Synthesis of 2,4,5-Trisubstituted Oxazoles with Complementary Regioselectivity from α-Oxoketene Dithioacetals and β-(Methylthio)-β-(het)aryl-2-propenones

Article abstract of DOI:10.1021/acs.joc.8b00900

An efficient protocol for the synthesis of 2,5-substituted 4-acyloxazoles and the related 2,4-substituted 5-acyloxazoles with complementary regioselectivity from the corresponding α-oxoketene dithioacetals or β-(het)aryl/(methylthio)enone precursors has been reported. In the first protocol, the α-oxoketene dithioacetals or β-(methylthio)enones were converted to the corresponding α-bromo-β-(methylthio)enones followed by copper catalyzed inter/intramolecular annulation of these intermediates with various primary amides affording 2-(het)aryl/alkyl-4-(het)aroyl-5-(methylthio)/(het)aryloxazoles via concomitant formation of the C4-N and C5-O bond via enamide intermediates. In the second approach, the starting α-oxoketene dithioacetals or β-(methylthio)-β-(het)arylenones were subjected to base induced conjugate addition-elimination with various primary amides to furnish β-aroylenamides, which, on subsequent iodine catalyzed intramolecular oxidative C-H functionalization/C-O bond formation, afforded the corresponding regioisomeric 2-(het)aryl/alkyl-4-(methylthio)/(het)aryl-5-(het)aroyloxazoles in excellent yields. The methodology has also been extended for the synthesis of regioisomeric 4- or 5-aminooxazoles and 4- or 5-(n-butyl)oxazoles from the corresponding 4- or 5-(methylthio)oxazoles.

Full text of DOI:10.1021/acs.joc.8b00900

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Article
Synthesis of 2,4,5-Trisubstituted Oxazoles with
Complementary Regioselectivity from #-Oxoketene
Dithioacetals and #-(Methylthio)-#-(het)aryl-2-propenones
Siripuram Vijay Kumar, Anand Acharya, and Hiriyakkanavar Ila
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00900 • Publication Date (Web): 10 May 2018
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Synthesis of 2,4,5-Trisubstituted Oxazoles with Complementary
Regioselectivity from α-Oxoketene Dithioacetals and β-
(Methylthio)-β-(het)aryl-2-propenones
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Siripuram Vijay Kumar,§ Anand Acharya,§ Hiriyakkanavar Ila*
New Chemistry Unit,
Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR)
Jakkur, Bangaloreꢀ560064
India
Corresponding Email: hila@jncasr.ac.in
§These authors contributed equally to this work
1. NBS/CCl4, rt
alk/(Het)Ar
O
1.
O
O
O
NH2
2.
H2N
(Het)Ar
(Het)Ar
O
N
(Het)Ar
(Het)Ar/MeS
O
(Het)Ar
(Het)Ar/MeS
base
N
(Het)Ar
CuI (10 mol%)
SMe/Het(Ar)
SMe
2. I2 (20 mol%)
TBHP (1 equiv.)
dioxane, 90 °C
alk/(Het)Ar
O
DMEDA (20 mol%)
Cs2CO3 (2 equiv.)
toluene, 100 °C
ABSTRACT
An efficient protocol for the synthesis of 2,5ꢀsubstituted 4ꢀacyloxazoles and the
related 2,4ꢀsubstituted 5ꢀacyloxazoles with complementary regioselectivity from the
corresponding αꢀoxoketene dithioacetals or βꢀ(het)aryl/(methylthio)enone precursors has
been reported. In the first protocol, the αꢀoxoketene dithioacetals or βꢀ(methylthio)enones
were converted to the corresponding αꢀbromoꢀβꢀ(methylthio)enones followed by copper
catalyzed inter/intramolecular annulation of these intermediates with various primary amides
affording 2ꢀ(het)aryl/alkylꢀ4ꢀ(het)aroylꢀ5ꢀ(methylthio)/(het)aryloxazoles via concomitant
formation of C4ꢀN and C5ꢀO bond via enamide intermediates. In the second approach, the
starting αꢀoxoketene dithioacetals or βꢀ(methylthio)ꢀβꢀ(het)arylenones were subjected to base
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induced conjugate additionꢀelimination with various primary amides to furnish βꢀ
aroylenamides, which, on subsequent iodine catalyzed intramolecular oxidative CꢀH
functionalization/CꢀO bond formation, afforded the corresponding regioisomeric 2ꢀ
(het)aryl/alkylꢀ4ꢀ(methylthio)/(het)arylꢀ5ꢀ(het)aroyloxazoles in excellent yields. The
methodology has also been extended for the synthesis of regioisomeric4ꢀ (or 5ꢀ
)aminooxazoles and 4ꢀ (or 5ꢀ)ꢀ(nꢀbutyl)oxazoles from the corresponding 4ꢀ (or 5ꢀ
)(methylthio)oxazoles.
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INTRODUCTION
Oxazole heterocycle represents an important structural motif, which constitutes key
substructure of several potent therapeutics and biologically active naturally occurring
compounds,1 isolated from marine invertebrates and microorganisms.2 Many of the oxazole
derivatives display antibacterial, antifungal, antiꢀinflammatory and antitumor activities and
act as enzyme inhibitors and peptidomimetics and represent valuable synthetic targets in
medicinal chemistry and pharmaceuticals.3 Oxazole derivatives have also found applications
in functional materials,4 as efficient luminophores for liquids and plastic scintillators,
fluorescent probes for biological systems, corrosion inhibitors, components of laser dyes,
sensors, receptors, polymers and ligands for catalysis.5 This has generated considerable
interest in the synthesis of this class of heterocycles in recent years with development of
several efficient synthetic methods.6ꢀ21
The classical methods for oxazole synthesis, include cyclization of acyclic
precursors,6 transition metal catalyzed coupling of prefunctionalized oxazoles6 and
dehydrogenation/dehydroelimination of oxazolines.6,7 Cyclization approaches are much more
effective due to diversity of the substrates, among which, RobinsonꢀGabriel condensation
using αꢀacylaminoketones and its modified versions,3a,6,8 have been frequently utilized earlier
to prepare a range of highly substituted oxazoles. However, this method requires the use of
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Bronsted or Lewis acid catalysts/reagents, which limits overall functional group tolerance of
the transformation. The other previously reported syntheses include the Cornforth protocol9
improved by Yokoyama,10 catalytic decomposition of diazocarbonyl compounds in presence
of nitriles or amides,11 photolysis and pyrolysis of Nꢀacylisoxazolones.6 Among recently
reported methods, oxidative or photocatalytic [3+2] annulations of benzylamines with
prefunctionalized ketones/esters, have been well studied as straightforward procedures.12
Other recent examples include cycloaddition of activated methylene isocyanoacetates with αꢀ
ketoacids/esters,13aꢀecatalytic enantioselective αꢀaddition of isocyanides to alkylidene
malonate,13f Pd catalyzed imidoylative cyclization of αꢀisocyanoacetamides,14 Cu(I)
catalyzed cycloaddition of acyl azide with 1ꢀalkynes,15 gold catalyzed three component
annulations of benzylimines,16 tandem azaꢀWittig reaction of acyl chloride and
vinyliminophosphoranes,17 gold catalyzed formal [3+2] cycloadditions of Nꢀylides,18 or
dioxazoles,19a or Nꢀ(pivalolyloxy)amides19b with alkynes, catalytic asymmetric carbonylꢀene
reaction of β,γꢀunsaturated αꢀketoesters with 5ꢀmethyleneoxazolines,19c photoredox catalyzed
three component cyclization of 2Hꢀazirines,19d methods based on cyclizationꢀ isomerization
of propargylamides,20 oxidative annulations of enaminoesters/ketones or amides in presence
of hypervalent iodine reagents,21 oxidative [2+2+1] cycloannulation of alkynes and
nitriles,22aꢀecopper mediated oxidative dehydrogenative annulations of aldehydes, amines and
molecular oxygen.22f
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Among the various methods for oxazole synthesis, cyclization of enamide derivatives
provides a facile access to oxazoles through intramolecular carbonꢀoxygen bond formation.
These enamide precursors are generated in several ways. For example, enamides bearing the
βꢀvinylic Cꢀheteroatom bonds (CꢀBr, CꢀI, CꢀOMe) serve as stable, easily accessible starting
materials, which are shown to undergo intramolecular cyclization in the presence of various
organic or inorganic bases or acids to provide a broad range of oxazoles under milder
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conditions6,.23ꢀ24 Thus, Ferreira and coworkers23aꢀb have reported synthesis of βꢀhaloenamides
via sequential dehydration of Nꢀacylꢀβꢀhydroxy amino acids and subsequent halogenations
with NBS or iodine, followed by treatment with DBU to afford 2,5ꢀdisubstituted oxazoleꢀ4ꢀ
carboxylates (Scheme 1, route a). On the other hand, Reissig25 has described synthesis of 2,4ꢀ
disubstituted 5ꢀacetyloxazoles via TFA mediated cyclization of βꢀalkoxyꢀβꢀketoenamides
(Scheme 1, route b).
