Room temperature copper(II)-catalyzed oxidative cyclization of enamides to 2,5-disubstituted oxazoles via vinylic C-H functionalization

Article abstract of DOI:10.1021/jo301332s

A copper(II)-catalyzed oxidative cyclization of enamides to oxazoles via vinylic C-H bond functionalization at room temperature is described. Various 2,5-disubstituted oxazoles bearing aryl, vinyl, alkyl, and heteroaryl substituents could be synthesized in moderate to high yields. This reaction protocol is complementary to our previously reported iodine-mediated cyclization of enamides to afford 2,4,5-trisubstituted oxazoles.

Full text of DOI:10.1021/jo301332s

Article
pubs.acs.org/joc
Room Temperature Copper(II)-Catalyzed Oxidative Cyclization of
Enamides to 2,5-Disubstituted Oxazoles via Vinylic C−H
Functionalization
Chi Wai Cheung and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,
United States
S
* Supporting Information
ABSTRACT: A copper(II)-catalyzed oxidative cyclization of
enamides to oxazoles via vinylic C−H bond functionalization at
room temperature is described. Various 2,5-disubstituted oxazoles
bearing aryl, vinyl, alkyl, and heteroaryl substituents could be
synthesized in moderate to high yields. This reaction protocol is
complementary to our previously reported iodine-mediated
cyclization of enamides to afford 2,4,5-trisubstituted oxazoles.
copper-catalyzed amidation of vinyl halides to form enamides,
followed by intramolecular cyclization promoted by iodine
(Scheme 2).10 Unfortunately, the synthesis of mono- and
disubstituted oxazoles still remained a limitation under the
reported reaction conditions, and 2,5-disubstituted oxazoles
were instead generated via a domino copper-catalyzed C−N/
C−O coupling sequence starting from 1,2-dihaloalkenes and
amides. Thus, the development of a direct cyclization of
enamides to oxazoles without the need for a β-vinylic functional
group remains an important challenge.
Recently, several examples of transition-metal-catalyzed
methods for the direct vinylic C−H functionalization of
enamides have been described.11 Moreover, copper, as an
inexpensive and readily available metal, has been widely utilized
to facilitate C−O bond formation, via oxidative C−H
functionalization, for the formation of various heterocycles.12
We thus reasoned that a Cu-catalyzed direct oxidative
cyclization of enamides to oxazoles via vinylic C−H
functionalization might be plausible. In fact, during the
preparation of this manuscript, Wendlandt and Stahl disclosed
a similar method for the Cu-mediated oxidative cyclization of
enamides to 2,5-disubstituted oxazoles (eq 1).13 Their method
INTRODUCTION
■
Substituted oxazoles can be found in a wide variety of
biologically active molecules of interest to the drug discovery
community. Oxazole-containing biologically active natural
products,1 especially the diazonamide1b and phorboxazole1c
families, exhibit anticancer properties, and a number of
synthetic trisubstituted2 and 2,5-disubstituted3 oxazoles have
been evaluated to show activity against diabetes,2b Gram-
positive and Gram-negative bacterial infections,3a breast
cancer,3b and pancreatic cancer3c (Figure 1). Moreover,
substituted oxazoles can be utilized in agrochemicals,4
fluorescent dyes,5 and polymers6 and also as ligands for
transition-metal catalysis.7 Consequently, the development of
synthetic methods to access functionalized oxazoles is of great
importance to synthetic organic chemists.
To date, various synthetic methods have been developed for
the synthesis of substituted oxazoles.8−10 In particular, a
common strategy has been to convert an acyclic precursor to
an oxazole ring.8a−d,i,9,10 A versatile cyclization strategy is the
Robinson−Gabriel condensation,8a−d which has been utilized
to prepare a range of highly substituted and complex oxazoles
(Scheme 1A). However, this method requires the use of
Bronsted acid catalysts or Lewis acid reagents, which limits the
̈
overall functional group tolerance of the transformation.
Alternatively, enamides can serve as stable and easily accessible
starting materials to afford oxazoles.9,10 Enamides bearing the β-
vinylic Cheteroatom bonds (C−Br,9a−d C−I,9e,f and C−S9g)
have been isolated or generated in situ, which undergo facile
intramolecular vinylation of the amide oxygen to provide a
broader range of oxazoles under milder conditions (Scheme
1B). While this strategy is effective, a method for the cyclization
of enamides to oxazoles, without the need for further vinylic
C−H functionalization, would be a more direct and convenient
means of obtaining the same products (Scheme 1C).
is attractive as it uses oxygen as the oxidant, albeit with a
stoichiometric quantity of copper(II) chloride, to promote this
cyclization. Herein, we report a method for the synthesis of a
broad range of 2,5-disubstituted oxazoles via stepwise Cu-
Our group previously reported the development of a
sequential synthesis of 2,4,5-trisubstituted oxazoles via initial
Received: June 26, 2012
© XXXX American Chemical Society
A
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Figure 1. Selected biologically active oxazoles.
nicotinate (40 mol %) as a ligand for copper increased the yield
up to 78% (Table 1, entry 3). A number of electronically varied
substituted pyridine ligands were evaluated (Table 1, entries 3−
7), and ethyl nicotinate was identified as the optimal ligand. In
an attempt to reduce the loading of ethyl nicotinate, we found
that by slightly increasing the amount of copper catalyst to 7.5
mol %, the amount of ethyl nicotinate could be lowered to 15
mol % while maintaining a high yield of product (Table 1, entry
9). The use of CuBr2 was also found to be much more effective
than the other transition metal salts (CuCl2, FeBr2, and FeCl2)
(Table 1, entries 11−13).16 In the absence of CuBr2, only a
trace of 2a was obtained (Table 1, entry 14).
Scheme 1. Approaches to Oxazole Synthesis via Cyclization
With good reaction conditions, we set out to examine the
substrate scope for the process (Table 2). The process tolerates
a range of ortho-, meta-, and para-substituents on either or both
aromatic rings of the enamide intermediate to generally afford
2,5-diaryloxazoles in good yields. Notably, chloro- and bromo-
substituted diaryloxazoles (2d, 2l, and 2m) could be prepared,
which render them as suitable substrates for further
functionalization via a range of cross-coupling methods.
Moreover, these conditions described also provide access to
2,5-diaryloxazoles bearing fluoro and trifluoromethyl substitu-
ents (2e, 2f, 2n, and 2o), which are often highly desirable in the
synthesis of novel therapeutics.17 Ortho-substitution on the
enamide aryl groups was also well-tolerated, affording the
corresponding oxazoles in high yields (2p, 2q). The presence of
a highly electron-withdrawing nitro group on the benzamide
region (2g, 2h) or of a strongly π-donating methoxy group on
the β-styryl region (2i)18 led to lower yields of the
corresponding oxazoles.
catalyzed amidation of vinyl halides to form enamides, followed
by subsequent Cu-catalyzed oxidative cyclization, promoted by
potassium persulfate, of the enamide intermediates under
ambient conditions (Scheme 3).
RESULTS AND DISCUSSION
■
We began our studies by subjecting (E)-N-styrylbenzamide
(1a) to a catalytic amount of copper(II) bromide, using
potassium persulfate as an oxidant (Table 1, entry 1). Despite
complete conversion of 1a, 2,5-diphenyloxazole (2a) was
obtained in only 14% yield.14 The use of tetrabutylammonium
bromide (TBAB) as an additive,15 which probably aids in the
regeneration of CuBr2, led to a significant increase in yield
(59%, Table 1, entry 2). Further, we found that the use of ethyl
Next, we sought to extend this methodology to include 2,5-
disubstituted oxazoles bearing vinyl, alkyl, and heterocyclic
Scheme 2. Sequential Synthesis of Trisubstituted Oxazoles via Coupling and Cyclization
B
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Scheme 3. Improved Cu-Catalyzed Oxidative Cyclization of Enamides to 2,5-Disubstituted Oxazoles
a
CuBr, is then oxidized by K2S2O8 and reacts with TBAB to
regenerate the CuBr2 catalyst (Scheme 4, transformation iv).
Table 1. Optimization of Oxidative Cyclization of Enamide
CONCLUSION
■
In summary, we have developed an efficient room temperature
catalytic oxidative cyclization of enamides to generate 2,5-
disubstituted oxazoles by using catalytic amounts of CuBr2 in
conjunction with K2S2O8 as an oxidant. This reaction protocol
can tolerate enamide substrates bearing aryl, heteroaryl, vinyl,
and/or alkyl substituents to afford the corresponding oxazoles
in moderate to high yields. This transformation is comple-
mentary to the iodine-promoted cyclization of enamides to
2,4,5-trisubstituted oxazoles previously reported by our group.
catalyst
conversion
% yield of
b
c
entry
(x mol %)
ligand (y mol %)
none
(%)
2a
d
e
1
CuBr2 (5)
CuBr2 (5)
CuBr2 (5)
CuBr2 (5)
CuBr2 (5)
CuBr2 (5)
CuBr2 (5)
CuBr2 (5)
CuBr2 (7.5)
CuBr2 (10)
100
100
100
100
100
100
100
100
100
100
39
14
2
none
59
78
62
59
64
54
66
84
80
3
ethyl nicotinate (40)
3-nitropyridine (40)
3-cyanopyridine (40)
2-fluoropyridine (40)
pyridine (40)
4
5
6
7
EXPERIMENTAL SECTION
■
8
ethyl nicotinate (10)
ethyl nicotinate (15)
ethyl nicotinate (20)
ethyl nicotinate (10)
ethyl nicotinate (40)
ethyl nicotinate (40)
ethyl nicotinate (15)
General Information. Nuclear magnetic resonance spectra were
recorded on a Bruker 400 MHz instrument at ambient temperature.
All 1H NMR spectra were measured in parts per million (ppm) relative
to the signals for tetramethylsilane (TMS) added into the deuterated
chloroform (CDCl3) (0 ppm) or the signals for residual dimethyl
sulfoxide (DMSO) in deuterated DMSO (DMSO-d6) (2.50 ppm).
Data for 1H NMR were reported as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, qu = quintet, m =
multiplet, br = broad, ovrlp = overlap), coupling constants, and
integration. All 13C NMR spectra were reported in ppm relative to
CDCl3 (77.16 ppm)20 or DMSO-d6 (25.12 ppm).20 All 19F NMR
spectra were reported in ppm relative to a CFCl3 external standard (0
ppm). Anhydrous acetonitrile (99.8%) was purchased from Alfa Aesar.
Other commercial materials were used as received unless otherwise
noted. Flash column chromatography was performed using Silicycle
silica gel (ultra pure grade). (E)-(2-bromovinyl)benzene,21 (E)-1-(2-
bromovinyl)-4-methoxybenzene,21 (E)-1-(2-bromovinyl)-4-methyl-
benzene,21 (E)-1-(2-bromovinyl)-4-chlorobenzene,21 (E)-1-iododec-
1-ene,22 ((1E)-4-bromobuta-1,3-dien-1-yl)benzene23 ((3Z):(3E) =
2.6:1.0), and (E)-3-(3,4-dimethoxyphenyl)acrylamide24 were prepared
according to the literature procedures.
9
10
11
12
13
14
f
e
CuCl2 (5)
2
e
FeBr2 (20)
75
24
f
FeCl2 (20)
49
0
e
none
50
2
a
Reaction conditions: enamide (0.2 mmol), tetrabutylammonium
bromide (TBAB) (0.24 mmol), K2S2O8 (0.26 mmol), CuBr2 (x mol
%), ligand (y mol %), acetonitrile (2 mL), rt, 24 h, argon atmosphere.
Determined by GC. Isolated yield. No TBAB was added. GC yield
using n-dodecane as an internal standard. Tetrabutylammonium
b
c
d
e
f
chloride (TBAC) (1.2 equiv) was used.
substitution (Table 3). Enamides bearing the styryl groups
could be cyclized to afford the styryloxazoles (4a,b), including
the natural product annuloline (4c).19 Enamides bearing both
cyclic and acyclic alkyl groups were also viable substrates (4d−
f), although, interestingly, the cyclohexyl ring of oxazole 4f was
partially oxidized to 1-cyclohexenyl (4f′) during the course of
the reaction. We were particularly pleased to discover that
enamides bearing electron-rich 2-furyl, 2- and 3-thienyl, and N-
benzoyl-5-indolyl groups survived the oxidizing conditions to
afford the corresponding oxazoles in moderate to high yields
(4g−k). Unfortunately, an oxazole containing an N-methyl-2-
pyrrolyl group at the 2-position, as well as oxazoles bearing N-
tosyl-2-pyrrolyl and 2-thienyl groups at the 5-position, could
not be efficiently synthesized using the current conditions.
Moreover, oxazoles with pyridyl groups, as well as an oxazole
bearing a N-methyl-2-imidazolyl group at the 2-position, could
be generated only in low yields.
