Rearrangement reactions; 14: Synthesis of functionalized thiazoles via attack of heteroatom nucleophiles on allenyl isothiocyanates

Article abstract of DOI:10.1055/s-2005-872203

Treatment of allenyl isothiocyanates with sulfur-, oxygen-, nitrogen- or hydride-containing nucleophiles such as propane-2-thiol, thiophenol, hydrogen sulfide, alcohols, phenol or aqueous NaOH, NH₃, primary or secondary aliphatic or aromatic amines, N,N,N′,N′-tetramethylguanidine or sodium cyanoborohydride resulted in ring closure to generate thiazoles bearing a functionality at position C-2 in most cases. Moreover, we report the first examples of aromatic miazole-2-phosphonates prepared by the same strategy using dialkyl or diphenyl phosphites as nucleophiles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872203

2920
PAPER
Rearrangement Reactions; 14:1 Synthesis of Functionalized Thiazoles via
Attack of Heteroatom Nucleophiles on Allenyl Isothiocyanates
S
ynthesis of Funct
l
ionalize
a
d Thiazole
u
s
s Banert,* Baker Jawabrah Al-Hourani, Stefan Groth, Kai Vrobel
Institut für Chemie, Technische Universität Chemnitz, Strasse der Nationen 62, 09111 Chemnitz, Germany
Fax +49(371)5311839; E-mail: klaus.banert@chemie.tu-chemnitz.de
Received 8 April 2005; revised 27 May 2005
Dedicated to Professor Wolfgang Kirmse on the occasion of his 75th birthday
R2
R2
Abstract: Treatment of allenyl isothiocyanates with sulfur-, oxy-
[3,3]
R1
C
gen-, nitrogen- or hydride-containing nucleophiles such as propane-
2-thiol, thiophenol, hydrogen sulfide, alcohols, phenol or aqueous
NaOH, NH3, primary or secondary aliphatic or aromatic amines,
N,N,N¢,N¢-tetramethylguanidine or sodium cyanoborohydride re-
sulted in ring closure to generate thiazoles bearing a functionality at
position C-2 in most cases. Moreover, we report the first examples
of aromatic thiazole-2-phosphonates prepared by the same strategy
using dialkyl or diphenyl phosphites as nucleophiles.
SCN
R1
NCS
1
2
R1
a R1 = R2 = H
N
b R1 = H, R2 = Me
c R1 = Me, R2 = H
d R1 = CH2OAc, R2 = H
S
R2
Key words: allenes, isothiocyanates, addition reactions, ring clo-
sure, heterocycles
3
Scheme 1
Recently, we reported2 that the well known3 isomerization
of allyl thiocyanate to allyl isothiocyanate can be trans-
ferred to propargyl thiocyanates 1 as an alternative start-
Table 1 Transformation of 2a to Thiazoles 5a–o via Attack of
Heteroatom Nucleophiles NuH 4
N
C
NuH
ing material yielding allenyl isothiocyanates
2
4
Nu
(Scheme 1). However, in general this [3,3]-sigmatropic
rearrangement 1 → 2 can be performed only by the tech-
nique of flash vacuum pyrolysis (FVP) successfully be-
cause neat (undiluted) cumulenes, such as 2, tend to
exothermic spontaneous polymerization even at room
temperature. Whereas allenyl isothiocyanates like 2a and
2b can be obtained nearly quantitatively in hundred-gram
batches per day, there are some limitations in other cases
such as 2c and 2d. Flash vacuum pyrolysis of 1c leads to
equilibrium with 2c (ratio 1c/2c = 17:83) while rearrange-
ment 1d → 2d is nearly irreversible. However, the yield
of 2d is limited to 73% since the precursor 1d cannot be
vaporized without decomposition.
S
NCS
2a
5a−o
4
a
b
c
d
e
f
NuH
Yield of 5 (%)
Refa
5
Me2CHSH
PhSHb
70
87
83
88
90
69
52
68
59
45
82
40
67
56
95
(MeO)2P(O)H
(PhCH2O)2P(O)H
(PhO)2P(O)H
MeOH
6
We present now the reactions of the isothiocyanates 2
with sulfur-, phosphorus-, oxygen-, nitrogen- and hy-
dride-containing nucleophiles leading to thiazole4 deriva-
tives. Thus, the chemistry of 2 illustrates that allenyl
isothiocyanates act predominantly as synthetic equiva-
lents of synthons 3.
g
h
i
Me2CHOH
PhOHc
NH3
7
8
j
CH3CH2CH2NH2
PhNH2
k
l
Thiazole 5b was prepared (87% yield) by treating the al-
lene 2a at room temperature with sodium thiophenolate
generated from 4b and NaH (Table 1). On the other hand,
the reaction of propane-2-thiol (4a) with the same allene
2a at room temperature gave heterocycle 5a (70% yield)
without the need of any base.
Ph2NH
m
n
o
MeO2CCH2NH2
o-MeO2CC6H4NH2
(Me2N)2C=NH
a References to compounds 5 prepared by other methods.
b Thiophenol in the presence of NaH.
c With addition of NaOH.
SYNTHESIS 2005, No. 17, pp 2920–2926
Advanced online publication: 23.08.2005
DOI: 10.1055/s-2005-872203; Art ID: T04805SS
x
x.
x
x
.
2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Functionalized Thiazoles
2921
Using dialkyl or diphenyl phosphites for nucleophilic ad- substituted thiazoles 5p (35%) and 5q (86%), respectively
dition to 2a could give rise to C–P bond formation, but (Scheme 2). It is important to mention that the isothiocy-
treating of the appropriate phosphites 4c–e with allene 2a anate 2a did not react with either dibenzoazepine or indole
did not lead to heterocyclic products. Repeating the same even after several days at room temperature. This can be
reaction, however, in the presence of K2CO3, which serves attributed to the poor availability of the lone pair of
as a heterogeneous catalyst, gives newly substituted thia- amines bearing two aromatic substituents. In the case of
zoles 5c–e in very good yields. Actually, these are the first indole, the lone pair at the nitrogen atom is involved with-
examples of aromatic substituted thiazoles bearing a in the aromaticity of the heterocyclic moiety causing a
phosphorus atom of a phosphonate group directly bonded significantly decreased nucleophilicity.
to the thiazole ring at C-2 position. Thus, the 13C NMR
spectra of heterocycles 5c–e revealed the significant
C(2)–P and C(4)–P couplings summarized in Table 2.