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Enamides have also been generated by copper catalyzed amidation of vinyl halides.
Thus, Buchwald and coꢀworkers26 have reported synthesis of 2,4,5ꢀtrisubstituted oxazoles via
copper catalyzed amidation of vinyl halides to form enamides followed by intramolecular
cyclization promoted by iodine (Scheme 1, route c). Glorious and coꢀworkers have developed
synthesis of disubstituted oxazoles via copper catalyzed annulations of 1,2ꢀdibromoolefins
with primary amides via intermediacy of βꢀbromoenamides (Scheme 1, route d).27 However
the reaction affords mixture of 2,4ꢀ and 2,5ꢀsubstituted oxazoles.
Recently, few examples of transition metal catalyzed methods for the direct
intramolecular vinylic CꢀH functionalization/CꢀO bond formation of enamides have also
been described.28 Thus, Buchwald has reported28a a copper(II) catalyzed oxidative cyclization
of enamides to 2,5ꢀdisubstituted oxazoles, via vinylic CꢀH bond functionalization (Scheme 1,
route e) as complement to previous work.26 Stahl and coworkers28b have recently described
the synthesis of a series of enamide intermediates prepared via Ruꢀcatalyzed antiꢀMarkonikov
hydroamidation of alkynes with amide. These enamides were subsequently converted to 2,5ꢀ
disubstituted oxazoles via Cu(II) mediated oxidative cyclization in presence of air (Scheme 1,
route f). Recently Jiang and coꢀworkers have developed an efficient one step synthesis of
trisubstituted oxazoles from amides and enolizable βꢀdiketones involving palladium catalyzed
sequential interꢀ and intramolecular CꢀN and CꢀO bond formation via oxidative sp2 CꢀH
functionalizaition (Scheme 1, route g).28c Synthesis of 2,5ꢀsubstituted oxazoles from Nꢀ
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arylethylamides via iodine catalyzed intramolecular C(sp3)ꢀH functionalization has also been
reported (Scheme 1, route h).28d Substituted oxazoles have also been obtained via
hypervalent iodine reagents mediated intramolecular oxidative cyclization of enamides.28f
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Scheme 1. Various strategies for the synthesis of enamides and their conversion to oxazoles
In this context, as part of our programme to develop new synthetic methods for the
construction of a broad range of heterocycles, from organosulfur building blocks,29 our
research group has recently reported an efficient protocol for the synthesis of 2ꢀphenylꢀ5ꢀ
(methylthio)ꢀ4ꢀfunctionalized oxazoles
3
via nucleophilic ring opening of 4ꢀ
[(bismethylthio)methylene]ꢀ5ꢀoxazolones 1A followed by silver carbonate mediated
intramolecular 5ꢀendo cyclization of the resulting functionalized enamides 2A (Scheme 2, eq.
1).6a We have further elaborated the synthetic scope of this strategy by developing an
efficient synthesis of 2ꢀphenylꢀ5ꢀ(het)arylꢀ4ꢀfunctionalized oxazoles 4 and related natural
products via nucleophilic ring opening of 4ꢀarylideneꢀ5ꢀoxazolones 1B and subsequent
copper catalyzed intramolecular cyclization of enamide precursors 2B (Scheme 2, eq. 2).6b
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Scheme 2. Previous syntheses of substituted oxazoles from enamide precursors
During the course of these studies, we became interested in developing a [3+2]
annulation approach for the synthesis of 2,4,5ꢀtrisubstituted oxazoles 5 and 6, with
complementary regioselectivity from the common two carbon precursors such as αꢀoxoketene
dithioacetals 7A30a or the corresponding βꢀ(methylthio)ꢀβꢀ(het)arylenones 7B29h and a
primary amides 8 via intermediacy of enamides 9 and 11 respectively (Scheme 3). Our
proposed strategy for the synthesis of oxazoles 5 and 6 from 7A or 7B is shown in the
Scheme 3. Thus, it was envisaged to synthesize 4ꢀacylꢀ5ꢀ(het)aryloxazoles 5 via copper
catalyzed cross coupling of various primary amides with 2ꢀbromoalkenes such as 10
(generated by 2ꢀbromination of 7 with Nꢀbromosuccinimide) and subsequent base mediated
intramolecular cyclization of the resulting enamides9 (Scheme 3). In continuation of these
studies, we further conceived of developing synthesis of regioisomeric 5ꢀacylꢀ4ꢀ
(het)aryloxazoles 6 from the same βꢀ(methylthio)enone precursors 7A and 7B as shown in
Scheme 3. We speculated a twoꢀstep approach via base mediated conjugate additionꢀ
elimination of primary amides to βꢀ(methylthio)enones 7 furnishing the corresponding
enamide precursors 11. Subsequent intramolecular cyclization of 11 through oxidative vinylic
CꢀH functionalization/CꢀO bond formation28 would provide the desiredregioisomeric 5ꢀ
acyloxazoles 6 (Scheme 3). We have successfully achieved these goals and describe in the
present paper, efficient syntheses of 2,4,5ꢀtrisubstituted oxazoles 5 and 6 with complementary
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regioselectivity from easily accessible common βꢀ(methylthio)enone precursors 7A and 7B
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and primary amides.
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Scheme 3. Present strategy for the synthesis of regioisomeric oxazoles 5 and 6
RESULTS AND DISCUSSION
The desired αꢀoxoketene dithioacetal/βꢀ(methylthio)ꢀβꢀ(het)arylenone precursors 7a-l
were prepared according to our earlier reported procedures in excellent yields by reacting
various (het)arylmethylene ketones 12 with either CS2 (for 7a-e)30a or dithioesters 13 (for 7f-
l)29f in the presence of sodium hydride in DMF followed by alkylation with methyl iodide.
The corresponding αꢀbromoketene dithioacetals (10a-e) and αꢀbromoꢀβꢀ(methylthio)ꢀβꢀ
(het)arylenones (10f-l) were obtained in good yields by bromination of 7a-l with NBS in
CCl4 at room temperature according to our previously reported procedure (Scheme 4 and
Table 1).30b
Scheme 4. Synthesis of βꢀ(methylthio)enones 7a-l and αꢀbromoꢀβꢀ(methylthio)enones 10a-l
In the preliminary experiments, αꢀbromoketene dithioacetal 10a and the amide 8a
were selected as model substrates for optimization of reaction conditions for the formation of
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oxazole 5a.Screening of various copper catalysts (CuCl, CuBr, CuI, Cu2O, Cu powder),
ligands (Lꢀproline, 1,10ꢀphenanthroline, N, N’ꢀdimethylethylenediamine) and bases (Cs2CO3,
K2CO3, K3PO4) in the presence of various solvents (toluene, dioxane, DMF, DMSO) revealed
that the best results were obtained using 10 mol% of CuI as catalyst and 20 mol% of
DMEDA as ligand in the presence of 2 equiv. of Cs2CO3 as a base in refluxing toluene,
furnishing the desired 2ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(4ꢀmethoxybenzoyl)ꢀ5ꢀ(methylthio)oxazole 5a
in 90% yield (Scheme5). As is evident from these results, the reaction appears to proceed by
initial copper catalyzed intermolecular crossꢀcoupling of αꢀbromoenone 10a and the amide 8a
to give intermediate enamide 9a,which undergoes, in situ, base mediated intramolecular
cyclization yielding oxazole 5a in a twoꢀstep, oneꢀpot process (Scheme 5). However, our
attempts to isolate enamide 9a under varying reaction conditions were not successful.
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Scheme 5. Synthesis of oxazole 5a from αꢀbromoenone 10a and amide 8a
With the established optimized reaction conditions in hand, we next evaluated the
generality and scope of this reaction with respect to a range of substrates 10 and amides 8,
these results are presented in Table 1. Thus, the reaction was found to be equally efficient
with other αꢀaroyl (10b), (het)aroyl (10c) and ferrocenoyl (10d) ketene dithioacetals, which
afforded the respective 2ꢀaryl/alkylꢀ4ꢀacylꢀ5ꢀ(methylthio)oxazoles 5b-d in excellent yields on
copper catalyzed annulations with various substituted aromatic and aliphatic amides 8b-d
(Table 1,entries 2ꢀ4). Similarly, the reaction was found to be equally effective with various 2ꢀ
bromoꢀ3ꢀ(methylthio)ꢀ3ꢀ(het)arylenones 10f-k affording the corresponding 2,5ꢀbis(het)arylꢀ
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4ꢀ(het)aroyloxazoles 5f-k in excellent yields on cyclization with various primary amides 8fꢀk
under identical conditions (entries 6ꢀ11, Table 1). Entries 5 and 7 represent introduction of a
sterically incumbent pivaloyl and pyrenoyl groups at 4ꢀposition of oxazoles 5e and 5g
respectively. Similarly it was possible to introduce a 2ꢀalkylꢀ and 2ꢀstyryl group in oxazoles
5l-m by using an aliphatic amide like propionamide 8l and cinnamamide 8m respectively as
cyclization partners (Table 1, entries 12ꢀ13). On the other hand, cyclization of 10i with
benzyl carbamate 8n did not furnish the expected 2ꢀbenzyloxyoxazole 5n, the product
isolated was characterized as 2ꢀhydroxyoxazole 5n’ which is apparently formed by cleavage
of benzyl group under the reaction conditions (Table 1, entry 14).