Regarding the mechanism of copper(II)-catalyzed oxidative
cyclization of enamides to oxazoles, Wendlandt and Stahl have
proposed that CuCl2 acts as a single-electron oxidant, triggering
the cyclization via a radical pathway (eq 1).13 We concur; in our
case, CuBr2 most likely serves as a single-electron oxidant,
converting the electron-rich enamide 1a to an enamide radical
cation (Scheme 4, transformation i), which then cyclizes to
radical intermediate I (Scheme 4, transformation ii).13
Subsequent oxidation of I by CuBr2 provides the oxazole 2a
(Scheme 4, transformation iii). The reduced form of copper,
General Procedure for the Preparation of β-Aryl-vinyl
Bromides. Adapted from a previously reported procedure with
some modification.21 A 250 mL round-bottom flask equipped with a
Teflon-coated magnetic stir bar was charged with the cinnamic acid or
its derivatives (1.0 equiv), N-bromosuccinimide (NBS) (1.05 equiv),
and manganese(II) acetate tetrahydrate (Mn(OAc)2·4H2O) (20 mol
%), followed by acetonitrile and water (1:1). The reaction mixture was
stirred overnight at room temperature. The reaction mixture was then
washed with excess water and ethyl acetate in a separation funnel. The
aqueous fraction was further washed with ethyl acetate until most of
the product has been extracted as judged by TLC analysis. The
combined organic fraction was dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography (ethyl acetate (EtOAc)/hexanes = 1: 20) to afford
the desired vinyl bromide. The ratio of (E):(Z) isomers of vinyl
1
bromide was determined by H NMR spectroscopy.
(E)-4-(2-Bromovinyl)phenyl Acetate (S1)25 ((E):(Z) > 99:1).
Synthesized from trans-4-acetoxycinnamic acid (4.50 g, 21.8 mmol),
Mn(OAc)2·4H2O (1.07 g, 4.36 mmol), and NBS (4.07 g, 22.9 mmol)
in acetonitrile/water (50 mL/50 mL); 3.23 g, 13.4 mmol, 61%; off-
1
white solid. H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.4 Hz, 2H),
7.10−7.04 (ovrlp, 3H), 6.73 (d, J = 14.0 Hz, 1H), 2.30 (s, 3H).
(E)-1-Bromo-4-(2-bromovinyl)benzene (S2)26 ((E):(Z) > 99:1).
Synthesized from trans-4-bromocinnamic acid (13.4 g, 59.0 mmol),
C
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a
Table 2. Scope of Enamides bearing Aryl Groups
a
Reaction conditions: enamide (1 mmol), CuBr2 (7.5 mol %), ethyl nicotinate (15 mol %), TBAB (1.2 mmol), K2S2O8 (1.3 mmol), acetonitrile (10
b
mL), rt, 24 h, argon atmosphere; isolated yields based on an average of two runs. Enamide (0.8 mmol).
a
Table 3. Scope of Enamides Bearing Vinyl, Alkyl, and Heteroaryl Groups
a
Reaction conditions: enamide (1 mmol), CuBr2 (7.5 mol %), ethyl nicotinate (15 mol %), TBAB (1.2 mmol), K2S2O8 (1.3 mmol), acetonitrile (10
b
c
mL), rt, 24 h, argon atmosphere; isolated yields based on an average of two runs. CuBr2 (15 mol %), pyridine (60 mol %). CuBr2 (15 mol %),
d
1
ethyl nicotinate (30 mol %). An inseparable dehydrogenated co-product was isolated; ratio of 4f:4f′ was determined by H NMR spectroscopy.
e
Enamide (0.5 mmol).
D
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Scheme 4. Proposed Mechanism for Cu(II)-Catalyzed Oxidative Cyclization of 1a to 2a
Mn(OAc)2·4H2O (2.89 g, 11.8 mmol), and NBS (11.0 g, 62.0 mmol)
in acetonitrile/water (100 mL/100 mL); 6.07 g, 23.2 mmol, 39%; off-
white solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 2H),
7.16 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 14.0 Hz, 1H), 6.78 (d, J = 14.0
Hz, 1H).
130.7, 129.3, 128.7, 128.3, 126.3, 121.4, 116.2, 108.8, 105.7. IR (neat
cm−1) δ 1673, 1468, 1444, 1371, 1323, 1184, 1065, 882, 825, 793, 771,
737, 720, 696, 606. Anal. Calcd for C17H12BrNO: C, 62.60; H, 3.71.
Found: C, 62.79; H, 3.83.
Preparation of Enamides via Cu-Catalyzed Amidations of
Vinyl Halides. Adapted from a previously reported procedure with
some modification.10 An oven-dried 25 mL resealable screw-cap test
tube equipped with a Teflon-coated magnetic stir bar was charged with
vinyl halide (if solid), amide, CuI, and K2CO3. The tube was then
evacuated and backfilled with argon (this sequence was repeated a
total of three times). Vinyl halide (if liquid) and N,N′-dimethylethy-
lenediamine (DMEDA) were added into the tube followed by
anhydrous THF via syringe. The sealed tube was placed in a preheated
oil bath (80 °C). After stirring at the same temperature for 18 h, the
reaction mixture was allowed to cool to room temperature. The
reaction mixture was then extracted with ethyl acetate (EtOAc) (20
mL) and deionized water (100 mL) in a separation funnel. The
aqueous fraction was further extracted with EtOAc (2 × 10 mL). The
combined organic fractions were then dried over Na2SO4, filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography using the indicated solvent system as an eluent to
afford the enamide substrates.
(E)-1-(2-Bromovinyl)-4-fluorobenzene (S3)27 ((E):(Z) > 99:1).
Synthesized from trans-4-fluorocinnamic acid (12.0 g, 72.2 mmol),
Mn(OAc)2·4H2O (3.54 g, 14.4 mmol), and NBS (13.5 g, 75.8 mmol)
in acetonitrile/water (100 mL/100 mL); 7.31 g, 36.4 mmol, 50%; off-
1
3
white solid. H NMR (400 MHz, CDCl3) δ 7.29 (dd, JHH = 8.4 Hz,
4JHF = 5.6 Hz, 2H), 7.08 (d, J = 14.0 Hz, 1H), 7.04 (dd, 3JHH = 8.4 Hz,
3JHF = 8.4 Hz, 2H), 6.71 (d, J = 14.0 Hz, 1H).
(E)-4-(2-Bromovinyl)-1,2-difluorobenzene (S4)28 ((E):(Z) ≈
95:5). Synthesized from trans-3,4-difluorocinnamic acid (10.0 g, 54.3
mmol), Mn(OAc)2·4H2O (2.66 g, 10.9 mmol), and NBS (10.2 g, 57.0
1
mmol); 2.45 g, 11.2 mmol, 21%; pale-yellow oil. H NMR of (E)-
isomer (400 MHz, CDCl3) δ 7.14−7.08 (ovrlp, 2H), 7.02−6.99
(ovrlp, 2H), 6.72 (d, J = 14.4 Hz, 1H).
(E)-1-(2-Bromovinyl)-2-methylbenzene (S5)29 ((E):(Z) > 99:1).
Synthesized from trans-2-methylcinnamic acid (4.00 g, 24.7 mmol),
Mn(OAc)2·4H2O (1.21 g, 4.94 mmol), and NBS (4.62 g, 25.9 mmol)
in acetonitrile/water (80 mL/80 mL); 2.64 g, 13.4 mmol, 54%; pale-
(E)-N-Styrylbenzamide (1a).33 Synthesized from (E)-(2-
bromovinyl)benzene21 (900 mg, 4.92 mmol, 1.0 equiv), benzamide
(714 mg, 5.90 mmol, 1.2 equiv), K2CO3 (1.36 g, 9.84 mmol, 2.0
equiv), CuI (93.7 mg, 0.492 mmol, 10 mol %), DMEDA (212 μL, 1.97
mmol, 40 mol %), and THF (10.0 mL, 0.5 M); EtOAc/hexanes = 1:7,
then 1:4; 736 mg, 3.29 mmol, 67%; white solid. Mp: 178−180 °C (lit.:
172−173 °C).33 1H NMR (400 MHz, DMSO-d6) δ 10.67 (d, J = 7.6
Hz, 1H), 8.00 (d, J = 7.2 Hz, 2H), 7.70 (dd, J = 14.8 Hz, 8.0 Hz, 1H),
7.60 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.40 (d, J = 7.2 Hz,
2H), 7.31 (t, J = 7.6 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 6.50 (d, J = 14.8
Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 164.1, 136.6, 133.4,
131.9, 128.8, 128.5, 127.7, 126.3, 125.3, 124.2, 113.0. IR (neat cm−1)
3302, 1637, 1522, 1483, 1310, 1288, 1171, 1074, 953, 927, 746, 691.
(E)-4-Methoxy-N-styrylbenzamide (1b). Synthesized from (E)-
(2-bromovinyl)benzene21 (1.28 g, 7.0 mmol, 1.0 equiv), 4-
methoxybenzamide (1.27 g, 8.4 mmol, 1.2 equiv), K2CO3 (1.93 g,
14.0 mmol, 2.0 equiv), CuI (267 mg, 1.40 mmol, 20 mol %), DMEDA
(301 μL, 2.80 mmol, 40 mol %), and THF (14.0 mL, 0.5 M); EtOAc/
hexanes = 1:6, then 2:1; 1.09 g, 4.31 mmol, 62%; white solid. Mp:
190−192 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.49 (d, J = 10.0 Hz,
1H), 7.97 (d, J = 8.8 Hz, 2H), 7.66 (dd, J = 14.8 Hz, 10 Hz, 1H), 7.38
(d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.2 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H),
7.06 (d, J = 8.8 Hz, 2H), 6.44 (d, J = 14.8 Hz, 1H), 3.84 (s, 3H). 13C
NMR (100 MHz, DMSO-d6) δ 163.5, 162.2, 136.8, 129.6, 128.7,
126.1, 125.5, 125.2, 124.4, 113.7, 112.3, 55.4. IR (neat cm−1) 3336,
1665, 1636, 1603, 1524, 1486, 1288, 1252, 1179, 1028, 949, 844, 749,
694, 668. Anal. Calcd for C16H15NO2: C, 75.87; H, 5.97. Found: C,
75.61; H, 5.84.
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.30−7.27 (ovrlp, 2H),
7.21−7.12 (ovrlp, 3H), 6.60 (d, J = 14.0 Hz, 1H), 2.30 (s, 3H).
General Procedure for the Preparation of β-Heteroaryl-vinyl
Bromides. Adapted from a previously reported procedure.23 A 250
mL round-bottom flask was charged with a Teflon-coated magnetic stir
bar, (bromomethyl)triphenylphosphonium bromide30 (1.0 equiv), and
potassium tert-butoxide (KOtBu) (1.05 equiv). The reaction vessel was
evacuated and backfilled with argon (this sequence was repeated a
total of 3 times) and then cooled to −78 °C. Anhydrous THF (80
mL) was added slowly into the reaction mixture to give a yellow
suspension, which was stirred at −78 °C for 1 h. A solution of
carboxaldehyde (0.9 equiv) in anhydrous THF (10 mL) was then
introduced via syringe. The resulting reaction mixture was stirred at
−78 °C for 1 h, after which time it was gradually warmed to room
temperature and further stirred for 4 h. The mixture was diluted with
hexanes (100 mL) and filtered under vacuum. The filtrate was dried
over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (EtOAc/hexanes) to afford
the desired vinyl bromide. The ratio of (Z):(E) isomers was
1
determined by H NMR spectroscopy.
3-(2-Bromovinyl)thiophene (S6)31 ((Z):(E) = 4.3:1.0). Synthe-
sized from (bromomethyl)triphenylphosphonium bromide (12.1 g,
27.8 mmol), KOtBu (3.15 g, 28.1 mmol), and thiophene-3-
carboxaldehyde (2.80 g, 25.0 mmol); EtOAc/hexanes = 1:20; 1.96 g,
10.4 mmol, 41%; pale-yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.78
(d, J = 2.8 Hz, 1H), 7.47 (d, J = 5.2 Hz, 1H), 7.32−7.24 (ovrlp, 1.5H),
7.13−7.05 (ovrlp, 1.5H), 6.62 (d, J = 14.0 Hz, 0.23H), 6.22 (d, J = 8.0
Hz, 1H).
