A convenient synthesis of 2-mercapto-oxazoles via β-ketoazide and its application to a key intermediate of PI3Kγ inhibitors

Article abstract of DOI:10.3987/COM-13-12778

A convenient synthesis of 2-mercapto-oxazoles via the reaction of β-ketoazide with triphenylphosphine (TPP) and carbon disulfide and its application to the synthesis of a key intermediate of phosphoinositide 3-kinase γ (PI3Kγ) inhibitors are described. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-13-12778

HETEROCYCLES, Vol. 87, No. 9, 2013
1881
HETEROCYCLES, Vol. 87, No. 9, 2013, pp. 1881 - 1887. © The Japan Institute of Heterocyclic Chemistry
Received, 13th July 2013, Accepted, 31st July, 2013, Published online, 7th August, 2013
DOI: 10.3987/COM-13-12778
A CONVENIENT SYNTHESIS OF 2-MERCAPTO-OXAZOLES VIA
β-KETOAZIDE AND ITS APPLICATION TO A KEY INTERMEDIATE
OF PI3Kγ INHIBITORS
Yusuke Oka,* Tetsuya Yabuuchi, and Yoshinori Sekiguchi
Medicinal Chemistry Laboratories Taisho Pharmaceutical Co., Ltd. 1-403,
Yoshino-Cho, Kita-Ku, Saitama-Shi, Saitama 331-9530, Japan; e-mail:
y-oka@so.taisho.co.jp
Abstract – A convenient synthesis of 2-mercapto-oxazoles via the reaction of
β-ketoazide with triphenylphosphine (TPP) and carbon disulfide and its
application to the synthesis of a key intermediate of phosphoinositide 3-kinase γ
(PI3Kγ) inhibitors are described.
INTRODUCTION
Oxazoles are an important chemical class of heterocycles in the pharmaceutical industry and in natural
products chemistry.1 The biological activities of synthetic oxazoles and complex naturally occurring
derivatives continue to drive organic chemists to develop new synthetic methods.2,3 Of the available
synthetic approaches, iminophosphorane-mediated synthesis is pre-eminent because this method can
provide several kinds of alkyl, aryl, and secondary amine groups at the 2-position of 1,3-oxazoles.4,5
For an extensive structure-activity relationship (SAR) study, however, the introduction of a greater
variety of functional groups, such as tertiary amine, alkoxyl, and sulfonyl groups, into the 2-position of
1,3-oxazoles is needed, as we previously reported in a description of our phosphoinositide 3-kinase γ
(PI3Kγ) program (Figure 1).6 2-Mercapto-oxazole is an attractive intermediate for the development of
SAR studies because it can easily be converted into not only the corresponding thioether and alkyl
sulfonyl groups, but also 2-chloro-oxazole, which can be subjected to an SNAr displacement reaction. In
our previous paper, we used the reported method7 to prepare the desired compound 3 using
α-aminoketone 2 with carbon disulfide (Figure 1). However, the instability of 2 under acidic conditions
led to a low yield of intermediate 3, which made it difficult to apply this process to the multi-gram
synthesis of 3. In addition, the generation of toxic H2S gas was of concern during the cyclization step
using carbon disulfide.

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HETEROCYCLES, Vol. 87, No. 9, 2013
H2
Pd/C
. HCl
2HCl
O
CS2
. Na CO
NH2
aq
H2S
2
3
c
N
O
S
N
H
N
N
N
N
O
O
2
S
S
O
O
N
H
OR
N3
N
N
N
O
O
this work
N
N
SNAr
5
6
O
POCl3
S
S
O
O
S
O
N
H
N
SH
N
H
Cl
H
1
3
4
a key intermediate
N
H
NR'R"
ArI
CuI,1,10-phenanthroline
MeI, K2CO3
NaO -Bu
t
H2O2
Mo7O24(NH4)6·4H2O
O
N
N
N
O
N
N
S
S
O
N
H
N
O
O
N
H
S
N
S
O
O
O
S
S
N
H
7
8
9



PI3K IC50 = 12 nM
PI3K IC50 = 16 nM
PI3K IC50 = 22 nM
Figure 1. A key intermediate for PI3Kγ inhibitors
Herein, we report an easy and modified synthesis method for 2-mercapto-oxazole derivatives through an
iminophosphorane-mediated reaction and its application to the multi-gram scale preparation of a key
intermediate for PI3K inhibitors.
RESULTS AND DISCUSSION
The synthesis of 2-substituted oxazoles via iminophosphoranes derived from -ketoazide has been
reported.4 This methodology was applied to the synthesis of 2-mercapto-oxazole 3 via an
iminophosphorane-mediated reaction with carbon disulfide (Table 1). The reaction of β-ketoazide 1 with
carbon disulfide and triphenylphosphine (TPP) under the reported conditions (CHCl3, instead of CH2Cl2
or toluene)4b produced the desired 2-mercapto-oxazole 3 at low-isolated yields (yields of 31 % and 43 %,
respectively). The use of MeCN in place of the solvents described above improved the conversion of 1
into 3. In addition, ether series solvents, such as THF and dioxane, were found to enhance this reaction
(entries 4 and 5). When the reaction was carried out at 100 °C in dioxane, the yield was further improved
up to 78 % (entry 6). Under this condition, the multi-gram synthesis (up to a scale of 10 g) of
2-mercapto-oxazole 3 was successfully achieved (entry 7, 63 % yield). These results prompted us to
further investigate the substrate scope and limitations of this reaction under our optimized conditions
(Table 2).