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Table 1. Synthesis of 2ꢀ(het)aryl/alkylꢀ4ꢀacylꢀ5ꢀ(methylthio)/(het)aryloxazoles 5a-n from
10a-l
NH2
O
(Het)Ar/alk
8
O
O
O
H
N
CuI (10 mol%),
Cs2CO3 (2 equiv)
(Het)Ar
Br
(Het)Ar/alk
N
(Het)Ar
(Het)Ar
MeS
O
DMEDA (20 mol%)
Toluene, 100 °C, 3-8h
(Het)Ar/MeS
(Het)Ar/al
k
MeS
SMe/Het(Ar)
SMe/Het(Ar)
O
9
5
10
entry
10
8
5
yield (%)
O
O
NH2
MeO
Br
N
1
2
3
90
O
MeS
O
MeO
MeS
10a
SMe
OMe
OMe
8a
5a
O
O
O
NH2
O
Br
SMe
O
O
90
83
N
O
MeS
5b
MeS
10b
O
8b
O
O
NH2
Br
O
N
O
O
MeS
O
MeS
10c
SMe
Br
8c
5c
O
O
NH2
CF3
Fe
MeS
N
4
81
CF3
O
Fe
O
SMe
MeS
10d
8d
5d
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O
O
NH2
O
Br
N
5
6
80
88
MeS
O
MeS
SMe
Cl
Cl
10e
8e
5e
O
O
NH2 Cl
Br
O
Cl
N
O
O
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MeS
O
MeO
MeO
10f
SMe
8f
OMe
5f
O
OMe
OMe
O
NH2
Br
7
8
83
85
O
N
OMe
F
O
F
MeO
10g
8g
5g
MeO
O
O
N
Br
N
N
S
O
O
O
S
S
O
MeS
O
NH2
8h
S
10h
O
5h
O
O
O
Br
O
O
NH2
O
N
9
70
85
O
MeS
Me
O
5i
Me
Br
N
Br
N
10i
O
8i
NH2
Me
Me
F3C
O
Br
N
10
O
O
F3C
MeS
10j
O
O
MeO
O
8j
5j
OMe
N
O
O
Br
NH2
N
N
11
12
90
82
MeS
O
S
S
N
N
10k
8k
5k
5l
Me
Me
O
O
Br
NH2
NC
N
O
NC
N
MeS
O
10l
8l
N
N
N
O
Br
NH2
O
13
79
N
MeS
Ph
O
Ph
N
O
5m
N
10k
8m
Me
Me
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O
O
O
Br
O
O
O
NH2
N
14
MeS
Ph
O
O
OR
Me
O
Me
N
N
10i
10
8n
Me 5n
0
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, R = CH2Ph
5n', R = H
Me
8
(1.0 mmol), (1.1 mmol), Cs2CO3 (2 mmol), CuI (0.1 mmol) and DMEDA (0.2 mmol) in
Reaction conditions:
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toluene (5 mL) heated at 100 °C for 3-4 h.
The structures of these newly synthesized oxazoles 5a-n’were confirmed with the
help of spectral (1H and 13C NMR) and analytical data, besides regiochemistry was further
confirmed by Xꢀray crystallographic data of two of the oxazoles 5e and 5j (Supplementary
information).
Figure 1. ORTEP XꢀRay crystal structure display of 5e; ellipsoids drawn at 50% probability
level
Having successfully accomplished the synthesis of 2ꢀ(het)aryl/alkylꢀ5ꢀ
(methylthio)/(het)arylꢀ4ꢀacyloxazoles 5a-l (Table 1), we further conceived of synthesizing the
substituted 5ꢀacyloxazoles 6 with complementary regiochemistry at 4,5ꢀpositions (Scheme 3).
In a model experiment as proposed in Scheme 3, we first examined the synthesis of αꢀ
(methylthio)ꢀβꢀaroylenamide 11a via base mediated conjugate additionꢀelimination of
primary amide 8a on ketene dithioacetal 7a (Scheme 6). Thus, treatment of 7a with 8a in the
presence of NaH as base in DMF at 90 °C afforded the corresponding enamide 11a in 87%
yield (Scheme 6). Subsequent intramolecular oxidative CꢀH functionalization/CꢀO bond
formation of enamide 11a was attempted in presence of various iodine based reagents (I2,
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PIDA, PIFA, DMP)28dꢀi or copper catalysts(CuBr2, CuCl2, Cu(OAc)2, Cu(OTf)2).28aꢀb The best
results were obtained, when enamide 11a was reacted with 20 mol% of iodine in presence of
tꢀbutylhydroperoxide (TBHP) (1 equiv) as reoxidant28d in dioxane at 90 °C furnishing the
regioisomeric 2ꢀ(4ꢀmethoxyphenyl)ꢀ4ꢀ(methylthio)ꢀ5ꢀ(4ꢀmethoxybenzoyl) oxazole 6a in 85%
yield (Scheme 6).
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Scheme 6. Synthesis of regioisomeric 4ꢀ(methylthio)ꢀ5ꢀacyloxazole 6a from αꢀ
oxoketenedithioacetal 7a and amide 8a via enamide precursor 11a
The versatility of this novel protocol was established by synthesizing the other
regioisomeric 4ꢀ(methylthio)ꢀ5ꢀ(het)aroyloxazoles 6b-e (Table 2, entries 2ꢀ5) in excellent
yields by employing appropriate oxoketenedithioacetals 7b-e and amides 8b-e. The oxidative
CꢀH functionalization/CꢀO bond formation reaction proceeded efficiently, even, when the
crude enamides 11b-c were used without further purification, yielding the corresponding
oxazoles 6b-c in good yields (Table 2, entries 2ꢀ3). Similarly, the corresponding 2,4ꢀ
bis(het)arylꢀ5ꢀacyloxazoles 6f-k with complementary regioselectivity were also obtained in
excellent yields by iodine catalyzed intramolecular CꢀH functionalization/CꢀO bond
formation of enamides 11f-k (obtained from βꢀmethylthioꢀβꢀ(het)arylenones 7f-k and amides
8f-k) (Table 2, entries 6ꢀ11).
Table 2. Synthesis 2ꢀ(het)aryl/alkylꢀ4ꢀ(methylthio)/(het)arylꢀ5ꢀacyloxazoles 6a-k from 7a-k
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9
O
O
O
O
O
N
F3C
O
10
88
8j
O
F3C
N
H
F3C
MeS
OMe
MeO
N
MeO
7j
11j, 73%
6j
O
O
O
N
O
N
S
O
N
S
11
8k
92
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N
H
Me
MeS
N
Me
N
N
Me
7k
11k
, 75%
6k
o
7
8
11
Reaction conditions: (1.0 mmol), (1.1 mmol) and NaH (2.2 mmol) in DMF was heated at 90 C for 3-8 h and worked up;
(1.0
mmol), I2 (0.2 mmol) and TBHP (1.0 mmol) in dioxane heated at 90 oC for 8-10 h; enamides
without further purification were
a
11
used for I2 catalyzed intramolecular cyclization
The structure and regiochemistry of newly synthesized 2,4,5ꢀtrisubstituted oxazoles
6aꢀk were confirmed with the help of the spectral and analytical data and also by Xꢀray
crystallographic data of two of the regioisomeric oxazoles 6e and 6j (supplementary
information).
Figure 2. ORTEP XꢀRay crystal structure display of 6e; ellipsoids drawn at 50% probability
level
However we failed to obtain the corresponding 2ꢀethylꢀ, 2ꢀstyrylꢀ or 2ꢀ
hydroxyoxazoles 6lꢀn,since the base mediated addition of propionamide 8l, cinnamamide 8m
or benzyl carbamate 8n to βꢀ(methylthio)enones 7l, 7k and 7i respectively under previously
reported conditions, did not afford the desired enamides 11l-n yielding only intractable
reaction mixture ( Scheme 7).
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Scheme 7. Attempted synthesis of 2ꢀalkyl/styryl/hydroxyoxazoles6l-n
The versatility of this new methodology was further demonstrated by synthesis of
regioisomeric 5ꢀ(or 4ꢀ) amino substituted oxazole 15 and 17 as shown in the Scheme 8.Thus,
the oxidation of 5ꢀ (or 4ꢀ)ꢀ(methylthio)oxazoles 5c and 6c with mꢀCPBA in CH2Cl2 afforded
the corresponding 5ꢀ (or 4)ꢀ(methylsulfonyl)oxazoles 14c and 16c in high yields, which were
subjected to displacement reaction by either primary alkylamine such as (3,4ꢀ
dimethoxyphenyl)ethyl amine or secondary amine like Nꢀbenzylpiperazine, at room
temperature, furnishing the corresponding 5ꢀ (or 4ꢀ) primary or secondary amino substituted
oxazoles 15a-b and 17a-b respectively in excellent yields (Scheme 8).