The reaction of isothiocyanate 2a with diluted aqueous
NaOH or aqueous H2S afforded the two heterocycles 6a6
and 6b11 with 86% and 53% yields, respectively. The
structure of 6a was determined not only by its spectro-
Table 2 Some C–P Coupling Constants of Compounds 5c–ea
scopic data but also by treating with diazomethane12 to
give the known thiazole derivative 76 with a yield of 58%.
When the allene 2a was allowed to react with sodium cy-
anoborohydride in MeOH, the formation of the commer-
cially available thiazole 5r was observed. If 2a was
attacked by more reactive hydrides like NaBH4 in i-PrOH
or LiAlH4 in Et2O, the yield of 5r decreased to 17–18%,
and side-products such as 6b (37%) or N-allylmethyl-
amine (25%), were formed, respectively.
13C NMR
Compound No.
5c
245.8
26.2
6.2
–
5d
247.6
26.8
–
5e
C-2
1JPC (Hz)
3JPC (Hz)
2JPC (Hz)
2JPC (Hz)
3JPC (Hz)
2JPC (Hz)
3JPC (Hz)
4JPC (Hz)
256.6
28.4
–
C-4
–OCH3
–OCH2Ph
Phi
5.6
6.8
–
–
–
–
Phi
–
7.4
4.6
1.1
N
MgBr
Pho
–
–
N
Phm
–
–
N
S
5p (35%)
a No coupling was detected between the phosphorus atom and C-5 of
the thiazole moiety.
N
MgBr
Allene 2a could be reacted with alcohols 4f and 4g as well
as phenol (4h) to afford the substituted thiazoles 5f, 5g,
5h, respectively, with moderate yields. In the case of 4h,
NaOH was used to facilitate the reaction pathway due to
the well-known low nucleophilicity of phenol if compared
to that of alcohols on the one hand and that of phenolate
on the other hand.
N
N
S
C
5q (86%)
NCS
2a
HN
MeN
X = O
H2X
X
O
S
S
CH2N2
Unlike phenols, amines and even NH3 can be reacted with
isothiocyanate 2a in the absence of any base because of
the superior nucleophilicity of these nitrogen compounds.
Thus, treatment of allene 2a with amines 4i–l, 4m,9 4n
furnished the thiazoles 5i–n with moderate to very good
yields. In some cases, the transformations are highly exo-
thermic. Thus, dilution with an inert solvent and cooling
of the reaction mixtures are necessary. The cumulene 2a
is extremely reactive if compared to other isothiocyanates.
This is exemplified by the conversion of 2a with
diphenylamine (4l) leading to thiazole 5l already at room
temperature. Phenyl isothiocyanate is attacked by the
weak nitrogen nucleophile 4l only at 280 °C.10
7 (58%)
6
a X = O (86%)
b X = S (53%)
N
NaBH3CN
H
S
5r (46%)
Scheme 2
The synthesis of thiazoles from allenyl isothiocyanates is
not limited to the parent compound 2a but can be trans-
ferred to substituted compounds such as 2d, which was
generated with 73% yield through the [3,3]-sigmatropic
rearrangement of 4-thiocyanatobut-2-ynyl acetate (1d)13
at 400 °C and 3 × 10–6 mbar. The cumulene 2d was reacted
In the case of guanidine 4o, the resulting yield of the iso-
lated heterocycle 5o (95%) was excellent. Moreover, the
C–N bond formation was achieved via the reaction of al-
lene 2a with dibenzoazepinylmagnesium bromide and in-
dolylmagnesium bromide in THF to generate the newly
Synthesis 2005, No. 17, 2920–2926 © Thieme Stuttgart · New York

2922
K. Banert et al.
PAPER
silica gel 60. For the elemental analyses, Vario El (Elementar Anal-
ysensystem GmbH) was employed. Mariner 5229 from Applied
Biosystems was used for (HR)–MS spectra. The method applied
was the electrospray ionization.
with MeOH at room temperature to yield the novel thi-
azole 8 (Scheme 3).
Since allenyl isothiocyanates 2 act as synthetic equiva-
lents of synthons 3, the negatively charged part of these
synthons can be connected not only with a proton but also
with alternative electrophiles (Scheme 1). If NaH is react-
ed with an excess of diphenyl disulfide, a mixture of the
nucleophile sodium thiophenolate and the electrophile
diphenyl disulfide is formed. Treatment of this mixture
with the cumulene 2a afforded the thiazole 5b and the
main product 9, which can be explained by nucleophilic
attack of thiophenolate at 2a followed by ring closure and
a second nucleophilic attack of the resulting intermediate
at the sulfur atom of diphenyl disulfide (Scheme 3).
Warning: In the case of unstable products like 2a and 2d, it was use-
ful to minimize polymerization by dilution of the collected sub-
stance with a weighed quantity of an inert solvent before thawing
the trap.2c Otherwise, a dangerously vigorous reaction is possible
since undiluted allenyl isothiocyanates, especially 2a, tend to un-
dergo spontaneous exothermic polymerization at r.t. Some of the re-
actions of 2a with nucleophiles are also highly exothermic. If the
potential for evolution of heat is not known, the addition of the re-
agent should be performed dropwise while the other reaction part-
ner is stirred with cooling.
Some of the thiazole derivatives are already mentioned in short
communications.2a,2b,16
OAc
2-Isopropylsulfanyl-5-methylthiazole (5a)
N
C
Propane-2-thiol (4a; 300 mL, 247 g, 3.24 mol) was added to isothio-
cyanatopropa-1,2-diene (2a; 6.36 g, 65.6 mmol). After stirring at r.t.
for 14 d, the excess of propane-2-thiol was removed, and the crude
compound was distilled at 48 °C/0.01 Torr to give 5a (7.97 g, 46.0
mmol, 70%) as a colorless oil.
MeOH
AcO
MeO
S
NCS
8 (46%)
2d
IR (CCl4): 2981, 1443, 1365, 1240, 1153 cm–1.
