Efficient one-pot synthesis of substituted oxazoles from 3-trimethylsilylpropargylic alcohols and amides by gold-catalyzed substitution followed by cycloisomerization

Article abstract of DOI:10.3987/COM-18-S(T)81

3-Trimethylsilylpropargylic alcohols 1, on treatment with amides 2 in the presence of catalytic amounts of cationic gold(III), underwent propargylic substitution followed by cycloisomerization, in which the key feature is the -cation-stabilizing effect of

Full text of DOI:10.3987/COM-18-S(T)81

HETEROCYCLES, Vol. 97, No. , 2018, pp. -. © 2018 The Japan Institute of Heterocyclic Chemistry
Received, 28th February, 2018 Accepted, 18th April, 2018, Published online,
DOI: 10.3987/COM-18-S(T)81
.
EFFICIENT ONE-POT SYNTHESIS OF SUBSTITUTED OXAZOLES
FROM 3-TRIMETHYLSILYL PROPARGYLIC ALCOHOLS AND
AMIDES BY GOLD-CATALYZED SUBSTITUTION FOLLOWED BY
CYCLOISOMERIZATION
Nobuyoshi Morita,* Aoi Sano, Ayako Sone, Shino Aonuma, Arisa Matsunaga,
Yoshimitsu Hashimoto, and Osamu Tamura*
Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan;
E-mail: morita@ac.shoyaku.ac.jp, tamura@ac.shoyaku.ac.jp
This paper is dedicated to Prof. Dr. Kiyoshi Tomioka on the occasion of his 70th
birthday.
Abstract – 3-Trimethylsilyl propargylic alcohols 1, on treatment with amides 2 in
the presence of catalytic amounts of cationic gold(III), underwent propargylic
substitution followed by cycloisomerization, in which the key feature is the
E-cation-stabilizing effect of the silicon atom of 1.
Substituted oxazoles are common substructures in a huge number of natural products and biologically
active compounds,1 as well as in various reagents/intermediates used in organic synthesis.2 Among the
numerous procedures reported for the construction of substituted oxazoles, cycloisomerization of
propargylic amides 3 to substituted oxazoles 4 has attracted much attention (Scheme 1).1 These
transformations have employed transition metals3a (Pd,3b,cꢀFe,3d Au,3e-k etc.), as well as other reagents.4
However, the one-pot synthesis of substituted oxazoles 4 directly from propargylic alcohols 1 and amides
2 via 3 as intermediates remains a challenging task, because both propargylic substitution and the
subsequent cycloisomerization should proceed effectively under the same reaction conditions. Recently,
efficient
syntheses
of
substituted
oxazoles
4
were
achieved
via
propargylic
substitution/cycloisomerization of propargylic alcohols 1 and amides 2 using a combination of two
different transition metals (Ru/Au,5 Zn/Ru6), but these methods were applicable only to terminal
propargylic alcohols 1 (R1 = H), thus being limited to the formation of oxazoles 4 (R1 = H) having a
methyl group at the 5-position.

Recently, Zhan et al. reported a one-pot synthesis of substituted oxazoles 4 from propargylic alcohols 1
and amides 2 with using p-toluenesulfonic acid monohydrate (PTSA).7 Although this procedure has
wide scope for the preparation of substituted oxazoles 4 and is superior in that it uses only a single
catalyst, a stoichiometric amount of PTSA is needed in the reaction. Thus, more efficient synthetic
methods for substituted oxazoles 4 are still required.
O
O
R3
R3
NH2
R3
NH
R2
OH
R2
N
2
O
R2
R1
R1
propargylic substitution
R1
1
3
4
cycloisomerization
Scheme 1
We have developed gold(I)/(III)-catalyzed intramolecular reactions of propargylic alcohols for the
synthesis of heterocyclic compounds (cyclic ethers/piperidines/azepanes).8-10 We also extended this
procedure to gold-catalyzed intermolecular reaction of propargylic alcohols with carbon nucleophiles,
affording cyclic compounds (indenes/dihydropyrans).11,12 In particular, we achieved the gold-catalyzed
one-pot synthesis of dihydropyrans 5’ from propargylic alcohols 1’ (R2 = CH2CH2OH) with active
methylene compounds 2’ via propargylic substitution followed by cyclization (Scheme 2, eq. 1).12
Based on this result, we envisioned the possible development of a gold-catalyzed one-pot synthetic
procedure for substituted oxazoles 4 from propargylic alcohols 1 with amides 2 instead of active
methylene compounds 2’ (Scheme 2, eq. 2).
O
O
O
O
O
2'
R1
O
R3
R4
R3
R4
(eq. 1)
R4
ClCH2CH2Cl
R2
R1
O
R3
5'
OH
R2
cat. Au
O
R3
O
R3
R1
E+
F-
R3
NH
R2
N
N
1' (R2 = CH2CH2OH)
1 (R1 = TMS, R2 = Aryl)
O
R2
O
(eq. 2)
R2
2
R3
toluene
NH2
TMS
TMS
3
4
5,6
E
Scheme 2

