Synthesis of 2-phenyl-4,5-substituted oxazoles by copper-catalyzed intramolecular cyclization of functionalized enamides

Article abstract of DOI:10.1021/jo3021192

An efficient two-step synthesis of 2-phenyl-4,5-substituted oxazoles involving intramolecular copper-catalyzed cyclization of highly functionalized novel β-(methylthio)enamides as the key step has been reported. These enamides are obtained by nucleophilic

Full text of DOI:10.1021/jo3021192

Article
pubs.acs.org/joc
Synthesis of 2‑Phenyl-4,5-Substituted Oxazoles by Copper-Catalyzed
Intramolecular Cyclization of Functionalized Enamides
S. Vijay Kumar,† B. Saraiah,† N. C. Misra,‡ and H. Ila*,†
†New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore-560064, Karnataka, India
‡Department of Chemistry, Indian Institute of Technology, Kanpur-208016, Uttar Pradesh, India
S
* Supporting Information
ABSTRACT: An efficient two-step synthesis of 2-phenyl-4,5-substituted oxazoles involving intramolecular copper-catalyzed
cyclization of highly functionalized novel β-(methylthio)enamides as the key step has been reported. These enamides are
obtained by nucleophilic ring-opening of newly synthesized 4-[(methylthio)hetero(aryl)methylene]-2-phenyl-5-oxazolone
precursors by alkoxides, amines, amino acid esters and aryl/alkyl Grignard reagents, thus leading to the introduction of an ester,
N-substituted carboxamide or acyl functionalities at 4-position of the product oxazoles. Synthesis of two naturally occurring 2,5-
diaryloxazoles, i.e., texamine and uguenenazole, via two-step hydrolysis−decarboxylation of the corresponding 2,5-diaryloxazole-
4-carboxylates has also been described. Similarly, three of the serine-derived oxazole-4-carboxamides were elaborated to novel
trisubstituted 4,2′-bisoxazoles through DAST/DBU-mediated cyclodehydration−dehydrohalogenation sequence. The present
protocol is complementary and an improvement to our previously reported silver carbonate-induced cyclization of β-
bis(methylthio)enamides to 2-phenyl-5-(methylthio)-4-substituted oxazoles.
direct C−H arylation/alkenylation of prefunctionalized oxazo-
les12a−e and metalation reactions.4,12f−m The other newly
developed methods include copper-catalyzed cycloamidation
of vinyl halides,13 catalyzed cycloisomerization of propargyla-
mides,4,14 Rh-catalyzed amidation of α-diazo-β-keto carbox-
ylate,4,8c,15 iodine/copper-catalyzed tandem oxidative cycliza-
tion,8b,16 cycloaddition of activated methylene isonitriles,4,17
and miscellaneous approaches.18 Despite the availability of
these elegant methods, only a few reports deal with efficient
and regioselective synthesis of 2,4,5-trisubstituted oxazo-
les4,8c,9,13a,b,15,16a,18 with flexible substitution pattern at all
positions.
Our own contribution in this regard centered on a substrate
controlled protocol, in which highly functionalized N-benzoyl-
β-bis(methylthio)enamide precursors 2 were generated by
nucleophilic ring-opening of a common 4-bis(methylthio)-
methylene-2-phenyloxazole-5-one template 1 by various oxy-
gen, nitrogen and carbon nucleophiles.4,19 These enamide
INTRODUCTION
■
Oxazole structural motifs have attracted considerable attention
from both synthetic and medicinal chemists because of their
presence in a wide range of natural products1 and their pivotal
role as synthetic intermediates.2 Thus, several of the complex
natural products containing oxazole moiety such as Diazo-
namide A, Ulapualide A, Hennoxazole A, Telomestatin,
Leucamide A, and Virginiamycin M1 display significant
biological activity as cytotoxic, antifungal, antibacterial,
antitumor and antiviral agents.1,3,4 Also, 2,4- and 2,4,5-
substituted oxazole subunits are frequently encountered in
many pharmaceuticals, lead structures,4,5 and new functional
compounds with interesting photophysical properties.6 This has
stimulated renewed interest in the chemistry and synthesis of
these important classes of heterocycles,1,4,7 and many synthetic
protocols have been devised to access their general structures.8
The most important classical procedures for synthesis of
oxazoles include cyclodehydration of acyclic precursors
exemplified by Robinson−Gabriel synthesis and its improved
versions,4,9 biomimetic approach involving cyclization of serine
derivatives,1,4,10 transition metal-catalyzed cross-coupling,4,11
Received: September 26, 2012
Published: November 6, 2012
© 2012 American Chemical Society
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intermediates were subsequently transformed into 2-phenyl-5-
(methylthio)-4-alkoxycarbonyl/amido/acyloxazoles 3 by silver
carbonate (4 equiv) induced 5-endo cyclization (Scheme 1).
The 2,5-diaryloxazoles are also of considerable interest due to
their ability to scintillate light in presence of ionizing
radiation.24 Similarly 2-substituted-5-(3-indolyl)oxazole ring
system occurs in several natural products ranging from simple
pimprinine alkaloids,25 pimprinine 9a, pimprinethine 9b, WS-
30581A, WS-30581B 9c,d, labradorin 1 and labrodorin 2 9e,f,25
through trisubstituted martefragin A 1026a,b to complex marine
natural product diazonamide A 1126c displaying a range of
biological activity (Figure 1).25c,e,26a,c
Scheme 1. Synthesis of 2-Phenyl-4,5-Substituted Oxazoles
via Silver Carbonate-Induced Intramolecular Cyclization of
Enamide Precursors
We therefore envisaged a related transformation as depicted
in Scheme 2 and successfully executed it to develop a general
Scheme 2. Proposed Strategy for the Synthesis of 2-Phenyl-
5-(hetero)aryl-4-Functionalized Oxazoles
The 5-(methylthio)oxazoles were either dethiomethylated with
Raney Ni to 5-unsubstituted oxazoles 4 or transformed into 5-
alkyl/arylaminooxazoles 5 in two steps involving peracid
oxidation and replacement of 5-methylsulfonyl group by
primary and secondary amines (Scheme 1). It should be
noted that despite broad scope and versatile applications of
Robinson−Gabriel and related oxazole synthesis involving
cyclodehydration of α-acylaminoketones, only a limited number
of examples deal with intramolecular cyclization of enamides
precursors.13,20 In continuation of this work, along with our
ongoing interest in design and development of new general
efficient methods for novel five- and six-membered hetero-
cycles,21 we sought to explore possible utilization of this
strategy for the synthesis of 4-substituted 2,5-di(hetero)-
aryloxazoles by installation of a (hetero)aryl group at 5-
position of oxazoles. The 2,5-diaryloxazoles comprising of
annuloline 6,22 balsoxine 7a,23a texamine 7b,23b,d texaline
7c23c,d and halfordinol 8a23e are among the first relatively
simple naturally occurring oxazoles to be isolated (Figure 1).
protocol for diversity oriented synthesis of 2-phenyl-5-
(hetero)aryl-4-substituted oxazoles 14 by a sequential nucleo-
philic ring-opening of newly synthesized 4-[methylthio(aryl/
heteroaryl)methylene]-2-phenyl-5-oxazolone precursors 12 fol-
lowed by copper-catalyzed intramolecular cyclization of the
resulting highly functionalized enamide intermediates 13
(Scheme 2). The results of these studies have been reported
in this paper along with the synthesis of two naturally occurring
2,5-diaryloxazoles, i.e., texamine and uguenenazole, following
this protocol.
RESULTS AND DISCUSSION
■
The desired 2-phenyl-4-[(methylthio)(aryl/heteroaryl)-
methylene]-5-oxazolones 12a−i were synthesized in good
yields by reacting 2-phenyl-5-oxazolone 15 with appropriate
(hetero)aryl dithioesters 16 in the presence of sodium hydride
in DMF followed by alkylation of the resulting thiolate salts
with methyl iodide (Scheme 3). The structures of all these
newly synthesized 4-arylidene oxazolone precursors 12a−i were
established with the help of spectral and analytical data. The 1H
and 13C NMR spectra of 12a−i revealed that these compounds
exist as mixture of E/Z stereoisomers (Scheme 3). The
oxazolone precursors 12a−i were next subjected to nucleophilic
ring-opening in the presence of various alkoxides (Scheme 4).
Thus 12a was allowed to react with sodium ethoxide in ethanol
at room temperature for 2−3 h furnishing exclusively α-
[(methylthio)(4-methoxyphenyl)methylene]-N-benzoylglyci-
nate 17a (Ar = 4-MeOC6H4, R1 = Et) in 88% yield. Similarly
the other substituted open chain ethyl- (17b−f), n-butyl-,
benzyl- and t-butyl esters (17g−i) were obtained in high yields
on treatment of the corresponding oxazolones 12 with either
sodium ethoxide, n-butoxide, benzyloxide or tert-butoxide
under identical conditions (Scheme 4).27
Intramolecular 5-endo cyclization of the open-chain esters
17a−i to the desired 2-phenyl-4-carboalkoxy-5-(hetero)-
aryloxazoles 18 was next examined under the influence of
various cyclizing agents reported earlier.4 Thus 17a underwent
facile cyclization in the presence of excess of silver carbonate (4
equiv) in refluxing acetonitrile yielding the corresponding ethyl
2-phenyl-5-(4-methoxyphenyl)oxazole-4-carboxylate 18a in
85% yield (Table 1, entry 1). On the other hand, the yield of
Figure 1. Selected examples of natural products containing 2,5-
di(hetero)aryl/alkylloxazole moiety.
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a
Scheme 3. Synthesis of Novel 2-Phenyl-4-[methylthio(aryl/heteroaryl)methylene]-5-oxazolone Precursors 12a−i
a
Reaction conditions: 15 (1.0 mmol), 16 (1.0 mmol), NaH (2 equiv) in DMF at 0 °C for 1 h, and then MeI (1.0−1.5 equiv) at −20 °C for 30 min.
All products 12a−i were obtained as a mixture of E/Z isomers.