(E)-4-Methyl-N-styrylbenzamide (1c).34 Synthesized from (E)-
(2-bromovinyl)benzene21 (1.10 g, 6.0 mmol, 1.0 equiv), 4-
methylbenzamide (973 mg, 7.2 mmol, 1.2 equiv), K2CO3 (1.66 g,
12.0 mmol, 2.0 equiv), CuI (229 mg, 1.20 mmol, 20 mol %), DMEDA
(258 μL, 2.4 mmol, 40 mol %), and THF (12.0 mL, 0.5 M); EtOAc/
hexanes = 1:7, then 1:4; 960 mg, 4.05 mmol, 67%; off-white solid. Mp:
188−190 °C (lit.: 194−195 °C).34 1H NMR (400 MHz, DMSO-d6) δ
10.56 (d, J = 10.0 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.67 (dd, J = 14.8
Hz, 10.0 Hz, 1H), 7.40 (d, J = 7.2 Hz, 2H), 7.34−7.28 (ovrlp, 4H),
7.16 (t, J = 7.2 Hz, 1H), 6.47 (d, J = 14.8 Hz, 1H). 2.38 (s, 3H). 13C
(5-(2-Bromovinyl)-1H-indol-1-yl)(phenyl)methanone (S7)
((Z):(E) = 20:1). Synthesized from (bromomethyl)triphenyl-
phosphonium bromide (8.72 g, 20.0 mmol), KOtBu (2.35 g, 21.0
mmol), and 1-benzoyl-1H-indole-5-carboxaldehyde32 (4.49 g, 18.0
mmol); EtOAc/hexanes = 1:12; 3.68 g, 11.3 mmol, 63%; white solid.
Mp: 66−68 °C. 1H NMR of (Z) isomer (400 MHz, CDCl3) δ 8.37 (d,
J = 8.8 Hz, 1H), 8.01 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.65−7.58
(ovrlp, 2H), 7.52 (t, J = 8.0 Hz, 2H), 7.31 (d, J = 3.6 Hz, 1H), 7.17 (d,
J = 8.0 Hz, 1H), 6.62 (d, J = 4.0 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3) 168.6, 135.7, 134.4, 132.6, 132.1, 130.8,
E
dx.doi.org/10.1021/jo301332s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
NMR (100 MHz, DMSO-d6) δ 163.9, 142.0, 136.7, 130.5, 129.1,
128.7, 127.7, 126.2, 125.2, 124.2, 112.6, 21.0. IR (neat cm−1) 3219,
1624, 1523, 1485, 1309, 1285, 1185, 961, 835, 761, 737, 693, 636.
(E)-4-Chloro-N-styrylbenzamide (1d). Synthesized from (E)-(2-
bromovinyl)benzene21 (1.10 g, 6.0 mmol, 1.2 equiv), 4-chlorobenza-
mide (778 mg, 5.0 mmol, 1.0 equiv), K2CO3 (1.38 g, 10.0 mmol, 2.0
equiv), CuI (191 mg, 1.0 mmol, 20 mol %), DMEDA (215 μL, 2.0
mmol, 40 mol %), and THF (10.0 mL, 0.5 M). EtOAc/hexanes = 1:7,
then 1:4; 821 mg, 3.18 mmol, 64%; pale-yellow solid. Mp: 187−188
180−181 °C. (lit.: 178−179 °C).35 1H NMR (400 MHz, DMSO-d6) δ
10.97 (d, J = 9.6 Hz, 1H), 8.81 (s, 1H), 8.43−8.39 (ovrlp, 2H), 7.82 (t,
J = 8.0 Hz, 1H), 7.65 (dd, J = 14.4 Hz, 9.6 Hz, 1H), 7.41 (d, J = 8.0
Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 6.51 (d, J =
14.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 161.9, 147.8, 136.3,
134.7, 134.1, 130.3, 128.8, 126.5, 126.4, 125.4 123.8, 122.3, 114.0. IR
(neat cm−1) 3301, 1638, 1524, 1348, 1177, 1074, 944, 909, 864, 818,
750, 714, 692, 666.
(E)-N-(4-Methoxystyryl)benzamide (1i).36 Synthesized from
(E)-1-(2-bromovinyl)-4-methoxybenzene21 (1.53 g, 7.2 mmol, 1.2
equiv), benzamide (727 mg, 6.0 mmol, 1.0 equiv), K2CO3 (1.66 g, 12.0
mmol, 2.0 equiv), CuI (343 mg, 1.8 mmol, 30 mol %), DMEDA (387
μL, 3.6 mmol, 60 mol %), and THF (12.0 mL, 0.5 M); EtOAc/
hexanes = 1:2, then 2:1. The isolated white solid was further purified
by recrystallization from acetone/methanol/hexanes (∼3:1:5) via slow
evaporation with the aid of a rotary evaporator; 741 mg, 2.93 mmol,
49%; white solid. Mp: 192−193 °C. 1H NMR (400 MHz, DMSO-d6)
δ 10.55 (d, J = 9.6 Hz, 1H), 7.97 (d, J = 7.2 Hz, 2H), 7.61−7.50
(ovrlp, 4H), 7.33 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.44 (d,
J = 14.4 Hz, 1H), 3.74 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ
163.9, 158.0, 133.5, 131.8, 129.0, 128.5, 127.6, 126.5, 122.4, 114.2,
112.8, 55.1. IR (neat cm−1) 3319, 1636, 1605, 1504, 1484, 1285, 1244,
1177, 1031, 942, 846, 811, 690, 664.
1
°C. H NMR (400 MHz, DMSO-d6) δ 10.71 (d, J = 10.0 Hz, 1H),
8.01 (d, J = 8.8 Hz, 2H), 7.65 (dd, J = 14.8 Hz, 10.0 Hz, 1H), 7.61 (d, J
= 8.8 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.70 (t, J = 7.6 Hz, 2H), 7.17
(t J = 7.2 Hz, 1H), 6.48 (d, J = 14.8 Hz, 1H). 13C NMR (100 MHz,
DMSO-d6) δ 163.0, 136.8, 136.5, 132.1, 129.6, 128.7, 128.6, 126.3,
125.3, 124.0, 113.3. IR (neat cm−1) 3330, 1641, 1523, 1479, 1279,
1171, 1091, 1013, 941, 843, 747, 692, 670. Anal. Calcd for
C15H12ClNO: C, 69.91; H, 4.69. Found: C, 69.91; H, 4.75.
(E)-4-Fluoro-N-styrylbenzamide (1e). Synthesized from (E)-(2-
bromovinyl)benzene21 (1.32 g, 7.2 mmol, 1.2 equiv), 4-fluorobenza-
mide (835 mg, 6.0 mmol, 1.0 equiv), K2CO3 (1.66 g, 12.0 mmol, 2.0
equiv), CuI (229 mg, 1.2 mmol, 20 mol %), DMEDA (258 μL, 2.4
mmol, 40 mol %), and THF (12.0 mL, 0.5 M); EtOAc/hexanes = 1:7,
then 1:4; 813 mg, 3.37 mmol, 56%; off-white solid. Mp: 181−183 °C.
1H NMR (400 MHz, DMSO-d6) δ 10.66 (d, J = 10.0 Hz, 1H), 8.07
(dd, 3JHH = 8.4 Hz, 4JHF = 5.6 Hz, 2H), 7.67 (dd, J = 14.4 Hz, 10.0 Hz,
1H), 7.40−7.34 (ovrlp, 4H), 7.30 (t, J = 8.0 Hz, 2H), 7.17 (t, J = 7.6
Hz, 1H), 6.48 (d, J = 14.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
(E)-4-(2-Benzamidovinyl)phenyl Acetate (1j). Synthesized from
(E)-4-(2-bromovinyl)phenyl acetate (S1) (1.86 g, 7.7 mmol, 1.1
equiv), benzamide (848 mg, 7.0 mmol, 1.0 equiv), K2CO3 (1.26 g, 9.1
mmol, 1.3 equiv), CuI (400 mg, 2.1 mmol, 30 mol %), DMEDA (452
μL, 4.2 mmol, 60 mol %), and THF (14.0 mL, 0.5 M); EtOAc/
hexanes = 1:6, then 2:3. The isolated white solid was further purified
by recrystallization from EtOAc/methanol (∼3:1) via slow evapo-
ration with the aid of a rotary evaporator; 474 mg, 1.69 mmol, 24%;
1
3
δ 164.3 (d, JCF = 248.1 Hz), 163.0, 136.6, 130.4 (d, JCF = 9.1 Hz),
4
2
129.8 (d, JCF = 2.7 Hz), 128.7, 126.3, 125.3, 124.1, 115.5 (d, JCF
=
21.7 Hz), 113.1. 19F NMR (376 MHz, DMSO-d6) δ −108.4. IR (neat
cm−1) 3343, 1642, 1599, 1525, 1483, 1286, 1222, 1158, 942, 846, 747,
692, 655, 624, 604. Anal. Calcd for C15H12FNO: C, 74.67; H, 5.01.
Found: C, 74.85; H, 5.20.
1
white solid. Mp: 205−207 °C. H NMR (400 MHz, DMSO-d6) δ
10.66 (d, J = 10.0 Hz, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.65 (dd, J = 14.8
Hz, 10.0 Hz, 1H), 7.61−7.51 (ovrlp, 3H), 7.43 (d, J = 8.4 Hz, 2H),
7.06 (d, J = 8.4 Hz, 2H), 6.48 (d, J = 14.4 Hz, 1H), 2.26 (s, 3H). 13C
NMR (100 MHz, DMSO-d6) δ 169.3, 164.1, 148.9, 134.3, 133.3,
132.0, 128.5, 127.7, 126.2, 124.3, 122.1, 112.1, 20.9. IR (neat cm−1)
3304, 1755, 1639, 1505, 1371, 1331, 1226, 1016, 949, 915, 796, 694.
Anal. Calcd for C17H15NO3: C, 72.58; H, 5.37. Found: C, 72.39; H,
5.27.
(E)-N-Styryl-4-(trifluoromethyl)benzamide (1f). Synthesized
from (E)-(2-bromovinyl)benzene21 (915 mg, 5.0 mmol, 1.5 equiv),
4-(trifluoromethyl)benzamide (630 mg, 3.33 mmol, 1.0 equiv), K2CO3
(921 mg, 6.67 mmol, 2.0 equiv), CuI (317 mg, 1.67 mmol, 50 mol %),
DMEDA (215 μL, 2.0 mmol, 60 mol %), and THF (7.0 mL, 0.5 M);
EtOAc/hexanes = 1:7, then 1:4; 668 mg, 2.29 mmol, 69%; off-white
solid. Mp: 206−208 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (d, J
= 10.0 Hz, 1H), 8.18 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.68
(dd, J = 14.8 Hz, 10.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 2H), 7.31 (t, J =
(E)-N-(4-Methylstyryl)benzamide (1k).13 Synthesized from (E)-
1-(2-bromovinyl)-4-methylbenzene21 (1.38 g, 7.0 mmol, 1.0 equiv),
benzamide (1.02 mg, 8.4 mmol, 1.2 equiv), K2CO3 (1.93 g, 14.0 mmol,
2.0 equiv), CuI (267 mg, 1.4 mmol, 20 mol %), DMEDA (300 μL, 2.8
mmol, 40 mol %), and THF (14.0 mL, 0.5 M); EtOAc/hexanes = 1:7,
then 1:4; 1.18 g, 4.98 mmol, 71%; off-white solid. Mp: 174−176 °C
(lit.: 178−179 °C).13 1H NMR (400 MHz, DMSO-d6) δ 10.61 (d, J =
9.6 Hz, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.66−7.57 (ovrlp, 2H), 7.53 (t, J
= 7.6 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.45
(d, J = 14.8 Hz, 1H), 2.27 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ
164.0, 135.5, 133.7, 133.4, 131.9, 129.4, 128.5, 127.6, 125.2, 123.4,
113.0, 20.8. IR (neat cm−1) 3301, 1638, 1531, 1506, 1309, 1285, 1170,
956, 925, 794, 692. Anal. Calcd for C16H15NO: C, 80.98; H, 6.37.
Found: C, 80.71; H, 6.41.
7.6 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 6.52 (d, J = 14.8 Hz, 1H). 13C
2
NMR (100 MHz, DMSO-d6) δ 162.9, 137.1, 136.4, 131.7 (q, JCF
=
3
31.7 Hz), 128.8, 128.6, 126.5, 125.5 (q, JCF = 3.3 Hz), 125.4, 123.91
(q, 1JCF = 270.6 Hz), 123.88, 113.8. 19F NMR (376 MHz, DMSO-d6)
δ −61.7. IR (neat cm−1) 3336, 1645, 1527, 1487, 1323, 1169, 1154,
1111, 1064, 1015, 941, 856, 770, 749, 688, 666. Anal. Calcd for
C16H12F3NO: C, 65.98; H, 4.15; Found: C, 65.75; H, 4.20.
(E)-4-Nitro-N-styrylbenzamide (1g). Synthesized from (E)-(2-
bromovinyl)benzene21 (1.10 g, 6.0 mmol, 1.0 equiv), 4-nitro-
benzamide (1.20 g, 7.2 mmol, 1.2 equiv), K2CO3 (1.66 g, 12.0
mmol, 2.0 equiv), CuI (229 mg, 1.2 mmol, 20 mol %), DMEDA (258
μL, 2.4 mmol, 40 mol %), and THF (12.0 mL, 0.5 M); EtOAc/
hexanes = 1:4, then 1:2; 609 mg, 2.27 mmol, 38%; yellow solid. Mp:
224−225 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (d, J = 8.8 Hz,
1H), 8.36 (dd, J = 8.8 Hz, 1.6 Hz, 2H), 8.20 (dd, J = 8.8 Hz, 2.0 Hz,
2H), 7.64 (dd, J = 14.4 Hz, 9.6 Hz, 1H), 7.41 (d, J = 7.6 Hz, 2H), 7.31
(t, J = 7.6 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 6.51 (d, J = 14.8 Hz, 1H).
