Synthesis of 2,5-bis(hetero)aryl 4′-substituted 4,5′- bisoxazoles via copper(I)-catalyzed domino reactions of activated methylene isocyanides with 2-phenyl- and 2-(2-thienyl)-4-[(aryl/heteroaryl)(methylthio) methylene]oxazol-5(4 H)-ones

Article abstract of DOI:10.1021/jo400317g

An efficient straightforward synthesis of 2,5,4′-trisubstituted 4,5′-bisoxazoles via copper(I)-catalyzed domino reactions of 2-phenyl- and 2-(2-thienyl)-4-[(aryl/heteroaryl)methylene]-5-oxazolones with activated methylene isocyanides has been reported. The overall domino process comprised of formation of one C-C and two C-O bonds involves initial nucleophilic ring opening of oxazolones by cupriomethylene isocyanides followed by sequential construction of two oxazole rings in the presence of copper catalyst. The broad substrate scope and excellent functional group compatibility of the reaction has been demonstrated by employing a variety of heteroaryl- and aryl-substituted oxazolones and activated methylene isocyanides, yielding bisoxazoles with three potential points of diversity. A probable mechanism for this novel copper-catalyzed domino process has been proposed.

Full text of DOI:10.1021/jo400317g

Article
pubs.acs.org/joc
Synthesis of 2,5-Bis(hetero)aryl 4′-Substituted 4,5′-Bisoxazoles via
Copper(I)-Catalyzed Domino Reactions of Activated Methylene
Isocyanides with 2‑Phenyl- and 2‑(2-Thienyl)-4-[(aryl/
heteroaryl)(methylthio)methylene]oxazol-5(4H)‑ones
Somaraju Yugandar, Anand Acharya, and Hiriyakkanavar Ila*
New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore-50064, India
S
* Supporting Information
ABSTRACT: An efficient straightforward synthesis of 2,5,4′-
trisubstituted 4,5′-bisoxazoles via copper(I)-catalyzed domino
reactions of 2-phenyl- and 2-(2-thienyl)-4-[(aryl/heteroaryl)-
methylene]-5-oxazolones with activated methylene isocyanides
has been reported. The overall domino process comprised of
formation of one C−C and two C−O bonds involves initial
nucleophilic ring opening of oxazolones by cupriomethylene
isocyanides followed by sequential construction of two oxazole
rings in the presence of copper catalyst. The broad substrate
scope and excellent functional group compatibility of the reaction has been demonstrated by employing a variety of heteroaryl-
and aryl-substituted oxazolones and activated methylene isocyanides, yielding bisoxazoles with three potential points of diversity.
A probable mechanism for this novel copper-catalyzed domino process has been proposed.
pharmacological properties have stimulated considerable
interest in the synthesis of compounds containing directly
linked 2,4′-bisoxazole (or tris- and polyoxazole) cores. Thus, a
plethora of iterative methods have been reported for the
construction of C2−C4′-linked polyoxazole subunits. Among
them, the biomimetic cyclocondensation of serine derived
peptide precursors to oxazoline and subsequent oxidation or
dehydrative cyclization of acyclic amide intermediates is a
popular approach to the polyoxazole moiety,6,9,15 although
chemoselective amide N−H insertion of rhodium carbenoids
(derived from the dirhodium(II)-catalyzed reaction of diazo-
carbonyl compounds) has also been1b−e developed as a useful
iterative oxazole synthesis.16 The other isolated methods
include intramolecular cyclization of α-alkynylglycine deriva-
tives,17 photolysis and pyrolysis of N-acylisoxazol-5-ones,18
SNAr substitution with the TosMIC anion in 2-chlorooxazole,19
Pummerer20 and Chan type21 rearrangements and ring
enlargement of N-acylaziridine derivatives,22 and silver-
mediated cross-condensation of amide and α-bromoketones.23
Recently, metal-catalyzed reactions, i.e. Stille,24a Negishi,24b and
especially Suzuki−Miyaura cross-coupling12c,25 and direct
arylation,14,24c have also been developed for the synthesis of
bis- and trisoxazoles. Although they differ greatly in their
synthetic strategies, these methods share a common linear
approach involving a large number of consecutive steps; each
time an oxazole ring needs to be introduced, it necessarily
requires synthesis of complicated acyclic precursors prior to
INTRODUCTION
■
The oxazole heterocycle is a fundamental ring system found
throughout in chemistry in areas such as natural products,
pharmaceuticals, agrochemicals, peptidomimetics, and poly-
mers.1 Naturally occurring oxazoles range in structures from
relatively simple 2,5-disubstituted derivatives (pimprinine and
pimprinethine)2 to more complex biologically important bis-
and trisoxazoles containing cyclic peptides and macrolides.1b−e
Examples include hennoxazole A3 with a 2,4′-bisoxazole moiety
displaying strong antiherpes simplex virus activity. Diazonamide
A (cytotoxic activity),4 Muscoride A,5 and IB 012116 are other
examples of natural products having two contiguous 2,4′-
bisoxazole motifs in their cyclic frameworks. Macrolides such as
ulapualide A,7 mycalolide A,8a,b kabiramides8b,c with potent
antifungal activity, and cyclic peptide YM-2163919 (telomerase
inhibitor) contain three contiguous 2,4′-oxazole rings. On the
other hand, telomestatin,10 a C2−C4′-linked macrocyclic
heptaoxazole, has been shown to be the most powerful
telomerase inhibitor described to date, which has found
application in cancer chemotherapy. A few examples of
biologically active bis-, tris-, and polyoxazoles are shown in
Chart 1. These naturally occurring polyoxazoles display a C2−
C4′ linkage as a result of their biosynthesis from amino acids
such as serine and threonine.1d,e,11 To the best of our
knowledge, no example of a naturally occurring 4,5′-bisoxazole
has been reported, and only a few examples of synthetic
2,2′-,12a 2,5′-,12b 4,4′-,12c 4,5′-,13 and 5,5′-bisoxazoles14 are
known in the literature.
The unique and complex structure of these bis- and
trisoxazole containing natural products and their important
Received: February 12, 2013
Published: March 15, 2013
© 2013 American Chemical Society
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Chart 1. Biologically Active Natural Products Incorporating Bis-, Tris-, and Polyoxazoles
Scheme 1. Synthesis of 2,4,5-Trisubstituted Oxazoles
cyclization. Therefore, more efficient improved methods for
bisoxazole synthesis from readily available precursors are
desirable.
molecular cyclization of functionalized β-(methylthio)enamides
6, which were obtained by ring opening of the newly
synthesized oxazolone precursors 4 by various oxygen,
nitrogen, and carbon nucleophiles (Scheme 1).28
As part of our program to develop new synthetic methods for
the construction of a wide range of small-molecule heterocyclic
libraries with potential biological activity,26 we have reported a
substrate-controlled, diversity-oriented synthesis of 2-phenyl-5-
(methylthio) 4-substituted oxazoles 2 and other heterocycles
using the general 2-phenyl-4-bis(methylthio)methyleneoxazol-
5(4H)-one 1 as a versatile synthetic template.27 The overall
strategy involves nucleophilic azalactone ring opening of 1 by
various oxygen (alkoxide), nitrogen (amines), and carbon
nucleophiles (Grignard reagents) followed by further synthetic
transformations of the resulting open-chain enamide adducts 3
(Scheme 1).27a,b In continuation of these studies, as a further
extension of this strategy, we have recently described the
synthesis of a new class of 5-oxazolone-based synthons, i.e., 2-
phenyl-4-[(aryl/heteroaryl)(methylthio)methylene]oxazol-
5(4H)-ones 4, and utilized them to develop a two-step
synthesis of a variety of 5-aryl and 5-heteroaryl 4-functionalized
oxazoles 5 and related natural products (Scheme 1).28 The key
step in this new protocol involves copper-catalyzed intra-
During the course of these studies, we further anticipated
that the use of activated methylene isocyanides29 as the
pronucleophiles, instead of common nucleophiles, in the ring
opening of oxazolone precursors 1 or 4 would bring about a
different kind of rearrangement−cyclization process. The rich
chemistry of anionized α-isocyanoacetate and tosylmethyl
isocyanide developed by Schollkopf29a,b and van Leusen,30
respectively, is mainly due to the exploitation of nucleophilicity
of the α-carbon atom, which can add to a variety of polar
(hetero)multiple bonds, along with the electrophilicity of the
divalent carbon atom of the isonitrile functionality resulting in
efficient construction of C−C and C−X (X = C, N, O, S)
bonds in a formal cycloaddition process to generate various
heterocycles. In recent years, activated methylene isocyanides
have emerged as versatile intermediates, participating in various
types of base-mediated cocyclization reactions with various
multiple bonds and other reactive species, leading to a diverse
class of nitrogen heterocycles.31,32
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We have recently reported efficient syntheses of 2,3,4-
substituted pyrroles33 and imidazo[1,5-a]quinoxalines34 by
formal cycloaddition of activated methylene isocyanide anions
to polarized ketene dithioacetals and 2,3-substituted quinoxa-
lines, respectively. In continuation of these studies, along with
our ongoing research interest in 5-oxazolone-derived synthetic
templates,27,28 we envisaged that nucleophilic ring opening of
oxazolone 1 or 4 by an activated methylene isocyanide
pronucleophile would give the acyclic intermediate 7A having
a β-ketoisonitrile moiety, which would undergo facile proton
abstraction and subsequent intramolecular cyclization of the
resulting enolate 7B to the oxazole intermediate 7, as observed
earlier by Schollkopf and other workers in the acylation studies
of isocyanoacetate anion with various acylating agents.31b,35,36 It
was further speculated that the resulting α-(5-oxazolyl)-α-
benzoylamido intermediate 7 would also undergo cyclization
via an intramolecular 5-endo-trig process in the presence of a
base or metal catalyst with the formation of a second oxazole
ring (A),27,28 thus providing a facile access to novel 2,5,4′-
substituted 4,5′-bisoxazoles 8 (Scheme 2).37 We have
Scheme 3. Synthesis of 2-Phenyl- and 2-(2-Thienyl)-4-
[(aryl/heteroaryl)methylthiomethylene]oxazol-5-ones (4a−
h)
Scheme 2. Proposed Strategy for the Synthesis of
Bisoxazoles 8
Table 1. Optimization of Reaction Conditions for the
Formation of Bisoxazole 8aa from 4a and 12a in the
a
Presence of Different Bases
yield (%)
successfully achieved this goal and report in the present
paper a novel copper-catalyzed domino reaction involving ring
opening of 2-phenyl and 2-(2-thienyl)-4-[(heteroaryl/aryl)-
(methylthio)methylene]-5-oxazolones 4 with various activated
methylene isocyanide pronucleophiles and subsequent in situ
intramolecular cyclization of the resulting diversely function-
alized open-chain adducts 7, thus providing a straightforward
direct route to a wide range of 2,5,4′-substituted 4,5′-
bisoxazoles 8 in excellent yields.
