Bronsted acid-catalyzed propargylation/cycloisomerization tandem reaction: One-pot synthesis of substituted oxazoles from propargylic alcohols and amides

Article abstract of DOI:10.1021/jo8027533

An efficient one-pot propargylation/cycloisomerization tandem process has been developed for the synthesis of substituted oxazole derivatives from propargylic alcohols and amides with use of p-toluenesulfonic acid monohydrate (PTSA) as a bifunctional cata

Full text of DOI:10.1021/jo8027533

SCHEME 1. Synthesis of Oxazoles from Propargylic
Alcohols and Amides
Brønsted Acid-Catalyzed Propargylation/
Cycloisomerization Tandem Reaction: One-Pot
Synthesis of Substituted Oxazoles from
Propargylic Alcohols and Amides
Ying-ming Pan, Fei-jian Zheng, Hai-xin Lin, and
Zhuang-ping Zhan*
Department of Chemistry, College of Chemistry and
Chemical Engineering, and State Key Laboratory for
Physical Chemistry of Solid Surfaces, Xiamen UniVersity,
Xiamen 361005, People’s Republic of China
zpzhan@xmu.edu.cn
ReceiVed December 18, 2008
However, the one-pot synthesis of substituted oxazoles directly
from simple and readily available substrates is much less studied.
Recently, efficient propargylation/cycloisomerization sequential
reactions of propargylic alcohols with amides in the presence
of [Cp*RuCl(µ2-SMe)2RuCp*Cl]/AuCl3/NH4BF47 or Zn(OTf)2/
TpRuPPh3(CH3CN)2PF6,8 which led to the synthesis of substi-
tuted oxazoles, have been reported. Nevertheless, the previous
reports only exemplify terminal propargylic alcohols, and at least
two different catalysts are needed. To the best of our knowledge,
there is no propargylation/cycloisomerization tandem reaction
for the synthesis of substituted oxazoles in the presence of a
single catalyst reported in the literature. Herein, we describe a
one-pot PTSA-catalyzed propargylation/cycloisomerization tan-
dem reaction. The process is outlined in Scheme 1. PTSA acts
as a bifunctional catalyst and effectively catalyzes two reaction
processes in a single reaction vessel under the same conditions.
The reaction is completed rapidly under mild conditions and is
An efficient one-pot propargylation/cycloisomerization tan-
dem process has been developed for the synthesis of
substituted oxazole derivatives from propargylic alcohols and
amides with use of p-toluenesulfonic acid monohydrate
(PTSA) as a bifunctional catalyst. This method provides a
rapid and efficient access to substituted oxazoles.
Nucleophilic substitution and cyclization are two major
reactions of organic chemistry.1,2 More powerful and useful
transformations are possible when these two classes of reactions
are combined in a one-pot procedure. Propargylic substitution
and subsequent cycloisomerization recently developed in our
group are good examples of such transformations.3
To further extend the scope of the Lewis acid-catalyzed
propargylation/cycloisomerization tandem reaction, we sought
to explore the coupling of propargylic alcohols with amides and
the subsequent cycloisomerization for the synthesis of substi-
tuted oxazoles. In general, substituted oxazoles are accessed via
ring derivatization or cyclization of acyclic precursors.4-6
Among the variety of compounds that can be subjected to
cyclization, unsaturated amides are substrates of major interest.6
(5) For selected examples, see: (a) Elders, N.; Ruijter, E.; de Kanter, F. J. J.;
Groen, M. B.; Orru, R. V. A. Chem. Eur. J. 2008, 14, 4961. (b) Chudasama, V.;
Wilden, J. D. Chem. Commun. 2008, 3768. (c) Kawano, Y.; Togo, H. Synlett
2008, 217. (d) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J.-P. Eur. J. Org.
Chem. 2007, 4076. (e) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J.-P. Org.
Lett. 2007, 9, 3615. (f) Herrera, A.; Mart´ınez-Alvarez, R.; Ramiro, P.; Molero,
D.; Almy, J. J. Org. Chem. 2006, 71, 3026. (g) Wipf, P.; Fletcher, J. M.; Scarone,
L. Tetrahedron Lett. 2005, 46, 5463. (h) Lee, J. C.; Choi, H. J.; Lee, Y. C.
Tetrahedron Lett. 2003, 44, 123. (i) Addie, M. S.; Taylor, R. J. K. J. Chem.