Herein, we present the one-pot synthesis of substituted oxazoles 4 by gold-catalyzed propargylic
substitution followed by cycloisomerization promoted by the E-cation-stabilizing effect13 of the silicon
atom of 3-trimethylsilyl propargylic alcohol 1 (R1 = TMS). The trimethylsilylmethyl group at the
5-position in the oxazole ring 4 can be easily transformed into other substituents (see 5 and 6) in the
presence of fluoride ion with electrophiles.
We first examined propargylic substitution of 3-trimethylsilyl-propargylic alcohol 1a with benzamide
(2a) in the presence of an oxophilic gold(III) catalyst that can activate the hydroxyl group at the
propargylic position (Table 1). Gold(III) catalyst AuBr3 (5 mol%) afforded a trace amount of the
desired oxazole 4aa (entry 1), whereas cationic gold species generated from AuBr3 (5 mol%) and AgPF6
(15 mol%) gave the desired product 4aa in 33% yield (entry 2). Next, the effect of the counter anion of
silver catalysts was investigated. The reaction with AuBr3 (5 mol%) and AgOTf (15 mol%) gave the
desired product 4aa in good yield (entry 3). In contrast, the reaction with AuBr3 (5 mol%) and AgBF4
(15 mol%) afforded only a trace amount of the product 4aa (entry 4). The reaction was greatly
accelerated in the presence of AuBr3 (5 mol%) and AgOTf (15 mol%) in refluxing toluene, affording
oxazole 4aa in good yield (entry 5). Reducing the catalyst loading to 1 mol% AuBr3 and 3 mol%
AgOTf gave 37% yield of 4aa (entry 6). Finally, the catalyst system of AuBr3 (5 mol%) with AgOTf
(15 mol%) in refluxing toluene was identified as optimal for the formation of 4aa.14
Table 1. Optimization of reaction conditions for gold-catalyzed one-pot synthesis of substituted oxzazole
4aa from 3-trimethylsilyl propargylic alcohol 1a and benzamide (2a)
OH
O
Ph
Ph
N
catalyst
Ph
NH
Ph
TMS
1a
O
+
Ph
solvent, reflux
time
O
TMS
TMS
3aa
Ph
NH2
4aa
2a
entry
catalyst
AuBr3 (5 mol%)
time
4aa yield
solvent
ClCH2CH2Cl
ClCH2CH2Cl
1
2
3
4
5
6
5 days
2 days
2 days
2 days
1 h
trace
33%
74%
trace
75%
37%
AuBr3 (5 mol%)/AgPF6 (15 mol%)
AuBr3 (5 mol%)/AgOTf (15 mol%)
AuBr3 (5 mol%)/AgBF4 (15 mol%)
AuBr3 (5 mol%)/AgOTf (15 mol%)
AuBr3 (1 mol%)/AgOTf (3 mol%)
ClCH2CH2Cl
ClCH2CH2Cl
toluene
toluene
3 h