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Scheme 8. Synthesis of 4ꢀ (or 5ꢀ)primary and secondary amino substituted oxazoles
In a further elaboration of the reaction, the 4/5ꢀ (methylthio) groups in the oxazoles 5a
or 6a were replaced by nꢀbutyl group on treatment with nꢀbutylmagnesium bromide in the
presence of copper(I) bromide, yielding the corresponding regioisomeric 4ꢀ (or 5)ꢀ(nꢀbutyl)
substituted oxazoles 18a and 19a respectively in excellent yields (Scheme 9).
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Scheme 9. Synthesis of 4ꢀ (or 5ꢀ)ꢀ(nꢀbutyl)oxazoles
CONCLUSION
We have developed an efficient protocol for the synthesis of 2,5ꢀsubstituted 4ꢀ
acyloxazoles 5 (Table 1) and the corresponding 2,4ꢀsubstituted 5ꢀacyloxazoles 6 (Table 2)
with complementary regioselectivity from the corresponding αꢀoxoketene dithioacetals or βꢀ
(het)aryl/(methylthio)enone precursors by employing two strategies. In the first approach, the
αꢀoxoketene dithioacetals or βꢀ(methylthio)enones were converted to the corresponding αꢀ
bromo substituted intermediates by bromination with Nꢀbromosuccinimide. Subsequent
copper catalyzed intramolecular annulations of these αꢀbromoenones with various primary
amides afforded 2ꢀ(het)aryl/alkylꢀ4ꢀ(het)aroylꢀ5ꢀ(methylthio)/(het)aryloxazoles 5 in excellent
yields via concomitant formation of C4ꢀN and C5ꢀO bond, without isolation of intermediate
enamides (Table 1). In the second approach, the starting αꢀoxoketene dithioacetals or βꢀ
(methylthio)ꢀβꢀ(het)arylenones were subjected to base induced conjugate additionꢀ
elimination with various primary amides to furnish βꢀaroylenamides, which, on subsequent
iodine catalyzed intramolecular oxidative cyclization (through CꢀH functionalization/CꢀO
bond formation) afforded the corresponding regioisomeric 2ꢀ(het)aryl/alkylꢀ4ꢀ
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(methylthio)/(het)arylꢀ5ꢀ(het)aroyloxazoles 6 in excellent yields (Table 2). However, the
latter strategy was not successful for the synthesis of few regioisomeric oxazoles such as 6lꢀn
(Scheme 7), because of our failure to obtain the corresponding enamides 11lꢀn by base
mediated conjugate addition of the related amides 8lꢀn to enones 7. The methodology was
also extended for the synthesis of 4ꢀ (or 5ꢀ)ꢀaminooxazoles from the corresponding 4ꢀ (or 5ꢀ
)(methylthio)oxazoles via initial mꢀCPBA mediated oxidation of (methylthio) group to
(methylsulfonyl) group, followed by its replacement with primary or secondary alkylamines.
In a further elaboration, 4ꢀ (or 5ꢀ)(nꢀbutyl)oxazoles were obtained by replacement of
(methylthio) group with nꢀbutylmagnesium bromide in presence of Cu(I) bromide. Further
work to explore alternative routes for the synthesis of regioisomeric enamides such as 11lꢀn
and to examine the scope and limitations of these methodologies for the synthesis of
biologically important oxazoles are in progress in our laboratory.
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EXPERIMENTAL SECTION
General Information. All reagents were purchased from commercial suppliers and
used without further purification. Solvents were dried according to the standard procedures.
All the reactions were monitored by thin layer chromatography using standard TLC Silica gel
plates and visualized with UV light. Column chromatography was performed using silica gel
(100ꢀ200 mesh). Nuclear magnetic resonance spectra were recorded on (400 MHz) FTꢀNMR
spectrometer with CDCl3 (or) DMSOꢀd6 as solvent. Chemical shifts were reported in δ ppm
using residual solvent protons as internal standard (δ 7.26 for CDCl3 and δ 2.50 for DMSOꢀd6
1
13
in HꢀNMR, δ 77.16 for CDCl3 and δ 39.52 for DMSOꢀd6 in CꢀNMR). Coupling constants
were reported as J values in Hertz (Hz). Splitting patterns are designated as s (singlet), d
(doublet), t (triplet), q (quartet), quin (quintet), dd (double doublet), dt (doublet of triplet), td
(triplet of doublet), ddd (doublet of doublet of doublet), m (multiplet) and br (broad). Infrared
spectra of neat samples were recorded in ATR (attenuated total reflectance) mode using FTꢀ
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IR instrument and HRMS on QꢀTOF spectrometer. Melting points were recorded using an
electrothermal capillary melting point apparatus and are uncorrected. All the (het)aryl
dithioesters were prepared according to the literature procedure.36 All amides 8a-l and 8n
were purchased commercially except cinnamamide 8m which was prepared according to
literature procedure.32
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The desired αꢀoxoketene dithioacetal/βꢀ(methylthio)ꢀβꢀ(het)arylenone precursors 7a-
l29f,30a and the corresponding αꢀbromo derivatives 10a-l30b were prepared according to our
earlier reported procedures. The spectral and analytical data of the new αꢀoxoketene
dithioacetal/βꢀ(methylthio)ꢀβꢀ(het)arylenone precursors 7g-l and the corresponding new αꢀ
bromo derivatives 10b-l is given below. Since 10h and 10i were found to be unstable, they
were used as such for the next step without further purification.
(E/Z)-3-(3,4,5-Trimethoxyphenyl)-3-(methylthio)-1-(pyren-1-yl)prop-2-en-1-one
(7g).
Yellow solid (398 mg, 85%, E/Z = 55:45): mp 135ꢀ137 °C; Rf 0.5 (3:2 EtOAc/hexane); IR
(neat, cm–1) 1579, 1411, 1243, 1118, 840; 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 9.2 Hz,
0.55H), 8.54 (d, J = 9.2 Hz, 0.45H), 8. 30 (d, J = 8.0 Hz, 0.55H), 8.24ꢀ8.21 (m, 1.1H), 8.20ꢀ
8.09 (m, 3.0H), 8.07ꢀ8.03 (m, 1.35H), 8.01ꢀ7.97 (m, 1.1H), 7.90 (t, J = 8.0 Hz, 0.9H), 7.16 (s,
0.55H), 6.61 (s, 1.1H), 6.55 (s, 0.45H), 6.22 (s, 0.9H), 3.89 (s, 3.3H), 3.89 (s, 1.65H), 3.43 (s,
2.7H), 2.96 (s, 1.35H), 2.49 (s, 1.35H), 2.11 (s, 1.65H); 13C{1H} NMR (100 MHz, CDCl3) δ
195.1, 192.6, 164.1, 161.4, 153.5, 152.1, 138.6, 138.2, 135.0, 134.7, 134.2, 133.4, 132.7,
132.4, 131.3, 131.2, 130.9, 130.7, 129.5, 129.3, 129.1, 128.9, 128.7, 127.3, 127.1, 126.8,
126.5, 126.4, 126.3, 126.2, 126.1, 126.0, 125.8, 125.2, 125.1, 124.8, 124.6, 124.5, 124.4,
124.3, 123.7, 122.2, 106.3, 105.6, 61.1, 60.2, 56.5, 55.7 ,16.9, 16.7; HRMS (ESIꢀQꢀTOF)
m/z: [M+H]+ calcd for C29H25O4S 469.1474; found 469.1467.
(E/Z)-3-(Benzo[d][1,3]dioxol-5-yl)-2-bromo-3-(methylthio)-1-(thiazol-2-yl)prop-2-en-1-
one (7h). Yellow solid (244 mg, 80%, E/Z = 65:35): mp 110ꢀ112 °C; Rf 0.4 (2:3
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EtOAc/hexane); IR (neat, cm–1) 1627, 1536, 1481, 1231, 1016, 738; H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 3.2 Hz, 0.35H), 7.95 (d, J = 3.2 Hz, 0.65H), 7.62 (d, J = 3.2 Hz,
0.65H), 7.60 (d, J = 3.2 Hz, 0.35H), 7.50 (s, 0.65H), 7.22 (s, 0.35H), 6.92ꢀ6.81 (m, 3H), 6.02
(s, 1.3H), 5.99 (s, 0.7H), 2.53 (s, 1.05H), 2.09 (s, 1.95H); 13C{1H} NMR(100 MHz, CDCl3) δ
179.9, 177.1, 170.6, 169.7, 167.2, 166.1, 148.8, 148.6, 147.9, 147.5, 144.5, 144.4, 132.3,
131.3, 126.0, 125.9, 122.4, 122.2, 118.1, 111.9, 109.2, 108.9, 108.5, 108.2, 101.7, 101.5,
17.1, 16.9; HRMS (ESIꢀQꢀTOF) m/z: [M+Na]+ calcd for C14H11NO3S2Na 328.0078; found
328.0062.