Soc., Perkin Trans. 1 2000, 527. (j) Wipf, P.; Miller, C. P. J. Org. Chem. 1993,
58, 3604. (k) Doyle, M. P.; Buhro, W. E.; Davidson, J. G.; Elliott, R. C.; Hoekstra,
J. W.; Oppenhuizen, M. J. Org. Chem. 1980, 45, 3657. (l) Wasserman, H. H.;
Vinick, F. J. J. Org. Chem. 1973, 38, 2407.
(6) For selected examples, see: (a) Beccalli, E. M.; Borsini, E.; Broggini,
G.; Palmisano, G.; Sottocornola, S. J. Org. Chem. 2008, 73, 4746. (b) Mart´ın,
R.; Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 5521. (c) Schuh, K.; Glorius,
F. Synthesis 2007, 2297. (d) Merkul, E.; Mu¨ller, T. J. J. Chem. Commun. 2006,
4817. (e) Black, D. A.; Arndtsen, B. A. Tetrahedron 2005, 61, 11317. (f) Hashmi,
A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett. 2004, 6, 4391. (g)
Wipf, P.; Aoyama, Y.; Benedum, T. E. Org. Lett. 2004, 6, 3593. (h) Arcadi, A.;
Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F. Org. Lett. 2001, 3, 2501. (i)
Wipf, P.; Rahman, L. T.; Rector, S. R. J. Org. Chem. 1998, 63, 7132.
(7) Milton, M. D.; Inada, Y.; Nishibayashi, Y.; Uemura, S. Chem. Commun.
2004, 2712.
(1) Rossi, R. A.; Pierini, A. B.; Pen˜e´n˜ory, A. B. Chem. ReV 2003, 103, 71,
and references cited therein.
(2) Winnik, M. A. Chem. ReV. 1981, 81, 491, and references cited therein.
(3) (a) Zhan, Z.-P.; Cai, X.-B.; Wang, S.-P.; Yu, J.-L.; Liu, H.-J.; Cui, Y.-
Y. J. Org. Chem. 2007, 72, 9838. (b) Zhan, Z.-P.; Wang, S.-P.; Cai, X.-B.; Liu,
H.-J.; Yu, J.-L.; Cui, Y.-Y. AdV. Synth. Catal. 2007, 349, 2097. (c) Zhan, Z.-P.;
Yu, J.-L.; Liu, H.-J.; Cui, Y.-Y.; Yang, R.-F.; Yang, W.-Z.; Li, J.-P. J. Org.
Chem. 2006, 71, 8298. (d) Zhan, Z.-P.; Yang, W.-Z.; Yang, R.-F.; Yu, J.-L.;
Liu, H.-J. Chem. Commun. 2006, 3352.
(4) For recent reviews, see: (a) Yeh, V. S. C. Tetrahedron 2004, 60, 11995.
(b) Wipf, P. Chem. ReV. 1995, 95, 2115. (c) Palmer; D. C.; Venkatraman, S. In,
The Chemistry of Heterocyclic Compounds,A Series of Monographs, Oxazoles:
Synthesis, Reactions, and Spectroscopy Part A; Palmer, D. C., Ed.; John Wiley
& Sons: Hoboken, NJ, 2003.
(8) The zinc(II)-catalyzed propargylic substitution produces R-carbonyl amide.
Subsequent cycloisomerization of R-carbonyl amide affords the substituted
oxazole.
See: Kumar, M. P.; Liu, R.-S. J. Org. Chem. 2006, 71, 4951.