N
N
C
PhSSPh
NaH
1H NMR (CDCl3): d = 1.32 (d, 3J = 6.8 Hz, 6 H, 2 × CH3), 2.35 (d,
4J = 0.8 Hz, 3 H, CH3), 3.63 (sept, 3J = 6.8 Hz, 1 H, CH), 7.29 (q,
4J = 0.8 Hz, 1 H, H-4).
13C NMR (CDCl3): d = 11.9 (q), 23.1 (q, 2 × CH3), 40.1 (d), 134.9
(s), 140.6 (d), 160.9 (s).
SPh
+
PhS
PhS
S
S
NCS
5b (16%)
9 (74%)
2a
Scheme 3
MS: m/z (%) = 173 (15) [M+], 140 (25), 131 (100), 72 (36), 59 (35).
Some of the thiazoles formed by conversion of 2 are ap-
propriate for further cyclization reactions. For example,
the heterocyclic ester 5n underwent ring closure in the
presence of H2SO4 to yield the known14 compound 10
(Scheme 4). Even on purification over silica gel, 5n was
partially transformed to the product of cyclization, 10.
Anal. Calcd for C7H11NS2 (173.30): C, 48.52; H, 6.40; N, 8.08.
Found: C, 48.54; H, 6.33; N, 8.08.
5-Methyl-2-phenylsulfanylthiazole (5b)
Operating under anhyd N2, to a suspension of fresh 95% NaH
(0.070 g, 2.79 mmol) in anhyd THF (70 mL), thiophenol (4b; 0.322
g, 2.92 mmol) and then isothiocyanatopropa-1,2-diene (2a) 10% in
anhyd THF (0.275 g, 2.83 mmol) were added. After 45 min at r.t.,
the reaction mixture was diluted with H2O (10 mL) and extracted
with Et2O (50 mL). The organic layer was dried over MgSO4 and
the solvent was removed in vacuo to give the known compound 5b4
(0.51 g, 2.46 mmol, 87%) as a yellow liquid.
In conclusion, we have shown that the reactions of allenyl
isothiocyanates with heteroatom nucleophiles can be used
successfully for the synthesis of thiazoles. We will dem-
onstrate in a further publication that this concept is trans-
ferable to carbon nucleophiles yielding thiazole
derivatives by multiple carbon–carbon bond formation.
1H NMR (CDCl3): d = 2.60 (d, 4J = 1.2 Hz, 3 H, CH3), 7.37 (q, 4J =
1.2 Hz, 1 H, H-4), 7.54–7.57 (m, 5 H, Ph).
13C NMR (CDCl3): d = 11.8 (q), 128.7 (d), 129.3 (d), 132.5 (s),
MeO
O
132.6 (d), 135.9 (s), 140.9 (d), 162.1 (s).
C
O
N
H2SO4 (or SiO2)
– MeOH
N
Synthesis of Thiazoles 5c–e; General Procedure
Phosphites 4c–e (1.0 equiv) and isothiocyanatopropa-1,2-diene (2a)
10% in anhyd THF (1.5 equiv) were added to a suspension of
K2CO3 (3.0 equiv) in anhyd THF (20 mL). After 2–5 h at r.t., the
solvent and excess allene 2a were removed under vacuum to give
thiazoles 5c–e.
N
H
S
S
N
5n
10 (46%)
Scheme 4
Dimethyl 5-Methylthiazole-2-phosphonate (5c)
1H NMR spectra were recorded at 80 MHz, 200 MHz, 300 MHz and
400 MHz, 13C NMR spectra at 50 MHz, 75 MHz and 100 MHz.
Chemical shifts (d) are reported in ppm downfield from TMS. Cou-
pling constants (J) are reported in Hz, and spin multiplicities are in-
dicated by the following symbols: s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet). IR spectra were recorded in solutions of
CDCl3. TLC analyses were performed on Macherey–Nagel precoat-
ed silica gel Polygram Sil G/UV254 plates and viewed by UV. Chro-
matography refers to flash chromatography,15 carried out on Fluka
Using 2a (0.66 g, 6.80 mmol), following the general procedure,
compound 5c was obtained (0.78 g, 3.77 mmol, 83%) as a pale yel-
low oil. Purification was carried out by flash chromatography with
EtOAc–CH2Cl2 (6:4) as eluent.
IR (CDCl3): 3006, 1448, 1254 (P=O), 1044 cm–1.
4
1H NMR (CDCl3): d = 2.48 (d, J = 1.2 Hz, 3 H, CH3), 3.76 (d,
3JPH = 11.4 Hz, 6 H, 2 × OCH3), 7.70 (q, 4J = 1.2 Hz, 1 H, H-4).
Synthesis 2005, No. 17, 2920–2926 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Thiazoles
2923
2
13C NMR (CDCl3): d = 11.6 (q), 53.6 (q, d, JPC = 6.2 Hz, 2 ×
OCH3), 140.4 (s, C-5), 144.0 (d, d, 3JPC = 26.2 Hz, C-4), 153.2 (s, d,
1JPC = 245.8 Hz, C-2).
13C NMR (CDCl3): d = 12.3 (q, CH3), 21.8 (q, 2 × CH3), 74.7 (d,
CHO), 124.7 (s, C-5), 133.3 (d, C-4), 172.6 (s, C-2).
MS: m/z (%) = 157 (14) [M+], 115 (100), 87 (45), 60 (49), 43 (77).
Anal. Calcd for C6H10NO3PS (207.19): C, 34.78; H, 4.86; N, 6.76;
S, 15.48. Found: C, 34.48; H, 4.77; N, 6.62; S, 15.22
Anal. Calcd for C7H11NOS (157.24): C, 53.47; H, 7.05; N, 8.91.
Found: C, 52.95; H, 6.84; N, 8.51.
Dibenzyl 5-Methylthiazole-2-phosphonate (5d)
5-Methyl-2-phenoxythiazole (5h)
Using 2a (0.28 g, 2.88 mmol), following the general procedure,
compound 5d was obtained (0.60 g, 1.67 mmol, 88%) as a white
solid. Purification was carried out by flash column chromatography
with THF–n-hexane (4:6) as eluent. Crystallization can be executed
from Et2O and n-hexane; mp 45–46 °C.