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(
E/Z)-1-(Benzo[d][1,3]dioxol-6-yl)-3-(4-(dimethylamino)phenyl)-3-(methylthio)prop-2-
en-1-one (7i). Yellow solid (255 mg, 75%, E/Z = 80:20): mp 126ꢀ128 °C; Rf 0.5 (2:3
EtOAc/hexane); IR (neat, cm–1) 1602, 1506, 1248, 806; H NMR (400 MHz, CDCl3) δ 7.56
1
(dd, J = 1.6 Hz, 0.8H), 7.49 (d, J = 1.6 Hz, 0.8H), 7.47 (d, J = 1.6 Hz, 0.2H), 7.34 (d, J = 1.6
Hz, 0.2H), 7.25 (d, J = 8.8 Hz, 1.8H), 6.99 (s, 0.8H), 6.82 (d, J = 8.0 Hz, 0.8H), 6.76 (d, J =
8.0 Hz, 0.4H), 6.73 (d, J = 8.8 Hz, 1.6H), 6.59 (d, J = 8.8 Hz, 0.4H), 6.41 (s, 0.2H), 6.01 (s,
1.6H), 5.98 (s, 0.4H), 3.01 (s, 4.8H), 2.95 (1.2H), 2.41 (s, 0.6H), 2.04 (s, 2.4H); 13C{1H}
NMR (100 MHz, CDCl3) δ 187.8, 186.8, 164.6, 161.1, 151.3, 151.0, 150.9, 148.2, 147.9,
134.3, 134.1, 130.1, 129.5, 126.6, 124.8, 124.5, 123.8, 118.6, 114.6, 111.8, 111.4, 108.6,
108.3, 107.9, 107.7, 101.8, 101.7, 40.4, 40.3, 17.2, 16.6; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+
calcd for C19H20NO3S 342.1164; found 342.1158.
(
E/Z)-1-(4-(Trifluoromethyl)phenyl)-3-(4-methoxyphenyl)-3-(methylthio)prop-2-en-1-
one (7j). Yellow solid (288 mg, 82%, E/Z = 68:32): mp 73ꢀ75 °C; Rf 0.5 (1:4
1
EtOAc/hexane); IR (neat cm–1) 1603, 1495, 1319, 1248, 1065, 809; H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 8.4 Hz, 1.32H), 7.78 (d, J = 8.0 Hz, 0.68H), 7.61 (d, J = 8.4 Hz,
1.32H), 7.50 (d, J = 8.0 Hz, 0.68H), 7.20 (d, J = 8.8 Hz, 1.32H), 7.16 (d, J = 8.8 Hz, 0.68H),
6.97 (s, 0.66H), 6.89 (d, J = 8.8 Hz, 1.32H), 6.70 (d, J = 8.8 Hz, 0.68H), 6.41 (s, 0.34H), 3.77
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(s, 1.98H), 3.67 (s, 1.02H), 2.37 (s, 1.02H), 1.93 (s, 1.98H); 13C{1H} NMR(100 MHz,
CDCl3) δ 188.1, 187.1, 166.9, 163.2, 160.9, 160.5, 142.3, 141.8, 134.0, 133.6, 133.3, 133.0,
131.0, 130.3, 129.5, 128.8, 128.4, 125.7, 125.,65 125.61, 125.60, 125.34, 125.31, 125.27,
125.24, 122.5, 118.5, 115.3, 114.2, 113.8, 55.5, 55.3, 17.0, 16.6; HRMS (ESIꢀQꢀTOF) m/z:
[M+H]+ calcd for C18H16F3O2S 353.0823; found 353.0819.
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(E/Z)-3-(1-Methyl-1H-indol-3-yl)-3-(methylthio)-1-(pyridin-3-yl)prop-2-en-1-one (7k).
Brown semi solid (246 mg, 80%, E/Z = 70:30): Rf 0.4 (2:3 EtOAc/hexane); IR (neat, cm–1)
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2920, 1507, 1233, 1017, 741; H NMR (400 MHz, CDCl3) δ 9.18 (d, J = 1.6 Hz, 0.7H), 8.97
(d, J = 1.6 Hz, 0.3H), 8.72 (dd, J = 4.8 Hz, 1.6 Hz, 0.7H), 8.52 (dd, J = 4.8 Hz, 1.6H), 8.28
(dt, J = 8.0 Hz, 1.6 Hz, 0.7H), 7.96 (dt, J = 8.0 Hz, 1.6 Hz, 0.3H), 7.80 (d, J = 8.0 Hz, 0.7H),
7.45 (dt, J = 8.0 Hz, 0.8H), 7.41ꢀ7.37 (m, 1.7H), 7.33ꢀ7.29 (m, 1.4H), 7.24ꢀ7.16 (m, 2.0H),
7.14ꢀ7.07 (m, 0.6H), 6.54 (s, 0.3H), 3.86 (s, 2.1H), 3.72 (s, 0.9H), 2.52 (s, 0.9H), 2.19 (s,
2.1H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.2, 188.7, 150.9, 149.2, 149.1, 148.2, 136.9,
134.6, 134.2, 133.1, 132.1, 126.0, 123.5, 122.7, 122.0, 121.7, 121.5, 121.4, 120.8, 120.2,
119.2, 112.2, 111.6, 109.6, 33.0, 31.7, 16.7, 16.4; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd
for C18H17N2OS 309.1062; found 309.1055.
4-((Z)-3-(Methylthio)-3-(pyridin-3-yl)acryloyl)benzonitrile (7l). Yellow solid (196 mg,
70%): mp 116ꢀ118 °C; Rf 0.3 (3:7 EtOAc/hexane); IR (neat, cm–1) 2924, 2231, 1623, 1521,
1254, 814; 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.61 (dd, J = 2.4
Hz, 0.8 Hz, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.67 (dt, J = 7.6 Hz, 2.0
Hz, 1H), 7.41 (ddd, J = 7.6 Hz, 4.8 Hz, 0.8 Hz, 1H), 7.03 (s, 1H), 2.00 (s, 3H); 13C{1H}
NMR(100 MHz, CDCl3) δ 186.4, 163.5, 150.5, 148.4, 141.6, 135.6, 134.5, 132.6, 128.5,
123.5, 119.3, 118.2, 115.8, 16.9; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C16H13N2OS
281.0749; found 281.0744.
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][1,3]dioxol-6-yl)-2-bromo-3,3-bis(methylthio)prop-2-en-1-one
(10b).
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Obtained from 7b, semiꢀsolid (328 mg, 95%): Rf 0.5 (1:9 EtOAc/hexane); IR (neat, cm–1)
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2920, 1644, 1562, 1457, 1274, 745; H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 8.0 Hz, 1.6
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Hz, 1H), 7.40 (d, J = 1.6 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.06 (s, 2H), 2.46 (s, 3H), 2.17 (s,
3H); 13C{1H} NMR(100 MHz, CDCl3) δ 187.6, 152.7, 148.5, 137.7, 129.2, 126.9, 118.0,
108.9, 108.1, 102.1, 18.9, 16.3; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C12H12BrO3S2
346.9411 and 348.9391; found 346.9415 and 348.9394.
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2-Bromo-1-(furan-2-yl)-3,3-bis(methylthio)prop-2-en-1-one (10c). Obtained from 7c, offꢀ
white solid (283 mg, 97%): mp 259ꢀ261 °C; Rf 0.6 (1:9 EtOAc/hexane); IR (neat, cm–1) 1640,
1436, 1258, 1031, 784; 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 1.6 Hz, 0.8 Hz, 1H), 7.19
(dd, J = 3.6 Hz, 0.8 Hz, 1H), 6.57 (dd, J = 3.6 Hz, 1.6 Hz, 1H), 2.46 (s, 3H), 2.21 (s, 3H);
13C{1H} NMR(100 MHz, CDCl3) δ 177.2, 150.7, 148.0, 140.3, 120.5, 116.3, 112.8, 19.3,
16.5; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C9H10BrO2S2 292.9306 and 294.9285;
found 292.9311, 294.9290.
2-Bromo-(ferrocen-1-yl)-3,3-bis(methylthio)prop-2-en-1-one (10d).Obtained from 7d,
brown solid (336 mg, 82%): mp 259ꢀ261 °C; Rf 0.5 (1:4 EtOAc /hexane); IR (neat, cm–1)
1590, 1500, 1353, 1120, 702; 1H NMR (400 MHz, CDCl3) δ 4.77 (t, J = 2.0 Hz, 2H), 4.58 (t,
J = 2.0 Hz, 2H), 4.29 (s, 5H), 2.43 (s, 3H), 2.15 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3) δ
195.0, 138.1, 118.8, 72.9, 71.0, 70.2, 18.9, 16.5; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for
C15H16BrFeOS2 410.9175 and 412.9155; found 410.9150 and 412.9148
2-Bromo-4,4-dimethyl-1,1-bis(methylthio)pent-1-en-3-one (10e). Obtained from 7e,
colourless liquid (253 mg, 90%): Rf 0.6 (1:4 EtOAc/hexane); IR (neat, cm–1) 2968, 1689,
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1477, 1100, 751; H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 2.23 (s, 3H), 1.29 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 206.3, 134.0, 118.7, 43.9, 28.5, 18.9, 16.2; HRMS (ESIꢀ
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284.9811.