3148 J. Org. Chem. 2009, 74, 3148–3151
10.1021/jo8027533 CCC: $40.75 2009 American Chemical Society
Published on Web 03/18/2009

TABLE 1. Optimization of Formation of Substituted Oxazolesa
long reaction time was needed (Table 1, entry 8). Unfortunately,
both oxalic acid and hydrochloric acid failed to catalyze the
tandem reaction (Table 1, entries 9 and 10). In addition, it was
found that the solvent played a crucial role in this tandem
reaction (Table 1, entries 6 and 11-15). Acetonitrile and 1,2-
dichloroethane as solvents were also able to facilitate the
propargylation/cycloisomerization tandem reaction. However,
the use of toluene instead of 1,2-dichloroethane and acetonitrile
obviously reduced the reaction time from 24 to 0.8 h (Table 1,
entry 6 vs. entries 11 and 12). The results of solvents screened
showed that the reaction rates were influenced by various factors,
such as boiling point, polarity, etc. Among these factors, the
boiling point of solvents might be a main factor. However, the
detailed mechanism is still not clear.
entry
catalyst
solvent
time [h]
yield [%]b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
BiCl3 (10 mol %)
InCl3 (10 mol %)
FeCl3 (10 mol %)
Cu(OTf)2 (10 mol %)
Cu(OTf)2 (1 equiv)
PTSA (1 equiv)
PTSA (50 mol%)
TFA (1 equiv)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
DCE
24
24
24
24
24
0.8
24
4
24
24
24
24
24
24
24
35
0
36
57
59
90
78
84
0
oxalic acid (1 equiv)
HCl (1 equiv)c
0
With these optimal conditions in hand, we examined the scope
of this tandem reaction. Typical results are shown in Table 2.
To our delight, all the secondary propargylic alcohols 1 bearing
not only terminal alkyne groups but also internal alkyne groups
participated well in the tandem reaction, producing the prop-
argylation/cycloisomerization products in good yields with
complete regioselectivity. Among the benzylic-propargylic
alcohols 1a-d that were examined, propargylic alcohol 1a (R2
) TMS) gave the most desirable result, providing the substituted
oxazole in excellent yield (Table 2, entry 1). Propargylic alcohol
1h possessing an electron-donating group at the aryl ring (R1
) 4-MeOC6H4) reacted smoothly with amide 2a affording the
oxazole 4ha in 94% yield (Table 2, entry 8). Moreover,
substrates 1i and 1j possessing electron-withdrawing groups
(bromo and ester functionalities) at the aryl ring were also
successfully employed in the tandem reaction to give the
oxazoles 4ia and 4ja in 89% and 78% yields, respectively (Table
2, entries 9 and 10). Obviously, electron-rich propargylic
alcohols provided the desired products in higher yields than
electron-poor propargylic alcohols. Internal propargylic alcohols
1c and 1d (R2 ) n-Bu, Ph) also gave good results (Table 2,
entries 3 and 4). The reaction of terminal propargylic alcohol
1b (R2 ) H) with benzamide afforded the oxazole 4ba in good
yield after a somewhat long reaction time (Table 2, entry 2).
Additionally, propargylic alcohols 1e-g (R1 ) 1-naphthyl)
readily underwent propargylation/cycloisomerization tandem
reaction to afford the substituted oxazoles 4ea-ga in high yields
with complete regioselectivity (Table 2, entries 5-7). However,
the aliphatic propargylic alcohols, such as 3-phenylprop-2-yn-
1-ol (R1 ) H; R2 ) Ph) and 4-phenylbut-3-yn-2-ol (R1 ) CH3;
R2 ) Ph), failed to afford the substituted oxazoles. The results
suggested that the propargylation proceeded through a propar-
gylic cation intermediate. Instability of the propargylic cation
intermediate made the tandem reaction less favorable. For the
aromatic propargylic alcohols, the reaction is completed rapidly
under mild conditions and is tolerant of air, giving water as the
only byproduct. This is in sharp contrast to the Ru/Au-catalyzed
sequential reaction7 where the reactions were performed under
N2 atmosphere and the substrates were limited to propargylic
alcohols bearing terminal alkyne groups. It should be noted that
functional groups such as TMS, bromo, ester, and methoxy in
the propargylic alcohols were readily carried through the tandem
reaction, allowing for the subsequent elaboration of the products.