13C NMR (100 MHz, DMSO-d6) δ 162.4, 149.3, 138.9, 136.3, 129.1,
128.7, 126.6, 125.4, 123.8, 123.6, 114.2. IR (neat cm−1) 3306, 1636,
1598, 1518, 1482, 1310, 1285, 1170, 1109, 937, 865, 852, 749, 685.
Anal. Calcd for C15H12N2O3: C, 67.16; H, 4.51; Found: C, 67.04; H,
4.46.
(E)-N-(4-Chlorostyryl)benzamide (1l). Synthesized from (E)-1-
(2-bromovinyl)-4-chlorobenzene (1.31 g, 6.0 mmol, 1.0 equiv),
benzamide (872 mg, 7.2 mmol, 1.2 equiv), K2CO3 (1.66 g, 12.0
mmol, 2.0 equiv), CuI (286 mg, 1.5 mmol, 25 mol %), DMEDA (322
μL, 3.0 mmol, 50 mol %), and THF (12.0 mL, 0.5 M); EtOAc/
hexanes = 1:7, then 1:3; 987 mg, 3.83 mmol, 64%; pale yellow solid.
1
Mp: 181−183 °C. H NMR (400 MHz, DMSO-d6) δ 10.68 (d, J =
10.0 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.68 (dd, J = 14.8 Hz, 10.0 Hz,
1H), 7.60 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 7.42 (d, J = 8.4
Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 6.45 (d, J = 14.8 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6) δ 164.1, 135.7, 133.3, 132.0, 130.4, 128.6,
128.5, 127.7, 126.9, 125.0, 111.6. IR (neat cm−1) 3338, 1634, 1516,
1479, 1326, 1298, 1275, 1166, 1091, 1010, 945, 852, 808, 716, 692,
657. Anal. Calcd for C15H12ClNO: C, 69.91; H, 4.69. Found: C, 69.82;
H, 4.69.
(E)-3-Nitro-N-styrylbenzamide (1h).35 Synthesized from (E)-(2-
bromovinyl)benzene21 (1.54 g, 8.4 mmol, 1.4 equiv), 3-nitro-
benzamide (997 mg, 6.0 mmol, 1.0 equiv), K2CO3 (1.66 g, 12.0
mmol, 2.0 equiv), CuI (572 mg, 3.0 mmol, 50 mol %), DMEDA (387
μL, 3.6 mmol, 60 mol %), and THF (12.0 mL, 0.5 M); EtOAc/
hexanes = 1:5, then 1:2; 875 mg, 3.26 mmol, 54%; yellow solid. Mp:
F
dx.doi.org/10.1021/jo301332s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(E)-4-Bromo-N-(4-bromostyryl)benzamide (1m). Synthesized
from (E)-1-bromo-4-(2-bromovinyl)benzene (S2) (2.20 g, 8.4 mmol,
1.4 equiv), 4-bromobenzamide (1.20 g, 6.0 mmol, 1.0 equiv), K2CO3
(1.66 g, 12.0 mmol, 2.0 equiv), CuI (229 mg, 1.2 mmol, 20 mol %),
DMEDA (258 μL, 2.4 mmol, 40 mol %), and THF (12.0 mL, 0.5 M);
EtOAc/hexanes = 1:6, then 2:5. The isolated off-white solid was
further purified by recrystallization from acetone/EtOAc/hexanes
(∼1:1:2) via slow evaporation with the aid of a rotary evaporator; 1.02
14.0 mmol, 2.0 equiv), CuI (400 mg, 2.1 mmol, 30 mol %), DMEDA
(452 μL, 4.2 mmol, 60 mol %), and THF (14.0 mL, 0.5 M); EtOAc/
hexanes = 1:7, then 1:3; 1.23 g, 4.27 mmol, 61%; off-white solid. Mp:
179−181 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.87 (d, J = 9.6 Hz,
1H), 8.64 (s, 1H), 8.10−8.04 (ovrlp, 3H), 8.01 (d, J = 8.4 Hz, 1H),
7.68−7.60 (ovrlp, 3H), 7.51 (d, J = 7.6 Hz, 1H), 7.18−7.15 (ovrlp,
2H), 7.10 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 14.4 Hz, 1H), 2.33 (s, 3H).
13C NMR (100 MHz, DMSO-d6) δ 164.0, 135.3, 134.4, 134.2, 132.1,
130.7, 130.3, 129.0, 128.2, 128.1, 128.0, 127.7, 126.9, 126.3, 124.7,
124.2, 124.0, 110.6, 19.6. IR (neat cm−1) 3275, 1636, 1521, 1478,
1327, 1286, 1239, 1089, 951, 822, 741, 718. Anal. Calcd for
C20H17NO: C, 83.59; H, 5.96. Found: C, 83.41; H, 6.04.
1
g, 2.67 mmol, 45%; off-white solid. Mp: 227−230 °C. H NMR (400
MHz, DMSO-d6) δ 10.74 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 7.6 Hz, 2H),
7.74 (d, J = 7.6 Hz, 2H), 7.67 (dd, J = 14.0 Hz, 10.0 Hz, 1H), 7.46 (d, J
= 7.6 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 6.43 (d, J = 14.8 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6) δ 163.1, 135.9, 132.3, 131.5, 129.7,
127.3, 125.8, 124.9, 118.9, 112.0. IR (neat cm−1) 3309, 1639, 1588,
1521, 1477, 1334, 1274, 1170, 1072, 1008, 946, 938, 839, 804, 753,
700, 679. Anal. Calcd for C15H11Br2NO: C, 47.28; H, 2.91. Found: C,
47.03; H, 2.85.
N-((E)-Styryl)cinnamamide (3a).33 Synthesized from (E)-(2-
bromovinyl)benzene21 (1.32 g, 7.2 mmol, 1.2 equiv), trans-
cinnamamide (883 mg, 6.0 mmol, 1.0 equiv), K2CO3 (1.66 g, 12.0
mmol, 2.0 equiv), CuI (229 mg, 1.2 mmol, 20 mol %), DMEDA (258
μL, 2.4 mmol, 40 mol %), and THF (12.0 mL, 0.5 M); EtOAc/
hexanes = 1:4, then 2:1; 1.31 g, 5.26 mmol, 88%; yellow solid. Mp:
196−198 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.50 (d, J = 10.0 Hz,
1H), 7.65−7.57 (ovrlp, 4H), 7.46−7.38 (ovrlp, 5H), 7.29 (t, J = 7.6
Hz, 2H), 7.15 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 16.0 Hz, 1H), 6.28 (d, J
= 14.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 162.6, 140.6,
136.5, 134.6, 129.9, 129.0, 128.7, 127.8, 126.2, 125.2, 123.8, 120.9,
112.2. IR (neat cm−1) 3373, 3159, 3027, 1635, 1606, 1520, 1341, 1234,
1195, 983, 957, 748, 679.
N-((1E,3E)-4-Phenylbuta-1,3-dien-1-yl)benzamide (3b). Syn-
thesized from ((1E)-4-bromobuta-1,3-dien-1-yl)benzene ((3Z): (3E)
= 2.6: 1.0)23 (3.76 g, 18.0 mmol, 3.0 equiv), benzamide (727 mg, 6.0
mmol, 1.0 equiv), K2CO3 (1.66 g, 12.0 mmol, 2.0 equiv), CuI (229
mg, 1.2 mmol, 20 mol %), DMEDA (258 μL, 2.4 mmol, 40 mol %),
and THF (12.0 mL, 0.5 M); EtOAc/hexanes = 1:7, then 1:4; 1.13 g,
4.53 mmol, 70%; yellow solid. Mp: 179−181 °C. 1H NMR (400 MHz,
DMSO-d6) δ 10.62 (d, J = 10.0 Hz, 1H), 7.97 (d, J = 7.6 Hz, 2H), 7.59
(t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H),
7.36 (dd, J = 13.6 Hz, 10.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 2H), 7.18 (t, J
= 7.2 Hz, 1H), 7.03 (dd, J = 15.2 Hz, 11.2 Hz, 1H), 6.49 (d, J = 15.6
Hz, 1H), 6.36 (dd, J = 13.2 Hz, 11.6 Hz, 1H). 13C NMR (100 MHz,
DMSO-d6) δ 163.8, 137.6, 133.3, 131.9, 128.6, 128.5, 128.4, 128.1,
128.0, 127.6, 126.7, 125.8, 114.3. IR (neat cm−1) 3328, 3060, 1634,
1510, 1485, 1444, 1340, 1300, 1264, 1150, 1072, 968, 908, 795, 744,
688. HRMS (ESI) calcd for C17H15NO [M + H]: 250.1226; found
250.1235.
(E)-4-(tert-Butyl)-N-(4-fluorostyryl)benzamide (1n). Synthe-
sized from (E)-1-(2-bromovinyl)-4-fluorobenzene (S3) (1.21 g, 6.0
mmol, 1.0 equiv), 4-(tert-butyl)benzamide (1.28 g, 7.2 mmol, 1.2
equiv), K2CO3 (1.66 g, 12.0 mmol, 2.0 equiv), CuI (229 mg, 1.2
mmol, 20 mol %), DMEDA (258 μL, 2.4 mmol, 40 mol %), and THF
(12.0 mL, 0.5 M); EtOAc/hexanes = 1:7, then 1:4; 755 mg, 2.54
1
mmol, 42%; off-white solid. Mp: 181−182 °C. H NMR (400 MHz,
DMSO-d6) δ 10.55 (d, J = 9.6 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.62
(dd, J = 14.4 Hz, 9.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.43 (dd, 3JHH
4
3
3
= 8.8 Hz, JHF = 5.6 Hz, 2H), 7.12 (dd, JHH = 8.8 Hz, JHF = 8.8 Hz,
2H), 1.30 (s, 9H). 13C NMR (100 MHz, DMSO-d6) δ 163.9, 160.8 (d,
1JCF = 241.5 Hz), 154.8, 133.2 (d, JCF = 3.1 Hz), 130.6, 127.5, 126.9
4
(d, 3JCF = 8.7 Hz), 125.2, 124.2, 115.5 (d, 2JCF = 21.4 Hz), 111.6, 34.7,
30.9. 19F NMR (376 MHz, DMSO-d6) δ −115.9. IR (neat cm−1) 3243,
2968, 1633, 1532, 1495, 1319, 1302, 1283, 1233, 1171, 1155, 962, 852,
816, 749, 700. Anal. Calcd for C19H20FNO: C, 76.74; H, 6.78. Found:
C, 76.55; H, 6.91.
(E)-N-(3,4-Difluorostyryl)-3,4,5-trimethoxybenzamide (1o).
Synthesized from (E)-4-(2-bromovinyl)-1,2-difluorobenzene (S4)
(1.84 g, 8.4 mmol, 1.2 equiv), 3,4,5-trimethoxybenzamide (1.48 g,
7.0 mmol, 1.0 equiv), K2CO3 (1.93 g, 14.0 mmol, 2.0 equiv), CuI (400
mg, 2.1 mmol, 30 mol %), DMEDA (451 μL, 4.2 mmol, 60 mol %),
and THF (14.0 mL, 0.5 M); EtOAc/hexanes = 1:6, then 2:5; 1.27 g,
3.64 mmol, 52%; white solid. Mp: 158−159 °C. 1H NMR (400 MHz,
DMSO-d6) δ 10.55 (d, J = 9.6 Hz, 1H), 7.66 (dd, J = 14.8 Hz, 9.6 Hz,
1H), 7.53−7.48 (m, 1H), 7.35−7.28 (ovrlp, 3H), 7.23 (br, 1H), 6.41
(d, J = 14.8 Hz, 1H), 3.87 (s, 6H), 3.73 (s, 3H). 13C NMR (100 MHz,
DMSO-d6) δ 163.6, 152.7, 149.9 (dd, 1JCF = 243.1 Hz, 2JCF = 12.7 Hz),
(E)-3-(3,4-Dimethoxyphenyl)-N-((E)-4-methoxystyryl)-
acrylamide (3c). Synthesized from (E)-1-(2-bromovinyl)-4-methox-
ybenzene21 (1.41 g, 6.6 mmol, 1.1 equiv), (E)-3-(3,4-
dimethoxyphenyl)acrylamide24 (1.24 g, 6.0 mmol, 1.0 equiv), K2CO3
(1.66 g, 12.0 mmol, 2.0 equiv), CuI (343 mg, 1.8 mmol, 30 mol %),
DMEDA (387 μL, 3.6 mmol, 60 mol %), and THF (12.0 mL, 0.5 M);
EtOAc/hexanes = 1: 4, then 4:1. The isolated yellow solid was further
purified by recrystallization from acetone/EtOAc/hexanes (∼1:1:2)
via slow evaporation with the aid of a rotary evaporator; 1.31 g, 3.87
1
2
3
148.0 (dd, JCF = 243.5 Hz, JCF = 12.8 Hz), 140.7, 134.7 (dd, JCF
=
=
4
3
4
6.2 Hz, JCF = 3.6 Hz), 128.3, 125.7, 122.0 (dd, JCF = 6.2 Hz, JCF
2
2
2.9 Hz), 117.6 (d, JCF = 17.2 Hz), 113.7 (d, JCF = 17.5 Hz), 110.9,
105.3, 60.1, 56.1. 19F NMR (376 MHz, DMSO-d6) δ −138.3, −141.4.