We next investigated the gold-catalyzed one-pot synthesis of oxazoles 4 from 3-trimethylsilyl propargylic
alcohol 1a with various 4-substituted benzamides 2 (Table 2). The reaction of 1a and p-tolylamide (2b)
afforded the corresponding oxazole 4ab in 66% yield (entry 1). The reaction with p-methoxybenzamide
(2c) also gave the corresponding product 4ac in similar yield (entry 2), while the reaction with
p-chlorobenzamide (2d) furnished 4ad in 71% yield (entry 3), but the reaction with p-nitrobenzamide (2e)
afforded 4ae in only 18% yield (entry 4). There are two possible reasons for the low yield with
p-nitrobenzamide (2e). First, the gold catalyst might be deactivated by coordination of oxygen atom of the
nitro group of 2e. Second, the nucleophilicity of 2e might be decreased by the electron-withdrawing effect
of the nitro group on the aromatic ring.
Next, the reaction of 3-trimethylsilyl propargylic alcohol 1b bearing a naphthyl group at the propargylic
position with various amides 2 was examined (Table 3). The reaction of 1b with p-tolylamide (2b) gave
the corresponding product 4bb in 74% yield (entry 1), while the reaction with p-methoxybenzamide (2c)
furnished 4bc in 65% yield (entry 2), and the reaction with p-chlorobenzamide (2d) afforded the desired
product 4bd in 78% yield (entry 3).
Table 2. The gold-catalyzed one-pot synthesis of substituted oxazoles 4 from propargylic alcohol 1a with
various amides 2
OH
Ph
R
O
AuBr3 (5 mol%)
AgOTf (15 mol%)
1a
TMS
NH
Ph
+
N
O
O
R
toluene, reflux
time
Ph
NH2
TMS
TMS
4
R
2
entry
time
4
yield
2
1
2
2b: R = Me
7 h
6 h
4ab
4ac
66%
66%
2c: R = MeO
3
4
2d: R = Cl
1 h
1 h
4ad
4ae
71%
18%
2e: R = NO2

Table 3. The gold-catalyzed one-pot synthesis of substituted oxazoles 4 from propargylic alcohol 1b with
various amides 2
OH
R
O
AuBr3 (5 mol%)
TMS
1b
AgOTf (15 mol%)
NH
N
+
O
O
R
toluene, reflux
time
TMS
NH2
4
TMS
2
R
entry
2
time
4
yield
1
2
3
5 h
6 h
4 h
74%
65%
78%
2b: R = Me
2c: R = MeO
2d: R = Cl
4bb
4bc
4bd
To investigate the scope and limitations of the gold-catalyzed one-pot synthesis of substituted oxazoles 4,
we tried the reaction of propargylic alcohol 1a with acetamide (2f). In the case of acetamide (2f), the
reaction resulted in a complex mixture (Scheme 3). The reaction of propargylic alcohol 1c bearing a
methyl group at the propargylic position instead of an aryl group afforded neither amide 3cb nor oxazole
4cb (Scheme 4), which shows that stabilization of the cation at the propargylic position by the aryl group
is important for the propargylic substitution step.
OH
AuBr3 (5 mol%)
Ph
AgOTf (15 mol%)
1a
TMS
complex mixture
+
O
toluene, reflux
10 h
Me
NH2
2f
Scheme 3
OH
O
Me AuBr3 (5 mol%)
AgOTf (15 mol%)
1c
TMS
NH
Me
N
+
+
toluene, reflux
O
O
Me
1 h
TMS
NH2
TMS
4cb not detected
2b
3cb not detected
Scheme 4

We next tried the reaction of propargylic alcohol 1d bearing a phenyl group at the alkynic terminus
instead of the trimethylsilyl group of 1a,b (Scheme 5). The reaction of 1d with p-tolylamide (2b) gave
the propargylic substitution product 3db in a high yield without any formation of the corresponding
oxazole 4db, which shows that the trimethylsilyl group of 1a,b is important for the cycloisomerization
step.
OH
O
Ph
AuBr3 (5 mol%)
Ph
1d
AgOTf (15 mol%)
NH
Ph
N
+
O
Ph
toluene, reflux
1 h
O
Ph
Ph
NH2
3db 88%
4db
2b
Scheme 5
To confirm the reaction pathway, we examined the reaction of 3-trimethylsilyl propargylic alcohol 1a and
benzamide (2a) in the presence of 5 mol% of AuBr3 and 15 mol% of AgOTf in toluene at reflux for 15
min, which afforded propargylic substitution product 3aa in 43% yield (Scheme 6). Although the
reaction of propargyl amide 3aa with 5 mol% of AuBr3 and 15 mol% of AgOTf in refluxing toluene
without any additive afforded the oxazole 4aa in low yield, the addition of 1 eq. H2O to the reaction
dramatically promoted the cycloisomerization to give oxazole 4aa in good yield. These experiments
clearly indicate that the reaction proceeds via propargylic substitution product 3aa as an intermediate and
that the trimethylsilyl group in 3aa and H2O molecule accelerate the cyclization step.
OH
O
AuBr3 (5 mol%)
AuBr3 (5 mol%)
AgOTf (15 mol%)
AgOTf (15 mol%)
NH
TMS
N
1a
+
O
O
toluene, reflux
2 h
toluene, reflux
15 min
TMS
NH2
TMS
3aa 43%
2a
without H2O: 4aa 10%
with 1 eq. H2O: 4aa 76%
Scheme 6
A plausible mechanism of the gold-catalyzed one-pot synthesis of substituted oxazoles 4 from
propargylic alcohols 1 and amides 2 is shown in Scheme 7. Cationic gold species generated by gold
catalyst and silver catalyst would coordinate to the triple bond and oxygen atom of the hydroxyl group of
propargylic alcohol 18-12 to promote propargylic substitution (1→A→3). The propargylic substitution

