Copper(ii)-mediated oxidative cyclization of enamides to oxazoles

Article abstract of DOI:10.1039/c2ob25310k

The copper(ii)-mediated oxidative cyclization of enamides to oxazoles is reported. A range of 2,5-disubstituted oxazoles were prepared in moderate to good yields in two steps from simple amide and alkyne precursors.

Full text of DOI:10.1039/c2ob25310k

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PAPER
Copper(II)-mediated oxidative cyclization of enamides to oxazoles†
Alison E. Wendlandt and Shannon S. Stahl*
Received 11th February 2012, Accepted 22nd March 2012
DOI: 10.1039/c2ob25310k
The copper(II)-mediated oxidative cyclization of enamides to oxazoles is reported. A range of
2,5-disubstituted oxazoles were prepared in moderate to good yields in two steps from simple amide and
alkyne precursors.
Oxazoles are an important class of heterocycles that are ubi-
Introduction
quitous in biologically active molecules, including pharmaceuti-
cals and natural products.5 Annulation methods are among
numerous approaches used in the preparation of substituted oxa-
zoles. Recent examples include multicomponent coupling reac-
tions,6 intramolecular additions to alkynes,7 and oxidative and
non-oxidative condensation and substitution reactions.8 Several
methods are particularly relevant to the work described here.
Yoshimura and coworkers8a developed a heterocyclization
method involving base-mediated O-vinylation via O-addition/
HBr-elimination of β-bromoenamides. A similar method was
later implemented by Pattenden et al.8b Glorius and coworkers
have reported a method for copper-catalyzed coupling of
primary amides with 1,2-dihalogenated olefins, which affords
mixtures of 2,4- and 2,5-disubstituted oxazoles.8c Buchwald
et al. have developed a two-step, one-pot method for copper-
catalyzed cross-coupling of vinyl halides with primary amides,
followed by intramolecular O-vinylation via iodine-mediated
O-addition to the alkene and elimination of HI.8d
Copper(II)-mediated C–H oxidation reactions have been the
focus of extensive attention in recent years.1,2 Many applications
of these reactions are oxidative cyclizations involving hetero-
functionalization of arene C–H bonds.3 Two early examples,
reported by the groups of Buchwald3a and Nagasawa,3b,c feature
copper-catalyzed oxidative cyclization of substituted benzami-
dines and benzanilides to benzimidazoles (eqn (1)) and benzoxa-
zoles (eqn (2)), respectively. In connection with our broader
interest in the oxidative functionalization of alkenes,4 we won-
dered whether analogous C–H oxidation reactions could be
achieved with enamides (eqn (3)). Here, we present a method for
the synthesis of 2,5-disubstituted oxazoles via sequential anti-
Markovnikov hydroamidation of terminal alkynes, followed by
Cu-mediated cyclization of the resulting enamides.
ð1Þ
Each of the methods just noted requires access to vinyl halide
precursors. We envisioned a complementary route to oxazoles
originating from readily available terminal alkynes and primary
amides (Scheme 1). This strategy draws upon recent work of
Goossen and coworkers, who have shown that enamides may be
accessed efficiently via Ru-catalyzed anti-Markovnikov hydro-
amidation of alkynes.9
ð2Þ
ð3Þ
Results and discussion
Our efforts to develop Cu-mediated methods for oxidative cycli-
zation of enamides were initiated with N-[(E)-2-phenylethenyl]
benzamide 1 as the substrate. Use of the catalytic conditions
reported previously for oxidative cyclization of aromatic
substrates (eqn (1) and (2)) were not successful with 1. These
Department of Chemistry, University of Wisconsin – Madison, 1101
University Ave, Madison, WI, USA. E-mail: stahl@chem.wisc.edu;
Fax: +1 608 262 6143; Tel: +1 608 265 6288
†Electronic supplementary information (ESI) available: Additional reac-