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(E/Z)ꢀ2-Bromo-1-(furan-2-yl)-3-(4-methoxyphenyl)-3-(methylthio)prop-2-en-1-one (10f).
Obtained from 7f, offꢀwhite solid (316 mg, 90%, E/Z = 70:30): mp 93ꢀ95 °C; Rf 0.7 (1:4
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EtOAc/hexane); IR (neat, cm–1) 2925, 1646, 1458, 1249, 1016, 754; H NMR (400 MHz,
CDCl3) δ 7.67 (s, 0.3H), 7.47 (d, J = 8.8 Hz, 0.7H), 7.43 (s, 0.7H), 7.32 (d, J = 8.8 Hz, 0.3H),
7.11 (d, J = 8.8 Hz, 1.4 H), 7.00 (d, J = 3.6 Hz, 0.6H), 6.96 (d, J = 8.8 Hz, 0.6H), 6.74 (d, J =
8.8 Hz, 1.4H), 6.59 (dd, J = 2.8 Hz, 1.2 Hz, 0.3H), 6.36 (dd, J = 2.8 Hz, 1.2 Hz, 0.7H), 3.85
(s, 0.9H), 3.72 (s, 2.1H), 1.94 (s, 2.1H), 1.85 (s, 0.9H); 13C{1H} NMR (100 MHz, CDCl3) δ
178.4, 178.0, 160.3, 160.1, 150.8, 148.8, 147.8, 147.3, 143.0, 131.9, 130.9, 130.8, 128.3,
127.5, 120.6, 120.3, 114.1, 114.0, 112.8, 112.4, 110.9, 110.2, 55.4, 55.3, 17.3, 16.3; HRMS
(ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C15H14BrO3S 352.9847 and 354.9827; found 352.9843,
354.9829.
(E)-2-Bromo-3-(3,4,5-trimethoxyphenyl)-3-(methylthio)-1-(pyren-1-yl)prop-2-en-1-one
(10g). Obtained from 7g, yellow solid (464 mg, 85%): mp 122ꢀ124 °C; Rf 0.5 (1:1
EtOAc/hexane); IR (neat, cm–1) 1647, 1582, 1230, 1132, 745; H NMR (400 MHz, CDCl3)
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δ8.35 (d, J = 13.6 Hz, 1H), 8.18 (t, J = 7.2 Hz, 2H), 8.11 (d, J = 3.2 Hz, 1H), 8.08 (d, J = 3.2
Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.98 (m, 3H), 5.87 (s, 2H), 3.34 (s, 6H), 2.51 (s, 3H), 1.84
(s, 3H); 13C{1H} NMR(100 MHz, CDCl3) δ 196.7, 164.6, 156.6, 153.2, 140.0, 134.8, 133.8,
131.7, 131.3, 131.0, 130.9, 130.8, 129.9, 129.6, 129.5, 129.3, 127.4, 126.6, 126.5, 126.3,
126.0, 125.1, 124.7, 124.6, 124.5, 116.4, 116.2, 110.3, 105.1, 61.1, 56.4; HRMS (ESIꢀQꢀ
TOF) m/z: [M+H]+ calcd for C29H24BrO4S 547.0579 and 549.0558; found 547.0567 and
549.0547.
(
E/Z)-2-Bromo-1-(4-(trifluoromethyl)phenyl)-3-(4-methoxyphenyl)-3-(methylthio) prop-
2-en-1-one (10j). Obtained from 7j, offꢀwhite solid (377 mg, 88%, E/Z = 60:40): mp 115ꢀ117
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°C; Rf 0.5 (2:3 EtOAc/hexane); IR (neat, cm–1) 1669, 1604, 1321, 1248, 1125, 858; 1H NMR
(400 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 0.4H), 7.77 (d, J = 8.0 Hz, 0.4H), 7.70 (d, J = 8.8
Hz, 1.6H), 7.53ꢀ7.49 (m, 2H), 7.01ꢀ6.98 (m, 2H), 6.66 (d, J = 8.8Hz, 1.6H), 3.86 (s, 0.6 H),
3.68 (s, 2.4H), 1.95 (s, 2.4H), 1.80 (s, 0.6H); 13C{1H} NMR(100 MHz, CDCl3) δ 189.9,
189.0, 160.5, 160.4, 151.6, 143.1, 139.7, 138.2, 134.3, 133.9, 133.6, 133.3, 130.95, 130.93,
129.8, 129.6, 127.8, 127.3, 126.0, 125.93, 125.90, 125.86, 125.22, 125.19, 125.15, 125.11,
125.0, 122.3, 114.2, 111.6, 55.5, 55.3, 17.1, 16.4; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd
for C18H15BrF3O2S 430.9928 and 432.9908; found 430.9924 and 432.9906.
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(E)-2-Bromo-3-(1-methyl-1H-indol-3-yl)-3-(methylthio)-1-(pyridin-3-yl)prop-2-en-1-one
(10k). Obtained from 7k, yellow solid (347 mg, 90%): mp 120ꢀ122 °C; Rf 0.5 (2:3
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EtOAc/hexane); IR (neat, cm–1) 1630, 1504, 1257, 738; H NMR (400 MHz, CDCl3) δ 8.54
(d, J = 1.6 Hz, 1H), 8.13 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 7.66ꢀ7.64 (m, 1H), 7.47 (dt, J = 8.0 Hz,
2.0 Hz, 1H), 7.18ꢀ7.15 (m, 2H), 7.02ꢀ7.00 (m, 1H), 6.82 (s, 1H), 6.66 (dd, J = 7.6 Hz, 4.8 Hz,
1H), 3.53 (s, 3H), 2.09 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3) δ 190.2, 150.9, 149.2,
149.1, 136.9, 134.6, 133.1, 132.1, 125.9, 123.4, 121.7, 121.5, 120.2, 112.2, 111.6, 109.6,
32.9, 16.7 HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C18H16BrN2OS 387.0167 and
389.0146; found 387.0163 and 389.0144.
4-((E)-2-Bromo-3-(methylthio)-3-(pyridin-3-yl)acryloyl)benzonitrile (10l). Obtained from
7l, offꢀwhite solid (303 mg, 85%): mp 130ꢀ132 °C; Rf 0.5 (3:7 EtOAc/hexane); IR (neat, cm–
1
1) 2926, 2230, 1658, 1256, 748; H NMR (400 MHz, CDCl3) δ 8.80 (s, 0.33H), 8.68 (d, J =
4.0 Hz, 0.33H), 8.46 (d, J = 4.0 Hz, 0.67H), 8.36 (s, 0.67H), 8.08 (d, J = 8.4 Hz, 0.66H), 7.87
(dt, J = 12.0 Hz, 2.0 Hz, 0.33H), 7.82 (d, J = 8.4 Hz, 0.66H), 7.76 (d, J = 8.4 Hz, 1.34H),
7.62 (d, J = 8.4 Hz, 1.34H), 7.48 (dt, J = 12.0 Hz, 2.0 Hz, 0.67H), 7.44 (dd, J = 7.6 Hz, 4.8
Hz, 0.33H), 7.18 (dd, J = 7.6 Hz, 4.8 Hz, 0.67H), 1.96 (s, 2.01H), 1.85 (s, 0.99H); 13C{1H}
NMR (100 MHz, CDCl3) δ 188.5, 188.2, 150.5, 150.1, 149.3, 148.2, 140.5, 139.5, 138.2,
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136.8, 136.6, 132.8, 132.3, 131.5, 129.9, 129.8, 123.7, 123.4, 117.9, 117.8, 117.1, 116.5,
114.3, 113.1, 17.3, 16.4; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C16H12BrN2OS
358.9854 and 360.9833; found 358.9842 and 360.9823.
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General procedure for the synthesis of 2-(het)aryl/alkyl-4-acyl-5-(het)aryloxazoles 5a-n’.
To a stirring solution of αꢀbromo derivatives 10a-l (1.0 mmol) and the corresponding amides
8a-n (1.0 mmol) in toluene (5 mL), CuI (0.1 mmol, 19 mg), DMEDA (0.2 mmol, 17 mg) and
Cs2CO3 (2.0 mmol, 650 mg) were added under N2 atmosphere and the reaction mixture was
heated at 90 °C (monitored by TLC). It was then diluted with sat. NH4Cl solution (25 mL),
extracted with EtOAc (3 × 25 mL) and the combined organic layer was washed with water (3
× 25 mL), brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product
was purified by silica gel column chromatography using EtOAc/hexane as eluent.