entry
base
solvent
t (h)
T (°C)
7aa
8aa
1
2
DBU
DMF
THF
DMF
DMF
THF
DMF
DMF
DMF
DMF
DMF
10
10
10
10
25
25
25
25
24
25
60
60
86
88
84
83
tBuOK
NaH
3
60
4
Cs2CO3
Et3N
60
b
5
60
45 (41)
70
6
DBU
90
10
66
67
61
64
7
DBU
120
120
120
120
8
tBuOK
NaH
9
RESULTS AND DISCUSSION
■
10
Cs2CO3
The desired 2-phenyl-4-(heteroarylidene/arylidene)-5-oxazo-
lone precursors 4a−f were synthesized by condensation of 2-
phenyloxazol-5(4H)-one 9a with various aryl/heteroaryl
dithioesters 10 in the presence of sodium hydride in DMF
followed by alkylation of thiolate salts 11 with methyl iodide as
reported earlier.28 Further diversity in the 5-oxazolone
framework was introduced by synthesis of the corresponding
2-[(2-thienyl)]-4-[(heteroaryl/aryl)(methylthio)]-5-oxazolones
4g,h from the corresponding 2-(2-thienyl)-5-oxazolone 9b
following a similar procedure (Scheme 3).
a
Reaction conditions: 4a (0.3 mmol), 12a (1 equiv), and base (1
equiv) in 2 mL of solvent. Yield of recovered 4a.
b
only one product (86%), which was characterized as the acyclic
adduct 7aa bearing an oxazole B ring (Table 1, entry 1). Use of
other bases such as potassium tert-butoxide, sodium hydride,
and cesium carbonate, which are commonly employed in
similar protocols, also yielded only the product 7aa in 83−88%
yields at lower temperature (entries 2−4, Table 1). On the
other hand, use of a weaker base such as triethylamine
furnished 7aa in decreased yield (45%) along with unreacted
4a, even after a prolonged reaction time (entry 5). Formation
of oxazole derivative 7aa from 4a and 12a is in line with our
predicted course of reaction35,36 involving nucleophilic ring
opening of 4a by isocyanoacetate anion followed by base-
The reaction of oxazolone 4a with ethyl isocyanoacetate 12a
in the presence of various bases and Cu catalysts was selected as
the model reaction for optimizing reaction conditions for the
formation of bisoxazole 8aa (Tables 1 and 2). Thus, when 4a
was reacted with 12a in the presence of DBU as base at 60 °C
for 10 h, analysis of the reaction mixture showed formation of
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providing efficient synthesis of 4-oxoindeno[1,2-b]pyrroles
and pyrrolo[3,2-c]quinolin-4-ones, respectively, via a formal
[3 + 2] cycloaddition and subsequent intramolecular aryl C−C
coupling of the resulting organocopper intermediate.
Table 2. Optimization of Reaction Conditions for the
Formation of Bisoxazole 8aa from 4a and Isocyanoacetate
12a in the Presence of Copper Catalysts
a
Encouraged by these findings, we conducted a detailed study
of the reaction of oxazolone 4a with ethyl isocyanoacetate
(12a) and various copper catalysts, and the results are depicted
in Table 2. A detailed survey of the screening of various
combinations of catalysts and ligands revealed that most of the
copper catalysts employed in these reactions demonstrated
moderate to good activity in the formation of bisoxazole 8aa
under varying conditions, whereas CuI (10 mol %) in the
presence of cesium carbonate in DMF turned out to most
efficiently and effectively promote the formation of 8aa within 4
h at 90 °C in 75% yield (Table 2, entry 12). With copper
powder and Cu(I) oxide as catalysts, in the presence or absence
of ligand, 8aa was obtained in lower yields (61−68%) requiring
higher temperature and prolonged reaction time (entries 3−6),
whereas formation of only open-chain oxazole adduct 7aa was
observed at reduced temperature and time with copper powder
under identical conditions (entries 1 and 2). On the other
hand, in the presence of Cu2O/phen, the bisoxazole 8aa was
obtained only in 22% yield along with open-chain adduct 7aa as
the major product (entry 7). Similarly, other copper catalysts
such as CuCl, CuBr, and CuI in the presence of PPh3 or
Cs2CO3 also gave inferior results (entries 8−11), whereas a
combination of CuI/PPh3 and Cs2CO3 (entry 13) resulted in a
significantly increased yield of 8aa (entry 13).40 Use of Ag2CO3
(in a stoichiometric amount) was found to be less effective and
did not show complete conversion of 7aa to 8aa even after a
prolonged time (entry 15). Similarly, decreasing the catalyst
loading to 5 mol % of CuI gave 8aa only in slightly reduced
yield (70%), requiring a longer time (10 h) for completion of
the reaction (entry 14). As a control experiment, when 4a was
reacted with 12a in the absence of CuI, using 1 equiv of
Cs2CO3 under conditions identical with those described in
entry 14, the bisoxazole 8aa was formed in only traces along
with 7aa as the major product (entry 16), thus showing that the
presence of CuI as catalyst facilitates the formation of
bisoxazole 8aa from 7aa (entry 16 vs entry 14).40 Among the
solvents we tested, DMF showed the best results, whereas other
solvents such as 1,4-dioxane, toluene, acetonitrile and ethyl
acetate (with CuI/Cs2CO3) gave the desired product 8aa only
in moderate yields.
The scope and limitations of this novel base-induced and
copper-catalyzed domino reaction for bisoxazole synthesis was
next examined by employing a variety of acceptor-substituted
methylene isocyanides 12b−e in the reaction with oxazolone 4a
(Table 3). The results of these studies reveal that the reaction
of 4a with tosylmethyl isocyanide (12b), N- morpholino-α-
isocyanoacetamide (12c), 4-chlorobenzyl isocyanide (12d), and
4-pyridylmethyl isocyanide (12e) in the presence of bases such
as potassium tert-butoxide and DBU afforded the correspond-
ing 4′-substituted bisoxazoles 8ab−8ae in moderate to good
yields requiring higher temperature and longer reaction time
(Table 3, entries 1−8). However, increased yields of
bisoxazoles 8ab−8ae (76−91%) were obtained under copper-
catalyzed reaction conditions in the presence of CuI/Cs2CO3,
which efficiently promoted the reaction at lower temperature
(90 °C) within 4−6 h (Table 3, entries 9−12). Therefore, these
optimized reaction conditions (CuI/Cs2CO3) were employed
throughout in our subsequent studies.
yield (%)
entry
cat.
solvent
t (h) T (°C)
7aa
80
8aa
1
2
3
4
Cu powder/PPh3
Cu powder/phen
Cu powder/PPh3
Cu powder/phen
Cu2O
dioxane
dioxane
dioxane
dioxane
DMF
2
2
90
90
78
12
17
24
18
20
20
25
20
10
4
100
100
100
90
68
65
61
66
22
b
5
6
Cu2O/PPh3
Cu2O/phen
CuCI/PPh3
DMF
7
dioxane
dioxane
dioxane
DMF
100
100
100
90
72
8
trace
70
9
CuBr/PPh3
10
10
Cul/PPh3
25
55
c
11
CuCI/Cs2CO3
Cul/Cs2CO3
Cul/PPh3/ Cs2CO3
Cul/Cs2CO3
Ag2CO3
DMF
90
15
70
c
12
DMF
90
75
d
13
DMF
10
10
20
10
90
70
e
14
f
DMF
90
70
15
CH3CN
DMF
80
38
81
52
g
16
Cs2CO3
90
trace
a
Reaction conditions: all reactions were performed with 0.3 mmol of
4a and 1 equiv of 12a in 2 mL of solvent. Catalyst (10 mol %) and
ligand (20 mol %). Cu2O (10 mol %). Catalyst (10 mol %) and
Cs2CO3 (1 equiv). Cul (10 mol %), PPh3 (20 mol %) and Cs2CO3 (1
b
c
d
e
f
equiv). Catalyst (5 mol %) and base (1 equiv). Stoichiometric
g
amount of Ag2CO3. Cs2CO3 (1 equiv).
induced spontaneous intramolecular cyclization of the newly
formed α-acylisocyanoacetate moiety in the initially formed
open-chain intermediate 7aa (Scheme 2). No trace of the
desired bisoxazole 8aa could be detected in the reaction
mixture. However when the reaction of 4a and 12a in the
presence of DBU was continued for a longer time (25 h) at
higher temperature (90 °C), formation of 8aa was observed,
albeit in 10% yield along with 7aa (70%) (Table 1, entry 6),
whereas increasing the reaction temperature to 120 °C resulted
in complete disappearance of 7aa, furnishing the bisoxazole 8aa
in increased yield of 66% along with a polymeric mixture
(Table 1, entry 7). Similarly, the bisoxazole 8aa was observed as
the exclusive product in 61−67% overall yield with tBuOK,
NaH, or Cs2CO3 as base at higher temperatures and longer
reaction times (Table 1, entries 8−10).