PTSA (1 equiv)
PTSA (1 equiv)
PTSA (1 equiv)
PTSA (1 equiv)
PTSA (1 equiv)
75
83
51
48
0
CH3NO2
DCM
THF
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), and catalyst in
solvent (2 mL) at reflux. b Isolated yield of pure product based on
propargylic alcohol 1a c The concentration of hydrochloric acid is 12
mol/L.
tolerant of air, giving water as the only byproduct. A wide range
of secondary propargylic alcohols bearing not only terminal
alkyne groups but also internal alkyne groups can effectively
be employed, and a number of functional groups, such as TMS,
vinyl, bromo, chloro, ester, and methoxy, are tolerated under
the reaction conditions. All of the propargylic alcohols used
are readily available.
Initially, propargylic alcohol 1a (0.5 mmol) was treated with
benzamide 2a (0.6 mmol) in the presence of 10 mol % of BiCl3
in toluene at reflux for 24 h and the desired product 4aa was
isolated in 35% yield along with uncyclized alkynyl-amide 3aa
in 56% yield (Table 1, entry 1).9 With other Lewis acids, such
as Cu(OTf)2, FeCl3, and InCl3, the propargylation proceeded
smoothly to afford alkynyl-amide 3aa in high yields, but
subsequent intramolecular cycloisomerization led to low yields,
or did not afford cyclized product (Table 1, entries 2-4).
Furthermore, no improvement in yield could be obtained even
in the presence of 1 equiv of Cu(OTf)2 (Table 1, entry 5). We
reasoned that the poor catalyst activity of Lewis acids might
be ascribed to their weak acidity. Accordingly, we began
searching for the appropriate Brønsted acid that would readily
catalyze the propargylation/cycloisomerization tandem reaction.
Gratifyingly, switching the catalyst to PTSA (1 equiv) furnished
the substituted oxazole 4aa in 90% yield after 0.8 h at reflux
(Table 1, entry 6). Notably, a very slow reaction rate was
observed when the catalytic amount of PTSA decreased from
1 equiv to 50 mol % (Table 1, entry 7 vs entry 6). With 50
mol % of PTSA, the propargylation proceeded rapidly to afford
alkynyl-amide 3aa in excellent yield, but subsequent intramo-
lecular cycloisomerization was sluggish. The results showed that
a stoichiometric amount of PTSA was required to counteract
the basicity of the oxazole 4aa and keep an acidic atmosphere
during cycloisomerization. Trifluoroacetic acid (TFA) also
effectively promoted the tandem reaction, although a somewhat
A variety of amides 2 were also employed to examine the
generality of the method. Both aromatic amides and aliphatic
amides could be efficiently incorporated into the oxazole
framework. The tandem reaction proceeded smoothly when the
aryl groups of the aromatic amides were substituted with
(9) We have reported that the BiCl3-catalyzed nucleophilic substitution of
propargylic alcohols with benzamide affords the alkynyl-amides in good yields,
see ref 3d.
J. Org. Chem. Vol. 74, No. 8, 2009 3149

TABLE 2. Synthesis of Substituted Oxazoles 4 from Propargylic
Alcohols 1 and Amides 2a
SCHEME 2. Synthesis of Keto-amide 5ak from Propargylic
Alcohol 1a and 2-Pyrrolidinone 2k
electron-donating (Table 2, entries 11 and 12) and electron-
withdrawing groups (Table 2, entries 14 and 15). Electron-rich
groups are beneficial to the tandem reaction. Aliphatic amides
required slightly longer reaction times, but maintained high
yields (Table 2, entries 16-19). Interestingly, attempted pro-
pargylation/cycloisomerization of propargylic alcohol 1a with
2-pyrrolidinone 2k led not to the expected product 4ak, but to
the keto-amide 5ak in 68% yield (Scheme 2).10 We propose
that the intramolecular cycloisomerization of alkynyl-amide 3ak
affords the cyclized product 4ak, and the instability of 4ak
makes the ring-opening reaction possible to afford keto-amide
5ak through the attack of water in the presence of proton acid.