Scheme 4. Synthesis of Novel 2-Phenyl-5-(hetero)aryloxazole-4-carboxylates
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heterocycles by copper-catalyzed C−C and C−heteroatom
bond formations.29,30 A few methods relevant to the present
work are mentioned here. Thus, Pattenden and co-workers
have reported a cupric bromide-mediated cyclization of
bromoenamides20b for construction of oxazole ring. Recently
Stahl et al. have described intramolecular oxidative cyclization
of enamides induced by cupric chloride (2 equiv) furnishing
2,5-aryl/alkyloxazoles in moderate to good yields.31 On the
other hand, Glorius and co-workers have developed a method
by copper-catalyzed coupling of primary amides with 1,2-
dihalogenated olefins affording a mixture of 2,4- and 2,5-
substituted oxazoles via bromoenamide intermediates.13a
Buchwald13b has reported a two-step one-pot methodology
for substituted oxazoles involving copper-catalyzed cross
coupling of primary amide with vinyl bromide followed by
iodine mediated intramolecular O-vinylation of the resulting
enamide intermediates. During the preparation of this manu-
script, the same workers have reported an elegant synthesis of a
broad range of 2,5-disubstituted oxazoles involving Cu(II)-
catalyzed oxidative cyclization of enamide intermediates under
ambient conditions employing potassium persulfate as
promoter.13c
For our studies, enamide 17a was chosen as model substrate
for its cyclization to oxazole 18a under copper catalysis (Table
1). Initial studies were performed by screening various copper
catalysts (10 mol %) in the absence of base in DMF at 90 °C,
affording the oxazole 18a in maximum yield of 65% (Table 1,
entries 3−5). However in the presence of Cs2CO3 as base (1
equiv), in the absence of any ligand, the oxazole 18a was
obtained in increased yields (Table 1, entries 6−9), and CuI
proved to be best choice among catalysts investigated, yielding
18a in 79% yield after 7 h (Table 1, entry 8). Subsequently our
study focused on cyclization of 17a by testing various ligands
(entries 10−13), and it was found that use of 1,10-
phenanthroline as ligand significantly improved the catalyst
efficiency, affording 18a in 92% yield within 3 h (Table 1, entry
13). Further screening of bases including K2CO3, t-BuOK or t-
BuOLi revealed that no obvious improvement in yields was
achieved and Cs2CO3 was the base of choice (Table 1, entries
14−16). Among solvent selection, DMF was clearly the best
solvent compared to toluene, DMA or DMSO (Table 1, entries
13, 17−19). A low catalytic loading was not effective, resulting
in diminished yield of 18a with prolonged reaction time (Table
1, entry 20). Further screening of reaction temperature or
reaction time did not show any improvement in yield of 18a;
therefore, CuI (10 mol %) in the presence of 1,10-
phenanthroline (20 mol %) as ligand and Cs2CO3 (1equiv)
Table 1. Optimization of Reaction Conditions for
Cyclization of Enamide 17a to Oxazole 18a
a
time
(h)
% yield
entry
reagent/catalyst
base
solvent
18a
1
Ag2CO3 (4 equiv)
Ag2CO3 (2 equiv)
Cu2O
−
−
−
−
−
CH3CN
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
toluene
DMA
DMSO
DMF
4
12
15
15
15
12
12
7
85
58
63
62
65
70
71
79
69
81
75
78
92
79
81
80
71
70
72
85
2
3
4
CuCl
5
CuI
6
CuCl
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
7
CuBr
8
CuI
9
Cu powder
CuI/L-proline
CuI/TMEDA
CuI/Py
12
8
10
11
12
10
10
3
13 CuI/Phen
14
15
16
17
18
19
20
CuI/Phen
CuI/Phen
CuI/Phen
CuI/Phen
CuI/Phen
CuI/Phen
10
10
10
10
10
10
10
tBuOK
tBuOLi
Cs2CO3
Cs2CO3
Cs2CO3
CuI (5 mol %)/Phen Cs2CO3
a
Reactions were performed using 17a (1 mmol) in 3 mL of solvents
with 10 mol % of Cu catalyst, 20 mol % of ligand and 1 equiv of base
at 90 °C.
18a was drastically reduced (58%) when the reaction was
performed with 2 equiv of silver carbonate under identical
conditions even for prolonged time (Table 1, entry 2). The
other previously utilized cyclizing agents (Et3N/C6H6,
Cs2CO3/dioxane, CuBr2/DBU, etc.)4 were also not found to
be very effective, yielding 18a in unsatisfactory yields (with
maximum yield of 67% with Et3N/C6H6). Therefore, in view of
the large amount and high cost of silver carbonate employed in
this cyclization, we envisaged a related transformation of these
highly functionalized enamides 17 to oxazoles 18 by means of
copper-catalyzed cyclization reactions, which provide a
promising alternative mainly due to their high efficiency, mild
reaction conditions and low cost.28 Over the past years,
remarkable progress has been achieved in the synthesis of
Scheme 5. Synthesis of 2-Phenyl-5-(hetero)aryloxazole Natural Products
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Scheme 6. Synthesis of 2,5-Di(hetero)aryloxazole-4-carboxamides
as base in DMF at 90 °C were used as optimal conditions
(Table 1, entry 13) throughout our studies.
Having established the facile ring closing copper-catalyzed
cyclization protocol for a broad range of 2,5-(hetero)-
aryloxozole-4-carboxylates 18a−i, we exploited these newly
synthesized oxozole-4-carboxylates as precursors for 2,5-
di(hetero)aryloxazole natural products by removal of 4-ester
functionality through a two-step hydrolysis and decarboxylation
protocol (Scheme 5). Hodgetts and Kershaw11a have
synthesized balsoxine 7a following this strategy from ethyl 2-
phenyl-5-(3,4-bismethoxyphenyl)oxazole-4-carboxylate 18b,
which was obtained in six steps from ethyl 2-aminooxazole
carboxylate in Suzuki−Miyaura approach. Hoarau and co-
workers32 have reported a five-step synthesis of balsoxine 7a
and texaline 7c (Figure 1) and other 2,5-di(hetero)aryloxazoles
by regiocontrolled palladium-catalyzed 2- and 5-(hetero)-
arylation of oxazole-4-carboxylates and subsequent hydrol-
ysis−decarboxylation (CuO) of the resulting 2,5-di(hetero)-
aryl-4-carboxylates.32 We undertook the synthesis of two
With an optimized catalytic system in hand, we next explored
the generality of this copper-catalyzed cyclization reaction with
various open chain enamide esters 17b−i (Scheme 4). Thus
acyclic ethyl esters bearing substituted aryl (17b,c), furyl (17d),
3-indolyl (17e) and 3-pyridyl (17f) moieties readily underwent
cyclization under these optimized conditions providing the
corresponding ethyl 2-phenyl-5-(hetero)aryloxazole-4-carbox-
ylates 18b−f in excellent overall yields (Scheme 4). Similarly
the n-butyl and benzyl 2-phenyl-5-(3-indolyl)-oxozole-4-
carboxylates 18g,h could be obtained in excellent yields from
the acyclic precursors 17g,h. Interestingly, the corresponding t-
butyl 2,5-diaryloxazole-4-carboxylate 18i could also be obtained
in 80% yield from 17i, without any side reactions under
identical conditions (Scheme 4).
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Scheme 7. Synthesis of 2,5-Substitued 4,2′-Bisoxazole-4′-carboxylates
Scheme 8. Synthesis of 2,5-Di(hetero)aryl-4-acyloxazoles
natural products, i.e., texamine 7b (isolated from Amyris
texana),23b,d,33a−d uguenenazole 8b (recently isolated form
Vepris uguenensis),33b,34 and 2-phenyl-5-(3-indolyl)oxazole 20
from the respective 2,5-di(hetero)aryloxazole-4-carboxylates
18a, 18c and 18e as shown in the Scheme 5. Thus the oxazole
esters were subjected to hydrolysis in ethanolic NaOH
furnishing the respective carboxylic acids 19 in nearly
quantitative yields. Thermal decarboxylation of 19a, 19c and
19e in H2O/DMF (1:1) afforded uguenenazole 8b, texamine
7b, and 2-phenyl-5-(3-indolyl)-oxazole 20, respectively, in 69−
71% overall yields in a four-step sequence (Scheme 5).
Having optimized the reaction conditions for copper-
catalyzed 5-endo cyclization of enamides bearing a carboxylate
functionality, we next evaluated the scope of the reaction for
the synthesis of 2,5-di(hetero)aryloxazole-4-carboxamides 22
by ring-opening of 12 with various primary and secondary
amines followed by copper-catalyzed 5-endo cyclization of the
resulting enamides 21 (Scheme 6). We were pleased to find
that 4-(hetero)arylideneoxazolones 12a,b and 12h underwent
smooth ring-opening with primary and secondary aliphatic
acyclic/cyclic amines to afford the corresponding open-chain
adducts 21a−d in excellent yields.27 Similarly, aromatic amines
with both electron donating and withdrawing groups also
reacted smoothly with few selected oxazolones (12e,f,h)
yielding acyclic precursors 21e−g in good yields.27 The ring-
opening of 12 was found to be equally facile with amino acid
esters (phenylalanine, tryptophan and serine) leading to novel
peptidomimetic motifs 21h−l in moderate to good yields.27
Further, to our delight, the optimized copper-catalyzed reaction
conditions turned out to be equally successful for intra-
molecular cyclization of acyclic amide precursors 21a−l
furnishing the novel 2-phenyl-5-(hetero)aryloxazole-4-carbox-
amides 22a−l in excellent yields (Scheme 6). Thus, a diverse
range of 2,5-disubstituted oxazole-4-carboxamides derived from
primary aliphatic/aromatic and cyclic secondary amines and
amino acid derivatives 22a−l could be readily synthesized in
two steps from easily accessible precursors. The newly
synthesized serine-derived 2,5-disubstitued oxazole-4-(β-
hydroxy)amides 22j−l were subjected to one-pot dehydrative
cyclization−dehydrohalgenation by sequential treatment with
diethylaminosulphur trifluoride (DAST) at −78 °C for 30 min
and bromotrichloromethane/DBU to furnish 2,5-substitued
4,2′-bisoxazole-4′-carboxylates 24a−c in 70−75% yields
(Scheme 7).10a The 4,2′-bisoxazoles are common motifs in
many natural products (diazonamide, hennoxazole A, telomes-
tatin) displaying a broad range of biological activity.1
Finally, after successful implementation of this two-step
protocol for the introduction of 4-carboxylate and 4-
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phenyloxazol-5-one 1535 (0.5 g, 3.0 mmol) in DMF (10 mL) was
added dropwise at 0 °C. The reaction mixture was stirred at room
temperature for 0.5−1 h, cooled to −20 °C, followed by addition of
MeI (0.28 mL, 4.5 mmol) and further stirring at room temperature for
30 min. It was then poured into saturated NH4Cl solution (100 mL),
extracted with EtOAc (3 × 50 mL), washed with water (2 × 50 mL),
brine (1 × 50 mL), dried over Na2SO4, and the solvent was removed
under reduced pressure to give crude products, which were purified by
column chromatography over silica gel using EtOAc−hexane as eluent.