Isothiocyanatopropa-1,2-diene (2a; 11.0 g, 113 mmol) was added to
a mixture of phenol (4h; 193 g, 2.06 mol) and 40% NaOH (25 mL).
After 12 d at r.t., the excess of phenol was removed at 30 °C/0.001
Torr, and the crude compound was distilled at 67.5 °C/0.001 Torr to
yield 5h (14.7 g, 76.9 mmol, 68%) as a colorless oil.
IR (CCl4): 3065, 2921, 1595, 1481, 1287, 1023 cm–1.
1H NMR (CDCl3): d = 2.33 (d, 4J = 1.3 Hz, 3 H, CH3), 6.87 (q, 4J =
1.3 Hz, 1 H, H-4), 7.08–7.49 (m, 5 H, Ph).
IR (CDCl3): 3034, 1455, 1264 (P=O), 1001 cm–1.
4
1H NMR (CDCl3): d = 2.47 (d, J = 1.2 Hz, 3 H, CH3), 5.15 (dd,
3JPH = 12 Hz, 2J = 8.1 Hz, 2 H, CH2), 5.16 (dd, 3JPH = 11.7 Hz, 2J =
8.1 Hz, 2 H, CH2), 7.26–7.31 (m, 10 H, 2 × Ph), 7.74 (q, 4J = 1.2 Hz,
1 H, H-4).
13C NMR (CDCl3): d = 12.2 (q), 119.7 (d, 2 × Pho), 125.3 (d, Php),
127.5 (s, C-5), 129.7 (d, 2 × Phm), 134.1 (d, C-4), 155.4 (s, Phi),
171.2 (s, C-2).
13C NMR (CDCl3): d = 11.5 (q), 68.5 (t, d, 2JPC = 5.6 Hz, 2 × CH2),
127.7 (d, 4 × Ph), 128.20 (d, 2 × Php), 128.22 (d, 4 × Ph), 135.2 (s,
d, 3JPC = 6.8 Hz, 2 × Phi), 140.2 (s, C-5), 143.9 (d, d, 3JPC = 26.8 Hz,
C-4), 154.0 (s, d, 1JPC = 247.6 Hz, C-2).
Anal. Calcd for C10H9NOS (191.25): C, 62.80; H, 4.74; N, 7.32.
Found: C, 63.04; H, 5.00; N, 7.37.
Anal. Calcd for C18H18NO3PS (359.38): C, 60.16; H, 5.05; N, 3.90;
S, 8.92. Found: C, 59.98; H, 5.29; N, 3.84; S, 9.03.
5-Methylthiazol-2-ylamine (5i)
Isothiocyanatopropa-1,2-diene (2a; 2.41 g, 24.8 mmol) was added
to an aqueous solution of NH3 (200 mL, 25%) and THF (75 mL).
After 3 d at r.t., THF was removed under reduced pressure. The
aqueous layer was extracted with Et2O (3 ×), dried (MgSO4) and
concentrated to afford 5i (1.68 g, 14.7 mmol, 59%) as a yellow sol-
id; mp 89–91 °C; Lit.7 94–95 °C.
Diphenyl 5-Methylthiazolephosphonate (5e)
Using 2a (0.31 g, 3.20 mmol), following the general procedure, thi-
azole 5e was formed (0.64 g, 1.92 mmol, 90%) as a colorless oil. Pu-
rification was carried out by flash column chromatography with
THF–n-hexane (2:8) as eluent.
1H NMR (CDCl3): d = 2.27 (d, 4J = 1.3 Hz, 3 H, CH3), 5.50 (br, 2
IR (CDCl3): 3076, 1491, 1275 (P=O), 1026 cm–1.
H, NH2), 6.69 (q, 4J = 1.3 Hz, 1 H, H-4).
4
1H NMR (CDCl3): d = 2.45 (d, J = 1.2 Hz, 3 H, CH3), 7.08–7.26
13C NMR (CDCl3): d = 11.8 (q), 122.6 (s, C-5), 134.9 (d, C-4),
167.1 (s, C-2).
(m, 10 H, 2 × Ph), 7.79 (q, 4J = 1.2 Hz, 1 H, H-4).
13C NMR (CDCl3): d = 11.6 (q), 120.4 (d, d, 3JPC = 4.6 Hz, 4 × Pho),
125.3 (d, d, 4JPC = 1.1 Hz, 4 × Phm), 129.5 (d, 2 × Php), 141.5 (s, C-
5), 144.4 (d, d, 3JPC = 28.4 Hz, C-4), 149.6 (s, d, 2JPC = 7.4 Hz, 2 ×
Phi), 152.0 (s, d, 1JPC = 256.6 Hz, C-2).
(5-Methylthiazol-2-yl)propylamine (5j)
Propylamine (4j; 1.48 g, 25 mmol) was added slowly under cooling
to 10% isothiocyanatopropa-1,2-diene in anhyd Et2O (2.43 g, 25
mmol). After stirring for 3 d at r.t., the mixture was filtrated, Et2O
was removed under vacuum, and the crude product was recon-
densed at 80–100 °C/0.005 Torr to yield 5j (1.75 g, 11.2 mmol,
45%) as a yellow solid. Recrystallization was done from n-hexane
to give yellow crystals; mp 59 °C.
Anal. Calcd for C16H14NO3PS (331.33): C, 58.00; H, 4.26; N, 4.23;
S, 9.68. Found: C, 57.60; H, 4.35; N, 4.30; S, 9.94.
2-Methoxy-5-methylthiazole (5f)
Isothiocyanatopropa-1,2-diene (2a; 4.31 g, 44.4 mmol) was stirred
in MeOH (500 mL) for 5 d at r.t. Then the excess MeOH was re-
moved by distillation, and the crude compound was distilled at 48
°C/26 mbar to give the known compound 5f6 (3.96 g, 30.7 mmol,
69%) as a colorless oil. The reaction time can be shortened signifi-
cantly if 2a is reacted with MeOH in the presence of a base. For
comparison, compound 5f was also prepared by the known proce-
dure.6
IR (CCl4): 3207 (NH), 2966, 1590, 1459, 1338, 1175 cm–1.