The crystal structure of oxazole 4ja (Table 2, entry 10) has
been determined by X-ray diffraction and is shown in Figure
1. The X-ray crystal structure reveals that the dihedral angle
between plane 1 (defined by atoms C5-C10) and plane 2 (O1,
N1, and C1-C3) is 2.43 (0.2)°, and the dihedral angle between
plane 2 (O1, N1, and C1-C3) and plane 3 (C12-C17) is 6.56
(0.2)°. The planarity and the bond lengths (see the Supporting
Information for details) are consistent with the π system
delocalization that is extended over the whole molecule. We
reasoned that these synthetic compounds would have good
photophysical properties, especially substituted oxazoles with
long conjugation lengths. Synthesis and the potential optoelec-
tronic applications of analogous oligomers by the PTSA-
catalyzed propargylation/cycloisomerization tandem reaction are
currently going on in our laboratory.
In summary, we have developed a highly efficient method
for the synthesis of the substituted oxazoles via PTSA-catalyzed
propargylation/cycloisomerization tandem reaction. PTSA, work-
ing as a bifunctional catalyst, catalyzes two mechanistically
distinct processes in a single-pot under the same reaction
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), and PTSA (0.5
mmol) in toluene (2 mL) at reflux. See the Supporting Information for
details. b Isolated yield of pure product based on propargylic alcohol 1.
FIGURE 1. X-ray crystal structure of oxazole 4ja. The thermal
ellipsoids are at the 50% probability level.
3150 J. Org. Chem. Vol. 74, No. 8, 2009

purified by silica gel column chromatography (EtOAc/hexane) to
conditions. The reaction is completed rapidly under mild
conditions and is tolerant of air, giving water as the only
byproduct. Propargylic alcohols bearing terminal or internal
alkyne groups are readily available. This facile methodology
allows rapid access to a variety of substituted oxazoles.
afford 2,4-diphenyl-5-((trimethylsilyl)methyl)oxazole (4aa) as a
1
yellow oil (138 mg, 90% yield). H NMR (CDCl3, 400 MHz) δ
0.14 (s, 9H), 2.41 (s, 2H), 7.27-7.32 (m, 1H), 7.41-7.45 (m, 5H),
7.72-7.75 (m, 2H), 8.04-8.06 (m, 2H); 13C NMR (CDCl3, 100
MHz) δ -1.1, 16.4, 125.9, 126.7, 126.9, 127.8, 128.5, 128.7, 129.7,
132.9, 134.3, 147.2, 158.6; IR (film) 3061, 2954, 1595, 1494, 1448,
1250 cm-1; ESI-MS m/z (%) 308 (100) [M + H+], 330 (21) [M +
Na+]. Anal. Calcd for C19H21NOSi: C, 74.22; H, 6.88; N, 4.56.
Found: C,74.09; H, 7.11; N, 4.31.
Experimental Section
A typical experimental procedure for the reaction of 1-phenyl-
3-(trimethylsilyl)prop-2-yn-1-ol (1a) with benzamide (2a) catalyzed
by 1 equiv of PTSA is described below: to a 5-mL flask were
successively added 1-phenyl-3-(trimethylsilyl)prop-2-yn-1-ol (1a)
(102 mg, 0.5 mmol), benzamide (2a) (72.6 mg, 0.6 mmol), toluene
(2.0 mL), and p-toluenesulfonic acid monohydrate (PTSA, 95 mg,
0.5 mmol). The reaction mixture was stirred at reflux and monitored
periodically by TLC. Upon completion, the toluene was removed
under reduced pressure by an aspirator, and then the residue was
Acknowledgment. The research was financially supported
by the National Natural Science Foundation of China (No.
20772098), the Program for New Century Excellent Talents in
Fujian Province University, and NFFTBS (No. J0630429).
Supporting Information Available: Experimental proce-
dures and spectra data for all compounds, and X-ray data for
compound 4ja. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) The trimethylsilyl group might not be tolerated under the acidic condition
(e.g., p-toluenesulfonic acid, InCl3) for a long time and fell off during workup.
See: (a) Feng, X.-B.; Tan, Z.; Chen, D.; Shen, Y.-M.; Guo, C.-C.; Xiang, J.-N.;
Zhu, C.-L. Tetrahedron Lett. 2008, 49, 4110. (b) Reference 3a.
JO8027533
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