alcohol (50 mL) and treated by dropwise addition with a solution of cold
ammonia in methanol (7 N, 91 mL, 640 mmol). A precipitate formed upon
addition of the ammonia solution. The suspension was stirred vigorously at
08C for 15 min and was then filtered, washed with cold ethanol (3 ꢀ 20 mL),
and dried to afford N-9-fluorenylmethoxycarbonyl thiourea (16.8 g, 70%) as
1
an off-white solid. M.P.: 197–2008C. H NMR (DMSO-d6), d: 4.28 (1H, t,
CH), 4.33 (2H, d, CH2), 7.32–7.45 (4H, m, 4 Ph-H), 7.83–7.91 (4H, m, 4
Ph-H), 8.99 (1H, s, NH-H), 9.33 (1H, s, NH-H), 11.29 (1H, s, NH). 13C
NMR (DMSO-d6), d: 46.00, 67.19, 120.14, 125.62, 127.13, 127.83, 140.70,
143.3, 153.05, 181.34. IR (KBr): 3353, 3249, 1731, 1597, 1530, 1451,
1320, 1204, 1106, 966, 759, 739 cm21. EI-HRMS m/e calcd for
C16H14N2O2S (Mþ) 298.0776, found 298.0770. Anal. Calcd. For
C16H14N2O2S: C 64.41, H 4.73, N 9.39. Found: C 64.51, H 4.59, N 9.20.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-thiazole-4-carboxylic acid
(5). A dioxane (40mL) solution of N-9-fluorenylmethoxycarbonyl thiourea

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1895
(5.96 g, 20mmol) was treated with bromopyruvate (3.34 g, 20mmol). The
reaction mixture was refluxed for 1 hr. At this time the resultant precipitate was
filtered and washed with ethyl ether (3 ꢀ 20mL) to afford 2-(9H-fluoren-9-
ylmethoxycarbonylamino)-thiazole-4-carboxylic acid (7.1g, 97%) as a white
solid. The crude material was re-crystalized from methanol to provide a white
crystalline solid (1.5g from 2 g, 75%). M.P.: 224–2268C. 1H NMR (DMSO-d6),
d: 4.32 (1H, t, CH), 4.45 (2H, d, CH2), 7.34–7.45 (4H, m, 4 Ph-H), 7.77–7.92
(4H, m, 4 Ph-H), 7.97 (1H, s, thiazole-H), 12.29 (1H, s, COOH). 13C NMR
(DMSO-d6), d: 46.25, 67.19, 120.22, 122.27, 127.18, 127.84, 140.77, 142.48,
143.39, 153.94, 159.52, 162.27. IR (KBr): 3120, 3044, 2967, 2889, 1746,
1721, 1576, 1329, 1259, 1181, 958, 759, 740 cm21. EI-HRMS m/e calcd for
C19H14N2O4S (Mþ) 366.0674, found 366.0679. Anal. Calcd. For C19H14N2O4S:
C 62.29, H 3.85, N 7.65. Found: C 62.41, H 3.74, N 7.56.
REFERENCES
1. Barone, R.; Chanon, M.; Gallo, R. VI. Application of aminothiazoles. In
Thiazole and Its Derivatives, The Chemistry of Heterocycle Compounds;
Metzger, J.V., Ed.; John Wiley & Sons Inc.: New York, 1979; Vol. 34,
part 2, 132–171.
2. Derwent World Drug Index; Derwent Information: 14 Great Queen Street,
London WC2B 5DF, UK.
3. Plouvier, B.; Houssin, R.; Bailly, C.; Henichart, J.P. Synthesis and DNA-
binding study of a thiazole-containing analog of netropsin. J. Heterocycl.
Chem. 1989, 26 (6), 1643–1647.
4. Kim, H.; Kahn, M. The synthesis of aminoazole analogs of lysine and argi-
nine. The Mitsunobu reaction with lysinol and argininol. Synlett. 1999,
6 (8), 1239–1240.
5. Schiavi, B.; Ahond, A.; Poupat, C.; Potier, P. Preparation of N-tert-butox-
ycarbonylthiourea opens the way to protected 2-aminothiazoles. Synth.
Commun. 2002, 32 (11), 1671–1674.
6. Iwanowicz, E.J.; Poss, M.A.; Lin, J. Preparation of N, N 0-bis-tert-butoxy-
carbonylthiourea. Synth. Commun. 1993, 23 (10), 1443–1445.
Received in the USA January 3, 2004

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