IR (neat cm−1) 3286, 1638, 1581, 1493, 1413, 1337, 1234, 1124, 995,
942, 868, 847, 814, 754, 708, 674. Anal. Calcd for C18H17F2NO4: C,
61.89; H, 4.91. Found: C, 61.91; H, 5.00.
1
mmol, 64%; yellow solid. Mp: 195−197 °C. H NMR (400 MHz,
DMSO-d6) δ 10.29 (d, J = 10.4 Hz, 1H), 7.54 (d, J = 15.6 Hz, 1H),
7.45 (dd, J = 14.8 Hz, 10.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.21 (d, J
= 1.6 Hz, 1H), 7.18 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 6.99 (d, J = 8.4 Hz,
1H), 6.86 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 15.6 Hz, 1H), 6.20 (d, J =
14.8 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.73 (s, 3H). 13C NMR (100
MHz, DMSO-d6) δ 162.7, 157.9, 150.5, 148.9, 140.4, 129.1, 127.5,
126.4, 122.1, 121.7, 118.6, 114.2, 111.8, 111.7, 110.2, 55.5, 55.4, 55.0.
IR (neat cm−1) 3260, 1640, 1622, 1503, 1440, 1339, 1240, 1190, 1137,
1020, 964, 947, 845, 807, 691, 585. Anal. Calcd for C20H21NO4: C,
70.78; H, 6.24. Found: C, 70.48; H, 6.13.
(E)-2-Methyl-N-(2-methylstyryl)benzamide (1p). Synthesized
from (E)-1-(2-bromovinyl)-2-methylbenzene (S5) (1.18 g, 6.0 mmol,
1.0 equiv), 2-methylbenzamide (973 mg, 7.2 mmol, 1.2 equiv), K2CO3
(1.66 g, 12.0 mmol, 2.0 equiv), CuI (343 mg, 1.8 mmol, 30 mol %),
DMEDA (397 μL, 3.6 mmol, 60 mol %), and THF (12.0 mL, 0.5 M);
EtOAc/hexanes = 1:7; then 1:4; 890 mg, 3.54 mmol, 59%; white solid.
1
Mp: 184−185 °C. H NMR (400 MHz, DMSO-d6) δ 10.57 (d, J =
10.0 Hz, 1H), 7.54−7.47 (ovrlp, 3H), 7.40 (t, J = 7.2 Hz, 1H), 7.31−
7.28 (ovrlp, 2H), 7.18−7.15 (ovrlp, 2H), 7.09 (t, J = 7.2 Hz, 1H), 6.56
(d, J = 14.8 Hz, 1H), 2.41 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz,
DMSO-d6) δ 166.5, 135.9, 135.6, 135.1, 134.1, 130.7, 130.2, 130.0,
127.4, 126.2, 126.2, 125.6, 124.3, 124.0, 110.3, 19.5. IR (neat cm−1)
3263, 1637, 1517, 1471, 1322, 1281, 1170, 1098, 946, 782, 742, 729,
703, 663. Anal. Calcd for C17H17NO: C, 81.24; H, 6.82. Found: C,
81.02; H, 6.81.
(E)-N-(Dec-1-en-1-yl)benzamide (3d). Synthesized from (E)-1-
iododec-1-ene22 (2.24 g, 8.4 mmol, 1.2 equiv), benzamide (848 mg,
7.0 mmol, 1.0 equiv), K2CO3 (1.93 g, 14.0 mmol, 2.0 equiv), CuI (267
mg, 1.4 mmol, 20 mol %), DMEDA (301 μL, 2.80 mmol, 40 mol %),
and THF (14.0 mL, 0.5 M) at 70 °C; EtOAc/hexanes = 1:10, then
1
(E)-N-(2-Methylstyryl)-2-naphthamide (1q). Synthesized from
(E)-1-(2-bromovinyl)-2-methylbenzene (S5) (1.66 g, 8.4 mmol, 1.2
equiv), 2-naphthamide (1.20 g, 7.0 mmol, 1.0 equiv), K2CO3 (1.93 g,
1:7; 1.19 g, 4.6 mmol, 66%; white solid. Mp: 69−70 °C. H NMR
(400 MHz, DMSO-d6) δ 10.14 (d, J = 9.6 Hz, 1H), 7.91 (d, J = 7.2 Hz,
2H), 7.55 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.2 Hz, 2H), 6.83 (dd, J =
G
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14.4 Hz, 9.6 Hz, 1H), 5.46 (dt, J = 14.4 Hz, 7.2 Hz, 1H), 2.02 (td, J =
6.9 Hz, 6.8 Hz, 2H), 1.35−1.25 (ovrlp, 12H), 0.85 (t, J = 6.8 Hz, 3H).
13C NMR (100 MHz, DMSO-d6) δ 163.5, 133.7, 131.5, 128.3, 127.4,
123.6, 113.3, 31.3, 29.61, 29.56, 28.9, 28.7, 28.6, 22.1, 13.9. IR (neat
cm−1) 3322, 2922, 2850, 1636, 1518, 1488, 1326, 1294, 1260, 1185,
961, 857, 795, 725, 692, 638. Anal. Calcd for C17H25NO: C, 78.72; H,
9.71. Found: C, 78.91; H, 9.62.
Hz, 2H), 7.23 (dd, J = 4.8 Hz, 3.6 Hz, 1H), 7.16 (t, J = 7.2 Hz, 1H),
6.44 (d, J = 14.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 158.8,
138.8, 136.5, 132.2, 129.3, 128.7, 128.2, 126.3, 125.3, 123.7, 112.7. IR
(neat cm−1) 3223, 1615, 1526, 1487, 1413, 1353, 1307, 1288, 1171,
958, 850, 757, 719, 690. Anal. Calcd for C13H11NOS: C, 68.09; H,
4.84. Found: C, 67.83; H, 4.81.
(E)-N-Styrylfuran-2-carboxamide (3j). Synthesized from (E)-(2-
bromovinyl)benzene21 (1.10 g, 6.0 mmol, 1.0 equiv), furan-2-
carboxamide (800 mg, 7.2 mmol, 1.2 equiv), K2CO3 (1.66 g, 12.0
mmol, 2.0 equiv), CuI (229 mg, 1.2 mmol, 20 mol %), DMEDA (259
μL, 2.4 mmol, 40 mol %), and THF (12.0 mL, 0.5 M); EtOAc/
hexanes = 1:7, then 1:4; 843 mg, 3.95 mmol, 66%; off-white solid. Mp:
184−185 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (d, J = 9.6 Hz,
1H), 7.94 (s, 1H), 7.59 (dd, J = 14.8 Hz, 10.0 Hz, 1H), 7.38−7.27
(ovrlp, 5H), 7.15 (t, J = 7.2 Hz, 1H), 6.69 (m, 1H), 6.48 (d, J = 14.8
Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 155.2, 147.0, 146.0,
136.5, 128.7, 126.3, 125.3, 123.1, 115.1, 113.1, 112.3. IR (neat cm−1)
3205, 1628, 1584, 1519, 1486, 1465, 1308, 1263, 1177, 1018, 961, 863,
739, 689. Anal. Calcd for C13H11NO2: C, 73.23; H, 5.20. Found: C,
72.95; H, 5.06.
(E)-N-(2-(1-Benzoyl-1H-indol-5-yl)vinyl)thiophene-3-carbox-
amide (3k). Synthesized from 5-(2-bromovinyl)-1H-indol-1-yl)-
(phenyl)methanone ((Z):(E) = 20:1) (S7) (1.17 g, 3.59 mmol, 1.2
equiv), thiophene-3-carboxamide (380 mg, 2.99 mmol, 1.0 equiv),
K2CO3 (826 mg, 5.98 mmol, 2.0 equiv), CuI (171 mg, 0.90 mmol, 30
mol %), DMEDA (194 μL, 1.8 mmol, 60 mol %), and THF (6.0 mL,
0.5 M); EtOAc/hexanes = 1:5, then 1:2. 310 mg, 0.83 mmol, 28%;
pale yellow solid. Mp: 208−210 °C. 1H NMR (400 MHz, DMSO-d6)
δ 10.49 (d, J = 10.0 Hz, 1H), 8.36 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H),
7.75 (d, J = 8.0 Hz, 2H), 7.71−7.66 (ovrlp, 5 H), 7.59 (t, J = 7.6 Hz,
2H), 7.45 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 3.6 Hz, 1H), 6.71 (d, J = 3.6
Hz, 1H), 6.55 (d, J = 14.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
δ 168.0, 159.6, 136.7, 134.1, 134.0, 132.6, 132.0, 131.2, 130.1, 129.0,
128.7, 128.6, 127.1, 127.0, 123.4, 122.1, 117.6, 116.1, 112.8, 108.6. IR
(neat cm−1) 3274, 1679, 1633, 1527, 1459, 1367, 1335, 1285, 1190,
1067, 945, 881, 806, 766, 697. Anal. Calcd for C22H16N2O2S: C, 70.95;
H, 4.33. Found: C, 70.65; H, 4.59.
General Procedure for the Optimization of Cu(II)-Catalyzed
Oxidative Cyclization of Enamide (Table 1). A oven-dried 20 mL
resealable screw-cap test tube equipped with a Teflon-coated magnetic
stir bar was charged with (E)-N-styrylbenzamide (1a) (0.2 mmol, 1.0
equiv), tetrabutylammonium halide (TBAB or TBAC) (0.24 mmol,
1.2 equiv), potassium persulfate (K2S2O8) (0.26 mmol, 1.3 equiv),
metal catalyst (5−20 mol %), and ligand (0−40 mol %) (if solid). The
tube was then evacuated and backfilled with argon (this sequence was
repeated a total of three times). Ligand (0−40 mol %) (if liquid) was
added into the tube followed by anhydrous acetonitrile (2.0 mL, 0.1
M) via syringe. The sealed tube was then vigorously stirred at room
temperature for 24 h. After completion, n-dodecane (20 μL, 0.088
mol) was added into the reaction mixture. The reaction mixture was
extracted with ethyl acetate (3 mL) and deionized water (10 mL).
Aliquots from the organic fractions were filtered through silica gel for
GC analysis to determine the reaction conversion and the GC yield of
2,5-diphenyloxazole 2a using n-dodecane as an internal standard. The
aqueous fraction was further washed with ethyl acetate (2 × 3 mL).
The combined organic fractions were dried over Na2SO4, filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography using ethyl acetate (EtOAc)/hexanes (1:12) as an
eluent to afford 2a to determine the isolated yield.
(E)-N-Styrylpivalamide (3e).37 Synthesized from (E)-(2-
bromovinyl)benzene21 (1.10 g, 6.0 mmol, 1.0 equiv), pivalamide
(728 mg, 7.2 mmol, 1.2 equiv), K2CO3 (1.70 g, 12.0 mmol, 2.0 equiv),
CuI (229 mg, 1.2 mmol, 20 mol %), DMEDA (259 μL, 2.4 mmol, 40
mol %), and THF (6.0 mL, 1.0 M); EtOAc/hexanes = 1:10; 974 mg,
4.79 mmol, 80%; white solid. Mp: 146−147 °C. 1H NMR (400 MHz,
DMSO-d6) δ 9.65 (d, J = 10.0 Hz, 1H), 7.45 (dd, J = 14.8 Hz, 10.0 Hz,
1H), 7.31 (d, J = 7.2 Hz, 2H), 7.27 (t, J = 7.2 Hz, 2H), 7.22 (t, J = 7.2
Hz, 1H), 6.33 (d, J = 14.8 Hz, 1H), 1.18 (s, 9H). 13C NMR (100
MHz, DMSO-d6) δ 175.6, 136.9, 128.7, 125.9, 125.0, 124.4, 111.4,
38.3, 27.0. IR (neat cm−1) 3279, 2973, 1632, 1524, 1474, 1398, 1303,
1285, 1235, 1183, 952, 746, 718, 691.