With the base-mediated tandem ring-opening cyclization of
4a with isocyanoacetate 12a to bisoxazole 8aa in hand, we
further became interested in its copper-catalyzed variant with a
view to enhance the efficiency of the reaction under milder
reaction conditions.28 Recently, great progress has been made
in the use of transition-metal-catalyzed reactions of activated
methylene isocyanides with double and triple bonds.31 Thus, de
Meijere and co-workers38a,b and Yamamoto et al.38c,d have
independently reported the copper-catalyzed formal cyclo-
addition reactions of isocyanoacetates and alkynes furnishing
oligosubstituted pyrroles in good yields. Cai and co-workers
have recently described novel copper-catalyzed domino
reactions of activated methylene isocyanides with 1-(2-
haloaryl)-2-yn-1-ones39a and N-(2-haloaryl)propiolamides,39b
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a
Table 3. Synthesis of Bisoxazoles 8ab−8ae Using 4a and Isocyanides 12b−e
a
b
Reaction conditions: 4a (0.3 mmol), 12 (1 equiv) and base (1 equiv) in 2 mL of DMF. Reaction conditions: CuI (10 mol %) and Cs2CO3 (1
c
equiv). Structures of 8ab−8ae and 12b−e are as follows:
Having established the copper-catalyzed reaction conditions
Scheme 4. Synthesis of 2,5-Bis(heteroaryl/aryl)-4′-
for the formation of bisoxazoles 8aa−8ae from 4a and 12a−e
(Table 3), the reaction of various substituted 2-phenyl and 2-
(2-thienyl)-4-[(aryl/heteroaryl)(methylthio)methylene]oxazol-
5(4H)-ones 4b−h with activated methylene isocyanides 12a−e
was carried with a view to enhance the substrate scope of the
reaction for a diversity-oriented synthesis of a variety of novel
2,5′-bisoxazoles carrying a wide range substituents at the 2-, 5-,
and 4′- positions of two bisoxazole rings. These results are
summarized in Schemes 4−8. Thus, 2-phenyl-5-(3,4-bisme-
thoxyphenyl)-, 2-phenyl-5-(2-thienyl)-, 2-phenyl-5-[2-(1-N-
methyl)pyrrolyl], and 2-phenyl-5-[3-(1-N-methyl)indolyl]-4′-
carbethoxybisoxazoles (8ba−8fa) and the corresponding 2-
thienyl derivative 8ga were obtained in overall high yields,
when ethyl isocyanoacetate 12a was reacted with oxazolones
4b−g under standard copper-catalyzed reaction conditions
(Scheme 4). The novel domino reaction was found to be
equally facile with tosylmethyl isocyanide 12b, which readily
reacts with oxazolones 4b and 4e−g under identical reaction
conditions furnishing 2,5 bis(hetero)aryl-4′-tosyl-4,5′-bisoxa-
zoles 8bb and 8eb−8gb in 67−77% yields (Scheme 5).
Similarly the corresponding bisoxazoles 8cc, 8ec, 8fc, and 8hc
carrying a 4′-(N-morpholino)amide functionality could also be
prepared in excellent yields by employing N-(morpholino)-
carbethoxy-4,5′-bisoxazoles 8
isocyanoacetamide 12c as a reaction partner with oxazolones
4c,e,f,h, respectively (Scheme 6). The versatility of the reaction
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Scheme 5. Synthesis of 2,5-Bis(heteroaryl/aryl)-4′-tosyl-4,5′-
Scheme 7. Synthesis of 2,5-Bis(heteroaryl/aryl)-4′-(4-
bisoxazoles 8
chlorophenyl)-4,5′-bisoxazoles 8
was further demonstrated by employing the less acidic 4-
chlorobenzyl isocyanide 12d, which also reacted smoothly with
various 4-(aryl/heteroaryl)methyleneoxazolones 4c−g under
similar conditions, providing 2,5-bis(heteroaryl/aryl)-4′-(4-
chlorophenyl)bisoxazoles 8cd−8gd in excellent yields (Scheme
7). Further substituent diversity was introduced by installation
of a 4-pyridyl moiety in the 4′-position of the bisoxazole
framework by reacting 4-pyridylmethyl isocyanide 12e with
various oxazolones (4b−f,h) under identical conditions,
yielding product bisoxazoles 8be−8fe and 8he in high yields
(Scheme 8). The synthesis of these novel pyridyl-substituted
bisoxazoles, especially the 5,4′-bis(pyridyl) derivative 8fe, is
particularly noteworthy, since the pyridyl group is an important
pharmacophore in various pharmaceutically important com-
pounds.
Scheme 8. Synthesis of 2,5-Bis(heteroaryl/aryl)-4′-(4-
pyridyl)-4,5′-bisoxazoles 8
On the basis of our experimental observations and literature
precedent, a plausible mechanism for this novel copper-
catalyzed domino process leading to bisoxazoles 8 from
oxazolones 4 and isocyanides 12 is depicted in Schemes 9
and 10. Thus, the initiating step appears to be the formation of
α-cuprioisocyanide species A or its tautomer A1 by reaction of
isocyanides with CuI in the presence of base. Subsequent
nucleophilic ring opening of the lactone ring of oxazolone 4 by
intermediate A and/or A1 generates the acyclic α-acylisonitrile
intermediate B, which exists in equilibrium with the copper
enolate C in the basic medium. The intermediate C undergoes
facile intramolecular cyclization by attack on the isonitrile
carbon to furnish the 2-oxazolocopper intermediate D (Scheme
9). The C−Cu bond in the intermediate D is protonated by
isocyanide 12, furnishing the initially formed oxazole (B ring)
containing acyclic product 7 at lower temperature, with the
regeneration of the copper intermediate A and/or A1, thus
completing the catalytic cycle for the formation of initial
product 7.
Scheme 6. Synthesis of 2,5-Bis(heteroaryl/aryl)-4′-(N-morpholinocarbonyl)-4,5′-bisoxazoles
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bases such as potassium tert-butoxide or DBU also furnished
8aa in lower yields, requiring more drastic reaction conditions
(Table 4, entries 4 and 5). These observations evidently show
that the formation of a second oxazole ring (A) of bisoxazole 8
by intramolecular cyclization of the intermediate 7 is facilitated
in the presence of Cu(I) catalyst.
Scheme 9. Proposed Mechanism for Cu(I)-Catalyzed
Formation of Bisoxazoles 8 from 4
On the basis of known mechanisms of Ullman -type
condensations41 along with the related mechanistic studies on
the synthesis of benzoazoles by Cu(I)-catalyzed intramolecular
cyclization of o-halobenzanilides,42 we propose two possible
mechanisms for the formation of the A ring of bisoxazole 8 via
copper-catalyzed intramolecular cyclization of the β-
(methylthio)vinylenamide functionality present in the inter-
mediate 7 (Schemes 9 and 10).
Thus, the coordination of the amide functionality of 7 with
cuprous ion first forms the chelated intermediate E,43 which
undergoes intramolecular nucleophilic substitution at the
electrophilic double bond through the transition state
intermediate F (Scheme 9). Subsequent Cs2CO3-assisted
elimination of MeSH in the intermediate F and decomposition
of the resulting bisoxazole−Cu complex furnishes the
bisoxazole 8 along with the regenerated Cu(I) catalyst (Scheme
9). The present mechanism is similar to that proposed by
Paine41e and later by Ma and co-workers in their detailed study
of Cu(I)-catalyzed coupling reactions of aryl halides with α-
amino acids, involving a π-complex intermediate.44 Alter-
natively, the initially formed intermediate E can undergo
oxidative addition, forming the CuIII-containing transient
intermediate G (Scheme 10). Subsequent reductive elimination
of G in the presence of Cs2CO3 affords the bisoxazole 8 and
Cu(I) catalyst.41a−d,42a−c In the absence of literature examples
of Cu(I)-catalyzed coupling reactions of aryl/vinyl thioethers
with nitrogen or oxygen nucleophiles, we prefer the former
mechanism involving intramolecular nucleophilic substitution
of the methylthio group in the intermediate F (Scheme 9).
However, further study is required to investigate the detailed
mechanism and role of the copper catalyst in this trans-
formation.
Scheme 10. Proposed Alternate Mechanism for Copper-
Catalyzed Formation of Bisoxazoles 8 from Acyclic
Precursors 7
Regarding the possible mechanism for the formation of a
second oxazole ring (A) of the bisoxazole 8 from the
intermediate D or 7 at higher temperature, our studies reveal
that intramolecular cyclization of 7aa to 8aa is much more
efficient in the presence of copper catalyst (CuI/Cs2CO3),
giving bisoxazole 8aa in 88% yield within 4 h (Table 4, entry 1),
whereas under base-induced conditions (Cs2CO3/DMF), in the
absence of CuI, the reaction was not complete even after 36 h,
providing 8aa in maximum yield of 65% along with unreacted
starting material (Table 4, entries 2 and 3). Similarly, other
CONCLUSION
■
In conclusion, we have demonstrated a novel, mild, and
efficient Cu(I)-catalyzed domino process from readily acces-
sible oxazolones 4 and activated methylene isocyanides 12,
providing a straightforward direct route for diversity-oriented
synthesis of hitherto unreported 2,5,4′-trisubstituted 4,5′-
bisoxazoles. The reaction displays broad substrate scope and
excellent functional group compatibility by employing a wide
range of substituted oxazolones and isocyanides furnishing
bisoxazoles with three potential points of diversity. The overall
domino process comprised of the formation of one C−C and
two C−O bonds involves initial acylation of cupriomethylene
isocyanides (α-cupriomethylene isocyanides) by nucleophilic
ring opening of oxazolones followed by sequential construction
of two oxazole rings in the presence of copper catalyst. It
should be noted that although transition-metal-catalyzed
synthesis of oxazolines by reaction of carbonyl compounds
with activated methylene isocyanoacetate is a well-documented
efficient methodology,45 the analogous catalytic process for
oxazole formation via α-acylation of activated methylene
isocyanides has not been much explored.46
Table 4. Intramolecular Cyclization of Open-Chain Adduct
7aa to Bisoxazole 8aa
a
entry reagent conditions
solvent T (°C) t (h) yield of 8aa (%)
1
2
3
4
5
Cul/Cs2CO3
Cs2CO3
Cs2CO3
tBuOK
DMF
DMF
DMF
DMF
DMF
90
90
90
90
90
4
25
36
30
32
88
b
b
60 (24)
65 (20)
63
DBU
59
We believe that the synthesis reported herein can find
application in a number of fields, including combinatorial and
solid phase synthesis, as well as in automation, increasing the
a
b
Reaction conditions: catalyst (10 mol %), base (1 equiv). Yield of
recovered 7aa given in parentheses.