product 3 would be transformed into gold species E via cyclization involving the oxygen atom of the
amide of 3 (B→C→D→E).15 Notably, the E-cation-stabilizing effect of silicon13 at the terminal
position is important for the cyclization to E, since no oxazole was formed when 3-phenylpropargylic
alcohol 1d was used in place of 3-trimethylsilyl propargylic alcohol 1a,b (Scheme 5). In addition, the
E-cation-stabilizing effect of silicon13 at the terminal position is important for the deauration step
(E→F→G). Finally, intermediate G undergoes isomerization to give oxazoles 4. Although the exact
role of water molecule remains unclear, one possibility would be that the water molecule plays a role as
the career of proton in the reaction.
O
O
2
OH
R1
OH
R1
Au+
R2
NH
R1
R2
Au+
Au+
H2N
Si
Si
A
1
3
Si
R2
R2
R2
O
R2
H
N
N
H
H
O
N
+
O
N
O
R1
R1
H+
+
R1
Si
R1
Si
Au
Si
Au
Si
Au+
Au
C
B
D
E
E-cation-stabilizing effect
R2
R2
O
R2
R2
O
N
N
N
N
+
O
R1
O
R1
R1
R1
+
Si
Au
Si
Si
Au
Si
H
H
H
F
G
4
E-cation-stabilizing effect
Scheme 7
The trimethylsilylmethyl group in oxazoles 4 synthesized in this procedure is a very useful functionality
for further elaboration (Scheme 8). For example, the treatment of oxazole 4ac with TBAF in THF
afforded oxazole 5ac in 91% yield. Moreover, the reaction of oxazole 4ac with TBAF16 in the presence
of benzaldehyde in THF furnished oxazole 6ac in 79% yield. The hydroxyl group of 6ac also affords a
high degree of freedom for additional transformations if required.

MeO
MeO
MeO
TBAF
TBAF
N
N
N
O
O
Ph
PhCHO
THF
79%
THF
91%
Ph
O
Ph
OH
Si
Me
Ph
5ac
4ac
6ac
Scheme 8
In summary, we present a gold-catalyzed synthesis of substituted oxazoles 4 from 3-trimethylsilyl
propargylic alcohols 1 and amides 2 via propargylic substitution followed by cycloisomerization in one
pot. The E-cation-stabilizing effect of the silicon atom of propargylic alcohol 1 is important for the
cycloisomerization. Further synthetic use of TMS group in the products 4 and the role of water in the
reaction will be reported elsewhere.
ACKNOWLEDGEMENTS
This research was supported by the Research Foundation for Pharmaceutical Sciences.
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14. Procedure for the synthesis of 2,4-diphenyl-5-[(trimethylsilyl)methyl]oxazole (4aa): AuBr3 (5.4 mg,
0.012 mmol, 5 mol%) and AgOTf (9.4 mg, 0.037 mmol, 15 mol%) were added to a solution of
3-trimethylsilyl propargylic alcohols 1 (50 mg, 0.25 mmol) and benzamide (2a) (36 mg, 0.29
mmol) in toluene (3 mL) at room temperature and the mixture was heated at reflux. After
complete consumption of propargylic substitution product 3aa (the reaction was monitored by thin
layer chromatography), the solvent was removed in vacuo and the crude product was subjected to
column chromatography on silica gel (hexane:AcOEt = 30:1) to give 2,4-diphenyl-5-

[(trimethylsilyl)methyl]oxazole (4aa) (53 mg, 75%) as colorless oil. 1H-NMR (300 MHz, CDCl3) δ
8.07-8.03 (2H, m), 7.75-7.72 (2H, m), 7.48-7.40 (5H, m), 7.33-7.26 (1H, m), 2.41 (2H, s), 0.14 (9H,
s); 13C-NMR (75 MHz, CDCl3) δ 158.7, 147.2, 134.3, 132.9, 129.7, 128.7, 128.5, 127.8, 127.0,
126.7, 125.9, 16.5, -1.1.
15. In the cyclization step, an allene intermediate can also be considered. See, ref.5.
16. The reaction was conducted with the TBAF dried by MS4A for a week.