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(4-Methoxyphenyl)(2-(4-methoxyphenyl)-5-(methylthio)oxazol-4-yl)methanone
(5a).
Obtained from 10a and amide 8a, offꢀwhite solid (320 mg, 90%): mp 104ꢀ105 °C; Rf 0.4 (1:4
EtOAc/hexane); IR (neat, cm–1) 2963, 1598, 1467, 1250, 760; 1H NMR (400 MHz, CDCl3) δ
8.54 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 7.00ꢀ6.97 (m, 4H), 3.88 (s, 3H), 3.87 (s,
13
3H), 2.69 (s, 3H); C{1H} NMR(100 MHz, DMSO–d6) δ 184.2, 163.4, 161.7, 159.8, 156.7,
136.0, 132.8, 130.2, 128.1, 119.6, 114.4, 113.6, 55.53, 55.51, 14.4; HRMS (ESIꢀQꢀTOF) m/z:
[M+H]+ calcd for C19H18NO4S 356.0957; found 356.0949.
(2-tert-Butyl-5-(methylthio)oxazol-4-yl)(benzo[
d
][1,3]dioxol-5-yl)methanone
(5b).
Obtained from 10b and amide 8b, pale yellow solid (287 mg, 90%): mp 106ꢀ108 °C; Rf 0.4
1
(1:9 EtOAc/hexane); IR (neat, cm–1) 2965, 1581, 1480, 1249, 850; H NMR (400 MHz,
CDCl3) δ 8.21 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 6.87 (d, J =8.0 Hz, 1H),
6.03 (s, 2H), 2.60 (s, 3H), 1.42 (s, 9H); 13C{1H} NMR(100 MHz, CDCl3) δ 183.5, 169.3,
156.9, 151.5, 147.7, 134.3, 131.7, 127.1, 110.3, 107.9, 101.7, 34.2, 28.5, 14.1; HRMS (ESIꢀ
QꢀTOF) m/z: [M+H]+ calcd for C16H18NO4S 320.0957; found 320.0953.
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(Furan-2-yl)(5-(methylthio)-2-phenyloxazol-4-yl)methanone (5c). Obtained from 10c and
amide 8c, offꢀwhite solid (236 mg, 83%): mp 130ꢀ132 °C; Rf 0.5 (1:9 EtOAc/hexane); IR
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(neat, cm–1) 1608, 1498, 856, 762; H NMR (400 MHz, CDCl3) δ 8.16 (dd, J = 3.6 Hz, 0.8
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Hz, 1H), 8.05ꢀ8.02 (m, 2H), 7.71 (dd, J = 1.6 Hz, 0.8 Hz, 1H), 7.50ꢀ7.48 (m, 3H), 6.61 (dd, J
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= 3.6 Hz, 1.6 Hz, 1H), 2.72 (s, 3H); C{1H} NMR(100 MHz, CDCl3) δ 172.9, 160.0, 157.3,
151.3, 147.3, 134.4, 130.9, 129.1, 126.7, 126.4, 121.9, 112.3, 14.2; HRMS (ESIꢀQꢀTOF) m/z:
[M+H]+ calcd for C15H12NO3S 286.0538; found 286.0526.
(2-(3-(Trifluoromethyl)phenyl)-5-(methylthio)oxazol-4-yl)(ferrocen-1-yl)methanone
(5d). Obtained from 10d and amide 8d, maroon solid (381 mg, 81%): mp 190ꢀ192 °C; Rf 0.4
(1:4 EtOAc/hexane); IR (neat, cm–1) 1606, 1495, 1119, 695; H NMR (400 MHz, CDCl3) δ
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8.28ꢀ8.25 (m, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 5.47 (t, J = 2.0 Hz, 2H),
4.62 (t, J = 2.0 Hz, 2H), 4.19 (s, 5H), 2.74 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3) δ 189.3,
158.1, 156.0, 136.4, 131.9, 129.7, 129.3, 127.9, 127.1 (J = 3.6 Hz), 123.0, 122.9, 78.4, 72.8,
71.5, 70.2, 14.3; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C22H17F3FeNO2S 472.0282;
found 472.0291.
1-(2-(4-Chlorophenyl)-5-(methylthio)oxazol-4-yl)-2,2-dimethylpropan-1-one
(5e).
Obtained from 10e and amide 8e, offꢀwhite solid (247 mg, 80%): mp 97ꢀ99 °C; Rf 0.7 (1:4
EtOAc/hexane); IR (neat, cm–1) 2926, 1645, 1482, 1087, 835; 1H NMR (400 MHz, CDCl3) δ
7.92 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 2H), 2.67 (s, 3H), 1.41 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3) δ 200.5, 157.8, 157.1, 136.7, 134.6, 129.3, 127.5, 125.5, 43.8, 26.5, 14.1;
HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C15H17ClNO2S 310.0669 and 312.0639; found
310.0668 and 312.0637.
(2-(2-Chlorophenyl)-5-(4-methoxyphenyl)oxazol-4-yl)(furan-2-yl)methanone
(5f).
Obtained from 10f and amide 8f, yellow solid (333 mg, 88%): mp 153ꢀ155 °C; Rf 0.4 (1:4
EtOAc/hexane); IR (neat, cm–1) 1634, 1493, 1179, 855, 766; H NMR (400 MHz, CDCl3) δ
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8.32 (d, J = 9.2 Hz, 2H), 8.19 (dd, J = 3.2 Hz, 0.4 Hz, 1H), 8.14ꢀ8.11 (m, 1H), 7.72 (dd, J =
1.2 Hz, 0.4 Hz, 1H), 7.58ꢀ7.56 (m, 1H), 7.43ꢀ7.42 (m, 2H), 7.01 (d, J = 9.2 Hz, 2H), 6.62 (dd,
J = 3.2 Hz, 1.2 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3) δ 174.1, 161.7,
156.2, 156.1, 152.3, 147.4, 132.9, 132.8, 131.7, 131.6, 130.9, 130.4, 127.2 ,125.5, 122.9,
119.8, 114.1, 112.5, 55.6; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C21H15ClNO4
380.0690 and 382.0660; found 380.0674 and 382.0652.
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(2-(4-Fluorophenyl)-5-(3,4,5-trimethoxyphenyl)oxazol-4-yl)(pyren-1-yl)methanone (5g).
Obtained from 10g and amide 8g, yellow solid (462 mg, 83%): mp 192ꢀ194 °C; Rf 0.4 (2:3
EtOAc/hexane); IR (neat, cm–1) 1498, 1128, 929, 840; 1H NMR (400 MHz, CDCl3) δ 8.69 (d,
J = 9.6 Hz, 1H), 8.28ꢀ8.26 (m, 2H), 8.23 (d, J = 3.2 Hz, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 8.12
(d, J = 8.0 Hz, 1H), 8.09ꢀ8.04 (m, 4H), 7.40 (s, 2H), 7.16ꢀ7.11 (m, 2H), 3.82 (s, 3H), 3.78 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.6, 164.6 (1JCꢀF = 250 Hz), 158.2, 155.3, 153.3,
140.3, 136.4, 133.8, 133.0, 130.9, 130.3, 129.6, 129.4, 129.2, 128.3, 127.3, 126.5, 126.4,
126.1, 125.0, 124.9, 124.6, 123.8, 123.0, 122.6, 116.4, 116.1, 105.8, 61.1, 56.3; HRMS (ESIꢀ
QꢀTOF) m/z: [M+H]+ calcd for C35H25FNO5 558.1717; found 558.1699.
(2-(Benzo[b]thiophen-2-yl)-5-(benzo[d][1,3]dioxol-5-yl)oxazol-4-yl)(thiazol-2-
yl)methanone (5h). Obtained from 10h and amide 8h, pale yellow solid (367 mg, 85%): mp
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179ꢀ180 °C; Rf 0.5 (3:7 EtOAc/hexane); IR (neat, cm–1) 2212, 1609, 1467, 1202, 813; H
NMR (400 MHz, CDCl3) δ 8.16 (d, J = 2.0 Hz, 1H), 8.04 (s, 1H), 7.94 (dd, J = 8.0 Hz, 1.6
Hz, 1H), 7.89ꢀ7.86 (m, 2H), 7.81 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.45 ꢀ7.40 (m,
2H), 6.93 (d, J = 8.4 Hz, 1H), 6.06 (s, 2H); 13C{1H} NMR(100 MHz, CDCl3) δ 176.6, 156.6,
154.8, 150.3, 148.1, 144.9, 141.0, 139.5, 133.0, 128.4, 126.9, 126.5, 125.8, 125.3, 125.0,
124.0, 122.7, 120.6, 108.7, 108.5, 101.9; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for
C22H13N2O4S2 433.0317; found 433.0310.