All oxazolones 12a−i were obtained as mixture of E/Z stereo-
isomers. The E/Z stereochemistry of 12a−i was established on the
basis of chemical shift value of methylthio group, which appears at
higher δ value in E isomer because of the deshielding effect of cis
carbonyl group of azalactone.
carboxamide functionalities in the trisubstituted oxazoles 18
and 22 (Schemes 4, 6), we next focused our studies on the
synthesis of 2,5-substituted 4-acyl(aroyl)oxazoles via ring-
opening of oxazolones 12 with alkyl/aryl Grignard reagents
25a−d (Scheme 8). Thus, treatment of 12a with n-
butylmagnesium bromide 25a gave the α-acylenamide 26a
(72%) exclusively with no trace of conjugate addition−
elimination product.27 The enamide 26a was subjected to
copper-catalyzed cyclization under optimized conditions to
furnish the 2-phenyl-5-(4-methoxyphenyl)-4-(n-pentanoyl)-
oxazole 27a in 90% yield. Similarly, the ring-opening of 12a
and 12f with aryl Grignard reagents 25b,c also proceeded
smoothly, leading to 4-aroyloxazoles 27b,c in excellent yields
after subsequent cyclization of the resulting enamides 26b,c
under copper catalysis.27 The versatility of the methodology
was further demonstrated by the synthesis of two 2-phenyl-5-
(hetero)aryl-4-thienoyloxazoles 27d,e in high yields under
identical sequence by initial treatment of either 12e or 12h with
2-thienyl Grignard reagent 25d (Scheme 8).
(E/Z) 4-[(4-Methoxyphenyl)(methylthio)methylene]-2-phe-
nyloxazol-5(4H)-one (12a). Obtained from oxazolone 15 and
dithioester 16a, (E:Z = 60:40), yellow solid (0.805 g, 80%): mp
134−136 °C; Rf 0.6 (1:4 EtOAc:hexane); IR (KBr, cm−1) 3076, 2959,
1
2928, 2834, 1768, 1627, 1502, 1298, 1251, 1173, 1008, 820, 695; H
NMR (400 MHz, CDCl3) δ 8.11−8.08 (m, 1.2H), 7.98−7.96 (m,
0.8H), 7.56−7.40 (m, 3.8H), 7.35−7.32 (m, 1.2H), 7.04−6.98 (m,
2H), 3.89 (s, 1.2H), 3.87 (s, 1.8H), 2.27 (s, 1.8H), 2.22 (s, 1.2H); 13C
NMR (100 MHz, CDCl3) δ 165.2, 162.6, 161.4, 161.2, 160.1, 159.1,
157.6, 156.9, 132.6, 132.3, 132.2, 131.0, 129.4, 128.9, 128.2, 128.1,
127.9, 127.7, 126.8, 126.3, 126.2, 124.9, 114.4, 114.1, 55.6, 55.5, 17.4,
16.9; HRMS (ESI) m/z calcd for C18H15NO3S [M + Na]+ 348.0670,
found 348.0681.
(E/Z) 4-[(1-Methyl-1H-indol-3-yl)(methylthio)methylene]-2-
phenyloxazol-5(4H)-one (12h). Obtained from oxazolone 15 and
dithioester 16h, (E:Z = 64:36), yellow solid (0.84 g, 78%): mp 186−
188 °C; Rf 0.5 (1:2 EtOAc:hexane); IR (KBr, cm−1) 3106, 2927, 1767,
1727, 1619, 1522, 1325, 1131, 887, 693; 1H NMR (400 MHz, CDCl3)
δ 8.12−8.09 (m, 1.34H), 7.99−7.97 (m, 0.66H), 7.93 (d, J = 8 Hz,
0.33H), 7.73 (s, 0.33H), 7.71 (s, 0.67H), 7.56 (s, 1H), 7.53−7.42 (m,
3H), 7.40−7.37 (m, 1H), 7.33−7.31 (m, 1.34H), 7.27 (d, J = 1.2 Hz,
0.33H), 7.25−7.23 (m, 0.67H), 3.92 (s, 0.99H), 3.89 (s, 2.01H), 2.45
(s, 2.01H), 2.44 (s, 0.99H); 13C NMR (100 MHz, CDCl3) δ 165.2,
163.1, 158.3, 157.8, 151.8, 151.5, 138.0, 137.8, 135.2, 133.8, 132.1,
131.9, 128.9, 128.8, 127.6, 127.4, 126.7, 126.65, 126.59, 126.3, 123.2,
123.0, 122.0, 121.8, 121.7, 121.2, 111.6, 110.3, 110.2, 108.5, 33.73,
33.65, 18.7, 18.1; HRMS (ESI) m/z calcd for C20H16N2O2S [M +
Na]+ 371.0830, found 371.0833.
(E/Z) 4-[Methylthio(pyridin-3-yl)methylene]-2-phenyloxa-
zol-5(4H)-one (12i). Obtained from oxazolone 15 and dithioester
16i, (E:Z = 57:43), yellow solid (0.55 g, 75%): mp 100−102 °C; Rf 0.3
(1:1 EtOAc:hexane); IR (KBr, cm−1) 2920, 1760, 1619, 1572, 1008,
867, 702; 1H NMR (400 MHz, CDCl3) δ 8.72−8.71 (m, 1.14H), 8.62
(d, J = 1.6 Hz, 0.86H), 8.11−8.09 (m, 1.14H), 7.96−7.94 (m, 0.86H),
7.81 (dt, J = 7.6 Hz, 1.8 Hz, 0.43H), 7.71 (dt, J = 8 Hz, 1.8 Hz, 0.57H),
7.59−7.47 (m, 2.7H), 7.45−7.41 (m, 1.3H), 2.32 (s, 1.71H), 2.2 (s,
1.29H); 13C NMR (100 MHz, CDCl3) δ 164.7, 162.5, 161.5, 160.3,
152.0, 151.7, 151.1, 150.8, 150.6, 149.6, 137.7, 136.9, 133.2, 132.9,
131.1, 130.8, 129.6, 129.5, 129.12, 129.0, 128.2, 128.0, 125.9, 125.8,
123.6, 123.5, 17.1, 16.9; HRMS (ESI) m/z calcd for C16H12N2O2S [M
+ H]+ 297.0698, found 297.0698.
Nucleophilic Ring-Opening of 2-Phenyl 4-[(methylthio)-
(hetero)arylidene]-oxazole-5-ones 12 with Sodium Alkoxides:
General Procedure for the Synthesis of α-[(Methylthio)-
(hetero)arylidene]-N-benzoylglycinates 17a−i. To a stirred
suspension of the corresponding sodium alkoxide [freshly prepared
from sodium (20 mg, 1.0 mmol) in the respective alkanol (5 mL)], a
solution of the appropriate 5-oxazolone 12 (0.325 g, 1.0 mmol) in 10
mL of alkanol was added dropwise, and the reaction mixture was
further stirred at room temperature for 2−3 h (monitored by TLC). It
was then concentrated under reduced pressure, poured into water
(100 mL), extracted with EtOAc (3 × 50 mL), and washed with brine
(1 × 50 mL). The organic layer was dried (Na2SO4) and evaporated,
and the residue was triturated with diethyl ether to give open-chain
esters 17a−i as white solids. All the open-chain esters 17a−i were
CONCLUSION
■
In summary, we have developed an efficient two step synthesis
of highly functionalized 2-phenyl-4,5-substitued oxazoles from
readily available novel 4-[(methylthio)(aryl/heteroary)-
methylene]-2-phenyl-5-oxazolone precursors 12. The overall
process involves highly regioselective nucleophilic ring-opening
of 12 by oxygen, nitrogen and carbon nucleophiles and
subsequent copper-catalyzed intramolecular cyclization of the
resulting functionalized β-[(methylthio)hetero(aryl)]enamides
to 2-phenyl-4,5-substituted oxazoles as the key step. The
protocol displays broad substrate scope and wide functional
group compatibility with flexible substitution at 4,5-positions of
oxazoles. The 4-carboxylate functionality can be easily removed
to readily afford the corresponding 2,5-di(hetero)aryloxazoles,
and the method is applied for the synthesis of 2,5-di(hetero)-
aryloxazole natural products texamine 7b, uguenenazole 8b and
2-phenyl-5-(3-indolyl) oxazole 20 in overall high yields
(Scheme 5). Additionally, the amino acid derived enamides
21h−l provide access to a range of chiral potentially biologically
relevant oxazoles 22h−l (Scheme 6). The ease of further
elaboration was demonstrated by facile dehydrative cycliza-
tion−aromatization of serine-derived oxazoles 22j−l to 4,2′-
bisoxazoles 25a−c (Scheme 7), which are structural compo-
nents of several biologically active bisoxazole-containing natural
products. The copper-catalyzed cyclization of these highly
functionalized β-(methylthio)enamides to oxazoles comple-
ments the growing collection of copper-catalyzed heterocycliza-
tion reactions and provides practical and economical advantage
over previously reported4 silver carbonate mediated cyclization
(requiring 4 equiv of Ag2CO3) in terms of inexpensive copper
catalyst and better yields. We believe that the present method is
attractive for further library construction for diversity oriented
synthesis of oxazoles as well as related natural products. The
easy availability of starting materials along with the convenience
and efficiency of the present method should make it useful
complement to the existing methods for the synthesis of
multisubstituted oxazoles.
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of 4-[(Methylthio)(aryl/
heteroaryl)methylene]-2-phenyloxazol-5-ones (12a−i). To a
stirred suspension of NaH (0.31 g, 7.8 mmol) and appropriate
(hetero)aryl dithioester (3.0 mmol) in DMF (10 mL), a solution of 2-
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1
found to be inseparable mixture of E/Z stereoisomers from their H
product 21e was separated as pure solid on trituration with diethyl
ether, whereas products 21f,g, 21i−k were purified by column
chromatography over silica gel using EtOAc:hexane as eluent.27 The
open-chain precursor 21l from oxazolone 12h and serine ethyl ester
could not be purified by column chromatography and was used as such
for Cu-catalyzed cyclization without purification.