1H NMR (CDCl3): d = 0.97 (t, 3J = 7.4 Hz, 3 H, CH2CH3), 1.65 (m,
2 H, CH2CH3), 2.26 (d, 4J = 1.5 Hz, 3 H, 5-CH3), 3.15 (t, J = 7.4
3
Hz, 2 H, NHCH2), 6.08 (br s, 1 H, NH), 6.70 (br q, 4J = 1.5 Hz, 1 H,
H-4).
13C NMR (CDCl3): d = 11.4 (q), 11.9 (q), 22.5 (t), 47.7 (t), 120.2 (s),
135.3 (d), 169.5 (s).
MS: m/z (%) = 156 (32) [M+], 127 (100), 114 (75), 100 (22), 73 (34).
1H NMR (CDCl3): d = 2.30 (d, 4J = 1.5 Hz, 3 H, CH3), 4.02 (s, 3 H,
OCH3), 6.75 (q, 4J = 1.5 Hz, 1 H, H-4).
Anal. Calcd for C7H12N2S (156.25): C, 53.81; H, 7.74; N, 17.93.
Found: C, 53.77; H, 7.81; N, 17.85.
2-Isopropoxy-5-methylthiazole (5g)
Propan-2-ol (4g; 200 mL) was reacted with isothiocyanatopropa-
1,2-diene (2a; 2.36 g, 24.3 mmol) at r.t. for 91 h. The excess of pro-
pan-2-ol was removed at 19.5–20.5 °C/10 Torr, and the crude resi-
due was recondensed at 35 °C/0.007 Torr to afford 5g (2.0 g, 12.7
mmol, 52%) as a colorless oil.
(5-Methylthiazol-2-yl)phenylamine (5k)
To freshly distilled aniline (100 mL), isothiocyanatopropa-1,2-di-
ene (2a; 4.06 g, 41.8 mmol) was added slowly. The reaction mixture
was stirred at r.t. for 6 d. The excess of aniline was removed at 50
°C/0.001 Torr, and the residue was crystallized from cyclohexane to
give 5k (6.49 g, 34.1 mmol, 82%) as colorless crystals (mp 116 °C;
Lit.8 118 °C).
1H NMR (CDCl3): d = 2.42 (d, 4J = 1.3 Hz, 3 H, CH3), 7.01 (q, 4J =
1.3 Hz, 1 H, H-4), 7.03–7.12 (m, 1 H, Php), 7.34–7.45 (m, 4 H, Ph),
9.92 (br, 1 H, NH).
IR (CCl4): 2981, 1509, 1467, 1286, 1159 cm–1.
1H NMR (CDCl3): d = 1.34 (d, 3J = 6.4 Hz, 6 H, 2 × CH3), 2.24 (d,
4J = 1.6 Hz, 3 H, CH3), 5.06 (sept, 3J = 6.4 Hz, 1 H, CHO), 6.69 (q,
4J = 1.6 Hz, 1 H, H-4).
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K. Banert et al.
PAPER
13C NMR (CDCl3): d = 11.7 (q), 117.7 (d, 2 × Pho), 121.2 (s, C-5),
122.2 (d, Php), 129.3 (d, 2 × Phm), 134.7 (d, C-4), 141.1 (s, Phi),
164.7 (s, C-2).
atile substances were removed at 20 °C/0.001 Torr to yield 5o (1.12
g, 5.23 mmol, 95%) as a brown oil.
IR (CCl4): 2920, 1515, 1473, 1386, 1016 cm–1.
1H NMR (CDCl3): d = 2.29 (d, 4J = 1.2 Hz, 3 H, CH3), 2.81 [s, 12
(5-Methylthiazol-2-yl)diphenylamine (5l)
H, 2 × N(CH3)2], 6.85 (q, 4J = 1.2 Hz, 1 H, H-4).
Isothiocyanatopropa-1,2-diene (2a; 0.99 g, 10.2 mmol) was added
dropwise to freshly distilled diphenylamine (20.0 g, 118 mmol) in
THF (10 mL). After 14 d at r.t., the solvent was evaporated, and the
excess of diphenylamine was removed at 100 °C/0.001 Torr. The
crude product was purified by column chromatography with Et2O–
n-pentane (1:1) as eluent to afford 5l (1.08 g, 4.05 mmol, 40%) as a
colorless solid; mp 74–75 °C.
1H NMR (CDCl3): d = 2.26 (d, 4J = 1.3 Hz, 3 H, CH3), 6.94 (q, 4J =
1.3 Hz, 1 H, H-4), 7.00–7.35 (m, 10 H, 2 × Ph).
13C NMR (CDCl3): d = 11.8 (q), 125.2 (s, C-5), 125.29 (d, 2 × Php),
125.32 (d, 4 × Ph), 129.4 (d, 4 × Ph), 136.2 (d, C-4), 145.5 (s, 2 ×
Phi), 167.7 (s, C-2).
13C NMR (CDCl3): d = 12.5 (q), 39.7 (q, 4 × CH3), 125.2 (s), 136.0
(d), 162.2 (s), 171.9 (s).
Anal. Calcd for C9H16N4S (212.32): C, 50.91; H, 7.60; N, 26.39; S,
15.10. Found: C, 50.40; H, 7.60; N, 26.49; S, 15.71.
5-(5-Methylthiazol-2-yl)-10,11-dihydro-5H-dibenzo[b,f]aze-
pine (5p)
10,11-Dihydro-5H-dibenzo[b,f]azepine (0.50 g, 2.56 mmol) in an-
hyd THF (2 mL) was added dropwise to a solution of isopropylmag-
nesium bromide (calculated to be 0.377 g, 2.56 mmol, prepared
from 0.0622 g of Mg and 0.315 g of isopropyl bromide) in anhyd
THF (4 mL). The mixture was stirred for 2 h at r.t., and then 10%
isothiocyanatopropa-1,2-diene (2a) in anhyd THF (0.372 g, 3.84
mmol) was added, over a period of 5 min under N2 gas at 0 °C. After
stirring for 3 h at r.t., Et2O (15 mL) was added and, then the mixture
was washed with sat. aq NH4Cl (20 mL). The organic layer was sep-
arated, and the aqueous layer was extracted with Et2O (3 × 10 mL).