HETEROCYCLES, Vol. 87, No. 9, 2013
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Table 1. Effects of solvents on the synthesis of 2-mercapto-oxazole 3
O
N
O
N
CS2(1.5 eq)
PPh3(1.5 eq)
N3
N
S
S
N
H
N
H
O
O
SH
solvent
rt, 1 h
then 50 °C, 2 h
1
3
yield (%)a
entry
solvent
1
2
CHCl3
31
43
toluene
3
4
MeCN
THF
51
67
63
5
6
7
dioxane
dioxane
dioxane
78b,c
63b,d
Solvent screening was conducted by 100 mg scale (entries 1-5).
a Isolated yield.
b Temp.; 100 °C.
c 500 mg scale.
d 15 g scale.
The iminophosphorane-mediated reaction of -ketoazides 10 with carbon disulfide generally produced
the corresponding oxazoles 11 at good yields, as shown in Table 2. Phenyl groups with an
electron-donating substituent, such as a methoxy group or p-bromine atom, produced oxazoles at high
yields (entries 2-5). Changing the position of the electron-donating substituents (o-, m-, and p-methoxy)
gave products in moderate to good yields (entries 2-4). By contrast, an attempt to introduce an
electron-withdrawing substituent (methyl ester group) into the p-position of the phenyl group resulted in a
low yield. This feature was just as valid for π-electron-deficient heteroaromatic rings, such as a 2-pyridine
analogue 10g (entries 6 and 7). When α-methyl β-ketoazide 10h and t-butyl β-ketoazide 10i were applied,
the corresponding oxazoles were obtained at yields of 94 % and 86 %, respectively. These results suggest
that this synthetic methodology tends to be susceptible to an electronic effect, rather than to a steric
hindrance.
A plausible mechanism for the sequence of the reaction is shown in Scheme 1. First, the β-ketoazide
reacted with TPP to yield an iminophosphorane (Staudinger reaction), which then underwent an
aza-Wittig type reaction with the carbon disulfide to yield an isothiocyanate intermediate (III). The
subsequent intramolecular cyclization of the carbonyl group (or the enol form) to the isothiocyanate

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HETEROCYCLES, Vol. 87, No. 9, 2013
moiety produced the 2-mercapto-oxazoles. The low yields, in the case of a phenyl ring with an
electron-withdrawing group or an π-electron-deficient pyridine ring, may be due to the low electron
density across the carbonyl group of intermediate III.8
Table 2. Results of the preparation of 2-mercapto-oxazoles using various kinds of substrates
R2
R2
CS2(1.5 eq)
PPh3(1.5 eq)
N3
N
R1
R1
dioxane
100 °C
O
O
SH
10
11
yield (%)a
82
R1
R2
H
entry
1
11
*
*
N
O
SH
N
10a
10b
11a
O
2
3
88
73
H
H
O
SH
O
O
11b
O
*
N
O
SH
10c
11c
O
O
*
*
N
4
5
H
H
65
88
O
SH
N
10d
10e
11d
Br
O
SH
Br
11e
*
*
O
O
N
6
7
28
18
H
H
O
O
SH
O
10f
11f
N
N
N
N
O
SH
SH
10g
11g
*
*
8
9
Me
H
94
86
O
11h
10h
10i
N
O
11i
SH
a Isolated yield.