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(Benzo[
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][1,3]dioxol-5-yl)(2-(4-bromophenyl)-5-(4-(dimethylamino)phenyl)oxazol-4-
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yl)methanone (5i). Obtained from 10i and amide 8i, yellow solid (343 mg, 70%): Rf 0.6 (1:4
EtOAc/hexane); IR (neat, cm–1) 2920, 1609, 1482, 1249, 767; 1H NMR (400 MHz, CDCl3) δ
8.01ꢀ7.96 (m, 4H), 7.87 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.61 (d, J =
8.6 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 8.8 Hz, 2H), 6.05 (s, 2H), 3.04 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.6, 156.7, 156.5, 151.7, 151.6, 147.8, 132.9, 132.6,
132.2, 129.4, 128.1, 127.4, 126.1, 125.0, 114.8, 111.6, 110.5, 107.9, 101.8, 40.2; HRMS
(ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C25H20BrN2O4 491.0606 and 493.0586; found 491.0609
and 493.0579.
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(4-(Trifluoromethyl)phenyl)(2-(furan-2-yl)-5-(4-methoxyphenyl)oxazol-4-yl)methanone
(5j). Obtained from 10j and amide 8j, offꢀwhite solid (351 mg, 85%): mp 140ꢀ142 °C; Rf 0.5
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(1:4 EtOAc/hexane); IR (neat, cm–1) 2932, 1605, 1358, 764; H NMR (400 MHz, CDCl3) δ
8.24 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.61 (dd, J = 1.6
Hz, 0.8 Hz, 1H), 7.14 (dd, J = 3.2 Hz, 0.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.58 (dd, J = 3.2
Hz, 1.6 Hz, 1H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.4, 161.8, 155.8,
151.3, 145.2, 142.1, 140.9, 134.2, 133.8, 133.2, 130.8, 130.1, 125.3 (q, J = 3.6 Hz), 119.5,
114.2, 112.9, 112.2, 55.6; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C22H15F3NO4
414.0953; found 414.0947.
(5-(1-Methyl-1H-indol-3-yl)-2-(thiophen-2-yl)oxazol-4-yl)(pyridin-3-yl)methanone (5k).
Obtained from 10k and amide 8k, yellow solid (346 mg, 90%): mp 133ꢀ135 °C; Rf 0.4 (3:7
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EtOAc/hexane); IR (neat, cm–1) 1643, 1603, 1386, 880, 705; H NMR (400 MHz, CDCl3) δ
9.54 (s, 1H), 9.16 (s, 1H), 8.78 (s, 1H), 8.58 (d, J = 7.6 Hz, 1H), 8.34 (t, J = 4.8 Hz, 1H), 7.84
(d, J = 3.2 Hz, 1H), 7.50 (d, J = 4.8 Hz, 1H), 7.47ꢀ7.36 (m, 4H), 7.19 (t, J = 4.0 Hz, 1H), 3.93
(s, 3H); 13C{1H} NMR(100 MHz, CDCl3) δ 185.4, 155.9, 153.3, 152.4, 151.8, 137.8, 137.4,
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135.1, 134.4, 131.8, 129.4, 128.8, 128.3, 128.26, 126.1, 123.43, 123.13, 122.1, 121.8, 110.3,
33.8; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for C22H16N3O2S 386.0963; found 386.0960.
4-(2-Ethyl-5-(pyridin-3-yl)oxazole-4-carbonyl)benzonitrile (5l). Obtained from 10l and
amide 8l, offꢀwhite solid (248 mg, 82%): mp 82ꢀ83 °C; Rf 0.4 (3:7 EtOAc/hexane); IR (neat,
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cm–1) 2231, 1660, 1345, 902, 775; H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 8.68 (d, J =
4.0 Hz, 1H), 8.50 (dt, J = 8.4 Hz, 1.6 Hz, 1H), 8.26 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz,
2H), 7.42 (dd, J = 8.0 Hz, 4.8 Hz, 1H), 2.93 (q, J = 7.6 Hz, 2H), 1.43 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 186.6, 164.,5 153.5, 151.2, 148.9, 140.9, 135.4, 134.7,
132.1, 131.0, 123.88, 123.4, 118.3, 116.2, 21.8, 11.2 HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd
for C18H14N3O2 304.1086; found 304.1076.
(E
)-(5-(1-Methyl-1
H
-indol-3-yl)-2-styryloxazol-4-yl)(pyridin-3-yl)methanone
(5m).
Obtained from 10k and amide 8m, offꢀwhite solid (319 mg, 79%): mp 125ꢀ127 °C; Rf 0.39
(1:4 EtOAc/hexane); IR (neat, cm–1) 2231, 1660, 1345, 902, 775; H NMR (400 MHz,
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CDCl3) δ 9.48 (s, 1H), 9.16 (s, 1H), 8.78 (d, J = 3.6 Hz, 1H), 8.54 (dt, J = 8.0 Hz, 2.0 Hz,
1H), 8.35 (dd, J = 4.8 Hz, 3.2 Hz, 1H), 7.66ꢀ7.61 (m, 3H), 7.46ꢀ7.37 (m, 7H), 7.04 (d, J =
15.6 Hz, 1H), 3.93 (s, 3H); 13C{1H} NMR(100 MHz, CDCl3) δ 185.6, 156.9, 156.1, 152.2,
151.6, 137.8, 137.4, 136.7, 135.5, 135.2, 134.6, 132.1, 129.5, 129.1, 127.4, 126.1, 123.4,
123.2, 122.1, 121.1, 113.5, 110.3, 103.7, 33.8; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for
C26H20N3O2 406.1556; found 406.1561.
Benzo[d][1,3]dioxol-5-yl(5-(4-(dimethylamino)phenyl)-2-hydroxyoxazol-4-yl)methanone
(5n’). Obtained from 10i and amide 8n, yellow solid (275 mg, 78%): mp 172ꢀ174 °C; Rf 0.2
(3:7 EtOAc/hexane); IR (neat, cm–1) 2231, 1660, 1345, 902, 775; H NMR (400 MHz,
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CDCl3) δ 7.89 (d, J = 8.8 Hz, 2H), 7.56 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H),
6.88 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.65 (s, 1H), 6.05 (s, 2H), 3.08 (s, 6H);
13C{1H} NMR(100 MHz, CDCl3) δ 185.5, 183.0, 153.4, 150.9, 148.2, 131.4, 130.7, 129.2,
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122.7, 122.4, 111.2, 108.3, 107.2, 101.8, 91.1, 40.2; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd
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for C19H17N2O5 353.1127; found 353.1121.
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Synthesis of (Z)-4-methoxy-N-(3-(4-methoxyphenyl)-1-(methylthio)-3-oxoprop-1-en-1-
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yl)benzamide (11a) from ketene dithioacetal 7a and amide 8a. To a stirring solution of
oxoketenedithioacetal7a (1.0 mmol, 254 mg) and amide 8a (1.0 mmol, 151 mg) in DMF (5
mL), NaH (60% emulsion in paraffin) (2.0 mmol, 80 mg) was added and the reaction mixture
was heated at 90 °C (monitored by TLC). It was then cooled to room temperature, diluted
with sat. NH4Cl solution (25 mL), extracted with EtOAc (3 × 25mL) and the combined
organic layer was washed with water (3 × 25 mL), brine, dried (Na2SO4) and concentrated
under reduced pressure. The crude product was purified by silica gel column chromatography
using EtOAc/hexane as eluent to get pure 11a.Offꢀwhite solid (310 mg, 87%): mp 91ꢀ93 °C;
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Rf 0.4 (2:3 EtOAc/hexane); IR (neat, cm–1) 1677, 1558, 1227, 1020, 756; H NMR (400
MHz, CDCl3) δ 14.94 (s, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.00 (d, J =
8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.11 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 2.45 (s, 3H);
13C{1H} NMR(100 MHz, CDCl3) δ 187.2, 165.8, 164.3, 163.4, 163.1, 132.0, 130.3, 129.8,
125.1, 114.3, 114.0, 94.7, 55.59, 55.57, 15.8; HRMS (ESIꢀQꢀTOF) m/z: [M+H]+ calcd for
C19H19NO4S 358.1113; found 358.1096.
The remaining enamides11bꢀe, 11fꢀk were also prepared by the above general procedure for
11a from the corresponding S,Sꢀacetals7b-e or βꢀ(methylthio)propenones7f-k and theamides
8b-k. The spectral and analytical data for 11dꢀf and 11iꢀk is given below, whereas the
enamides11bꢀc and 11gꢀh were used as such for the next step without further purification.
(Z)-N-(3-Ferrocenyl-1-(methylthio)-3-oxoprop-1-en-1-yl)-3-(trifluoromethyl)benzamide
(11d). Obtained from 7d and amide 8d, reddishꢀbrown solid (381 mg, 81%): mp 212ꢀ214 °C;
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Rf 0.5 (1:4 EtOAc/hexane); IR (neat, cm–1) 1684, 1559, 1425, 1100, 740; H NMR (400
MHz, CDCl3) δ 14.90 (s, 1H), 8.38 (s, 1H), 8.26 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H),
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