NMR spectra.27
(E/Z) Ethyl 2-benzamido-3-(4-methoxyphenyl)-3-
(methylthio)acrylate (17a). Obtained from oxazolone 12a and
sodium ethoxide, (E:Z = 40:60), white solid (0.326 g, 88%): mp 146−
148 °C; Rf 0.4 (1:1 EtOAc:hexane); IR (KBr, cm−1) 3326, 2983, 2926,
1
1715, 1658, 1511, 1467, 1288, 1244, 1028, 709; H NMR (400 MHz,
N-[1-(3,4-Dimethoxyphenethylamino)-3-(4-methoxyphen-
yl)-3-(methylthio)-1-oxoprop-2-en-2-yl]benzamide (21a). Ob-
tained from the oxazolone 12a and 3,4-dimethoxyphenylethylamine,
(Procedure A) as single stereoisomer, white solid (0.373 g, 80%): mp
132−134 °C; Rf 0.4 (3:2 EtOAc:hexane); IR (KBr, cm−1) 3264, 2920,
DMSO-d6) δ 9.9 (s, 0.6H), 9.4 (s, 0.4H), 7.98 (d, J = 7.6 Hz, 1.2H),
7.60−7.57 (m, 1.2H), 7.53−7.48 (m, 1.8H), 7.40−7.36 (m, 0.8H),
7.19 (d, J = 8.8 Hz, 0.8H), 7.15 (d, J = 8.8 Hz, 1.2H), 7.0 (d, J = 8.8
Hz, 1.2H), 6.95 (d, J = 8.8 Hz, 0.8H), 4.15 (q, J = 7.2 Hz, 0.8H), 3.80
(q, J = 7.2 Hz, 1.2H), 3.79 (s, 1.8H), 3.72 (s, 1.2H), 1.9 (s, 1.8H), 1.78
(s, 1.2H), 1.18 (t, J = 7.2 Hz, 1.2H), 0.79 (t, J = 7.2 Hz, 1.8H); 13C
NMR (100 MHz, DMSO-d6) δ 166.1, 165.3, 164.5, 163.7, 159.5,
158.9, 151.1, 144.3, 133.8, 133.2, 131.8, 131.4, 129.9, 129.5, 128.4,
128.2, 127.8, 127.7, 127.5, 127.3, 123.5, 120.7, 113.8, 113.7, 60.2, 59.9,
55.2, 55.1, 16.1, 14.9, 14.1, 13.5. Anal. Calcd for C20H21NO4S: C,
64.67; H, 5.70; N, 3.77. Found: C, 64.57; H, 5.67; N, 3.71.
1
1633, 1517, 1261, 1028, 764; H NMR (400 MHz, CDCl3) δ 7.46−
7.41 (m, 3H), 7.32−7.29 (m, 3H), 7.22 (d, J = 8.8 Hz, 2H); 6.87 (d, J
= 8.8 Hz, 2H), 6.82−6.80 (br m, 1H), 6.79 (d, J = 1.6 Hz, 1H), 6.76
(dd, J = 8.4 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.84 (s, 3H), 3.79 (s,
3H), 3.77 (s. 3H), 3.63 (q, J = 6.8 Hz, 2H), 2.87 (t, J = 6.8 Hz, 2H),
1.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 165.4, 159.8,
149.1, 147.7, 141.5, 133.4, 132.0, 131.8, 129.9, 128.7, 127.6, 127.3,
125.4, 120.9, 114.5, 112.3, 111.5, 55.9, 55.4, 41.2, 35.2, 16.4; HRMS
(ESI) m/z calcd for C28H30N2O5S [M + H]+ 507.1954, found
507.1934.
N-(1-(4-Benzylpiperazin-1-yl)-3-(1-methyl-1H-indol-3-yl)-3-
(methylthio)-1-oxoprop-2-en-2-yl)benzamide (21d). Obtained
from oxazolone 12h and N-benzylpiperazine (Procedure A) as single
stereoisomer, white solid (0.384 g, 85%): mp 158−160 °C; Rf 0.3 (1:1
EtOAc:hexane); IR (KBr, cm−1) 3370, 2921, 2810, 1632, 1531, 1467,
1301, 741, 696; 1H NMR (400 MHz, CDCl3) δ 8.45 (br s, 1H), 7.94−
7.92 (m, 3H), 7.56−7.46 (m, 3H), 7.36−7.28 (m, 2H), 7.18−7.14 (m,
5H); 7.11−7.09 (m, 2H), 3.78 (s, 3H), 3.54 (br s, 1H), 3.40 (br s.
2H), 3.19 (d, J = 12.4 Hz, 1H), 3.10 (d, J = 12.4 Hz, 1H), 3.01 (br s,
1H), 2.42 (br s, 1H), 2.13 (br s, 1H), 1.99 (s, 3H), 1.78 (br s, 1H),
1.09 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 165.1, 164.3, 137.8,
137.2, 133.5, 132.1, 130.3, 129.2, 128.8, 128.3, 127.6, 127.2, 127.1,
122.6, 120.6, 120.2, 119.1, 109.7, 108.4, 62.9, 52.2, 51.8, 46.6, 41.4,
33.1, 15.6. Anal. Calcd for C31H32N4O2S: C, 70.96; H, 6.15; N, 10.68.
Found: C, 71.04; H, 6.11; N, 10.63.
(E/Z) n-Butyl 2-benzamido-3-(1-methyl-1H-indol-3-yl)-3-
(methylthio)acrylate (17g). Obtained from oxazolone 12h and
sodium n-butoxide, (E:Z = 45:55), white solid (0.290 g, 80%): mp
144−146 °C; Rf 0.4 (2:3 EtOAc:hexane); IR (KBr, cm−1) 3297, 2956,
1
2925, 1711, 1660, 1526, 1466, 1300, 1170, 742, 710; H NMR (400
MHz, CDCl3) δ 8.12 (s, 0.55H), 7.93 (d, J = 7.2 Hz, 1H); 7.80 (d, J =
8 Hz, 0.55H), 7.62 (d, J = 8 Hz, 0.45H), 7.58−7.54 (m, 0.62H), 7.50−
7.47 (m, 1.2H), 7.43−7.27 (m, 4.26H), 7.24−7.23 (m, 0.86H), 7.15
(td, J = 8 Hz, 0.8 Hz, 1H), 7.10 (s, 0.51H), 4.34 (t, J = 6.4 Hz, 0.9H),
3.90 (t, J = 6.4 Hz, 1.1H), 3.81 (s, 1.35H), 3.79 (s, 1.65), 2.0 (s,
1.35H), 1.98 (s, 1.65H), 1.74 (quin, J = 7.2 Hz, 0.9H), 1.45 (sex, J =
7.2 Hz, 0.9H), 1.14 (quin, J = 7.2 Hz, 1.1H). 0.94 (t, J = 7.2 Hz,
1.35H), 0.77 (sex, J = 7.2 Hz, 1.1H), 0.59 (t, J = 7.2 Hz, 1.65H); 13C
NMR (100 MHz, CDCl3) δ 165.3, 165.2, 164.8, 137.3, 137.2, 133.7,
133.4, 132.2, 131.8, 130.0, 129.5, 128.8, 128.6, 127.6, 127.4, 127.2,
125.9, 125.6, 124.1, 122.8, 122.6, 121.0, 120.5, 120.3, 120.2, 110.1,
109.7, 109.5, 65.4, 65.2, 33.3, 33.1, 30.7, 30.1, 19.4, 18.7, 17.0, 15.7,
13.9, 13.6. Anal. Calcd for C24H26N2O3S: C, 68.22; H, 6.20; N, 6.63.
Found: C, 68.32; H, 6.17; N, 6.57.
Ethyl 2-(2-benzamido-3-(methylthio)-3-(thiophen-2-yl)-
acrylamido)-3-hydroxypropanoate (21j). Obtained from oxazo-
lone 12e and serine ethyl ester (Procedure B) as single stereoisomer,
off-white solid (0.303 g, 70%): mp 100−102 °C; Rf 0.4 (3:2
EtOAc:hexane); IR (KBr, cm−1) 3403, 2977, 2918, 1735, 1640, 1518,
(E/Z) t-Butyl 2-benzamido-3-(4-methoxyphenyl)-3-
(methylthio)acrylate (17i). Obtained from oxazolone 12a and
sodium t-butoxide, (E:Z = 50:50), white solid (0.330 g, 90%): mp
165−167 °C; Rf 0.4 (2:3 EtOAc:hexane); IR (KBr, cm−1) 3212, 2977,
1
1
2925, 1689, 1646, 1506, 1256, 1160, 1021, 706; H NMR (400 MHz,
1467, 1283, 1193, 703; H NMR (400 MHz, CDCl3) δ 8.24 (br s,
DMSO-d6) δ 9.73 (s, 0.5H), 9.24 (s, 0.5H), 7.97 (d, J = 7.2 Hz, 1H);
7.59−7.56 (m, 1.5H), 7.52−7.45 (m, 1.5H), 7.38 (t, J = 7.6 Hz, 1H),
7.19 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 8.8 Hz,
1H), 6.94 (d, J = 8.8 Hz, 1H), 3.79 (s, 1.5H), 3.73 (s, 1.5H), 1.87 (s,
1.5H), 1.77 (s, 1.5H), 1.43 (s, 4.5H), 1.09 (s, 4.5H); 13C NMR (100
MHz, DMSO-d6) δ 166.2, 165.2, 163.6, 162.6, 159.4, 158.9, 149.3,
142.6, 134.1, 133.4, 131.8, 131.3, 130.1, 129.5, 128.4, 128.2, 128.1,
127.7, 127.67, 127.3, 124.9, 122.2, 113.8, 113.6, 80.4, 79.8, 55.3, 55.1,
27.8, 27.2, 16.1, 14.9. Anal. Calcd for C22H25NO4S: C, 66.14; H, 6.31;
N, 3.51. Found: C, 66.15; H, 6.11; N, 3.71.
Nucleophilic Ring-Opening of 2-Phenyl 4-[(methylthio)-
(hetero)arylidene]-oxazole-5-ones 12 with Amines and
Amino Acid Esters: General Procedure for the Synthesis of
α-[(Methylthio)(hetero)arylidene]-(N-benzoyl)-N-glycinamides
21a−l. Procedure A. A solution of appropriate oxazolone 12 (0.9
mmol) and respective amine/amino acid ester (0.9 mmol) in EtOH
(15 mL) was stirred at room temperature for 35−40 h (monitored by
TLC). The ethanol was evaporated under reduced pressure, and the
residue was triturated with diethyl ether to give 21 as white solids,
which were filtered and crystallized (EtOAc) for characterization. The
products 21a−d and 21h were obtained following this procedure
either as pure stereoisomers or as E/Z mixtures.27 The product 21h
from oxazolone 12a and phenylalanine ester was purified by column
chromatography on silica gel to give single stereoisomer.
1H), 7.65 (d, J = 7.6 Hz, 2H), 7.52−7.51 (m, 1H), 7.46 (dd, J = 5.2
Hz, 0.8 Hz, 1H), 7.39−7.36 (m, 2H), 7.28 (dd, J = 3.6 Hz, 1.2 Hz,
1H), 7.11 (dd, J = 5.2 Hz, 3.6 Hz, 1H); 7.07 (br d, J = 6.8 Hz, 1H),
4.69 (ddd, J = 8 Hz, 3.2 Hz, 2,8 Hz, 1H), 4.42 (dd, J = 11.6 Hz, 2.8 Hz,
1H), 4.29 (q, J = 7.2 Hz, 2H), 3.95 (br d, J = 11.6 Hz, 1H), 3.75 (br s,
1H), 2.17 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.6, 165.1, 164.3, 138.3, 132.6, 132.4, 131.1, 129.3, 128.9,
128.7, 128.0, 127.6, 122.3, 62.2, 61.7, 56.0, 17.6, 14.3; HRMS (ESI)
m/z calcd for C20H22N2O5S2 [M + H]+ 435.1048, found 435.1024.