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156.3, 156.1, 155.5, 155.4, 149.5, 149.3, 148.3, 148.1, 132.1, 131.7,
131.66, 131.4, 129.3, 129.1, 128.9, 128.5, 128.4, 128.1, 128.0, 126.3,
125.1, 123.7, 110.7, 109.6, 108.8, 108.6, 101.8, 17.3, 16.6; HRMS
(ESI) m/z calcd for C16H11NO4S2 [M + H]+ 346.0208, found
346.0192.
popularity of these novel bisoxazoles, in view of the medicinal
importance of natural products containing this versatile
scaffold.
EXPERIMENTAL SECTION
General Procedure for the Base-Induced Reaction of 4-[(4-
Methoxyphenyl)(methylthio)methylene]-2-phenyloxazol-
5(4H)-one (4a) with Ethyl Isocyanoacetate (12a). To a stirred
solution of oxazolone 4a (97.6 mg, 0.3 mmol) and 12a (33.9 mg, 0.3
mmol) in DMF or THF (2 mL) was added the appropriate base
(DBU, tBuOK, NaH, Cs2CO3, Et3N) (0.3 mmol), and the reaction
mixture was further stirred at room temperature for 10−25 h (Table
1). It was then poured into saturated NH4Cl solution (50 mL) and
extracted with EtOAc (3 × 25 mL), the extract was washed with water
(2 × 30 mL) and brine (30 mL) and dried (Na2SO4), and the solvent
was removed under reduced pressure to give a mixture of acyclic
adduct 7aa and bisoxazole 8aa, which were purified by column
chromatography on silica gel using EtOAc/hexane as eluent. The
yields of products 7aa and 8aa isolated in various experiments are
given in Table 1 (entries 1−10).
■
General Information. All the chemicals were commercially
purchased and used without further purification. Solvents were dried
according to the standard procedures. All the reactions were
monitored by thin-layer chromatography using Merck TLC silica gel
plates and visualized with UV light. Flash chromatography was
performed using Merck silica gel (100−200 mesh). Nuclear magnetic
resonance spectra were recorded on a 400 MHz Fourier transform
NMR spectrometer with CDCl3, DMSO-d6, or acetone-d6 as solvent.
Chemical shifts were reported in δ ppm (parts per million) using
residual solvent protons as internal standard (δ 7.26 for CDCl3, δ 2.50
1
for DMSO-d6, and δ 2.05 for acetone-d6 in H NMR, δ 77.16 for
CDCl3 and δ 39.5 for DMSO-d6 in 13C NMR). Coupling constants
were reported as J values in hertz (Hz). Splitting patterns are
designated as s (singlet), d (doublet), t (triplet), q (quartet), dd
(doublet of doublets), ddd (doublet of doublets of doublets), td
(triplet of doublets) m (multiplet) and br (broad). Infrared spectra
were recorded with an FTIR instrument and HRMS on a Q-TOF
spectrometer. Melting points were recorded using an electrothermal
capillary melting point apparatus and are uncorrected.
(E/Z)-Ethyl 5-[1-benzamido-2-(4-methoxyphenyl)-2-(methylthio)-
vinyl]oxazole-4-carboxylate (7aa): obtained as a yellow solid (E:Z =
22:78); mp 104−106 °C; Rf = 0.35 (1/1 EtOAc/hexane); IR (KBr,
cm−1) 3262, 3135, 1700, 1662, 1605, 1574, 1511, 1479, 1285, 1246,
1
1171, 1095, 1045; H NMR (400 MHz, CDCl3) δ 8.62 (s, 0.38H),
7.96 (s, 0.62H), 7.90 (d, J = 6.8 Hz, 0.64H), 7.85 (s, 0.62H), 7.58−
7.55 (m, 2.38H), 7.50−7.44 (m, 3H), 7.37−7.33 (m, 1.24H), 7.14 (dd,
J = 6.4 Hz, 2.0 Hz, 0.76H), 6.96 (dt, J = 8.8 Hz, 2.4 Hz, 1.24H), 6.79
(dd, J = 7.0 Hz, 1.8 Hz, 0.76H), 4.37−4.27 (m, 2H), 3.83 (s, 1.86H),
3.78 (s, 1.14H), 1.98 (s, 1.14H), 1.92 (s, 1.86H), 1.37−1.30 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 165.3, 161.7, 161.6, 160.3, 159.8,
152.7, 152.3, 149.6, 149.3, 139.4, 138.9, 133.8, 133.6, 132.1, 132.0,
131.0, 130.9, 129.1, 128.8, 128.7, 127.6, 127.3, 127.2, 127.1, 119.1,
119.0, 114.6, 114.0, 61.4, 61.3, 55.5, 55.3, 16.0, 15.7, 14.4, 14.3; HRMS
(ESI) m/z calcd for C23H22N2O5S [M + Na]+ 461.1147, found
461.1144.
The desired activated methylene isocyanides 12a,47 12c,48 12d,49
and 12e50 were prepared according to the reported procedures,
whereas the corresponding tosylmethyl isocyanide 12b was
commercially purchased. The dithioesters 10a−c,51a 10g,51a
10d,e,26e,51b and 10f51c required for the synthesis of 5-oxazolone
precursors 4a−h were prepared according to the reported methods in
the literature.
General Procedure for the Synthesis of 2-Phenyl- and 2-(2-
Thienyl)-4-[(aryl/heteroaryl)(methylthio)methylene]oxazol-5-
ones (4a−h). The oxazalones 4a−h were prepared following our
earlier reported procedure28 by reaction of the corresponding 2-
phenyl- (9a) and 2-(2-thienyl)-oxazol-5-ones (9b) (3.0 mmol) with
the appropriate heteroaryl/aryl dithioesters 10 (3.0 mmol) in the
presence of sodium hydride (0.31 g, 7.8 mmol) in DMF (10 mL)
followed by treatment with methyl iodide (0.28 mL, 4.5 mmol) and
workup as reported.28 2-Phenyl-4-[(aryl/heteroaryl)(methylthio)-
methylene]-5-oxazolones 4a−f were characterized by comparison of
their spectral and analytical data with those reported.28 The spectral
and analytical data of the unknown oxazolones 4g,h are given below.
(E/Z)-4-[(Methylthio)(2-thienyl)methylene]-2-(2-thienyl)oxazol-
5(4H)-one (4g): obtained from 2-(2-thienyl)oxazolone 9b and
dithioester 10c (Ar = 2-thienyl) (E:Z = 78:22), brown solid (0.571
g, 62%); mp 128−130 °C; Rf = 0.5 (1/4 EtOAc/hexane); IR (KBr,
2-Phenyl-5-(4-methoxyphenyl)-4′-carbethoxy-4,5′-bisoxazole
(8aa): obtained as a pale yellow solid; mp 128−130 °C; Rf = 0.5 (1/1
EtOAc/hexane); IR (KBr, cm−1) 3129, 2977, 2931, 2842, 1712, 1505,
1
1256, 1174, 1091, 1034; H NMR (400 MHz, CDCl3) δ 8.15−8.12
(m, 2H), 8.05 (s, 1H), 7.53(d, J = 8.8 Hz, 2H), 7.51−7.49 (m, 3H),
6.92 (d, J = 8.8 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 1.11 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) δ 160.5, 160.3,
159.3, 152.8, 150.2, 147.1, 131.2, 129.5, 129.4, 127.4, 126.2, 126.0,
121.8, 119.3, 114.7, 60.7, 55.4, 13.6; HRMS (ESI) m/z calcd for
C22H18N2O5 [M + Na]+ 413.1113, found 413.1115.
General Procedure for Copper(I)-Catalyzed Domino Reac-
tions of 2-Phenyl- and 2-(2-Thienyl)-4-[(aryl/heteroaryl)-
(methylthio)methylene]-5-oxazolones (4a−h) with Activated
Methylene Isocyanides (12a−e): Synthesis of 2,5-Bis(aryl/
heteroaryl) 4′-Substituted 4,5′-Bisoxazoles (8aa−8he). To a
stirred solution of the corresponding 5-oxazolone 4 (0.3 mmol) and
appropriate activated methylene isocyanides 12 (0.3 mmol) in DMF
(2 mL) was added CuI (5.7 mg, 10 mol %) under a nitrogen
atmosphere, followed by addition of Cs2CO3 (97.7 mg, 0.3 mmol).