(E)-N-Styrylcyclohexanecarboxamide (3f).35 Synthesized from
(E)-(2-bromovinyl)benzene21 (1.10 g, 6.0 mmol, 1.0 equiv), cyclo-
hexanecarboxamide (916 mg, 7.2 mmol, 1.2 equiv), K2CO3 (1.66 g,
12.0 mmol, 2.0 equiv), CuI (229 mg, 1.2 mmol, 20 mol %), DMEDA
(258 μL, 2.4 mmol, 40 mol %), and THF (6.0 mL, 1.0 M); EtOAc/
hexanes = 1: 10, then 1:7; 869 mg, 3.79 mmol, 63%; white solid. Mp:
151−152 °C. (lit.: 148−150 °C).35 1H NMR (400 MHz, DMSO-d6) δ
10.04 (d, J = 10.4 Hz, 1H), 7.41 (dd, J = 14.8 Hz, 10.4 Hz, 1H), 7.31
(d, J = 7.2 Hz, 2H), 7.26 (t, J = 7.2 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H),
6.15 (d, J = 14.8 Hz, 1H), 2.23 (m, 1H), 1.77−1.72 (ovrlp, 4H), 1.63
(d, J = 8.8 Hz, 1H), 1.43−1.35 (m, 2H), 1.29−1.12 (ovrlp, 3H). 13C
NMR (100 MHz, DMSO-d6) δ 173.3, 136.8, 128.6, 125.9, 125.0,
123.9, 111.0, 43.9, 29.0, 25.4, 15.2. IR (neat cm−1) 3262, 2933, 2850,
1665, 1634, 1536, 1444, 1252, 1227, 1194, 956, 748, 718, 688.
(E)-N-(2-(Thiophen-3-yl)vinyl)benzamide (3g). Synthesized
from 3-(2-bromovinyl)thiophene ((Z):(E) = 4.3: 1.0) (S6) (1.96 g,
10.4 mmol, 2.1 equiv), benzamide (606 mg, 5.0 mmol, 1.0 equiv),
K2CO3 (1.38 g, 10.0 mmol, 2.0 equiv), CuI (191 mg, 1.0 mmol, 20
mol %), DMEDA (215 μL, 2.0 mmol, 40 mol %), and THF (10.0 mL,
0.5 M); EtOAc/hexanes = 1:7, then 1:4; 821 mg, 3.58 mmol, 72%; off-
1
white solid. Mp: 147−149 °C. H NMR (400 MHz, DMSO-d6) δ
10.54 (d, J = 10.0 Hz, 1H), 7.97 (d, J = 7.2 Hz, 2H), 7.61−7.49 (ovrlp,
5H), 7.36 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 4.8 Hz, 1H), 6.52 (d, J =
14.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ 164.0, 138.5, 133.5,
131.8, 128.5, 127.6, 126.7, 124.7, 124.1, 120.1, 108.3. IR (neat cm−1)
3308, 1638, 1539, 1506, 1485, 1316, 1250, 1200, 952, 926, 771, 726,
672, 627. Anal. Calcd for C13H11NOS: C, 68.09; H, 4.84. Found: C,
67.81; H, 4.72.
(E)-N-Styrylthiophene-3-carboxamide (3h). Synthesized from
(E)-(2-bromovinyl)benzene21 (1.32 g, 7.2 mmol, 1.2 equiv),
thiophene-3-carboxamide (763 mg, 6.0 mmol, 1.0 equiv), K2CO3
(1.66 g, 12.0 mmol, 2.0 equiv), CuI (229 mg, 1.2 mmol, 20 mol %),
DMEDA (258 μL, 2.4 mmol, 40 mol %), and THF (12.0 mL, 0.5 M);
EtOAc/hexanes = 1:7, then 1:4; 990 mg, 4.32 mmol, 72%; off-white
solid. Mp: 166−167 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (d, J
= 9.6 Hz, 1H), 8.35 (dd, J = 2.4 Hz, 1.6 Hz, 1H), 7.66−7.60 (ovrlp,
3H), 7.39 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.16 (t, J = 7.2
Hz, 1H), 6.42 (d, J = 14.8 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
δ 159.6, 136.63, 136.60, 130.2, 128.8, 127.2, 127.0, 126.2, 125.2, 123.9,
112.5. IR (neat cm−1) 3230, 1619, 1531, 1486, 1304, 1283, 1262, 1165,
1071, 956, 853, 813, 721, 691. Anal. Calcd for C13H11NOS: C, 68.09;
H, 4.84. Found: C, 67.88; H, 4.75.
(E)-N-Styrylthiophene-2-carboxamide (3i). Synthesized from
(E)-(2-bromovinyl)benzene21 (1.32 g, 7.2 mmol, 1.2 equiv),
thiophene-2-carboxamide (763 mg, 6.0 mmol, 1.0 equiv), K2CO3
(1.66 g, 12.0 mmol, 2.0 equiv), CuI (229 mg, 1.2 mmol, 20 mol %),
DMEDA (258 μL, 2.4 mmol, 40 mol %), and THF (12.0 mL, 0.5 M);
EtOAc/hexanes = 1:7, then 1:4; 856 mg, 3.73 mmol, 62%; off-white
solid. Mp: 154−155 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (d, J
= 9.6 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.60
(dd, J = 14.8 Hz, 9.6 Hz, 1H), 7.39 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.2
General Procedure for Synthesis of Oxazoles via Cu(II)-
Catalyzed Oxidative Cyclization of Enamides (Tables 2 and 3).
Unless otherwise noted, an oven-dried 25 mL resealable screw-cap test
tube equipped with a Teflon-coated magnetic stir bar was charged with
enamide (1a−q, 3a−k) (1.0 mmol, 1.0 equiv), copper(II) bromide
(CuBr2) (16.8 mg, 0.075 mml, 7.5 mol %), tetrabutylammonium
bromide (TBAB) (387 mg, 1.2 mmol, 1.2 equiv), and potassium
persulfate (K2S2O8) (351 mg, 1.3 mmol, 1.3 equiv). The tube was then
evacuated and backfilled with argon (this sequence was repeated a
total of three times). Ethyl nicotinate (20.5 μL, 0.15 mmol, 15 mol %)
was added into the tube followed by anhydrous acetonitrile (10.0 mL,
H
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0.1 M) via syringe. The sealed tube was then vigorously stirred at
room temperature for 24 h. After completion, the reaction mixture was
extracted with ethyl acetate (10 mL) and deionized water (20 mL).
The aqueous fraction was further washed with ethyl acetate (2 × 5
mL). The combined organic fractions were dried over Na2SO4,
filtered, and concentrated in vacuo. The crude residue was purified by
flash chromatography using ethyl acetate (EtOAc)/hexanes as an
eluent to afford the oxazole products.
709, 691, 594. Anal. Calcd for C16H10F3NO: C, 66.44; H, 3.48. Found:
C, 66.19; H, 3.50.
2-(4-Nitrophenyl)-5-phenyloxazole (2g).40 Synthesized from
(E)-4-nitro-N-styrylbenzamide (1g) (268 mg); EtOAc/hexanes = 1:9;
58 mg, 22%; yellow solid. Mp: 201−203 °C (lit.: 207−208 °C).40 1H
NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.8 Hz, 2H), 8.27 (d, J = 8.8
Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.54 (s, 1H), 7.48 (t, J = 8.0 Hz,
2H), 7.40 (t, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 159.1,
153.0, 148.7, 133.0, 129.33, 129.25, 127.5, 127.0, 124.7, 124.44,
124.41. IR (neat cm−1) 1537, 1514, 1339, 1103, 951, 853, 822, 765,
709, 690. Anal. Calcd for C15H10N2O3: 67.67; H, 3.79. Found: C,
67.26; H, 4.10.
2,5-Diphenyloxazole (2a).38 Synthesized from (E)-N-styrylben-
zamide (1a) (233 mg); EtOAc/hexanes = 1:12; 175 mg, 79%; white
solid. Mp: 70−71 °C (lit.: 70−71 °C).38 1H NMR (400 MHz, CDCl3)
δ 8.08 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.46−7.36 (ovrlp,
6H), 7.28 (t, J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 161.1,
151.2, 130.3, 128.9, 128.8, 128.4, 128.0, 127.5, 126.3, 124.2, 123.5. IR
(neat cm−1) 1480, 1446, 1133, 1058, 952, 822, 775, 759, 705, 684.
Anal. Calcd for C15H11NO: C, 81.43; H, 5.01. Found: C, 81.39; H,
5.10.
2-(3-Nitrophenyl)-5-phenyloxazole (2h).41 Synthesized from
(E)-3-nitro-N-styrylbenzamide (1h) (268 mg); EtOAc/hexanes = 1:9;
116 mg, 44%; pale yellow solid. Mp: 148−149 °C (lit.: 148−150
°C).41 1H NMR (400 MHz, CDCl3) δ 8.89 (t, J = 1.6 Hz, 1H), 8.40
(dt, J = 7.6 Hz, 1.6 Hz, 1H), 8.28 (ddd, J = 8.0 Hz, 2.4 Hz, 1.2 Hz,
1H), 7.73 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 8.0 Hz, 1H), 7.48−7.45
(ovrlp, 3H), 7.38 (t, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
158.8, 152.4, 148.7, 131.8, 130.1, 129.11, 129.07, 129.00, 127.4, 124.6,
124.4, 123.9, 121.1. IR (neat cm−1) 1519, 1352, 1135, 940, 816, 768,
742, 710. Anal. Calcd for C15H10N2O3: C, 67.67; H, 3.79. Found: C,
67.39, H, 4.02.
2-(4-Methoxyphenyl)-5-phenyloxazole (2b).13 Synthesized
from (E)-4-methoxy-N-styrylbenzamide (1b) (253 mg); EtOAc/
hexanes = 1:10, then 1:8; 181 mg, 72%; white solid. Mp: 100−101
°C (lit.: 94−96 °C).13 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8
Hz, 2H), 7.66 (d, J = 7.6 Hz, 2H), 7.41−7.37 (ovrlp, 3H), 7.28 (t, J =
7.2 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 161.3, 161.2, 150.7, 128.9, 128.2, 127.9, 124.0, 123.3,
120.3, 114.2, 55.3. IR (neat cm−1) 1610, 1495, 1303, 1250, 1173, 1135,
1024, 828, 762, 736, 687, 615. Anal. Calcd for C16H13NO2: C, 76.48;
H, 5.21. Found: C, 76.29; H, 5.33.
5-(4-Methoxyphenyl)-2-phenyloxazole (2i).39 Synthesized
from (E)-N-(4-methoxystyryl)benzamide (1i) (253 mg); EtOAc/
hexanes = 1:10; 108 mg, 43%; off-white solid. Mp: 80−81 °C (lit.: 78−
79 °C).39 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz, 2H),
7.59 (d, J = 8.8 Hz, 2H), 7.46−7.38 (ovrlp, 3H), 7.29 (s, 1H), 6.92 (d,
J = 8.8 Hz, 2H), 3.77 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.5,
159.8, 151.3, 130.1, 128.8, 127.6, 126.1, 125.7, 121.9, 120.8, 114.4,
55.3. IR (neat cm−1) 1618, 1502, 1255, 1175, 1058, 1026, 951, 822,
813, 770, 713, 690. Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21.
Found: C, 76.19; H, 5.35.
4-(2-Phenyloxazol-5-yl)phenyl Acetate (2j). Synthesized from
(E)-4-(2-benzamidovinyl)phenyl acetate (1j) (281 mg); EtOAc/
hexanes = 1:10, then 1:5; 226 mg, 81%; off-white solid. Mp: 113−
115 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.0 Hz, 2H), 7.72
(d, J = 8.8 Hz, 2H), 7.50−7.43 (ovrlp, 3H), 7.41 (s, 1H), 7.18 (d, J =
8.8 Hz, 2H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.4,
161.3, 150.7, 150.6, 130.5, 128.9, 127.4, 126.3, 125.9, 125.4, 123.6,
122.3, 21.2. IR (neat cm−1) 1748, 1500, 1485, 1373, 1225, 1207, 1167,
1136, 1016, 953, 915, 844. HRMS (ESI) calcd for C17H13NO3 [M+H]:
280.0968; found 280.0966.
5-Phenyl-2-(p-tolyl)oxazole (2c).38 Synthesized from (E)-4-
methyl-N-styrylbenzamide (1c) (237 mg); EtOAc/hexanes = 1:10;
171 mg, 73%; white solid. Mp: 73 °C (lit.: 72−73 °C).38 1H NMR
(400 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 7.8 Hz,
2H), 7.41−7.37 (ovrlp, 3H), 7.28 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0
Hz, 2H), 2.36 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.3, 150.9,
140.6, 129.5, 128.9, 128.3, 128.1, 126.2, 124.8, 124.1, 123.3, 21.5. IR
(neat cm−1) 1495, 1134, 950, 822, 760, 730, 703, 688. Anal. Calcd for
C16H13NO: C, 81.68; H, 5.57. Found: C, 81.79; H, 5.69.
