Preparation of N-tert-butoxycarbonylthiourea opens the way to protected 2-aminothiazoles

Article abstract of DOI:10.1081/SCC-120004257

The preparation of N-tert-butoxycarbonylthiourea from thiourea and di-tert-butyldicarbonate in tetrahydrofuran is described. It has been successfully used for the preparation of 2-aminothiazole intermediates.

Full text of DOI:10.1081/SCC-120004257

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PREPARATION OF N-TERT-BUTOXYCARBONYLTHIOUREA
OPENS THE WAY TO PROTECTED 2-AMINOTHIAZOLES
a
b
a
a
Bruno Schiavi , Alain Ahond , Christiane Poupat & Pierre Potier
a
Institut de Chimie des Substances Naturelles du CNRS , Gif/Yvette Cedex, BP1, 91198,
France
b
Institut de Chimie des Substances Naturelles du CNRS , Gif/Yvette Cedex, BP1, 91198,
France
Published online: 16 Aug 2006.
To cite this article: Bruno Schiavi , Alain Ahond , Christiane Poupat & Pierre Potier (2002) PREPARATION OF N-TERT-
BUTOXYCARBONYLTHIOUREA OPENS THE WAY TO PROTECTED 2-AMINOTHIAZOLES, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:11, 1671-1674, DOI: 10.1081/SCC-120004257
To link to this article: http://dx.doi.org/10.1081/SCC-120004257
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SYNTHETIC COMMUNICATIONS, 32(11), 1671–1674 (2002)
PREPARATION OF
N-TERT-BUTOXYCARBONYLTHIOUREA
OPENS THE WAY TO PROTECTED
2
-AMINOTHIAZOLES
Bruno Schiavi, Alain Ahond,* Christiane Poupat,
and Pierre Potier
Institut de Chimie des Substances Naturelles du CNRS,
BP1, 91198 Gif/Yvette Cedex, France
ABSTRACT
The preparation of N-tert-butoxycarbonylthiourea from
thiourea and di-tert-butyldicarbonate in tetrahydrofuran is
described. It has been successfully used for the preparation
of 2-aminothiazole intermediates.
Key Words: 2-Aminothiazole; N-tert-Butoxycarbonylthiourea
The aminothiazole group is a very well known ‘‘pharmacophore’’. It
is, therefore, important to have in hand an easy and high yielding method to
[
1,2]
prepare it. Iwanowicz et al.
have efficiently prepared N,N-bis-tert-
butoxycarbonylthiourea 1 from the sodium salt of thiourea 2 and di-tert-
butyldicarbonate 3. Because of low concentrations, they could avoid the
formation of S-acylated products.
*
Corresponding author. E-mail: alain.ahond@icsn.cnrs-gif.fr
671
1
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1
672
SCHIAVI ET AL.
Because we were interested in obtaining N-tert-butoxy-carbonyl-
thiourea 4 as an intermediate to prepare protected 2-aminothiazoles, we
have used the same reagents but searched for convenient conditions to
reach our objective. By using higher concentrations, we obtained a mixture
of N-tert-butoxycarbonylthiourea (90%) 4 and N-N-bis-tert-butoxycarbo-
nylthiourea 1 (<5%); from this mixture, N-tert-butoxycarbonylthiourea
was easily purified by crystallization from heptane.
N-tert-butoxycarbonylthiourea 4, prepared by this procedure, was
found to be satisfactory for the preparation of 2-aminothiazole intermedi-
ates such as 7 and 8, on the way to the synthesis of marine metabolite
[3]
analogues.
EXPERIMENTAL
Melting points were determined using a Bu
¨
chi BS-540 and are
was measured using a Perkin-Elmer 241 MC (589 nm,
20 C), sample in EtOH solution; UV spectra were taken with a Varian
Cary 100 spectrometer, using EtOH solution. IR spectra were taken with
uncorrected; [ꢀ]
D
ꢀ
a Perkin-Elmer BX FT-IR spectrometer, using CHCl solution or KBr
3
1
13
pellet. The H and C NMR spectra were recorded on Bruker AC-200,
AC-250 or AC-300. Chemical ionization mass spectra were recorded on a