The reaction mixture was then stirred at 90 °C for 4−6 h (monitored
by TLC). It was then poured into saturated NH4Cl (50 mL) solution
and extracted with EtOAc (3 × 25 mL), the extract was washed with
water (2 × 30 mL) and brine (30 mL) and dried (Na2SO4), and the
solvent was evaporated under reduced pressure to give crude
bisoxazoles 8aa−8he, which were purified by column chromatography
over silica gel using EtOAc/hexane as eluent.
2-Phenyl-5-(4-methoxyphenyl)-4′-carbethoxy-4,5′-bisoxazole
(8aa): obtained from oxazolone 4a and isocyanide 12a, as a pale
yellow solid (89.9 mg, 75%) (under copper-catalyzed conditions);
spectral and analytical data have been given earlier.
2-Phenyl-5-(3,4-dimethoxyphenyl)-4′-carbethoxy-4,5′-bisoxazole
(8ba): obtained from oxazolone 4b and isocyanide 12a, pale yellow
solid (88.7 mg, 75%); mp 112−114 °C; Rf = 0.52 (1/1 EtOAc/
hexane); IR (KBr, cm−1) 3116, 2932, 2837, 1716, 1511, 1256, 1098,
703; 1H NMR (400 MHz, CDCl3) δ 8.14−8.13 (m, 2H), 8.06 (s, 1H),
1
cm−1) 3101, 2926, 1771, 1616, 1396, 852, 705; H NMR (400 MHz,
CDCl3) δ 7.99 (dd, J = 4.0 Hz, 1.2 Hz, 0.78H), 7.82−7.79 (m, 1H),
7.72 (dd, J = 4.8 Hz, 1.2 Hz, 0.78H), 7.63−7.60 (m, 1H), 7.59 (dd, J =
4.8 Hz, 1.2 Hz, 0.22H), 7.39 (dd, J = 3.6 Hz, 1.2 Hz, 0.22H), 7.21 (dd,
J = 5.2 Hz, 4.0 Hz, 0.78H), 7.19−7.15 (m, 1.22H), 2.58 (s, 2.6H), 2.49
(s, 0.4H); 13C NMR (100 MHz, CDCl3) δ 163.6, 156.0, 144.4, 140.3,
134.3, 134.2, 132.4, 132.3, 131.9, 131.3, 130.7, 129.3, 129.0, 128.9,
128.7, 128.6, 128.22, 128.19, 19.9, 18.0; HRMS (ESI) m/z calcd for
C13H9NO2S3 [M + H]+ 307.9874, found 307.9859.
(E/Z)-4-(Benzo[d][1,3]dioxol-5-yl(methylthio)methylene)-2-(2-
thienyl)oxazol-5(4H)-one (4h): obtained from oxazolone 9b and
dithioester 10g (Ar = 3,4-methylenedioxyphenyl) (E:Z = 34:66),
yellow solid (0.745 g, 72%); mp 126−128 °C; Rf = 0.4 (1/4 EtOAc/
hexane); IR (KBr, cm−1) 3102, 2926, 1772, 1608, 1476, 1425, 1205,
1
1028, 971, 719; H NMR (400 MHz, CDCl3) δ 7.79 (dd, J = 4.0 Hz,
1.2 Hz, 0.34H), 7.73 (dd, J = 3.6 Hz, 1.2 Hz, 0.66H), 7.60 (dd, J = 4.8
Hz, 1.2 Hz, 0.34H), 7.53 (dd, J = 4.8 Hz, 1.2 Hz, 0.66H), 7.15 (dd, J =
4.8 Hz, 3.6 Hz, 0.34H), 7.11 (dd, J = 5.0 Hz, 4.0 Hz, 0.66H), 7.01 (dd,
J = 8.0 Hz, 1.6 Hz, 0.66H), 6.97 (d, J = 1.6 Hz, 0.66H), 6.94 (s,
0.34H), 6.92−6.89 (m, 0.66H), 6.86 (dd, J = 8.0 Hz, 1.6 Hz, 0.34H),
6.81 (d, J = 1.6 Hz, 0.34H), 6.06 (s, 1.32H), 6.05 (s, 0.68H), 2.26 (s,
1.02H), 2.22 (s, 1.98H); 13C NMR (100 MHz, CDCl3) δ 164.6, 161.9,
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7.51−7.50 (m, 3H), 7.19 (dd, J = 8.4 Hz, 2.2 Hz, 1H), 7.09 (d, J = 2.2
Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 3.92 (s,
3H), 3.84 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.0, 160.3, 151.0, 150.9, 150.5, 149.3, 131.0, 130.3, 129.0,
127.5, 126.8, 126.7, 122.4, 120.5, 119.3, 111.4, 108.8, 61.5, 56.1, 56.0,
14.1; HRMS (ESI) m/z calcd for C23H20N2O6 [M + Na]+ 443.1219,
found 443.1225.
2-Phenyl-5-(2-thienyl)-4′-carbethoxy-4,5′-bisoxazole (8ca): ob-
tained from oxazolone 4c and isocyanide 12a, gray solid (96.0 mg,
79%); mp 138−140 °C; Rf = 0.5 (1/1 EtOAc/hexane); IR (KBr,
cm−1) 3111, 2928, 1725, 1297, 1184, 1079, 1026, 705; 1H NMR (400
MHz, CDCl3) δ 8.14−8.11 (m, 2H), 8.07 (s, 1H), 7.52−7.50 (m, 3H),
7.40 (dd, J = 5.2 Hz, 0.8 Hz, 1H), 7.36 (dd, J = 3.6 Hz, 0.8 Hz, 1H),
7.08 (dd, J = 5.2 Hz, 3.6 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.16 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8, 160.3, 151.1,
147.2, 146.7, 131.2, 131.0, 129.1, 128.8, 128.0, 127.7, 126.9, 126.8,
126.5, 122.8, 61.5, 14.1; HRMS (ESI) m/z calcd for C19H14N2O4S [M
+ Na]+ 389.0572, found 389.0573.
(d, J = 8.0 Hz, 2H), 7.65−7.61 (m, 3H), 7.48 (d, J = 9.0 Hz, 2H), 7.36
(d, J = 8.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 3.82 (s, 3H), 2.34 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 161.0, 160.3, 151.9, 151.0,
146.1, 145.1, 139.3, 136.8, 131.0, 129.8, 129.1, 128.9, 128.2, 126.9,
126.6, 120.7, 119.7, 114.6, 55.5, 21.8; HRMS (ESI) m/z calcd for
C26H20N2O5S [M + Na]+ 495.0991, found 495.0994.
2-Phenyl-5-(3,4-dimethoxyphenyl)-4′-(4-tosyl)-4,5′-bisoxazole
(8bb): obtained from oxazolone 4b and isocyanide 12b, pale yellow
solid (94.7 mg, 67%); mp 188−190 °C; Rf = 0.52 (1/1 EtOAc/
hexane); IR (KBr, cm−1) 3015, 2932, 2829, 1511, 1340, 1264, 1142,
1021; 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.16−8.13 (m,
2H), 7.69 (d, J = 8.0 Hz, 2H), 7.65−7.62 (m, 3H), 7.33 (d, J = 8.0 Hz,
2H), 7.08 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.97
(d, J = 2.0 Hz, 1H), 3.82 (s, 3H), 3.65 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 160.4, 151.9, 151.1, 150.7, 149.4, 146.1, 145.2,
139.5, 136.7, 131.1, 129.8, 129.1, 128.8, 126.8, 126.7, 120.9, 119.81,
119.79, 111.5, 109.3, 56.1, 56.0, 21.8; HRMS (ESI) m/z calcd for
C27H22N2O6S [M + Na]+ 525.1096, found 525.1093.
2-Phenyl-5-(1-methyl-3-indolyl)-4′-(4-tosyl)-4,5′-bisoxazole
(8eb): obtained from oxazolone 4e and isocyanide 12b, pale yellow
solid (109.5 mg, 77%); mp 216−218 °C; Rf = 0.45 (1/1 EtOAc/
hexane); IR (KBr, cm−1) 3130, 3066, 1649, 1574, 1328, 1152, 913; 1H
NMR (400 MHz, acetone-d6) δ 8.46 (s, 1H), 8.24−8.21 (m, 2H), 7.91
(d, J = 8.0 Hz, 1H), 7.87 (dd, J = 6.8 Hz, 1.6 Hz, 2H), 7.66−7.57 (m,
4H), 7.54 (d, J = 8.4 Hz, 1H), 7.35−7.30 (m, 3H), 7.25−7.21 (m,
1H), 3.86 (s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
158.4, 153.0, 149.2, 145.2, 145.0, 137.6, 136.7, 136.4, 131.0, 130.2,
129.8, 129.5, 127.9, 126.3, 125.9, 124.5, 122.7, 121.4, 119.7, 118.4,
110.8, 100.9, 33.0, 21.1; HRMS (ESI) m/z calcd for C28H21N3O4S [M
+ Na]+ 518.1150, found 518.1155.
2-Phenyl-5-(3-pyridyl)-4′-(4-tosyl)-4,5′-bisoxazole (8fb): obtained
from oxazolone 4f and isocyanide 12b, brown solid (107.8 mg, 72%);
mp 190−192 °C; Rf = 0.56 (6/4 EtOAc/hexane); IR (KBr, cm−1)
3123, 2928, 1335, 1152, 705, 667, 598; 1H NMR (400 MHz, CDCl3) δ
8.86 (d, J = 1.6 Hz, 1H), 8.66 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.16−8.14
(m, 2H), 8.00 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.89 (ddd, J = 9.0 Hz,
2.0 Hz, 0.8 Hz 1H), 7.57−7.53 (m, 3H), 7.38 (ddd, J = 9.0 Hz, 4.8 Hz,
0.4 Hz, 1H), 7.3 (d, J = 8.0 Hz, 2H), 2.41 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 160.8, 153.9, 150.6, 148.6, 146.6, 145.5, 143.7,
138.6, 136.0, 133.6, 131.8, 130.0, 129.5, 128.0, 126.6, 125.6, 124.2,
123.0, 122.8, 21.1; HRMS (ESI) m/z calcd for C24H17N3O4S [M +
Na]+ 466.0837, found 466.0838.