2-(4-Chlorophenyl)-5-phenyloxazole (2d).39 Synthesized from
(E)-4-chloro-N-styrylbenzamide (1d) (258 mg); EtOAc/hexanes =
1:10; 187 mg, 73%; white solid. Mp: 116−118 °C (lit.: 115−117
°C).39 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2H), 7.64
(d, J = 7.2 Hz, 2H), 7.41−7.33 (ovrlp, 5H), 7.23 (t, J = 7.2 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 160.1, 151.4, 136.3, 129.1, 128.9,
128.6, 127.8, 127.5, 125.9, 124.2, 123.5. IR (neat cm−1) 1477, 1403,
1132, 1087, 1009, 950, 824, 761, 731, 689. Anal. Calcd for
C15H10ClNO: C, 70.46; H, 3.94. Found: C, 70.17; H, 3.82.
2-Phenyl-5-(p-tolyl)oxazole (2k).13 Synthesized from (E)-N-(4-
methylstyryl)benzamide (1k) (237 mg). EtOAc/hexanes = 1:10; 124
mg, 53%; off-white solid. Mp: 77−78 °C (lit.: 77−78 °C).13 1H NMR
(400 MHz, CDCl3) δ 8.08 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.4 Hz,
2H), 7.46−7.40 (ovrlp, 3H), 7.35 (s, 1H), 7.19 (d, J = 8.0 Hz, 2H),
2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.8, 151.4, 138.4,
130.2, 129.6, 128.8, 127.6, 126.2, 125.3, 124.1, 122.8, 21.4. IR (neat
cm−1) 1543, 1500, 1476, 1446, 1133, 1055, 952, 817, 775, 709, 693,
504, 490. Anal. Calcd for C16H13NO: C, 81.68; H, 5.57. Found: C,
81.43; H, 5.81.
2-(4-Fluorophenyl)-5-phenyloxazole (2e).38 Synthesized from
(E)-4-fluoro-N-styrylbenzamide (1e) (241 mg). EtOAc/hexanes =
1:10; 170 mg, 71%; off-white solid. Mp: 84−85 °C (lit.: 81−82 °C).38
1H NMR (400 MHz, CDCl3) δ 8.04 (dd, 3JHH = 8.8 Hz, 4JHF = 5.2 Hz,
2H), 7.64 (d, 3JHH = 7.2 Hz, 2H), 7.41−7.37 (ovrlp, 3H), 7.29 (t, 3JHH
= 7.2 Hz, 1H), 7.11 (dd, 3JHH = 8.8 Hz, 3JHF = 8.8 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ 164.0 (d, 1JCF = 249.4 Hz), 160.3, 151.3, 128.9,
128.5, 128.3 (d, 3JCF = 8.6 Hz), 127.9, 124.1, 123.8 (d, 4JCF = 3.0 Hz),
2
123.4, 116.0 (d, JCF = 21.9 Hz). 19F NMR (376 MHz, CDCl3) δ
5-(4-Chlorophenyl)-2-phenyloxazole (2l).13 Synthesized from
(E)-N-(4-chlorostyryl)benzamide (1l) (258 mg); EtOAc/hexanes =
1:10; 175 mg, 69%; pale yellow solid. Mp: 104−105 °C (lit.: 102−104
°C).13 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H), 7.54
(d, J = 8.4 Hz, 2H), 7.45−7.39 (ovrlp, 3H), 7.36 (s, 1H), 7.33 (d, J =
8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 161.3, 150.2, 134.1,
130.4, 129.1, 128.8, 127.2, 126.5, 126.3, 125.3, 123.8. IR (neat cm−1)
1480, 1448, 1132, 1091, 1011, 951, 818, 772, 705, 686. Anal. Calcd for
C15H10ClNO: C, 70.46; H, 3.94. Found: C, 70.76; H, 3.84.
2,5-Bis(4-bromophenyl)oxazole (2m). Synthesized from (E)-4-
bromo-N-(4-bromostyryl)benzamide (1m) (381 mg). EtOAc/hexanes
−109.8. IR (neat cm−1) 1608, 1494, 1414, 1220, 1134, 952, 842, 756,
732, 685, 614. Anal. Calcd for C15H10FNO: C, 75.30; H, 4.21. Found:
C, 75.08; H, 4.32.
5-Phenyl-2-(4-(trifluoromethyl)phenyl)oxazole (2f).39 Synthe-
sized from (E)-N-styryl-4-(trifluoromethyl)benzamide (1f) (233 mg,
0.80 mmol, 1.0 equiv), CuBr2 (13.4 mg, 0.06 mmol, 7.5 mol %), TBAB
(310 mg, 0.96 mmol, 1.2 equiv), K2S2O8 (281 mg, 1.04 mmol, 1.3
equiv), ethyl nicotinate (16.4 μL, 0.12 mmol, 15 mol %), and
acetonitrile (8.0 mL, 0.1 M). EtOAc/hexanes = 1:10; 166 mg, 0.57
mmol, 72%; white solid. Mp: 110−111 °C (lit.: 109−111 °C).39 1H
NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.0 Hz, 2H), 7.69−7.65
(ovrlp, 4H), 7.43−7.39 (ovrlp, 3H), 7.32 (t, J = 7.6 Hz, 1H). 13C
1
= 1:10; 287 mg, 76%; white solid. Mp: 176−178 °C. H NMR (400
2
MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H),
7.57 (s, 4H), 7.44 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 160.7,
150.7, 132.34, 132.29, 127.9, 126.9, 126.3, 125.8, 125.1, 124.2, 122.7.
IR (neat cm−1) 1474, 1404, 1133, 1073, 1051, 1006, 950, 821, 730,
NMR (100 MHz, CDCl3) δ 159.7, 152.1, 131.8 (q, JCF = 32.6 Hz),
130.6, 129.0, 128.9, 127.7, 126.4, 125.9 (q, 3JCF = 3.5 Hz), 124.4, 124.0
(q, 1JCF = 270.7 Hz), 123.8. 19F NMR (376 MHz, CDCl3) δ −63.3. IR
(neat cm−1) 1485, 1414, 1324, 1168, 1102, 1055, 951, 843, 762, 750,
I
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The Journal of Organic Chemistry
Article
697. Anal. Calcd for C15H9Br2NO: C, 47.53; H, 2.39. Found: C, 47.17;
H, 2.35.
(E)-2-(3,4-Dimethoxystyryl)-5-(4-methoxyphenyl)oxazole
(Annuloline) (4c).38 Synthesized from (E)-3-(3,4-dimethoxyphenyl)-
N-((E)-4-methoxystyryl)acrylamide (3c) (339 mg), with CuBr2 (33.5
mg, 15 mol %) and ethyl nicotinate (41.0 μL, 30 mol %). EtOAc/
hexanes = 1:4, then 1:2. A yellow oily product was obtained, then
recrystallized from CH2Cl2/hexanes (∼1:2) by slow evaporation with
the aid of a rotary evaporator; 192 mg, 57%; yellow solid. Mp: 104−
106 °C (lit.: 104−107 °C).38 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J
= 8.8 Hz, 2H), 7.46 (d, J = 16.4 Hz 1H), 7.27 (s, 1H), 7.11−7.08
(ovrlp, 2H), 6.95 (d, J = 8.4 Hz, 2H), 6.88−6.82 (ovrlp, 2H), 3.93 (s,
3H), 3.90 (s, 3H), 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
160.7, 159.7, 150.6, 150.0, 149.2, 135.0, 128.7, 125.6, 122.1, 121.1,
120.8, 114.3, 112.0, 111.1, 108.8, 55.9, 55.8, 55.3. IR (neat cm−1) 1599,
1518, 1444, 1263, 1233, 1131, 1021, 972, 823, 800, 768, 613.
2-(4-(tert-Butyl)phenyl)-5-(4-fluorophenyl)oxazole (2n). Syn-
thesized from (E)-4-(tert-butyl)-N-(4-fluorostyryl)benzamide (1n)
(297 mg); EtOAc/hexanes = 1:10; 230 mg, 78%; off-white solid.
1
Mp: 76−77 °C. H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.8 Hz,
2H), 7.62 (dd, 3JHH = 9.6 Hz, 4JHF = 5.2 Hz, 2H), 7.47 (d, J = 8.4 Hz,
2H), 7.33 (s, 1H), 7.08 (dd, 3JHH = 8.8 Hz, 3JHF = 8.8 Hz, 2H), 1.34 (s,
1
9H). 13C NMR (100 MHz, CDCl3) δ 162.6 (d, JCF = 247.2 Hz),
161.3, 153.8, 150.1, 126.1, 125.9 (d, 3JCF = 8.1 Hz), 125.8, 124.6, 124.5
4
2
(d, JCF = 3.1 Hz), 123.0, 116.0 (d, JCF = 21.8 Hz), 34.9, 31.2. 19F
NMR (376 MHz, CDCl3) δ −112.7. IR (neat cm−1) 2951, 1499, 1227,
1140, 951, 827, 750, 708, 615. Anal. Calcd for C19H18FNO: C, 77.27;
H, 6.14. Found: C, 77.29; H, 6.14.
5-Octyl-2-phenyloxazole (4d). Synthesized from (E)-N-(dec-1-
5-(3,4-Difluorophenyl)-2-(3,4,5-trimethoxyphenyl)oxazole
(2o). Synthesized from (E)-N-(3,4-difluorostyryl)-3,4,5-trimethoxy-
benzamide (1o) (349 mg). EtOAc/hexanes = 1:2, then 1:1; 310 mg,
en-1-yl)benzamide (3d) (259 mg); EtOAc/hexanes = 1:15; 107 mg,
1
42%; pale-yellow oil. H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.2
1
Hz, 2H), 7.44−7.37 (ovrlp, 3H), 6.83 (s, 1H), 2.69 (t, J = 7.6 Hz, 2H),
1.68 (qu, J = 7.2 Hz, 2H), 1.38−1.27 (ovrlp, 10H), 0.88 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 160.6, 153.3, 129.9, 128.7, 127.9,
126.0, 123.6, 31.9, 29.31, 29.25, 29.2, 27.7, 25.7, 22.7, 14.2. IR (neat,
cm−1) 2928, 2856, 1597, 1551, 1490, 1449, 1354, 1123, 1066, 1025,
982, 825, 775, 711, 691. Anal. Calcd for C17H23NO: C, 79.33; H, 9.01.
Found: C, 79.32; H, 9.11.
90%; white solid. Mp: 145−146 °C. H NMR (400 MHz, CDCl3) δ
7.54−7.50 (m, 1H), 7.46−7.42 (m, 1H), 7.39 (s, 1H), 7.32 (s, 2H),
7.28−7.22 (m, 1H), 3.98 (s, 6H), 3.93 (s, 3H). 13C NMR (100 MHz,
1
2
CDCl3) δ 161.4, 153.6, 150.8 (dd, JCF = 244.6 Hz, JCF = 10.2 Hz),
1
2
150.3 (dd, JCF = 248.4 Hz, JCF = 10.1 Hz), 149.3, 140.4, 125.1 (dd,
3JCF = 6.5 Hz, JCF = 4.1 Hz), 124.0, 122.4, 120.5 (dd, JCF = 6.3 Hz,
4
3
4JCF = 4.0 Hz), 118.2 (d, JCF = 17.9 Hz), 113.4 (d, JCF = 19.2 Hz),
103.6, 61.0, 56.3. 19F NMR (376 MHz, CDCl3) δ −136.9, −137.4. IR
(neat cm−1) 2945, 2838, 1592, 1506, 1496, 1457, 1416, 1354, 1272,
1235, 1181, 1129, 1001, 841, 773, 728. Anal. Calcd for C18H15F2NO4:
C, 62.25; H, 4.35. Found: C, 62.44; H, 4.35.
2
2
2-(tert-Butyl)-5-phenyloxazole (4e).9d Synthesized from (E)-N-
styrylpivalamide (3e) (203 mg), with CuBr2 (33.5 mg, 15 mol %) and
ethyl nicotinate (41.0 μL, 30 mol %); EtOAc/hexanes = 1:10; 121 mg,
1
60%; pale-yellow oil. H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.6
Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.20 (s,
1H), 1.44 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 170.8, 150.6,
128.8, 128.4, 128.0, 124.0, 121.5, 33.8, 28.6. IR (neat cm−1) 2971,
1549, 1447, 1367, 1244, 1145, 1121, 1060, 961, 822, 762, 747, 688.
Anal. Calcd for C13H15NO: C, 77.58; H, 7.51. Found: C, 77.34; H,
7.71.
2-Cyclohexyl-5-phenyloxazole (4f) and 2-(1-Cyclohexenyl)-
5-phenyloxazole (4f′) (10: 1). Synthesized from (E)-N-styrylcyclo-
hexanecarboxamide (3f) (229 mg), with CuBr2 (33.5 mg, 15 mol %)
and ethyl nicotinate (41 μL, 30 mol %); EtOAc/hexanes = 1:20. 4f
and 4f′ were isolated as an inseparable, white product mixture (142
mg). The formation of 4f′ was further confirmed by GC−MS analysis
([M]+ of 4f: 227; [M]+ of 4f′: 225). The isolated yields of 4f and 4f′
were estimated to be 54% (123 mg, 0.54 mmol) and 6% (14 mg, 0.06
mmol), respectively, by comparing the ratio of the proton signals of 4f
and 4f′ by 1H NMR spectroscopy. The product mixture was
recrystallized from CH2Cl2/acetonitrile (∼2:1) by slow evaporation
with the aid of a rotary evaporator to afford a pure 4f as a white solid.