The organic phases were combined and dried (MgSO4). After re-
moval of the solvent, the residue was purified by flash chromatog-
raphy using Et2O–n-hexane (1:1) as eluent to give 5p as a pale
yellow-green solid (0.261 g, 0.893 mmol, 35%). Crystallization was
done from Et2O and n-hexane; mp 119–121 °C.
MS: m/z (%) = 266 (96) [M+], 265 (100), 225 (27), 77 (58), 51 (96),
50 (27), 39 (32).
Anal. Calcd for C16H14N2S (266.36): C, 72.15; H, 5.30; N, 10.52.
Found: C, 72.28; H, 5.41; N, 10.67.
Methyl (5-Methylthiazol-2-ylamino)acetate (5m)
Freshly distilled glycine methyl ester9 (4m; 0.84 g, 9.44 mmol) was
added to 10% isothiocyanatopropa-1,2-diene in anhyd Et2O (0.76 g,
7.82 mmol) at 0 °C. After 16 h at r.t., the work-up was carried out
using water and Et2O to yield 5m (0.98 g, 5.26 mmol, 67%) as a yel-
low solid. Recrystallization from n-hexane afforded yellow crys-
tals; mp 88 °C.
IR (CDCl3): 1504, 1446, 1324, 1150 cm–1.
1H NMR (CDCl3): d = 2.23 (d, 4J = 1.2 Hz, 3 H, CH3), 3.10 (s, 4 H,
2 × CH2), 6.83 (q, 4J = 1.2 Hz, 1 H, H-4¢), 7.24–7.59 (m, 8 H, 8 ×
Ar-H).
13C NMR (CDCl3): d = 11.73 (q, CH3), 30.79 (t, 2 × CH2), 122.08
(s, C-5¢), 127.13 (d, 2 × C), 127.83 (d, 2 × C), 128.64 (d, 2 × C),
130.51 (d, 2 × C), 136.38 (d, C-4¢), 136.97 (s, 2 × C), 142.74 (s, 2 ×
C), 169.59 (s, C-2¢).
IR (CCl4): 3422 (NH), 2953, 1751 (C=O), 1531, 1439, 1359, 1220
cm–1.
1H NMR (CDCl3): d = 2.28 (d, 4J = 1.2 Hz, 3 H, CH3), 3.78 (s, 3 H,
OCH3), 4.12 (s, 2 H, CH2), 5.10 (br s, 1 H, NH), 6.75 (q, 4J = 1.2
Hz, 1 H, H-4¢).
13C NMR (CDCl3): d = 11.8 (q, CCH3), 45.9 (t), 52.2 (q, OCH3),
122.1 (s, C-5¢), 135.3 (d, C-4¢), 167.1 (s), 170.8 (s).
Anal. Calcd for C18H16N2S (292.40): C, 73.94; H, 5.52; N, 9.58; S,
10.97. Found: C, 73.40; H, 5.54; N, 9.60; S, 10.61.
Anal. Calcd for C7H10N2O2S (186.23): C, 45.15; H, 5.41; N, 15.04.
Found: C, 45.36; H, 5.36; N, 15.05.
1-(5-Methylthiazol-2-yl)-1H-indole (5q)
Methyl 2-(5-Methylthiazol-2-ylamino)benzoate (5n)
Methyl 2-aminobenzoate (4n; 4.0 g, 26.5 mmol) was added to a so-
lution of 10% isothiocyanatopropa-1,2-diene (2a) in anhyd Et2O
(2.0 g, 20.5 mmol) under cooling. The mixture was concentrated by
evaporating about half of the Et2O and stirred at r.t. for 3 d. The sol-
vent was removed under vacuum, and the crude product was ex-
tracted with boiling n-hexane to give 5n (2.86 g, 11.5 mol, 56%) as
an orange oil with traces of 4n. Upon passing this oil through silica
gel using n-hexane–EtOAc (4:1) as eluent, partial ring closure of 5n
occurred to furnish 2-methyl-5H-thiazolo[2,3-b]quinazolin-5-one
(10).
1H NMR (CDCl3): d = 2.23 (d, 4J = 1.5 Hz, 3 H, CH3), 3.82 (s, 3 H,
OCH3), 6.81 (dd, J = 8.5 Hz, J = 8.2 Hz, 1 H), 6.85 (q, 4J = 1.5 Hz,
1 H, H-4¢), 7.41 (d, 3J = 8.2 Hz, 1 H), 7.90 (dd, J = 8.5 Hz, J = 8.2
Hz, 1 H), 8.40 (d, J = 8.2 Hz, 1 H), 10.94 (br s, 1 H, NH).
13C NMR (CDCl3): d = 11.4 (q), 52.0 (q), 112.3 (s), 117.0 (d), 119.6
(d), 124.3 (s), 131.0 (d), 134.7 (d), 136.0 (d), 144.0 (s), 161.5 (s),
166.9 (s).
1H-Indole (5.85 g, 50 mmol) in anhyd THF (10 mL) was added
dropwise to a solution of ethylmagnesium bromide (calculated to be
3.33 g, 25 mmol, prepared from 0.61 g of Mg and 2.72 g of ethyl
bromide) in anhyd THF (15 mL) at 0 °C. The mixture was stirred
for 90 min at the same temperature, then 10% isothiocyanatopropa-
1,2-diene (2a) in anhyd Et2O (1.94 g, 20 mmol) was added at 0–10
°C. After stirring overnight, the mixture was worked up with Et2O
and aq NH4Cl as usual. The solvent was removed under vacuum,
and the crude product was separated from the excess of indole by
flash chromatography using EtOAc–n-hexane (1:4) as eluent to
give 5q (3.64 g, 17 mmol, 85%). Recrystallization was done from
n-pentane to afford yellow crystals; mp 44 °C.
IR (CCl4): 3067, 2922, 1520, 1450, 1348, 1232 cm–1.
1H NMR (CDCl3): d = 2.44 (d, 4J = 1.2 Hz, 3 H, CH3), 6.77 (d, 3J =
3.5 Hz, 1 H, H-3), 7.22 (q, 4J = 1.2 Hz, 1 H, H-4¢), 7.23 (m, 1 H, H-
5), 7.34 (m, 1 H, H-6), 7.60 (d, 3J = 3.5 Hz, 1 H, H-2), 7.63 (d, 1 H,
H-7), 8.24 (d, 3J = 8.1 Hz, 1 H, H-4).