2-Phenyl-5-(1-methyl-2-pyrrolyl)-4′-carbethoxy-4,5′-bisoxazole
(8da): obtained from oxazolone 4d and isocyanide 12a, gray solid
(97.4 mg, 80%); mp 136−138 °C; Rf = 0.52 (3/7 EtOAc/hexane); IR
(KBr, cm−1) 3116, 2996, 1727, 1511, 1180, 1085, 728; 1H NMR (400
MHz, CDCl3) δ 8.10−8.08 (m, 2H), 7.99 (s, 1H), 7.50−7.49 (m, 3H),
6.78 (dd, J = 2.6 Hz, 1.6 Hz, 1H), 6.30 (dd, J = 3.6 Hz, 1.6 Hz, 1H),
6.13 (dd, J = 3.6 Hz, 2.6 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.82 (s,
3H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.9,
160.6, 150.6, 147.8, 145.0, 131.0, 129.7, 129.1, 126.9, 126.6, 126.3,
124.2, 120.1, 112.8, 109.0, 61.4, 36.0, 14.2; HRMS (ESI) m/z calcd for
C20H17N3O4 [M + Na]+ 386.1117, found 386.1116.
2-Phenyl-5-(1-methyl-3-indolyl)-4′-carbethoxy-4,5′-bisoxazole
(8ea): obtained from oxazolone 4e and isocyanide 12a, white solid
(92.5 mg, 78%); mp 168−170 °C; Rf = 0.35 (1/1 EtOAc/hexane); IR
(KBr, cm−1) 3105, 2978, 1706, 1587, 1410, 1278, 1203, 1114, 731; 1H
NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.13−8.11 (m, 2H), 7.78
(s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.64−7.56 (m, 4H), 7.30 (t, J = 7.2
Hz, 1H), 7.23 (t, J = 7.2 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H), 3.85 (s,
3H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.1,
159.7, 150.6, 148.9, 148.7, 137.0, 130.7, 130.0, 129.1, 128.5, 127.2,
126.5, 125.5, 123.2, 121.5, 121.0, 120.8, 110.0, 103.5, 61.4, 33.4, 14.1;
HRMS (ESI) m/z calcd for C24H19N3O4 [M + Na]+ 436.1273, found
436.1276.
2-Phenyl-5-(3-pyridyl)-4′-carbethoxy-4,5′-bisoxazole (8fa): ob-
tained from oxazolone 4f and isocyanide 12a, brown solid (87.8 mg,
72%); mp 146−148 °C; Rf = 0.5 (6/4 EtOAc/hexane); IR (KBr,
cm−1) 3079, 2925, 1719, 1417, 1297, 1095, 705; 1H NMR (400 MHz,
CDCl3) δ 8.88 (d, J = 1.6 Hz, 1H), 8.62 (dd, J = 4.8 Hz, 1.6 Hz, 1H),
8.16−8.14 (m, 2H), 8.08 (s, 1H), 7.89−7.86 (ddd, J = 8.0 Hz, 2.2 Hz,
0.8 Hz, 1H), 7.53−7.52 (m, 3H), 7.35 (ddd, J = 8.0 Hz, 4.8 Hz, 0.8
Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 161.7, 160.6, 151.2, 150.4, 148.1, 147.5, 147.1,
133.0, 131.5, 130.7, 129.2, 126.9, 126.4, 125.1, 124.2, 123.6, 61.6, 14.1;
HRMS (ESI) m/z calcd for C20H15N3O4 [M + Na]+ 384.0960, found
384.0964.
2,5-Bis(2-thienyl)-4′-carbethoxy-4,5′-bisoxazole (8ga): obtained
from oxazolone 4g and isocyanide 12a, brown solid (79.3 mg, 71%);
mp 163−165 °C; Rf = 0.2 (4/6 EtOAc/hexane); IR (KBr, cm−1) 3101,
2933, 2852, 1727, 1587, 1175, 1050, 720; 1H NMR (400 MHz,
CDCl3) δ 8.06 (s, 1H), 7.80 (dd, J = 3.6 Hz, 0.8 Hz, 1H), 7.51 (dd, J =
4.8 Hz, 0.8 Hz, 1H), 7.39 (dd, J = 5.2 Hz, 0.8 Hz, 1H), 7.35 (dd, J =
3.6 Hz, 0.8 Hz, 1H), 7.16 (dd, J = 5.2 Hz, 3.6 Hz, 1H), 7.07 (dd, J =
4.8 Hz, 3.6 Hz, 1H) 4.21 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 160.7, 156.6, 151.2, 146.9, 146.1,
2,5-Bis(2-thienyl)-4′-(4-tosyl)-4,5′-bisoxazole (8gb): obtained from
oxazolone 4g and isocyanide 12b, off-white solid (95.4 mg, 70%); mp
128−130 °C; Rf = 0.5 (4/6 EtOAc/hexane); IR (KBr, cm−1) 3109,
2954, 1587, 1330, 1153, 712, 602; 1H NMR (400 MHz, CDCl3) δ 8.02
(d, J = 8.0 Hz, 2H), 7.99 (s, 1H), 7.79 (dd, J = 3.6 Hz, 0.8 Hz, 1H),
7.53 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.43 (dd, J = 4.8 Hz, 0.8 Hz, 1H),
7.39 (dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H),7.18 (dd, J
= 4.8 Hz, 3.6 Hz, 1H), 7.09 (dd, J = 4.8 Hz, 3.6 Hz, 1H), 2.41 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 156.6, 150.9, 146.8, 145.2, 144.8,
139.9, 136.8, 129.8, 129.6, 129.1, 129.0, 128.8, 128.34, 128.26, 128.1,
128.0, 127.6, 121.3, 21.8; HRMS (ESI) m/z calcd for C21H14N2O4S3
[M + H]+ 455.0194, found 455.0174.
2-Phenyl-5-(4-methoxyphenyl)-4′-(N-morpholinocarbonyl)-4,5′-
bisoxazole (8ac): obtained from oxazolone 4a and isocyanide 12c,
yellow solid (112.6 mg, 85%); mp 163−165 °C; Rf = 0.2 (1/1 EtOAc/
hexane); IR (KBr, cm−1) 3142, 2960, 2852, 1630, 1505, 1436, 1253,
1
1121, 832; H NMR (400 MHz, CDCl3) δ 8.10−8.07 (m, 2H), 7.98
(s, 1H), 7.65 (d, J = 9.0 Hz, 2H), 7.51−7.47 (m, 3H), 6.98 (d, J = 9.0
Hz, 2H), 3.86 (s, 3H), 3.70−3.56 (m, 8H); 13C NMR (100 MHz,
DMSO-d6) δ 161.0, 160.3, 159.4, 151.6, 148.3, 142.0, 131.3, 131.1,
129.3, 128.2, 126.07, 126.0, 122.7, 119.2, 114.4, 66.0, 65.8, 55.4, 46.7,
41.7; HRMS (ESI) m/z calcd for C24H21N3O5 [M + Na]+ 454.1379,
found 454.1383.
131.1, 129.5, 128.9, 128.7, 128.5, 128.2, 127.9, 127.7, 126.9, 122.6,
61.5, 14.0; HRMS (ESI) m/z calcd for C17H12N2O4S2 [M + H]+
373.0317, found 373.0304.
2-Phenyl-5-(4-methoxyphenyl)-4′-(4-tosyl)-4,5′-bisoxazole (8ab):
obtained from oxazolone 4a and isocyanide 12b, pale yellow solid
(106.0 mg, 73%); mp 183−185 °C; Rf = 0.54 (1/1 EtOAc/hexane); IR
2-Phenyl-5-(2-thienyl)-4′-(N-morpholinocarbonyl)-4,5′-bisoxa-
zole (8cc): obtained from oxazolone 4c and isocyanide 12c, gray solid
(120.3 mg, 89%); mp 218−220 °C; Rf = 0.25 (8/2 EtOAc/hexane); IR
1
1
(KBr, cm−1) 3148, 2929, 2862, 1499, 1334, 1264, 1148, 1091; H
(KBr, cm−1) 3105, 2902, 2859, 1625, 1498, 1114, 919, 699; H NMR
NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.14−8.11 (m, 2H), 7.71
(400 MHz, CDCl3) δ 8.09−8.07 (m, 2H), 8.02 (s, 1H), 7.66 (dd, J =
3956
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3.6 Hz, 1.2 Hz, 1H), 7.50−7.49 (m, 3H), 7.46 (dd, J = 5.2 Hz, 1.2 Hz,
1H), 7.14 (dd, J = 5.2 Hz, 3.6 Hz, 1H), 3.76 (br s, 4H), 3.66 (br s,
2H), 3.59 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 161.1, 159.5,
151.8, 143.4, 141.0, 131.8, 131.5, 129.4, 129.1, 128.3, 127.9, 127.6,
126.2, 125.6, 123.2, 66.1, 65.8, 46.7, 41.8; HRMS (ESI) m/z calcd for
C21H17N3O4S [M + Na]+ 430.0837, found 430.0833.