Nucleophilic Ring-Opening of 2-Phenyl 4-[(methylthio)-
(hetero)arylidene]-oxazole-5-ones 12 with Grignard Reagents:
General Procedure for the Synthesis of Alkyl/(hetero)aryl-α-
(N-benzoyl)-β-[(methylthio)(hetero)arylidene]ketones 26a−e.
To a stirred, cooled (−20 °C) solution of the corresponding 5-
oxazolone 12 (2.0 mmol) in dry THF (10 mL), appropriate Grignard
reagent (2.3 mmol) [freshly prepared from the corresponding alkyl/
(hetero)aryl bromides (2.3 mmol) and magnesium metal (3.45 mmol)
in 10 mL of THF] was added slowly with the help of syringe. The
reaction mixture was further stirred for 2−3 h at −20 °C (monitored
by TLC), brought to room temperature and poured into saturated
NH4Cl solution (100 mL). It was then extracted with EtOAc (3 × 50
mL), washed with H2O, brine (1 × 50 mL), and the organic layer was
dried (Na2SO4) and evaporated under reduced pressure, and the
residue was triturated with diethyl ether to give open-chain ketones
26a−e as white solids.27
Procedure B. A solution of appropriate oxazolone 12 (0.9 mmol)
and the corresponding amine/amino acid ester (0.9 mmol) in EtOH
(15 mL) and trace of acetic acid (0.1 mL) was refluxed for 10−16 h
(monitored by TLC) and worked up as in the procedure A. The
N-(1-(4-Methoxyphenyl)-1-(methylthio)-3-oxohept-1-en-2-
yl)benzamide (26a). Obtained from oxazolone 12a and n-
butylmagnesium bromide as single stereoisomer, white solid (0.265
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g, 75%): mp 150−152 °C; Rf 0.4 (3:7 EtOAc:hexane); IR (KBr, cm−1)
3307, 2956, 1651, 1466, 1250, 1034, 709; 1H NMR (400 MHz,
CDCl3) δ 8.11 (br s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 7.57−7.54 (m,
1H), 7.51−7.46 (m, 2H), 7.26 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz,
2H), 3.84 (s, 3H), 2.24 (t, J = 7.6 Hz, 2H), 1.95 (s, 3H), 1.43 (quin, J
= 7.2 Hz, 2H), 1.08 (sex, J = 7.2 Hz, 2H), 0.719 (t, J = 7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 201.6, 160.5, 134.9, 133.2, 132.3,
131.4, 130.1, 128.9, 127.6, 127.3, 114.8, 114.5, 55.5, 42.1, 26.1, 22.2,
15.7, 13.9; HRMS (ESI) m/z calcd for C22H25NO3S [M + Na]+
406.1453, found 406.1452.
137.0, 134.1, 130.6, 128.9, 127.1, 126.7, 126.1, 124.5, 123.1, 121.7,
121.5, 110.1, 103.0, 65.1, 33.6, 31.1, 19.4, 13.9; HRMS (ESI) m/z
calcd for C23H22N2O3 [M + Na]+ 397.1528, found 397.1529.
N-(3,4-Dimethoxyphenethyl)-5-(4-methoxyphenyl)-2-phe-
nyloxazole-4-carboxamide (22a). Obtained from enamide 21a,
white solid (140 mg, 80%): mp 138−140 °C; Rf 0.5 (4:6
EtOAc:hexane); IR (KBr, cm−1) 3336, 2913, 2838, 1643, 1529,
1
1255, 836, 701; H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.8 Hz,
2H), 8.06−8.04 (m, 2H), 7.53−7.48 (m, 4H), 7.01 (d, J = 10 Hz, 2H),
6.84−6.81 (m, 3H), 3.87 (s, 3H), 3.86 (s, 3H), 3.85 (s, 3H), 3.69 (q, J
= 6.8, 2 Hz, 2H), 2.91 (t, J = 6.8 Hz, 2H) ; 13C NMR (100 MHz,
CDCl3) δ 161.7, 161.0, 157.9, 152,6, 149.2, 147.8, 131.8, 130.9, 130.1,
129.3, 129.0, 126.8, 126.6, 120.9, 120.1, 113.9, 112.2, 111.6, 56.1, 55.9,
55.5, 40.9, 35.8; HRMS (ESI) m/z calcd for C27H26N2O5 [M + Na]+
481.1739, found 481.1738.
(4-Benzylpiperazin-1-yl)[5-(1-methyl-1H-indol-3-yl)-2-phe-
nyloxazol-4-yl]methanone (22d). Obtained from enamide 21d, off-
white solid (158 mg, 87%): mp 160−162 °C; Rf 0.45 (4:6
EtOAc:hexane); IR (KBr, cm−1) 2909, 2802, 1624, 1442, 1228, 737;
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.21 (d, J = 6.8 Hz, 1H),
8.14 (d, J = 6.8, Hz, 2H), 7.54−7.47 (m, 3H), 7.40−7.29 (m, 8H),
3.94 (br s, 2H), 3.87 (s, 3H), 3.85 (br s, 2H), 3.55 (s, 2H), 2.58 (br s,
2H), 2.52 (br s, 2H); 13C NMR (100 MHz, CDCl3) δ 163.4, 157.3,
151.4, 137.9, 137.1, 132.1, 131.1, 130.4, 129.3, 129.0, 128.5, 127.6,
127.5, 127.4, 126.3, 126.0, 122.8, 121.2, 121.1, 109.9, 103.2, 63.1, 53.7,
53.1, 47.5, 42.7, 33.4; HRMS (ESI) m/z calcd for C30H28N4O2 [M +
Na]+ 499.2110, found 499.2113.
N-[3-(1-Methyl-1H-indol-3-yl)-3-(methylthio)-1-oxo-1-(thio-
phen-2-yl)prop-2-en-2-yl]benzamide (26e). Obtained from ox-
azolone 12h and 2-thienylmagnesium bromide (E:Z = 17:83), pale
yellow solid (0.604 g, 70%): mp 160−163 °C; Rf 0.4 (3:2
EtOAc:hexane); IR (KBr, cm−1) 3364, 2918, 1660, 1632, 1530,
1464, 1303, 1263, 742, 708 ; 1H NMR (400 MHz, DMSO-d6) δ 10.13
(s, 0.83H), 9.76 (s, 0.17H), 8.0 (d, J = 7.2 Hz, 1.66H), 7.85 (dd, J =
6.6 Hz, 4.8 Hz, 0.37H), 7.74 (d, J = 7.2 Hz, 1.06H), 7.60−7.57 (m,
1.3H), 7.53−7.42 (m, 4H), 7.32 (d, J = 8.0 Hz, 1H), 7.22 (s, 0.83H),
7.19−7.15 (m, 1H), 7.08 (t, J = 7.2 Hz, 0.83H), 6.99 (t, J = 7.2 Hz,
0.17H), 6.68 (dd, J = 4.8 Hz, 4.0 Hz, 0.83H), 3.87 (s, 0.51H), 3.64 (s,
2.49H), 2.05 (s, 2.49H), 1.85 (s, 0.51H); 13CNMR (100 MHz,
DMSO-d6) δ 184.6, 184.2, 165.3, 164.8, 145.5, 144.0, 137.3, 136.9,
135.2, 133.1, 133.0, 132.6, 132.4, 132.2, 131.9, 131.8, 131.5, 131.4,
131.3, 129.5, 129.1, 128.4, 128.1, 128.0, 127.69, 127.65, 127.6, 126.9,
126.3, 125.6, 122.0, 121.7, 120.1, 120.0, 119.9, 119.5, 110.4, 110.1,
109.6, 109.2, 32.8, 32.4, 16.2, 15.4; HRMS (ESI) m/z calcd for
C24H20N2O2S2 [M + Na]+ 455.0864, found 455.0862.
General Procedure for Copper-Catalyzed Intramolecular
Cyclization of Open-Chain Precursors 17a−i, 21a−l and 26a−
e: Synthesis of 2-Phenyl-5-(hetero)aryl-4-Substituted Oxazoles
18a−i, 22a−l and 27a−e. To a stirred solution of the corresponding
open-chain precursors 17, 21 or 26 (1.0 mmol) in DMF (3 mL) were
added CuI (19 mg, 0.1 mmol), 1,10-phenanthroline (36 mg, 0.2
mmol) and Cs2CO3 (32 mg, 1.0 mmol), and the reaction mixture was
heated at 90 °C with stirring for 2−3 h (monitored by TLC). It was
then poured into ice-cold water (20 mL), extracted with EtOAc (3 ×
10 mL), washed with brine (1 × 10 mL), dried over Na2SO4 followed
by removal of the solvent to give crude oxazoles, which were purified
by column chromatography over silica gel using EtOAc−hexane as
eluent.
Ethyl 5-(4-methoxyphenyl)-2-phenyloxazole-4-carboxylate
(18a). Obtained from enamide 17a, white solid (160 mg, 92%): mp
148−149 °C; Rf 0.5 (3:7 EtOAc:hexane); IR (KBr, cm−1) 2926, 1715,
1505, 1212, 1091, 709; 1H NMR (400 MHz, CDCl3) δ 8.16−8.15 (m,
2H), 8.11 (d, J = 8.8 Hz, 2H), 7.49−7.48 (m, 3H), 7.02 (d, J = 8.8 Hz,
2H), 4.46 (q, J = 7.21 Hz, 2H), 3.87 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 162.7, 161.3, 159.4, 155.6,
131.0,130.4, 128.9, 127.3, 126.9, 126.7, 119.9, 114.0, 61.5, 55.6, 14.5;
HRMS (ESI) m/z calcd for C19H17NO4 [M + Na]+ 346.1055, found
346.1051.
Ethyl 5-(3,4-dimethoxyphenyl)-2-phenyloxazole-4-carboxy-
late (18b).32 Obtained from enamide 17b, white solid (154 mg,
88%): mp 165−166 °C (lit. 165−166 °C);32 Rf 0.5 (4:6
EtOAc:hexane); IR (KBr, cm−1) 3030, 2836, 1711, 1513, 1259, 708;
1H NMR (400 MHz, CDCl3) δ 8.17−8.14 (m, 2H), 7.88 (d, J = 2 Hz,
1H), 7.76 (dd, J = 8.6 Hz, 2 Hz, 1H), 7.49 (m, 3H), 6.98 (d, J = 8.6
Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.99 (s, 3H), 3.97 (s, 3H), 1.44 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.6, 159.1, 155.2,
150.8, 148.7, 130.9, 128.8, 127.3, 126.8, 126.5, 121.9, 119.9, 111.8,
110.8, 61.39, 56.12, 55.99, 14.39; HRMS (ESI) m/z calcd for
C20H19NO5 [M + Na]+ 376.1161, found 376.1161.