HETEROCYCLES, Vol. 87, No. 9, 2013
1885
Scheme 1. Possible mechanism of iminophosphorane-mediated 2-mercapto-oxazole formation
CS2
PPh3
N3
N
R
R
O
O
SH
N
-N2
S
P
N
R
P Ph
Ph
R
N
S
C
O
(III)
O
R
S
Ph
Ph
Ph
Ph
(II)
O
S=PPh3
(I)
In conclusion, we have developed an iminophosphorane-mediated one-pot synthesis method for
producing 2-mercapto-oxazoles from β-ketoazide, carbon disulfide, and TPP. This method has been
applied to prepare 2-mercapto-oxazole 3, which is a key intermediate of PI3Kγ inhibitors, and appears
to be broadly applicable. The method described above enabled us not only to avoid the reduction step of
the azide group and the generation of H2S gas, but also to synthesize multi-gram quantities of
2-mercapto-oxazoles easily and reproducibly. Because of the availability of the starting materials and the
simplicity of this procedure, this synthetic approach may complement the existing methods for the
synthesis of 2-mercapto-oxazoles.
EXPERIMENTAL
1
The H NMR spectra were determined using TMS as an internal reference with a JEOL ECA600 NMR
13
spectrometer operating at 600 MHz. The C NMR spectra were determined using TMS as an internal
reference with a JEOL ECA500 NMR spectrometer operating at 126 MHz or a JEOL ECA600 NMR
spectrometer operating at 151 MHz. Low-resolution mass spectra (MS) were recorded using a Micromass
Platform LC mass spectrometer with an electrospray ionization (ESI)/atmospheric pressure chemical
ionization (APCI) dual source. High-resolution mass spectra (HRMS) were recorded using a Shimadzu
LCMS-IT-TOF mass spectrometer with an ESI/APCI dual source. Elemental analyses were performed
using a Perkin-Elmer 2400, a Yanaco MT-6, or an Elementar vario MICRO cube elemental analyzer, and
the results were within 0.4 % of the calculated values.
Typical Procedure for the Preparation of 2-Mercapto-oxazoles
N-[4-Methyl-5-(2-sulfanyl-1,3-oxazol-5-yl)-1,3-thiazol-2-yl]acetamide (3): Carbon disulfide (5.7 mL,
94 mmol) was added to a solution of β-ketoazide 1 (15 g, 63 mmol) and PPh3 (25 g, 94 mmol) in dioxane

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HETEROCYCLES, Vol. 87, No. 9, 2013
(300 mL). After being stirred for 0.5 h at room temperature, the reaction mixture was stirred at 100 °C for
4 h. Then, 1 M NaOH (500 mL) was added to the mixture, and the mixture was washed with CHCl3. The
water layer was acidified with AcOH and extracted using CHCl3-MeOH. The combined organic layer was
washed with brine, dried over MgSO4, filtered and evaporated in vacuo, and washed with AcOEt to
provide 3 (10 g, 63%): a pale yellow powder; 1H NMR (DMSO-d6, 600 MHz) δ 2.15 (s, 3H), 2.35 (s, 3H),
13
7.56 (s, 1H), 12.32 (s, 1H), 13.35 (br s, 1H); C NMR (DMSO-d6, 151 MHz) δ 16.40, 22.37, 109.87,
112.71, 141.20, 144.88, 156.26, 168.72, 176.84; MS m/z 256 (M+H)+, 278 (M+Na)+, 254 (M-H)-. Anal.
Calcd for C9H9N3O2S2 ·0.1H2O: C, 42.04; H, 3.61; N, 16.34. Found: C, 41.76; H, 3.48; N, 16.11.
5-(2-Methoxyphenyl)-1,3-oxazole-2-thiol (11d): a pale yellow powder; 1H NMR (DMSO-d6, 600 MHz)
δ 3.93 (s, 3 H) 7.07 (td, J = 7.64, 0.83 Hz, 1 H) 7.14 (d, J = 7.84 Hz, 1 H) 7.34-7.39 (m, 1 H) 7.55 (s, 1 H)
13
7.60 (dd, J = 7.84, 1.65 Hz, 1 H) 13.29 (br s, 1 H); C NMR (DMSO-d6, 151 MHz) δ 55.53, 111.38,
114.94, 115.08, 120.74, 124.32, 129.47, 143.88, 154.75, 176.53; MS m/z 208 (M+H)+, 230 (M+Na)+, 206
(M-H)-. Anal. Calcd for C10H9NO2S: C, 57.95; H, 4.38; N, 6.76. Found: C, 57.82; H, 4.34; N, 6.70.
1
Methyl 4-(2-sulfanyl-1,3-oxazol-5-yl)benzoate (11f): a pale yellow powder; H NMR (DMSO-d6, 600
MHz) δ 3.86 (s, 3H), 7.75 (d, J = 8.26 Hz, 2H), 8.03 (d, J = 8.26 Hz, 2H), 8.08 (s, 1H), 13.46 (br s, 1H);
13C NMR (DMSO-d6, 126 MHz) δ 52.20, 114.78, 123.18, 128.67, 128.77, 128.88, 129.95, 130.56, 146.15,
165.60, 177.67; MS m/z 236 (M+H)+, 258 (M+Na)+, 234 (M-H)-. HRMS m/z Calcd for C11H9NO3S
(M+H)+, 236.0376. Found: 236.0371.
4-Methyl-5-phenyl-1,3-oxazole-2-thiol (11h): a pale yellow powder; 1H NMR (CDCl3, 600 MHz) δ 2.39
13
(s, 3H), 7.32-7.39 (m, 1H), 7.40-7.48 (m, 2H), 7.52-7.60 (m, 2H), 12.00 (br s, 1H); C NMR (CDCl3,
151 MHz) δ 9.56, 120.79, 125.11, 126.92, 128.59, 128.91, 144.34, 176.54; MS m/z 192 (M+H)+, 214
(M+Na)+, 190 (M-H)-. HRMS m/z Calcd for C10H9NOS: (M+H)+, 192.0478. Found: 192.0483.
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8. Similar explanation has been reported.5b