13C NMR (CDCl3): d = 11.6 (q, CH3), 106.5 (d, C-3), 113.0 (d, C-
7), 121.1 (d, C-6), 121.9 (d, C-4), 123.6 (d, C-5), 126.3 (d, C-2),
127.7 (s, C-3a or C-5¢), 129.9 (s, C-3a or C-5¢), 134.9 (s, C-7a),
136.9 (d, C-4¢), 158.6 (s, C-2¢).
N-(5-Methylthiazol-2-yl)-N¢,N¢,N¢¢,N¢¢-tetramethylguanidine
(5o)
Isothiocyanatopropa-1,2-diene (2a; 10%) in anhyd THF (0.539 g,
5.56 mmol) was added dropwise to tetramethylguanidine (0.640 g,
5.56 mmol) in anhyd THF (10 mL) at 0 °C. After 3 h at r.t., the vol-
Anal. Calcd for C12H10N2S (214.29): C, 67.26; H, 4.70; N, 13.07; S,
14.96. Found: C, 66.96; H, 4.63; N, 12.83; S, 15.42.
Synthesis 2005, No. 17, 2920–2926 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Thiazoles
2925
5-Methyl-3H-thiazol-2-one (6a)
13C NMR (CDCl3): d = 20.7 (q, CH3), 63.4 (t, C-1¢), 85.6 (t, C-4¢),
100.8 (s, C-2¢), 138.9 (s, NCS), 170.2 (s, C=O), 207.3 (s, C-3¢).
Isothiocyanatopropa-1,2-diene (2a; 3.07 g, 31.6 mmol) was added
to a solution of NaOH (12.0 g, 300 mmol) in a mixture of H2O (1200
mL) and THF (1200 mL). After 30 min, the mixture was neutralized
with 5% H2SO4. The solvent was removed under vacuum, and the
crude product was extracted using a Soxhlet apparatus and CH2Cl2
for 1 d. After removing the solvent, the product was recrystallized
from Et2O to afford 6a (3.14 g, 27.3 mmol, 86%) as a colorless sol-
id; mp 137–138 °C (Lit.6 144–145 °C).
IR (CDCl3): 3160, 1690, 1660 cm–1.
1H NMR (CDCl3): d = 2.12 (d, 4J = 1.5 Hz, 3 H, CH3), 6.28 (q, 4J =
1.5 Hz, 1 H, H-4) 10.19 (br s, 1 H, NH).
2-Methoxy-5-methylthiazol-4-yl Methyl Acetate (8)
A solution of 2d (0.42 g, 2.49 mmol) in CHCl3 (20 mL) was added
to MeOH (100 mL). The clear yellow solution was stirred for 14 d
at r.t. Then the solvent was removed under vacuum, and the yellow
oily residue was purified by flash column chromatography using
neutral Al2O3 and CH2Cl2 to yield 8 (0.231 g, 1.15 mmol, 46%) as
a slightly yellow oil.
IR (CCl4): 1735 (C=O), 1536, 1247 cm–1.
1H NMR (CDCl3): d = 2.03 [s, 3 H, C(O)CH3], 2.27 (s, 3 H, 5-Me),
3.97 (s, 3 H, OCH3), 4.89 (s, 2 H, OCH2).
13C NMR (CDCl3): d = 13.7 (q), 116.3 (s), 116.4 (d), 176.1 (s).
MS: m/z (%) = 115 (100) [M+], 60 (49), 59 (84), 58 (19), 45 (22).
13C NMR (CDCl3): d = 11.0 (q, 5-CH3), 20.8 (q, CH3), 57.8 (q,
OCH3), 59.1 (t, CH2O), 124.9 (s), 139.3 (s), 170.7 (s), 171.6 (s).
5-Methyl-3H-thiazole-2-thione (6b)
ESI–MS: m/z [M + H]+ calcd for C8H11NO3S: 202.0532; found:
202.0555.
Isothiocyanatopropa-1,2-diene (2a; 1.00 g, 10.3 mmol) was added
dropwise to a saturated solution of H2S in a mixture of H2O (1000
mL) and THF (2000 mL). After stirring for 3 d at r.t., H2O and THF
were removed under reduced pressure. The residue was recrystal-
lized from CH2Cl2 to give 6b (0.72 g, 5.5 mmol, 53%) as a colorless
solid; mp 178–180 °C (Lit.11 178–179 °C).
1H NMR (CDCl3): d = 2.24 (d, 4J = 1.3 Hz, 3 H, CH3), 6.72 (q, 4J =
1.3 Hz, 1 H, H-4), 11.45 (br s, 1 H, NH).
13C NMR (CDCl3): d = 12.7 (q), 123.5 (d), 128.2 (s), 188.8 (s).
5-Methyl-2-phenylsulfanylthiazole (5b) and 2-Phenylsulfanyl-
5-(phenylsulfanylmethyl)thiazole (9)
Operating under anhyd N2, to a suspension of fresh 95% NaH
(0.070 g, 2.79 mmol) in anhyd THF (70 mL), diphenyl disulfide
(1.23 g, 5.64 mmol) was added. The mixture was stirred under Ar
for 1.5 h at 75 °C, followed by dropwise addition of the isothiocy-
anatopropa-1,2-diene (2a; 0.274 g, 2.82 mmol) in anhyd THF (30
mL) (the color changed to deep red). After stirring for 5 h at 75 °C,
the reaction mixture was stirred overnight at r.t. Thereafter it was
washed with sat. aq NH4Cl (150 mL) and extracted with Et2O (3 ×
100 mL). The combined organic layers were washed with water
(100 mL) and dried over MgSO4. The solvent was removed in vac-
uo, and the products were separated by flash chromatography with
Et2O–n-hexane (1:2) as eluent to give first 5b as a yellow oil (0.093
g, 0.45 mmol, 16%) and then 9 as a yellow oil (0.66 g, 2.10 mmol,
74%).