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N-TERT-BUTOXYCARBONYLTHIOUREA
1673
AEI MS-9 spectrophotometer with isobutane as a vector gas, electron
impact spectrum on AEI MS-50 spectrophotometer. Silica gel 60 was used
for flash column chromatography and silica gel 60F254 plates (0.25 mm,
Merck) were used for TLC.
Preparation of 4: To a stirred solution of thiourea 2 (2.2 g, 28.9 mmol)
ꢀ
in THF (200 ml) under argon at 0 C was added NaH (2.7 g, as 60% disper-
sion in mineral oil, 2.3 eq.); after 10 min, di-tert-butyldicarbonate 3 (6.6 g,
1
.05 eq.) in solution in THF (30 ml) was added.
ꢀ
The 0 C bath is removed and the reaction mixture stirred at room
temperature for 1 h. Dichloromethane (200 ml) was added and the organic
layer washed successively with an aqueous solution of saturated NaHCO3
(100 ml) and water (100 ml). The organic layer was dried over MgSO4,
filtered and concentrated in vacuo. Addition of heptane (500 ml) to the
ꢀ
1
residue provided 4.6 g of pure crystalline 4 (90%). M.p: 145 C; H NMR
1
3
(
(
CDCl ): ꢁ 1.61 (s, 9H); C NMR (CDCl ): ꢁ 182.1, 151.45, 84.0, 28.0; IR
3 3
CHCl , cm ): 1734; UV [ꢂnm (e)]: 263 (17000); Mass m/z (CI, 180 C): 177
M þ H) ; Anal. calcd for C H N O S: C, 40.89; H, 6.86; N, 15.90. Found:
ꢁ1
ꢀ
3
þ
(
C, 40.83; H, 6.88; N, 15.86.
6
12
2
2
Preparation of 2-tert-butoxycarbonyl-4-p-bromophenylthiazole 7: At
0
room temperature, N-Boc thiourea 4 (100 mg, 0.56 eq.) and 2,4 -dibromo-
acetophenone 5 (172 mg, 0.62 eq.) are stirred in acetone (8 ml) overnight; a
precipitate is formed, which is filtrated before being purified by flash-
chromatography (silica gel, eluent: CH Cl /MeOH 99/1): 180 mg of pure 7
2
2
ꢀ
1
are obtained (yield: 82%); white solid; m.p. 210 C (dcp.); H NMR (DMSO-
d ); ꢁ 1.57 [s, 9H, (CH ) ], 7.68 and 7.75 (2d, 2H, J ¼ 7.3 Hz, Ø-H), 7.71 (s, 1H,
6
3 3
1
3
H-5), 7.88 and 7.90 (2d, 2H, J ¼ 7.3 Hz, Ø-H); C NMR (DMSO-d ): ꢁ
6
2
1
1
7.85–27.90 (3 CH ), 81.25–81.95 (C-Me ), 91.8–96.75 (C-Br), 108.15–
3 3
08.25 (C-5), 120.7–121.6 (C-4), 127.4–129.9 (2C-Ar), 131.25–131.5 (2C-Ar),
32.4–133.55 (C-Ar), 145.05–147.95 (C-2), 159.0–159.85 (C¼O): some NMR
ꢁ
1
signals are split because of the presence of rotamers; IR (KBr, cm ): 1730;
þ
MS m/z (EI): 353–355 (M ), 253–255, 174; HRMS (CI, isobutane) m/z
þ
(
MH) calcd for C H BrN O S: 354.0259/356.0238, found 354.0027/
1
4
16
2
2
355.9995.
Preparation of the Intermediate 8: At first, the bromoketone 6b must be
4]
[
[3]
prepared, through the Swern oxidation of the corresponding alcohol 6a.
Oxalyle chloride (125 ml, 1.5 eq), in solution in CH Cl (2 ml) is added drop-
2
2
ꢀ
wise, under argon atmosphere at ꢁ78 C, to DMSO (163 ml) in solution in
CH Cl (2 ml). The mixture is stirred for 10 min; then, the alcohol 6a
2
2
(
378 mg, 0.95 mmol) solubilized in CH Cl (2 ml), is added dropwise. The
2 2
ꢀ
stirring is continued at ꢁ78 C for 15 min. After the dropwise addition of
triethylamine (668 ml, 6.5 eq), the reaction is still stirred at room temperature
for 45 min before being stopped with water (25 ml). The organic layer is