1H NMR of an inseparable mixture of 4f and 4f′ (400 MHz, CDCl3) δ
2,5-Di-o-tolyloxazole (2p). Synthesized from (E)-2-methyl-N-(2-
methylstyryl)benzamide (1p) (251 mg); EtOAc/hexanes = 1:12, then
1:10; 199 mg, 80%; white solid. Mp: 77−79 °C. 1H NMR (400 MHz,
CDCl3) δ 8.09 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.38 (s,
1H), 7.37−7.28 (ovrlp, 6H). 2.76 (s, 3H), 2.53 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 161.3, 150.4, 137.4, 134.9, 131.8, 131.3, 130.1,
128.9, 128.4, 127.5, 126.9, 126.5, 126.4, 126.2, 126.1, 22.3, 22.1. IR
(neat cm−1) 2956, 2921, 1489, 1451, 1152, 1127, 1053, 774, 758, 724,
714. Anal. Calcd for C17H15NO: C, 81.90; H, 6.06. Found: C, 81.94;
H, 6.09.
2-(Naphthalen-2-yl)-5-(o-tolyl)oxazole (2q). Synthesized from
(E)-N-(2-methylstyryl)-2-naphthamide (1q) (287 mg); EtOAc/
hexanes = 1:15, then 1:10; 221 mg, 78%; off-white solid. Mp: 108−
110 °C. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.10 (d, J = 8.4
Hz, 1H), 7.84−7.71 (ovrlp, 4H), 7.42−7.40 (ovrlp, 2H), 7.29 (s, 1H),
7.27−7.23 (m, 1H), 7.18−1.17 (ovrlp, 2H), 2.42 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 160.7, 150.7, 134.6, 134.0, 132.9, 131.2, 128.6,
128.5, 128.2, 127.8, 127.11, 127.06, 126.61, 126.57, 126.3, 126.1,
126.0, 124.5, 123.1, 22.0. IR (neat cm−1) 3057, 2953, 1721, 1463,
1375, 1277, 1195, 1130, 942, 859, 818, 752, 473. HRMS (ESI) calcd
for C20H15NO [M+H]: 286.1226; found 286.1231.
7.63−7.58 (ovrlp, 2.2 H), 7.39−7.35 (ovrlp, 2.2 H), 7.30−7.25 (ovrlp,
1.1 H), 7.21 (ovrlp, 1.1 H), 6.85 (br, 0.1 H), 2.83 (tt, 3J = 11.2 Hz, 3J =
3.6 Hz, 1H), 2.52 (br, 0.2 H), 2.25 (br, 0.2 H), 2.13−2.10 (m, 2H),
1.85−1.81 (m, 2H), 1.76−1.59 (ovrlp, 3.2H), 1.44−1.25 (ovrlp,
3.2H). 13C NMR of an inseparable mixture of 4f and 4f′ (100 MHz,
CDCl3) (1) 4f: δ 167.8, 150.5, 128.8, 128.4, 128.0, 123.9, 121.6, 37.6,
30.6, 25.8, 25.6. (2) 4f′: δ 162.4, 150.1, 131.4, 128.3, 128.1, 126.1,
(E)-5-Phenyl-2-styryloxazole (4a).13 Synthesized from N-((E)-
styryl)cinnamamide (3a) (249 mg); EtOAc/hexanes = 1:12; 138 mg,
56%; off-white solid. Mp: 98−100 °C (lit.: 97−100 °C).13 1H NMR
(400 MHz, CDCl3) δ 7.70 (d, J = 7.2 Hz, 2H), 7.59−7.55 (ovrlp, 3H),
7.46−7.32 (ovrlp, 7H), 6.99 (d, J = 16.4 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 161.2, 151.0, 135.9, 135.7, 129.3, 129.1, 129.0, 128.6,
128.1, 127.3, 124.3, 123.9, 114.0. IR (neat cm−1) 1520, 1480, 1133,
971, 942, 830, 753, 688. Anal. Calcd for C17H13NO: C, 82.57; H, 5.30.
Found: C, 82.19; H, 5.16.
1
124.0, 122.8, 25.5, 24.5, 22.1, 21.8. Mp of pure 4f: 88−90 °C. H
NMR of pure 4f (400 MHz, CDCl3) δ 7.61 (d, J = 7.8 Hz, 2H), 7.40
(t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.21 (s, 1H), 2.86 (tt, 3J =
3
11.2 Hz, J = 3.6 Hz, 1H), 2.15−2.11 (m, 2H), 1.87−1.82 (m, 2H),
1.75−1.60 (ovrlp, 3H), 1.46−1.26 (ovrlp, 3H). 13C NMR of pure 4f
(100 MHz, CDCl3) δ 168.0, 150.6, 128.9, 128.5, 128.1, 124.1, 121.7,
37.7, 30.8, 25.9, 25.8. IR of pure 4f (neat cm−1) 2922, 2854, 1551,
1448, 1117, 895, 835, 757, 705, 689. Anal. Calcd for C15H17NO (4f):
C, 79.26; H, 7.54. Found: C, 78.94; H, 7.57.
(E)-2-Phenyl-5-styryloxazole (4b).42 Synthesized from N-
((1E,3E)-4-phenylbuta-1,3-dien-1-yl)benzamide (3b) (249 mg), with
CuBr2 (33.5 mg, 15 mol %) and pyridine (48 μL, 60 mol %); EtOAc/
hexanes = 1:14; 99 mg, 40%; off-white solid. Mp: 81−82 °C (lit.: 82
°C).42 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 7.6 Hz, 2H), 7.49−
7.44 (ovrlp, 5H), 7.35 (t, J = 7.2 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H),
7.13 (t, J = 7.6 Hz, 2H), 6.90 (d, J = 16.4 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 161.1, 150.4, 136.4, 130.5, 129.5, 128.9, 128.3, 127.4,
126.62, 126.57, 126.4, 113.1. IR (neat cm−1) 1478, 1447, 1128, 961,
752, 824, 707, 693, 682. Anal. Calcd for C17H13NO: C, 82.57; H, 5.30.
Found: C, 82.28; H 5.46.
2-Phenyl-5-(thiophen-3-yl)oxazole (4g).8f Synthesized from
(E)-N-(2-(thiophen-3-yl)vinyl)benzamide (3g) (229 mg), with
CuBr2 (33.5 mg, 15 mol %) and ethyl nicotinate (41 μL, 30 mol
%); EtOAc/hexanes = 1:15, then 1:12; 134 mg, 59%; off-white solid.
1
Mp: 73−74 °C. H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.0 Hz,
2H), 7.56 (dd, J = 2.8 Hz, 1.2 Hz, 1H), 7.47−7.39 (ovrlp, 3H), 7.35
(dd, J = 5.2 Hz, 2.8 Hz, 1H), 7.32 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.26 (s,
J
dx.doi.org/10.1021/jo301332s | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
1H). 13C NMR (100 MHz, CDCl3) δ 160.5, 148.1, 130.3, 129.2, 128.8,
127.4, 126.9, 126.2, 124.5, 123.0, 120.6. IR (neat cm−1) 3107, 1611,
1500, 1447, 1396, 1130, 1066, 1022, 973, 849, 820, 772, 706, 689, 603.
Anal. Calcd for C13H9NOS: C, 68.70; H, 3.99. Found: C, 68.46; H,
3.94.
REFERENCES
■
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5-Phenyl-2-(thiophen-3-yl)oxazole (4h).43 Synthesized from
(E)-N-styrylthiophene-3-carboxamide (3h) (229 mg); EtOAc/hexanes
1
= 1:10; 171 mg, 75%; off-white solid. Mp: 71−72 °C. H NMR (400
MHz, CDCl3) δ 7.94 (dd, J = 2.8 Hz, 1.2 Hz, 1H), 7.65−7.63 (ovrlp,
3H), 7.40−7.33 (ovrlp, 4H), 7.38 (t, J = 7.6 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ 158.1, 150.5, 129.5, 128.9, 128.3, 127.9, 126.7, 125.9,
125.2, 124.1, 123.1. IR (neat cm−1) 1592, 1493, 1132, 852, 787, 761,
717, 695.
5-Phenyl-2-(thiophen-2-yl)oxazole (4i).38 Synthesized from
(E)-N-styrylthiophene-2-carboxamide (3i) (229 mg); EtOAc/hexanes
= 1:20, then 1:15; 106 mg, 47%; off-white solid. Mp: 63−65 °C (lit.:
59−61 °C).38 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 4.0 Hz, 1H),
7.65 (d, J = 8.0 Hz, 2H), 7.41−7.37 (ovrlp, 3H), 7.36 (s, 1H), 7.29 (t, J
= 7.6 Hz, 1H), 7.09 (t, J = 4.4 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 157.3, 150.8, 130.0, 128.9, 128.4, 128.3, 128.0, 127.7, 127.6, 124.1,
123.3. IR (neat cm−1) 3102, 1575, 1489, 1448, 1420, 1128, 1063, 945,
853, 823, 762, 718, 687.
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2-(Furan-2-yl)-5-phenyloxazole (4j).38 Synthesized from (E)-N-
styrylfuran-2-carboxamide (3j) (211 mg); EtOAc/hexanes = 1:10; 110
mg, 53%; off-white solid. Mp: 66−67 °C (lit.: 61−63 °C).38 1H NMR
(400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 2H), 7.57−7.56 (m, 1H),
7.42−7.39 (ovrlp, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 3.2 Hz,
1H), 6.54 (dd, J = 3.2 Hz, 1.6 Hz, 1H). 13C NMR (100 MHz, CDCl3)
δ 154.0, 150.9, 144.4, 143.0, 128.9, 128.6, 127.7, 124.2, 123.3, 111.9,
111.4. IR (neat cm−1) 1519, 1452, 1171, 1135, 1008, 939, 895, 749,
720, 685, 643, 592.
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methanone (4k). Synthesized from (E)-N-(2-(1-benzoyl-1H-indol-5-
yl)vinyl)thiophene-3-carboxamide (3k) (186 mg, 0.50 mmol, 1.0
equiv), CuBr2 (8.4 mg, 0.038 mmol, 7.5 mol %), TBAB (193 mg, 0.60
mmol, 1.2 equiv), K2S2O8 (176 mg, 0.65 mmol, 1.3 equiv), ethyl
nicotinate (10.2 μL, 0.075 mmol, 15 mol %), and acetonitrile (5.0 mL,
0.1 M). EtOAc/hexanes = 1:5; 109 mg, 0.29 mmol, 59%; pale yellow
Pam
4567. (c) Mazuela, J.; Tolstoy, P.; Pam
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I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 389. (b) Turchi, I. J. Ind. Eng.
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1
solid. Mp: 148−149 °C. H NMR (400 MHz, CDCl3) δ 8.46 (d, J =
8.8 Hz, 1H), 8.02 (dd, J = 3.2 Hz, 1.2 Hz, 1H), 7.95 (d, J = 1.2 Hz,
1H), 7.77−7.70 (ovrlp, 4H), 7.63 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.2
Hz, 2H), 7.43−7.41 (ovrlp, 2H), 7.35 (d, J = 3.6 Hz, 1H), 6.67 (d, J =
4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 168.5, 158.0, 151.0,
135.8, 134.2, 132.1, 131.2, 129.5, 129.3, 128.7, 126.7, 126.0, 125.1,
123.9, 122.6, 121.3, 116.9, 116.6, 108.6. IR (neat cm−1) 1686, 1598,
1457, 1367, 1336, 1191, 877, 724, 713. Anal. Calcd for C22H14N2O2S:
C, 71.33; H, 3.81. Found: C, 71.04; H, 3.97.
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ASSOCIATED CONTENT
■
S
* Supporting Information
All spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(9) For the cyclization of enamides bearing β-vinylic carbon-
heteroatom bonds, see the following. (i) C−Br bond: (a) Shin, C.;
Sato, Y.; Sugiyama, H.; Nanjo, K.; Yoshimura, J. Bull. Chem. Soc. Jpn.
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2000, 2415. (d) Schuh, K.; Glorius, F. Synthesis 2007, 15, 2297. (ii)
C−I bond: (e) Ferreira, P. M. T.; Monteiro, L. S.; Pereira, G. Eur. J.
Org. Chem. 2008, 4676. (f) Ferreira, P. M. T.; Castanheira, E. M. S.;
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sbuchwal@mit.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Monteiro, L. S.; Pereira, G.; Vilaca̧ , H. Tetrahedron 2010, 66, 8672.
We thank the National Institutes of Health (NIH) for financial
support (Grant GM58160). C.W.C. thanks the Croucher
Foundation (Hong Kong) for a Postdoctoral Fellowship. We
thank Dr. Meredeth A. McGowan (Massachusetts Institute of
Technology) for help with preparation of this manuscript.
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