2-Phenyl-5-(1-methyl-3-indolyl)-4′-(N-morpholinocarbonyl)-4,5′-
bisoxazole (8ec): obtained from oxazolone 4e and isocyanide 12c,
yellow solid (122.6 mg, 94%); mp 220−222 °C; Rf = 0.2 (9/1 EtOAc/
hexane); IR (KBr, cm−1) 3135, 2902, 2852, 1625, 1568, 1114, 737; 1H
NMR (400 MHz, acetone-d6) δ 8.32 (s, 1H), 8.19−8.16 (m, 2H), 8.04
(s, 1H), 8.00 (dt, J = 7.2 Hz, 1.2 Hz, 1H), 7.63−7.54 (m, 4H), 7.34−
7.30 (m, 1H), 7.26−7.22 (m, 1H), 3.97 (s, 3H), 3.58 (br s, 4H), 3.48
(br s, 2H), 3.41 (br s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 161.5,
158.7, 151.3, 146.0, 141.9, 136.7, 130.9, 130.4, 130.3, 129.4, 126.3,
125.8, 125.0, 122.6, 121.4, 121.1, 120.0, 110.7, 101.3, 66.0, 65.8, 46.7,
41.8, 33.1; HRMS (ESI) m/z calcd for C26H22N4O4 [M + Na]+
477.1539, found 477.1535.
2-Phenyl-5-(3-pyridyl)-4′-(N-morpholinocarbonyl)-4,5′-bisoxa-
zole (8fc): obtained from oxazolone 4f and isocyanide 12c, pale yellow
solid (118.1 mg, 87%); mp 210−212 °C; Rf = 0.40 (1/1 DCM/
acetone); IR (KBr, cm−1) 3092, 2978, 2865, 1625, 1505, 1108, 957;
1H NMR (400 MHz, CDCl3) δ 9.00 (br s, 1H), 8.66 (br s, 1H), 8.12−
8.09 (m, 2H), 8.04 (br d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.54−7.49 (m,
3H), 7.44−7.41 (m, 1H), 3.76−3.67 (m, 8H); 13C NMR (100 MHz,
CDCl3) δ 161.9, 161.6, 150.3, 150.1, 147.7, 146.1, 143.5, 134.0, 132.7,
131.5, 129.1, 126.9, 126.4, 125.9, 123.7, 66.9, 66.7, 47.5, 42.5; HRMS
(ESI) m/z calcd for C22H18N4O4 [M + Na]+ 425.1226, found
425.1228.
(dd, J = 3.6 Hz, 2.4 Hz, 1H), 3.74 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.4, 150.5, 143.0, 138.5, 136.8, 134.0, 130.9, 129.6, 129.0,
128.7, 128.3, 126.8, 126.4, 126.0, 125.5, 119.7, 113.2, 108.8, 35.7;
HRMS (ESI) m/z calcd for C23H16ClN3O2 [M + Na]+ 424.0829,
found 424.0829.
2-Phenyl-5-(1-methyl-3-indolyl)-4′-(4-chlorophenyl)-4,5′-bisoxa-
zole (8ed): obtained from oxazolone 4e and isocyanide 12d, reddish
brown solid (93.4 mg, 72%); mp 165−167 °C; Rf = 0.5 (3/7 EtOAc/
hexane); IR (KBr, cm−1) 3130, 3054, 2928, 1574, 1479, 1102, 907,
1
731; H NMR (400 MHz, acetone-d6) δ 8.37 (s, 1H), 8.21−8.18 (m,
2H), 7.96−7.90 (m, 3H), 7.64−7.57 (m, 4H), 7.48 (dt, J = 8.0 Hz, 0.8
Hz, 1H), 7.33−7.27 (m, 3H), 7.24−7.19 (m, 1H), 3.84 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 159.9, 150.7, 147.0, 139.3, 136.9, 136.2,
133.9, 130.7, 129.8, 129.1, 128.8, 128.6, 128.4, 127.3, 126.5, 125.5,
123.1, 122.4, 121.3, 120.8, 109.9, 103.0, 33.2; HRMS (ESI) m/z calcd
for C27H18ClN3O2 [M + Na]+ 474.0985, found 474.0982.
2-Phenyl-5-(3-pyridyl)-4′-(4-chlorophenyl)-4,5′-bisoxazole (8fd):
obtained from oxazolone 4f and isocyanide 12d, pale yellow solid
(99.8 mg, 74%); mp 148−150 °C; Rf = 0.42 (3/7 EtOAc/hexane); IR
1
(KBr, cm−1) 3142, 3035, 1662, 1555, 1518, 1089, 938, 699; H NMR
(400 MHz, acetone-d6) δ 8.88 (d, J = 2.1 Hz, 1H), 8.56 (dd, J = 4.8
Hz, 1.2 Hz, 1H), 8.44 (s, 1H), 8.23−8.20 (m, 2H), 8.04−8.01 (ddd, J
= 8.0 Hz, 2.1 Hz, 1.2 Hz, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.63−7.60 (m,
3H), 7.42 (ddd, J = 8.0 Hz, 4.8 Hz, 1.2 Hz, 1H), 7.37 (d, J = 8.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 161.8, 151.1, 150.1, 147.2,
146.2, 137.8, 137.7, 134.6, 133.1, 131.5, 129.3, 129.2, 128.8, 128.7,
126.9, 126.8, 126.5, 123.9, 123.5; HRMS (ESI) m/z calcd for
C23H14ClN3O2 [M + H]+ 400.0853, found 400.0857.
2,5-Bis(2-thienyl)-4′-(4-chlorophenyl)-4,5′-bisoxazole (8gd): ob-
tained from oxazolone 4g and isocyanide 12d, pale yellow solid (87.5
mg, 71%); mp 158−160 °C; Rf = 0.5 (2/8 EtOAc/hexane); IR (KBr,
2-(2-Thienyl)-5-(benzo[d][1,3]dioxol-5-yl)-4′-(N-morpholinocar-
bonyl)-4,5′-bisoxazole (8hc): obtained from oxazolone 4h and
isocyanide 12c, pale yellow solid (113.7 mg, 84%); mp 188−190
°C; Rf = 0.30 (8/2 EtOAc/hexane); IR (KBr, cm−1) 3096, 2926, 2844,
1
cm−1) 3101, 2926, 2859, 1720, 1602, 1521, 1234, 1094, 837, 712; H
NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.91 (dd, J = 5.1 Hz, 1.2
Hz, 1H), 7.89 (dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.77 (d, J = 8.8 Hz, 2H),
7.71 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.41 (dd, J
= 3.6 Hz, 1.2 Hz, 1H), 7.30 (dd, J = 5.1 Hz, 4.0 Hz, 1H), 7.13 (dd, J =
4.8 Hz, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 156.7, 151.1,
144.8, 137.9, 137.5, 130.4, 129.54, 129.49, 128.97, 128.93, 128.7,
128.6, 128.3, 128.2, 127.9, 127.7, 126.8, 124.0; HRMS (ESI) m/z calcd
for C20H11ClN2O2S2 [M + H]+ 411.0029, found 411.0015.
2-Phenyl-5-(4-methoxyphenyl)-4′-(4-pyridyl)-4,5′-bisoxazole
(8ae): obtained from oxazolone 4a and isocyanide 12e, off-white solid
(92.5 mg, 78%); mp 158−160 °C; Rf = 0.2 (4/6 EtOAc/hexane); IR
(KBr, cm−1) 2947, 2933, 2845, 1734, 1602, 1433, 1271, 1168, 845; 1H
NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.9 Hz, 2H), 8.13−8.16 (m,
2H), 8.08 (s, 1H), 7.73 (dd, J = 4.9 Hz, 1.6 Hz, 2H), 7.50−7.54 (m
3H), 7.49 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.8, 160.6, 151.1, 150.0, 146.1,
1
1640, 1501, 1457, 1243, 1104, 1041; H NMR (400 MHz, CDCl3) δ
7.97 (s, 1H), 7.73 (dd, J = 4.0 Hz, 1.2 Hz, 1H), 7.48 (dd, J = 5.2 Hz,
1.2 Hz, 1H), 7.23 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.15−7.13 (m, 2H),
6.88 (d, J = 8.4 Hz, 1H), 6.04 (s, 2H), 3.75−3.60 (m, 8H); 13C NMR
(100 MHz, CDCl3) δ 161.8, 156.8, 150.0, 148.9, 148.4, 148.1, 143.4,
132.2, 129.2, 129.1, 128.6, 128.2, 123.2, 121.5, 121.2, 108.9, 107.1,
101.7, 66.8, 66.7, 47.4, 42.5; HRMS (ESI) m/z calcd for C22H17N3O6S
[M + H]+ 452.0916, found 452.0903.
2-Phenyl-5-(4-methoxyphenyl)-4′-(4-chlorophenyl)-4,5′-bisoxa-
zole (8ad): obtained from oxazolone 4a and isocyanide 12d, white
solid (120.0 mg, 91%); mp 158−160 °C; Rf = 0.53 (3/7 EtOAc/
hexane); IR (KBr, cm−1) 3129, 2829, 1607, 1511, 1256, 1180, 1091,
931, 830; 1H NMR (400 MHz, CDCl3) δ 8.16−8.13 (m, 2H), 8.05 (s,
1H), 7.72 (d, J = 9.0 Hz, 2H), 7.52−7.49 (m, 3H), 7.45 (d, J = 9.0 Hz,
2H), 7.23 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 3.81 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 160.5, 160.3, 150.8, 149.4, 138.6,
141.0, 138.5, 135.6, 131.1, 129.1, 127.7, 126.8, 126.7, 123.1, 121.4,
119.8, 114.5, 55.2; HRMS (ESI) m/z calcd for C24H17N3O3 [M + H]+
396.1348, found 396.1337.
136.9, 134.1, 130.8, 129.4, 128.9, 128.5, 128.4, 127.5, 126.8, 126.5,
123.4, 119.8, 114.2, 55.4; HRMS (ESI) m/z calcd for C25H17ClN2O3
[M + Na]+ 451.0825, found 451.0821.