5-(1-Methyl-1H-indol-3-yl)-2-phenyl-N-[4-(trifluoromethyl)-
phenyl]oxazole-4-carboxamide (22g). Obtained from enamide
21g, white solid (153 mg, 85%): mp 258−260 °C; Rf 0.8 (3:7
EtOAc:hexane); IR (KBr, cm−1) 3351, 2942, 1673, 1581, 1326, 1114,
1
736; H NMR (400 MHz, CDCl3) δ 9.31 (br s, 1H), 9.02 (s, 1H),
8.36−8.33 (m, 1H), 8.21 (m, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.65 (d, J
= 8.4 Hz, 2H), 7.59−7.54 (m, 3H), 7.45−7.36 (m, 3H), 3.94 (s, 3H);
13C NMR (100 MHz, CDCl3) δ160.7, 156.9, 153.1, 141.4, 137.2,
134.7, 130.8, 129.2, 126.9, 126.5, 126.46, 126.43, 126.39, 126.1, 125.9,
123.1, 121.7, 121.5, 119.5, 110.2, 102.9, 33.6; HRMS (ESI) m/z calcd
for C26H18F3N3O2 [M + Na]+ 484.1249, found 484.1249.
(2S)-Ethyl 3-(1H-indol-3-yl)-2-(5-(1-methyl-1H-pyrrol-2-yl)-2-
phenyloxazole-4-carboxamido)propanoate (22i). Obtained from
enamide 21i, white solid (125 mg, 70%): mp 94−96 °C; Rf 0.5 (1:2
25
EtOAc:hexane); [α]D = +31.4 (c, 0.58, CHCl3); IR (KBr, cm−1)
1
3385, 3268, 3056, 2926, 1736, 1661, 1529, 1235, 741; H NMR (400
MHz, CDCl3) δ 8.12 (br s, 1H), 7.96 (m, 2H), 7.76 (d, J = 8.0 Hz,
1H), 7.65 (d, J = 8 Hz, 1H), 7.48−7.45 (m, 3H), 7.35 (d, J = 8.4 Hz,
1H), 7.22 (dd, J = 4 Hz, 1.6 Hz, 1H), 7.20 (t, 7.2 Hz, 1H), 7.12−7,10
(m, 2H), 6.79 (dd, J = 2.8 Hz, 1.6 Hz, 1H), 6.24 (dd, J = 4 Hz, 2.8 Hz,
1H), 5.08 (dt, J = 8 Hz, 2.8 Hz, 1H), 4.18−4.10 (m, 2H), 3.82 (s, 3H),
3.43 (dd, J = 5.6 Hz, 2.0 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ172.1, 160.9, 158.2, 146.5, 136.3, 130.9, 129.4,
128.9, 127.9, 126.9, 126.8, 126.6, 122.9, 122.3, 120.0, 119.8, 119.1,
116.4, 111.3, 110.6, 108.9, 61.6, 52.9, 36.5, 28.1, 14.2; HRMS (ESI)
m/z calcd for C28H26N4O4 [M + H]+ 483.2032, found 483.2033.
(2S)-Ethyl 3-hydroxy-2-[2-phenyl-5-(thiophen-2-yl)oxazole-
4-carboxamido]propanoate (22j). Obtained from enamide 21j,
off-white solid (133 mg, 75%): mp 194−196 °C; Rf 0.55 (1:1
25
EtOAc:hexane); [α]D = +20.0 (c, 0.55, CHCl3); IR (KBr, cm−1)
1
3384, 3332, 2956, 1740, 1640, 1531, 1269, 1058, 703; H NMR (400
MHz, CDCl3) δ 8.23 (dd, J = 4 Hz, 1.2 Hz, 1H), 8.13−8.06 (m, 2H),
8.07 (br d, J = 7.2 Hz, 1H), 7.52−7.50 (m, 4H), 7.16 (dd, J = 5.2 Hz,
1.2 Hz, 1H), 4.88 (dt, 7.2 Hz, 4.0 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H),
4.11 (dd, J = 4.4 Hz, 4.0 Hz, 2H), 2.61 (br s, 1H), 1.34 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 170.4, 161.9, 158.3, 149.0,
131.3, 130.1, 129.4, 129.1, 128.8, 127.9, 127.8, 126.8, 126.3, 63.9, 62.2,
55.0, 14.3; HRMS (ESI) m/z calcd for C19H18N2O5S [M + Na]+
409.0834, found 409.0833.
n-Butyl 5-(1-methyl-1H-indol-3-yl)-2-phenyloxazole-4-car-
boxylate (18g). Obtained from enamide 17g, white solid (160 mg,
90%): mp 144−145 °C; Rf 0.7 (1:3 EtOAc:hexane); IR (KBr, cm−1)
1
2996, 2867, 1693, 1567, 1220, 731; H NMR (400 MHz, CDCl3) δ
8.75 (s, 1H), 8.33−8.31 (m, 1H), 8.22 (d, J = 6.8 Hz, 2H), 7.55−7.49
(m, 3H), 7.42−7.35 (m, 3H), 4.44 (t, J = 7.2 Hz, 2H), 3.90 (s, 3H),
1.87 (quint, J = 7.2 Hz, 2H), 1.50 (quint, J = 7.2 Hz, 2H), 1.0 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 163.4, 157.9, 154.8,
1-[5-(4-Methoxyphenyl)-2-phenyloxazol-4-yl]pentan-1-one
(27a). Obtained from enamide 26a, white solid (157 mg, 90%): mp
78−80 °C; Rf 0.7 (1:4 EtOAc:hexane); IR (KBr, cm−1) 2925, 1679,
1496, 1255, 830, 706; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 9.2
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Article
Hz, 2H), 8.14−8.11 (m, 2H), 7.51−7.49 (m, 3H), 7.01 (d, J = 9.2 Hz,
2H), 3.89 (s, 3H), 3.15 (t, J = 7.6 Hz, 2H), 1.78−1.70 (m, 2H), 1.49−
1.40 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 197.4, 161.5, 158.1, 153.5, 134.4, 130.9, 130.1, 129.0, 127.0, 126.7,
120.2, 114.0, 55.5, 40.7, 26.4, 22.6, 14.2; HRMS (ESI) m/z calcd for
C21H21NO3 [M + Na]+ 358.1419, found 358.1418.
[5-(N-Methyl-1H-indol-3-yl)-2-phenyloxazol-4-yl](thiophen-
2-yl)methanone (27e). Obtained from enamide 26e, yellow solid
(150 mg, 85%): mp 214−218 °C; Rf 0.6 (1:4 EtOAc:hexane); IR
(KBr, cm−1) 2926, 1631, 1539, 1388, 1231, 730; 1H NMR (400 MHz,
CDCl3) δ 9.19 (s, 1H), 8.86 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 8.40−8.36
(m, 1H), 8.25 (m, 2H), 7.72 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.59−7.50
(m, 3H), 7.43−7.36 (m, 3H), 7.24 (dd, J = 4.8 Hz, 4.0 Hz, 1H), 3.92
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 178.2, 156.9, 155.6, 144.2,
137.4, 135.4, 135.2, 134.2, 131.7, 130.6, 129.1, 128.0, 127.3, 126.6,
126.2, 123.2, 121.9, 121.8, 110.2, 103.8, 33.7; HRMS (ESI) m/z calcd
for C23H16N2O2S [M + Na]+ 407.0830, found 407.0831.
5-(4-Methoxyphenyl)-2-phenyloxazole-4-carboxylic acid
(19a).9e Obtained from ester 18a, white solid (85 mg, 95%): mp
193−194 °C (lit. 192−194 °C);9e Rf 0.3 (EtOAc); IR (KBr, cm−1)
2933, 1690, 1513, 1256, 1183, 830, 706; 1H NMR (400 MHz, CDCl3)
δ 8.27 (d, J = 9.0 Hz, 2H), 8.13−8.10 (m, 2H), 7.53 (m, 3H), 7.03 (d,
J = 9.0 Hz, 2H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ163.5,
161.7, 158.6, 155.8, 131.4, 130.3, 129.1, 126.9, 126.1, 125.8, 119.1,
114.3, 55.6; HRMS (ESI) m/z calcd for C17H13NO4 [M + Na]+
318.0742, found 318.0742.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. C. N. R. Rao, FRS for encouragement, Council
of Scientific and Industrial Research (CSIR), New Delhi, and
JNCASR, Bangalore, for financial support, and Indian National
Science Academy, New Delhi, for INSA Senior Scientist
position (to H.I).
DEDICATION
■
Dedicated to Professor Lutz F. Tietze on his 70th birthday.
REFERENCES
■
(1) Reviews: (a) Palmer, D. C.; Tayler, E. C. Chemistry of Heterocyclic
Compounds, Oxazoles: Synthesis, Reactions, and Spectroscopy, Part A and
Part B; Wiley and Sons: Hoboken, N.J., 2004; Vol. 60. (b) Yeh, V. S.
C. Tetrahedron 2004, 60, 11995. (c) Wipf, P. Chem. Rev. 1995, 95,
2115. (d) Jin, Z. Nat. Prod. Rep. 2006, 23, 464. (e) Jin, Z. Nat. Prod.
Rep. 2009, 26, 382. (f) Lewis, J. R. Nat. Prod. Rep. 2000, 17, 57 and
earlier reviews in series. (g) Riego, E.; Hernandez, D.; Albericio, F.;
Alvarez, M. Synthesis 2005, 1907.
5-(Benzo[d][1,3]dioxol-5-yl)-2-phenyloxazole (7b) (Texa-
mine).23d Obtained from carboxylic acid 19c, white solid (29 mg,
70%): mp 135−137 °C (lit. 134−136.5 °C);23d Rf 0.6 (1:4
EtOAc:hexane); IR (KBr, cm−1) 2906, 1479, 1231, 1036, 704; 1H
NMR (400 MHz, CDCl3) δ 8.09−8.07 (m, 2H), 7.50−7.45 (m, 3H),
7.31 (s, 1H), 7.24 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.18 (d, J = 1.6 Hz,
1H), 6.89 (d, J = 8.0 Hz, 1H), 6.02 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 160.7, 151.2, 148.2, 147.9, 130.2, 128.8, 127.5, 126.2, 122.4,
122.3, 118.4, 108.9, 104.9, 101.4; HRMS (ESI) m/z calcd for
C16H11NO3 [M + H]+ 266.0817, found 266.0819.