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674
SCHIAVI ET AL.
separated, dried over anhydrous magnesium sulphate and evaporated. The
crude bromoketone 6b is purified by flash chromatography on silica gel
(eluent: CH Cl /MeOH 99:1) and directly put in reaction with N-Boc
2 2
thiourea 4 (200 mg, 1.13 eq) in acetone (15 ml). The mixture is stirred at
room temperature for 12 h; then, the reaction is stopped by adding solid
NaHCO : a filtration over Celite and a flash chromatography on silica gel
3
(
eluent: CH Cl /MeOH 99 : 1) provide 340 mg of the intermediate 8 (yield:
2
2
1
7
ꢁ
0
5%), as an amorphous solid; ꢀ
D
þ 37 (ethanol, c ¼ 1.4); H NMR (CDCl ):
3
ꢁ0.08 (s, 3H, CH -Si), 0.13 (s, 3H, CH -Si), 0.85 (s, 3H, CH thexyle),
3
3
3
.86 (s, 3H, CH thexyle), 0.89 [d, J ¼ 6.8 Hz, 6H, (CH ) CH], 1.33 (s, 3H,
3
3 2
CH C), 1.43 (s, 3H, CH C), 1.51 [s, 9H, (CH ) C], 1.65 [sept., J ¼ 6.8 Hz,
3
3
3 3
0
1
H, CH(CH ) ], 3.83 (dd, J ¼ 6.5 and 7.9 Hz, 1H, H-3 ), 3.99 (pseudo t,
3
2
0
0
0
J ¼ 7.5 Hz, 1H, H-3 ), 4.42 (m, 1H, H-2 ), 4.86 (d, J ¼ 4.6 Hz, H-1 ), 6.76
1
3
(
s, 1H, H-5), 8.25 (brs, 1H, NH); C NMR (CDCl ): ꢁ 10.25–10.35 [Si-
3
(
2
(
(
(
CH ) ], 18.7–18.8, 20.35–20.5 (4CH thexyle), 25.2 [Si-C(CH ) ], 25.45–
3
2
3
3 2
0
6.75 [C(CH ) ], 28.3 [C(CH ) ], 34.15 [CH(CH ) ], 65.3 (C-3 ), 71.3
3 2 3 3 3 2
0
0
C-2 ), 78.55 (C-1 ), 82.75 [C(CH ) ], 109.2 [C(CH ) ], 109.4 (C-5), 152.2
3
3
ꢁ
3 2
1
C-4), 159.2 (C-2); IR (CHCl , cm ): 1723; UV (ethanol, ꢂnm [e]) 259
5700); Mass m/z (CI, t ¼ 180 C): 473, 417, 373; HRMS (CI, isobutane)
3
ꢀ
ꢀ
þ
m/z (MH ) calcd for C H N O SSi: 473.2505, found 473.2517.
2
2
2
41
5
REFERENCES
1
2
. Iwanowicz, E.J.; Poss, M.A.; Lin, J. Synth. Commun. 1993, 23, 1443.
. Poss, M.A.; Iwanowicz, E.J.; Reid, J.A.; Gu, Z. Tetrahedron Lett. 1992,
33, 5933.
3
4
. Schiavi, B. Ph.D Thesis, Paris XI Orsay University, 2000.
. Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
Received in the Netherlands April 12, 2001