2-Phenyl-5-(3,4-dimethoxyphenyl)-4′-(4-pyridyl)-4,5′-bisoxazole
(8be): obtained from oxazolone 4b and isocyanide 12e, yellow solid
(86.1 mg, 72%); mp 159−161 °C; Rf = 0.4 (7/3 EtOAc/hexane); IR
(KBr, cm−1) 3060, 2934, 2840, 1599, 1511, 1259, 1026, 686; 1H NMR
(400 MHz, CDCl3) δ 8.54 (dd, J = 4.8 Hz, 1.6 Hz, 2H), 8.16−8.14 (m,
2H), 8.09 (s, 1H), 7.74 (dd, J = 4.8 Hz, 1.6 Hz, 2H), 7.54−7.52 (m,
3H), 7.16 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.83
(d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.6, 151.1, 150.5, 150.1, 150.0, 149.3, 141.1, 138.5, 135.8,
131.2, 139.1, 126.8, 126.7, 123.2, 121.3, 119.8, 119.6, 111.5, 109.1,
56.1, 56.0; HRMS (ESI) m/z calcd for C25H19N3O4 [M + H]+
426.1454, found 426.1454.
2-Phenyl-5-(2-thienyl)-4′-(4-chlorophenyl)-4,5′-bisoxazole (8cd):
obtained from oxazolone 4a and isocyanide 12d, white solid (110.1
mg, 82%); mp 150−152 °C; Rf = 0.65 (3/7 EtOAc/hexane); IR (KBr,
1
cm−1) 3085, 2991, 1561, 1518, 1479, 1089, 837, 699; H NMR (400
MHz, CDCl3) δ 8.15−8.12 (m, 2H), 8.08 (s, 1H), 7.78 (d, J = 8.0 Hz,
2H), 7.53−7.51 (m, 3H), 7.35 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.30−7.28
(m, 3H), 7.01 (dd, J = 5.2 Hz, 3.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 160.5, 151.0, 145.3, 137.81, 137.76, 134.4, 131.2, 129.6,
129.1, 128.7, 128.6, 128.0, 127.7, 126.84, 126.79, 126.6, 124.2; HRMS
(ESI) m/z calcd for C22H13ClN2O2S [M + Na]+ 427.0284, found
427.0286.
2-Phenyl-5-(2-thienyl)-4′-(4-pyridyl)-4,5′-bisoxazole (8ce): ob-
tained from oxazolone 4c and isocyanide 12e, gray solid (86.2 mg,
70%); mp 128−130 °C; Rf = 0.55 (7/3 EtOAc/hexane); IR (KBr,
2-Phenyl-5-(1-methyl-2-pyrrolyl)-4′-(4-chlorophenyl)-4,5′-bisoxa-
zole (8dd): obtained from oxazolone 4d and isocyanide 12d, off-white
solid (96.9 mg, 72%); mp 116−118 °C; Rf = 0.6 (1/1 EtOAc/hexane);
1
1
IR (KBr, cm−1) 3117, 2928, 2852, 1518, 1486, 1089, 932, 711; H
cm−1) 3085, 3060, 2928, 1662, 1599, 1410, 906, 705, 686; H NMR
NMR (400 MHz, CDCl3) δ 8.10−8.07 (m, 2H), 7.99 (s, 1H), 7.77 (d,
J = 8.6 Hz, 2H), 7.51−7.50 (m, 3H), 7.29 (d, J = 8.6 Hz, 2H), 6.71
(dd, J = 2.4 Hz, 1.6 Hz, 1H), 6.28 (dd, J = 3.6 Hz, 1.6 Hz, 1H), 6.087
(400 MHz, CDCl3) δ 8.58 (d, J = 6.0 Hz, 2H), 8.15−8.12 (m, 2H),
8.12 (s, 1H), 7.78 (dd, J = 4.8 Hz, 1.6 Hz, 2H), 7.55−7.51 (m, 3H),
7.38 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.34 (dd, J = 3.6 Hz, 1.2 Hz, 1H),
3957
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7.032 (dd, J = 5.2 Hz, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
160.6, 151.1, 150.0, 145.7, 140.2, 138.6, 136.3, 131.4, 129.2, 128.4,
128.04, 128.01, 127.1, 126.8, 126.5, 123.7, 121.6; HRMS (ESI) m/z
calcd for C21H13N3O2S [M + H]+ 372.0807, found 372.0809.
2-Phenyl-5-(1-methyl-2-pyrrolyl)-4′-(4-pyridyl)-4,5′-bisoxazole
(8de): obtained from oxazolone 4d and isocyanide 12e, brown solid
(98.8 mg, 80%); mp 148−150 °C; Rf = 0.53 (7/3 EtOAc/hexane); IR
(KBr, cm−1) 3092, 3061, 3006,1611, 1572, 1486, 1094, 937; 1H NMR
(400 MHz, CDCl3) δ 8.57 (dd, J = 4.8 Hz, 1.4 Hz, 2H), 8.10−8.08 (m,
2H), 8.02 (s, 1H), 7.78 (dd, J = 4.8 Hz, 1.4 Hz, 2H), 7.53−7.50 (m,
3H), 6.73 (dd, J = 2.8 Hz, 1.6 Hz, 1H), 6.32 (dd, J = 4.0 Hz, 1.6 Hz,
1H), 6.09 (dd, J = 4.0 Hz, 2.8 Hz, 1H), 3.77 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 160.6, 150.7, 149.7, 143.4, 140.7, 138.6, 135.3, 131.0,
129.0, 126.6, 126.4, 126.2, 125.0, 121.6, 119.5, 113.4, 108.9, 35.8;
HRMS (ESI) m/z calcd for C22H16N4O2 [M + H]+ 369.1352, found
369.1354.
2-Phenyl-5-(1-methyl-3-indolyl)-4′-(4-pyridyl)-4,5′-bisoxazole
(8ee): obtained from oxazolone 4e and isocyanide 12e, yellow solid
(96.0 mg, 80%); mp 188−190 °C; Rf = 0.33 (7/3 EtOAc/hexane); IR
(KBr, cm−1) 3061, 2810, 1619, 1580, 1486, 1376, 1110, 898; 1H NMR
(400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.51 (dd, J = 4.6 Hz, 1.6 Hz,
2H), 8.12 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.77 (dd, J = 4.6 Hz, 1.6
Hz, 2H), 7.72 (s, 1H), 7.65−7.59 (m, 3H), 7.52 (d, J = 8.4 Hz, 1H),
7.29 (td, J = 7.7 Hz, 1.2 Hz, 1H), 7.22 (td, J = 7.7 Hz, 1.2 Hz, 1H),
3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 150.8, 149.7,
147.5, 141.7, 138.8, 137.0, 134.8, 130.8, 129.1, 128.8, 127.2, 126.5,
125.4, 123.2, 122.0, 121.49, 121.46, 120.8, 110.1, 103.0, 33.4; HRMS
(ESI) m/z calcd for C26H18N4O2 [M + H]+ 419.1508, found 419.1511.
2-Phenyl-5-(3-pyridyl)-4′-(4-pyridyl)-4,5′-bisoxazole (8fe): ob-
tained from oxazolone 4f and isocyanide 12e, pale yellow solid
(96.4 mg, 78%); mp 138−140 °C; Rf = 0.40 (0.5/9.5 MeOH/DCM);
IR (KBr, cm−1) 3091, 3040, 1607, 1550, 1480, 1402, 1091, 938, 684;
1H NMR (400 MHz, CDCl3) δ 8.86 (br d, J = 2.0 Hz, 1H), 8.59−8.57
(m, 3H), 8.17−8.15 (m, 2H), 8.09 (s, 1H), 7.86 (ddd, J = 8.0 Hz, 2.2
Hz, 1.6 Hz, 1H), 7.79 (dd, J = 4.4 Hz, 1.6 Hz, 2H), 7.57−7.52 (m,
3H), 7.31 (ddd, J = 8.0 Hz, 5.0 Hz, 0.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 162.0, 151.2, 150.3, 150.1, 147.4, 146.7, 140.0, 138.3, 136.4,
133.3, 131.7, 129.3, 126.9, 126.4 126.3, 123.8, 123.6, 121.7; HRMS
(ESI) m/z calcd for C22H14N4O2 [M + H]+ 367.1195, found 367.1193.
2-(2-Thienyl)-5-(benzo[d][1,3]dioxol-5-yl)-4′-(4-pyridyl)-4,5′-bi-
soxazole (8he): obtained from oxazolone 4h and isocyanide 12e, off-
white solid (89.7 mg, 72%); mp 167−169 °C; Rf = 0.40 (1/1 EtOAc/
hexane); IR (KBr, cm−1) 3388, 3094, 2903, 1609, 1506, 1477, 1249,
1035, 720; 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.54 (br s,
2H), 7.93 (dd, J = 3.6 Hz, 1.0 Hz, 1H), 7.85 (dd, J = 5.2 Hz, 1.0 Hz,
1H), 7.67 (d, J = 3.6 Hz, 2H), 7.29 (dd, J = 5.2 Hz, 3.6 Hz, 1H), 7.06−
7.04 (m, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.05 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 156.9, 151.3, 149.2, 149.1, 149.0, 148.2, 140.8, 139.1,
135.5, 129.5, 128.9, 128.8, 128.3, 123.1, 120.9, 120.7, 108.9, 106.3,
101.7; HRMS (ESI) m/z calcd for C22H13N3O4S [M + H]+ 416.0705,
found 416.0705.
Bangalore, for financial support and the Indian National
Science Academy, New Delhi, for an INSA Senior Scientist
position (to H.I.).
DEDICATION
■
Dedicated to Professor Yoshinori Yamamoto on his 70th
Birthday.
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■
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail for H.I.: hila@jncasr.ac.in.
Notes
■
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. C. N. R. Rao, FRS, for encouragement, the
Council of Scientific and Industrial Research (CSIR) for
fellowships (to S.Y. and A.A.), New Delhi, and JNCASR,
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