5-(4-Methoxyphenyl)-2-phenyloxazole (8b) (Uguenenazo-
le).34a,b Obtained from carboxylic acid 19a, white solid (30 mg,
70%): mp 134−135 °C (lit. 133−135 °C);34 Rf 0.6 (1:4
EtOAc:hexane); IR (KBr, cm−1) 2957, 2831, 1507, 1255, 1022, 827,
701; 1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 6.2 Hz, 1.2 Hz, 2H),
7.66 (d, J = 8.8 Hz, 2H), 7.51−7.45 (m, 3H), 7.33 (s, 1H), 6.98 (d, J =
8.8 Hz, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.7,
160.0, 151.5, 130.3, 128.9, 127.7, 126.3, 125.9, 121.9, 121.0, 114.6,
55.5; HRMS (ESI) m/z calcd for C16H13NO2 [M + H]+ 252.1025,
found 252.1024.
(2) (a) Atkins, J. M.; Vedejs, E. Org. Lett. 2005, 7, 3351. (b) Zhang,
J.; Ciufolini, M. A. Org. Lett. 2009, 11, 2389. (c) Vedejs, E.; Barda, D.
A. Org. Lett. 2000, 2, 1033.
(3) Bagley, M. C.; Buck, R. T.; Lucy Hind, S.; Moody, C. J. J. Chem.
Soc., Perkin Trans. 1 1998, 591 and references therein.
(4) Misra, N. C.; Ila, H. J. Org. Chem. 2010, 75, 5195 and references
therein.
(5) (a) Kean, W. F. Curr. Med. Res. Opin. 2004, 20, 1275. (b) Desroy,
N.; Moreau, F.; Briet, S.; Le Fralliec, G.; Floquet, S.; Durant, L.;
Vongsouthi, V.; Gerusz, V.; Denis, A.; Escaich, S. Bioorg. Med. Chem.
2009, 17, 276. (c) Bey, E.; Marchais-Oberwinkler, S.; Werth, R.; Negri,
M.; Al-Soud, Y. A.; Kruchten, P.; Oster, A.; Frotscher, M.; Birk, B.;
Hartmann, R. W. J. Med. Chem. 2008, 51, 6725.
(6) (a) Iddon., B. Heterocycles 1994, 37, 1321. (b) Lukavenko, O. N.;
Eltsov, S. V.; Grigorovich, A. V.; Mchedlov-Petrossyan, N. O. J. Mol.
Liq. 2009, 145, 167.
(7) (a) Oxazoles: Boyd, G. V. In Science of Synthesis; Schaumann, E.,
Ed.; George Thieme Verlag; Stuttgart, Germany, 2002; Vol. 11, p 383.
(b) Hartner, F. W. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon
Press: Oxford, U.K., 1996; Vol. 3, p 261. (c) Turchi, I. J.; Dewar, M. J.
S. Chem. Rev. 1975, 75, 389.
(8) Recent papers on oxazole synthesis: (a) Ritson, D. J.; Spiteri, C.;
Moses, J. E. J. Org. Chem. 2011, 76, 3519 and references therein.
(b) Wan, C.; Gao, L.; Wang, Q.; Zhang, J.; Wang, Z. Org. Lett. 2010,
12, 3902 and references therein. (c) Shi, B.; Blake, A. J.; Campbell, I.
B.; Judkins, B. D.; Moody, C. J. Chem. Commun. 2009, 3291. (d) Xie,
H.; Yuan, D.; Ding, M.-W. J. Org. Chem. 2012, 77, 2594. (e) Zhong, C.
L.; Tang, B. Y.; Yin, P.; Chen, Y.; He, L. J. Org. Chem. 2012, 77, 4271.
(f) Austeri, M.; Rix, D.; Zeghida, W.; Lacour, J. Org. Lett. 2011, 13,
1394. (g) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 33, 8482.
(9) Recent papers: (a) Lechel, T.; Gerhard, M.; Trawny, D.;
Brusilowskij, B.; Schefzig, L.; Zimmer, R.; Rabe, J. P.; Lentz, D.;
Schalley, C. A.; Reissig, H.-U. Chem.Eur. J. 2011, 17, 7480 and
references therein. (b) Thompson, M. J.; Adams, H.; Chen, B. J. Org.
Chem. 2009, 74, 3856. (c) Pan, Y.-M.; Zheng, F.-J.; Lin, H.-X.; Zhan,
Z.-P. J. Org. Chem. 2009, 74, 3148. (d) Zhang, J.; Coqueron, P.-Y.;
Vors, J.-P.; Ciufolini, M. A. Org. Lett. 2010, 12, 3942. (e) Sanz-Cervera,
J. F.; Blasco, R.; Piera, J.; Cynamon, M.; Ibanez, I.; Murguia, M.;
Fustero, S. J. Org. Chem. 2009, 74, 8988.
Ethyl 2-phenyl-5-(1-methyl-1H-indol-3-yl)-[4,2′]bisoxazole-
4′-carboxylate (24c). Obtained from 22l, brown solid (33 mg,
70%): mp 214−216 °C; Rf 0.4 (3:7 EtOAc:hexane); IR (KBr, cm−1)
1
2926, 1717, 1577, 1307, 1113, 724; H NMR (400 MHz, CDCl3) δ
9.41 (s, 1H), 8.36−8.35 (m, 1H), 8.34 (s, 1H), 8.25 (br d, J = 6.8 Hz,
2H), 7.57−7.51 (m, 3H), 7.45−7.36 (m, 3H), 4.45 (q, J = 7.2 Hz,
2H), 3.96 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.5, 158.8, 157.7, 150.4, 143.1, 137.2, 134.4, 133.8, 130.7,
129.1, 127.0, 126.6, 125.9, 123.1, 121.6, 121.5, 121.1, 110.1, 103.1,
61.3, 33.8, 14.5; HRMS (ESI) m/z calcd for C24H19N3O4 [M + Na]+
436.1273, found 436.1272.
ASSOCIATED CONTENT
* Supporting Information
■
S
Characterization data, copies of 1H NMR, 13C NMR and
NOESY NMR spectra for all new compounds, stereochemical
assignment of enamide precursors 17a−i, 21a−l and 26a−e.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(10) (a) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R.
Org. Lett. 2000, 2, 1165 and references therein. (b) Murai, K.;
Takahara, Y.; Matsushita, T.; Komatsu, H.; Fujioka, H. Org. Lett. 2010,
12, 3456 and references therein. (c) Ferreira, P. M. T.; Monteiro, L. S.;
AUTHOR INFORMATION
Corresponding Author
*E-mail: hila@jncasr.ac.in.
■
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Pereira, G. Eur. J. Org. Chem. 2008, 4676 and references therein.
(d) Graham, T. H. Org. Lett. 2010, 12, 3614.
(g) Yadav, A. K.; Yadav, S. K.; Ila, H.; Junjappa, H. Synlett 2008, 2674.
(h) Misra, N. C.; Panda, K. J. Org. Chem. 2007, 72, 1246. (i) Yadav, A.
K.; Peruncheralathan, S.; Ila, H.; Junjappa, H. J. Org. Chem. 2007, 72,
1388. (j) Sundaram, G. S. M.; Singh, B.; Venkatesh, C.; Ila, H.;
Junjappa, H. J. Org. Chem. 2007, 72, 5020.
(22) Axelrod, B.; Belzile, J. R. J. Org. Chem. 1958, 23, 919.
(23) (a) Burke, B.; Parkins, H.; Talbot, A. M. Heterocycles 1979, 12,
349. (b) Domínguez, X. A.; Fuente, G. de la.; Gonzalez, A. G.; Reina,
M.; Timon, I. Heterocycles 1988, 27, 35. (c) Rastogi, N.; Abaul, J.; Goh,
K. S.; Devallois, A.; Philogene, E.; Bourgeois, P. FEMS. Immunol. Med.
Microbiol. 1998, 20, 267. (d) Giddens, A. C.; Boshoff, H. I. M.;
Franzblau, S. G.; Barry, C. E., III; Copp, B. R. Tetrahedron Lett. 2005,
46, 7355. (e) Crow, W. D.; Hodgkin, J. H. Tetrahedron Lett. 1963, 2,
85.
(24) (a) Dyer, A. An Introduction to Liquid Scintillation Coupling;
Heydon, London, U.K., 1974; p 12. (b) Krasovitsky, B. M.; Bolotin, B.
M. In Organic Luminiscent Materials; VCH: Weinheim, Germany,
1988. (c) Charier, S.; Ruel, O.; Baudin, J.-B.; Alcor, D.; Allemand, J.-F.;
Meglio, A.; Jullien, L.; Valeur, B. Chem.Eur. J. 2006, 12, 1097.
(d) Clapham, B.; Sutherland, A. J. Chem. Commun. 2003, 84.
(e) McCairn, M. C.; Hine, A. V.; Sutherland, A. J. J. Mater. Chem
2003, 13, 225. (f) Diwu, Z.; Zhang, C.; Klaubert, D. H.; Hougland, R.
P. J. Photochem. Photobiol., A 2000, 131, 95−100.
(25) (a) Joshi, B. S.; Taylor, W. I.; Bhate, D. S.; Karmarkar, S. S.
Tetrahedron 1963, 19, 1437. (b) Koyama, Y.; Yokose, K.; Dolby, L. J.
Agric. Biol. Chem. 1981, 45, 1285. (c) Fresneda, P. M.; Castaneda, M.;
Blug, M.; Molina, P. Synlett 2007, 324 and references therein. (d) Roy,
S.; Haque, S.; Gribble, G. W. Synthesis 2006, 3948. (e) Davies, J. R.;
Kane, P. D.; Moody, C. J.; Slawin, A. M. Z. J. Org. Chem. 2005, 70,
5840 and references therein.
(11) (a) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4, 2905.
(b) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5, 2911.
(c) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2006, 8,
2495. (d) Counceller, C. M.; Eichman, C. C.; Proust, N.; Stambuli, J.
P. Adv. Synth. Catal. 2011, 353, 79. (e) Hoffman, T. J.; Rigby, J. H.;
Arseniyadis, S.; Cossy, J. J. Org. Chem. 2008, 73, 2400. (f) Silva, S.;
Sylla, B.; Suzenet, F.; Tatibouet, A.; Rauter, A. P.; Rollin, P. Org. Lett.
2008, 10, 853.
(12) Direct C−H arylation/alkenylation: (a) Besselievre, F.; Piguel,
S.; Mahuteau-Betzer, F.; Grierson, D. S. Org. Lett. 2008, 10, 4029.