3,5-Dimethyl-3H-thiazol-2-one (7)
A solution of 6a (0.74 g, 6.4 mmol) in EtOH (50 mL) was added at
0 °C to freshly prepared solution of diazomethane12 in Et2O (1 M,
50 mL, 50 mmol). After 2 h at this temperature, the cooling bath was
removed and the reaction mixture was stored overnight. Thereafter
solvents were evaporated under vacuum to give a mixture of the
known compound 76 (0.48 g, 3.72 mmol, 58%) and small amounts
of 5f (0.08 g, 0.62 mmol, 10%).
1H NMR (CDCl3): d = 2.13 (d, 4J = 1.3 Hz, 3 H, CH3), 3.25 (s, 3 H,
Compound 9
IR (CCl4): 3080, 2920, 1583, 1478, 1402, 1039 cm–1.
NCH3), 6.24 (q, 4J = 1.3 Hz, 1 H, H-4).
1H NMR (CDCl3): d = 4.14 (d, 4J = 0.9 Hz, 2 H, CH2), 7.41 (t, 4J =
0.9 Hz, 1 H, H-4), 7.24–7.58 (m, 10 H, 2 × Ph).
13C NMR (CDCl3): d = 13.6 (q), 31.7 (q), 113.7 (s), 120.9 (d), 172.0
(s).
13C NMR (CDCl3): d = 31.2 (t), 127.2 (d), 128.9 (d), 129.3 (d),
129.6 (d), 130.9 (d), 131.6 (s), 133.4 (d), 134.2 (s), 137.4 (s), 141.5
(d), 165.4 (s).
5-Methylthiazole (5r)
To a solution of sodium cyanoborohydride (1.89 g, 30 mmol) in
MeOH (20 mL), 10% isothiocyanatopropa-1,2-diene (2a) in anhyd
Et2O (0.97 g, 10.0 mmol) was added at 5 °C. After 9 d at r.t., the
mixture was poured into ice/water and made alkaline using NaOH.
Normal work-up with Et2O led to 5r (0.46 g, 4.6 mmol, 46%; prod-
uct commercially available) after removal of the solvent.
1H NMR (CDCl3): d = 2.51 (d, 4J = 1.2 Hz, 3 H, CH3), 7.58 (q, 4J =
1.2 Hz, 1 H, H-4), 8.65 (s, 1 H, H-2).
MS: m/z = 99 [M+].
Anal. Calcd for C16H13NS3 (315.48): C, 60.91; H, 4.15; N, 4.44; S,
30.49. Found: C, 60.65; H, 4.36; N, 4.34; S, 30.69.
2-Methyl-5H-thiazolo[2,3-b]quinazolin-5-one (10)
To 5n (0.62 g, 2.50 mmol), still containing some 4n, concd H2SO4
(7 mL) was added. The mixture was stirred for 15 min at 40 °C and
then cooled down. Neutralization was carried out by using 10% of
aq NaOH solution. The crude sticky product was recrystallized
from EtOH to give 10 (0.25 g, 1.16 mmol, 46%) as colorless crys-
tals; mp 182 °C (Lit.14 183 °C).
1H NMR (DMSO-d6): d = 2.38 (d, 4J = 1.5 Hz, 3 H, CH3), 7.46 (dd,
J = 8.6, 8.2 Hz, 1 H), 7.59 (d, 3J = 8.2 Hz, 1 H), 7.79 (br q, 4J = 1.5
Hz, 1 H), 7.82 (dd, J = 8.6, 8.2 Hz, 1 H), 8.19 (d, J = 8.2 Hz, 1 H).
2-Isothiocyanatobuta-2,3-dienyl Acetate (2d)
Flash vacuum pyrolysis2c of 4-thiocyanato-but-2-ynyl acetate13 (1d;
0.62 g, 3.66 mmol) at 400 °C and 3 × 10–6 mbar (vaporization tem-
perature: 90–100 °C) gave yellow oily 2d (0.45 g, 2.66 mmol,
73%), which contained only a small amount of 1d.
13C NMR (DMSO-d6): d = 13.1 (q), 116.7, 117.8, 123.2, 125.3,
126.1, 126.6, 134.8, 147.9, 157.5, 158.3.
IR (CDCl3): 2036 (br, NCS), 1743 (C=O), 1225 cm–1.
1H NMR (CDCl3): d = 2.11 (s, 3 H, CH3), 4.69 (t, 5J = 2.1 Hz, 2 H,
CH2O), 5.42 (t, 5J = 2.1 Hz, 2 H, =CH2).
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2926
K. Banert et al.
PAPER
(4) For reviews on the synthesis of thiazoles, see: (a) Kikelj,
Acknowledgment
D.; Urleb, U. In Science of Synthesis, Vol. 11; Schaumann,
E., Ed.; Thieme: Stuttgart, 2002, 627. (b) Liebscher, J. In
Houben–Weyl, Vol. E 8b/Part 2; Schaumann, E., Ed.;
Thieme: Stuttgart, 1994, 4th ed, 1. (c) Dondoni, A.; Merino,
P. In Comprehensive Heterocyclic Chemistry II, Vol. 3;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1994, 373. (d) Sharma, S. Sulfur Rep.
1989, 8, 327.
B. J. A.-H. thanks the DAAD (Deutscher Akademischer Austausch-
dienst) for a Ph.D. fellowship. We are grateful to the Deutsche For-
schungsgemeinschaft and the Fonds der Chemischen Industrie for
continued financial support. Furthermore we thank Ms. Kerstin
Baake, Ms. Nermeen S. Gomaa, Mr. Holger Müller and Dr. Man-
fred Hagedorn for assistance in connection with some of the synthe-
ses.
(5) Bosco, M.; Forlani, L.; Liturri, V.; Riccio, P.; Todesco, P. E.
J. Chem. Soc. B 1971, 1373.
(6) Cornwell, S. P.; Kaye, P. T.; Kent, A. G.; Meakins, G. D. J.
Chem. Soc., Perkin Trans. 1 1981, 2340.
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(8) Eloy, F.; Deryckere, A. Chim. Ther. 1973, 8, 437.
(9) Jansen, M.; Potschka, H.; Brandt, C.; Löscher, W.;
Dannhardt, G. J. Med. Chem. 2003, 46, 64.
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Synthesis 2005, No. 17, 2920–2926 © Thieme Stuttgart · New York