(b) Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2008, 10,
2717. (c) Ackermann, L.; Barfusser, S.; Pospech, J. Org. Lett. 2010, 12,
724. (d) Besselivre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553.
(e) Cui, S.; Wojtas, L.; Antilla, J. C. Org. Lett. 2011, 13, 5040. (f) Yang,
F.; Xu, Z.; Wang, Z.; Yu, Z.; Wang, R. Chem.Eur. J. 2011, 17, 6321.
(g) Makida, Y.; Ohmiya, H.; Sawamura, M. Angew. Chem., Int. Ed.
2012, 51, 4122. (h) Ackermann, L.; Kornhaass, C.; Zhu, Y. Org. Lett.
2012, 14, 1824. (i) Verrier, C.; Fiol-Petit, C.; Hoarau, C.; Marsais, F.
Org. Biomol. Chem. 2011, 9, 6215. Metalation: (j) Williams, D. R.; Fu,
L. Org. Lett. 2010, 12, 808 and references therein. (k) Vedejs, E.;
Luchetta., L. M. J. Org. Chem. 1999, 64, 1011. (l) Lee, K.; Counceller,
C. M.; Stambuli, J. P. Org. Lett. 2009, 11, 1457. (m) Pippel, D. J.;
Mapes, C. M.; Mani, N. S. J. Org. Chem. 2007, 72, 5828.
(13) (a) Schuh, K.; Glorius, F. Synthesis. 2007, 2297. (b) Martin, R.;
Cuenca, A.; Buchwald, S. L. Org. Lett. 2007, 9, 5521. (c) Cheung, C.
W.; Buchwald, S. L. J. Org. Chem. 2012, 77, 7526. (d) Ferreira, P. M.
T.; Castanheira, E. M. S.; Monteiro, L. S.; Pereira, G.; Vilaca
̧ , H.
Tetrahedron 2010, 66, 8672.
(14) Recent papers: (a) Paradise, C. L.; Sarkar, P. R.; Razzak, M.; De
Brabander, J. K. Org. Biomol. Chem. 2011, 9, 4017. (b) Hashmi, A. S.
K. Angew. Chem., Int. Ed. 2010, 49, 5232. (c) Hashmi, A. S. K.;
Schuster, A. M.; Rominger, F. Angew. Chem., Int. Ed. 2009, 48, 8247.
(d) Meng, X.; Kim, S. Org. Biomol. Chem. 2011, 9, 4429. (e) Weyrauch,
J. P.; Hashmi, A. S. K.; Schuster, A.; Hengst, T.; Schetter, S.; Littmann,
A.; Rudolph, M.; Hamzic, M.; Visus, J.; Rominger, F.; Frey, W.; Bats, J.
W. Chem.Eur. J. 2010, 16, 956 and references therein. (f) Merkul,
E.; Muller, T. J. J. Chem. Commun. 2006, 4817.
(15) Shi, B.; Blake, A. J.; Lewis, W.; Campbell, I. B.; Judkins, B. D.;
Moody, C. J. J. Org. Chem. 2010, 75, 152 and references therein.
(16) (a) Wan, C.; Zhang, J.; Wang, S.; Fan, J.; Wang, Z. Org. Lett.
2010, 12, 2338. (b) Jiang, H.; Huang, H.; Cao, H.; Qi, C. Org. Lett.
2010, 12, 5561.
(17) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Smith, C. D.;
Tranmer, G. K. Org. Lett. 2006, 8, 5231. (b) Li, Y.; Xu, X.; Tan, J.; Xia,
C.; Zhang, D.; Liu, Q. J. Am. Chem. Soc. 2011, 133, 1775. (c) Mossetti,
R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2010, 12, 820.
(18) (a) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew. Chem.
2011, 123, 9093. (b) Cano, I.; Alvarez, E.; Carmen Nicasio, M.; Perez,
P. J. J. Am. Chem. Soc. 2011, 133, 191. (c) Pace, A.; Pierro, P.; Buscemi,
S.; Vivona, N.; Barone, G. J. Org. Chem. 2009, 74, 351. (d) Elders, N.;
Ruijter, E.; de Kanter, F. J. J.; Groen, M. B.; Orru, R. V. A. Chem.
Eur. J. 2008, 14, 4961.
(26) (a) Takahashi, S.; Matsunaga, T.; Hasegawa, C.; Saito, H.;
Fujita, D.; Kiuchi, F.; Tsuda, Y. Chem. Pharm. Bull. 1998, 46, 1527.
(b) Nishida, A.; Fuwa, M.; Fujikawa, Y.; Nakahata, E.; Furuno, A.;
Nakagawa, M. Tetrahedron Lett. 1998, 39, 5983. (c) Lindquist, N.;
Fenical, W.; Van Duyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1991, 113,
2303.
(27) For stereochemical assignment of open-chain enamide
precursors 17a−i, 21a−l, 26a−e, kindly see the discussion in the
Supporting Information.
(28) Recent reviews: Cu-catalyzed C−N bond formation: (a) Be-
letskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337.
(b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(c) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. Monnier, F.;
Taillefer, M. Angew Chem. Int. Ed. 2009, 48, 6954. (d) Surry, D. S.;
Buchwald, S. L. Chem. Sci. 2010, 1, 13 and references therein.
(29) Recent reviews: heterocycles synthesis by Cu-catalyzed C−N
bond formation reactions: (a) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054. (b) Hassan, J.; Sevignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (c) Chemler, S.
R.; Fuller, P. H. Chem. Soc. Rev. 2007, 36, 1153. (d) Liu, Y.; Wan, J.-P.
Org. Biomol. Chem. 2011, 9, 6873 and references therein. (e) Monnier,
F.; Taillefer, M. Angew. Chem., Int. Ed. 2008, 47, 3096. (f) Carril, M.;
SanMartin, R.; Dominguez, E. Chem. Soc. Rev. 2008, 37, 639.
(30) Recent papers on Cu-catalyzed heterocycles synthesis:
(a) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R.
C. Angew. Chem., Int. Ed. 2009, 48, 1138. (b) Feng, E.; Huang, H.;
Zhou, Y.; Ye, D.; Jiang, H.; Liu, H. J. Comb. Chem. 2010, 12, 422.
(c) Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749. (d) Li, Z.; Sun,
H.; Jiang, H.; Liu, H. Org. Lett. 2008, 10, 3263. (e) Malakar, C. C.;
Schmidt, D.; Conrad, J.; Beifuss, U. Org. Lett. 2011, 13, 1972. (f) Liao,
Q.; Zhang, L. Y.; Li, S.; Xi, C. J. Org. Lett. 2011, 13, 228. (g) Ma, D.
W.; Lu, X.; Shi, L.; Zhang, H.; Jiang, Y. W.; Liu, X. Q. Angew. Chem.,
Int. Ed. 2011, 50, 1118. (h) Cai, Q.; Zhou, F.; Xu, T.; Fu, L.; Ding, K.
Org. Lett. 2011, 13, 340. (i) Diao, X.; Xu, L.; Zhu, W.; Jiang, Y.; Wang,
H.; Guo, Y.; Ma, D. Org. Lett. 2011, 13, 6422. (j) Ueda, S.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2012, 51, 1. (k) Xu, L.; Jiang, y.; Ma, D.
Org. Lett. 2012, 14, 1150. (l) Murata, T.; Murai, M.; Ikeda, Y.; Miki,
K.; Ohe, K. Org. Lett. 2012, 14, 2296. (m) Jishkariani, D.; Dennis Hall,
(19) Amareshwar, V.; Misra, N. C.; Ila, H. Org. Biomol. Chem. 2011,
9, 5793.
(20) (a) Shin, C.-G.; Sato, Y.; Sugiyama, H.; Nanjo, K.; Yoshimura, J.
Bull. Chem. Soc. Jpn. 1977, 50, 1788. (b) Chattopadhyay, S. K.;
Kempson, J.; McNeil, A.; Pattenden, G.; Reader, M.; Rippon, D. E.;
Waite, D. J. Chem. Soc., Perkin Trans. 1 2000, 2415. (c) Das, J.; Reid, J.
A.; Kronenthal, D. R.; Singh, J.; Pansegrau, P. D.; Mueller, R. H.
Tetrahedron Lett. 1992, 33, 7835.
(21) Recent papers: (a) Singh, P. P.; Yadav, A. K.; Junjappa, H.; Ila,
H. Eur. J. Org. Chem. 2011, 4001. (b) Khan, T. A.; Kumar, S.;
Venkatesh, C.; Ila, H. Tetrahedron 2011, 67, 2961. (c) Yadav, A. K.;
Junjappa, H.; Ila, H. Eur. J. Org. Chem. 2010, 338. (d) Singh, P. P.;
Yadav, A. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2009, 50, 366.
(e) Kumar, S.; Ila, H. J. Org. Chem. 2009, 74, 7046. (f) Kumar, S.;
Peruncheralathan; Ila, H.; Junjappa, H. Org. Lett. 2008, 10, 965.
10762
dx.doi.org/10.1021/jo3021192 | J. Org. Chem. 2012, 77, 10752−10763

The Journal of Organic Chemistry
Article
C.; Oliferenko, A. A.; Leino, D.; Katritzky, A. R. J. Org. Chem. 2012,
77, 5813.
(31) Wendlandt, A. E.; Stahl, S. S. Org. Biomol. Chem. 2012, 10, 3866.
(32) Verrier, C.; Martin, T.; Hoarau, C.; Marsais, F. J. Org. Chem.
2008, 73, 7383.
(33) For other syntheses of 2,5-di(hetero)aryl oxazoles and related
natural products, see: (a) Besselievre, F.; Mahuteau-Betzer, F.;
Grierson, D. S.; Piguel, S. J. Org. Chem. 2008, 73, 3278. (b) Muto,
K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 169.
(c) Sengupta, S.; Mondal, S. Tetrahedron Lett. 1999, 40, 8685.
(d) Yoshizumi, T.; Satoh, T.; Hirano, K.; Matsuo, D.; Orita, A.; Otera,
J.; Miura, M. Tetrahedron Lett. 2009, 50, 3273.
(34) (a) Isolation: Cheplogoi, P. K.; Mulholland, D. A.; Coombes, P.
H.; Randrianarivelojosia., M. Phytochemistry 2008, 69, 1384. (b)
Synthesis: Besselievre, F.; Lebrequier, S.; Mahuteau-Betzer, F.; Piguel,
S. Synthesis 2009, 3511.
(35) Ashare, R.; Roy, J.; Mukerjee, A. K. Heterocycles 1986, 24, 1325.
10763
dx.doi.org/10.1021/jo3021192 | J. Org. Chem. 2012, 77, 10752−10763