tion screening data, experimental procedures and product characteriz-
ation data. See DOI: 10.1039/c2ob25310k
Scheme 1 Retrosynthetic strategy for the synthesis of oxazoles.
3866 | Org. Biomol. Chem., 2012, 10, 3866–3870
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Table 1 Optimization of copper-mediated annulation of enamidesa
Table 2 Substrate scope of copper-mediated annulation of enamidesa
Entry
Copper source
Additive
Yieldb (%)
Entry
Product
Yieldb (%)
1
2
3
4
5
6
7
8
2.0 equiv CuCl2
2.0 equiv CuCl2
2.0 equiv CuCl2
2.0 equiv CuCl2
2.0 equiv CuCl2
2.0 equiv CuCl2
2.0 equiv CuCl2
2.0 equiv Cu(OAc)2
2.0 equiv Cu(OTf)2
2.0 equiv CuCl2
1.0 equiv CuCl2
0.5 equiv CuCl2
—
8c
23
26
22
24
31
59
0.5 equiv pyridine
0.5 equiv Et3N
0.5 equiv DMAPd
0.5 equiv DBUe
0.5 equiv imidazole
2.0 equiv imidazole
2.0 equiv imidazole
2.0 equiv imidazole
2.0 equiv NMIf
1.0 equiv NMI
0.5 equiv NMI
1
2
R = H
R = OMe
67c
74c
3
4
5
R = H
R = OMe
R = NO2
72
69
49
6.8
10
9
10
11
12
67 (74)g
56
6
67
40
a Reaction conditions: reactions were run on 0.05 mmol scale, at 0.1 M
in a sealed vessel at 140 °C under air. b GC yield. c In toluene.
e 4-Dimethylaminopyridine.
e 1,8-Diazabicyclo[5.4.0]undec-7-ene.
g N-Methylimidazole. g NMR yield, 0.2 mmol scale.
7
29
conditions led to complete consumption of 1, but only trace
quantities of the desired 2,5-diphenyloxazole product 2 (see ESI,
Table S1†). Subsequent efforts to identify alternative conditions
compatible with the use of catalytic quantities of Cu were simi-
larly unsuccessful (see ESI†). Measurable yields of the desired
product 2 were obtained, however, by using stoichiometric
CuCl2 in toluene (Table 1, entry 1). Further screening of reaction
conditions revealed that higher product yields could be obtained
with dioxane as the solvent. Addition of various amine bases sig-
nificantly improved the reaction outcome (Table 1, entries 2–6),
and imidazole was the optimal base in the initial experiments
(31% yield, entry 6). The amine bases appear to serve as ligands
for CuII, evidenced by significant color changes and improved
Cu solubility upon their addition to the reaction mixture. Use of
chelating ligands, such as 2,2′-bipyridine and 1,10-phenanthro-
line, led to lower yields of 2 relative to reactions with imidazole
(Table S1†). Whereas a Cu : base stoichiometry of 4 : 1 was
optimal for some bases (e.g., DMAP; see ESI†) the best results
with imidazole were obtained with a 1 : 1 Cu : base stoichiometry
(59%, entry 7). Screening of alternative Cu sources [e.g.,
Cu(OAc)2, Cu(OTf)2] failed to improve the yield (entries 8
and 9). Subsequent screening showed that replacement of
imidazole with N-methylimidazole, NMI (Cu : NMI = 1 : 1) led
to the highest observed yield of 2 (67%, entry 10).
8
9
10
R = Cl
R = Me
R = tBu
57 (52)d
69
73
11
12
38
58
a Reaction conditions: 0.4 mmol enamide, 0.8 mmol CuCl2, and
0.8 mmol NMI in 0.1 M 1,4-dioxane in a sealed tube under air for 20 h
at 140 °C. b Isolated yield. c Average of two runs. d 0.9 mmol enamide,
1.8 mmol CuCl2, and 1.8 mmol NMI in a sealed tube under air for 20 h
at 140 °C.
efficient access to diverse secondary enamide substrates.9a,10 The
enamides obtained from this method are obtained initially with
(Z)-alkene stereochemistry, but (E)-enamides may be obtained
by Et3N-promoted isomerization of the crude hydroamidation
product at elevated temperatures. The geometry of the starting
enamide did not influence the outcome of the oxidative cycliza-
tion reactions; both (Z)- and (E)-1 afforded the oxazole 2 in the
same yield (78% and 74%, respectively; Table 1, entry 10 and
eqn (4)). This result does not appear to have implications for the
cyclization mechanism, however, because a control experiment
showed that (Z)-1 isomerizes to (E)-1 in the absence of CuCl2
under the cyclization conditions.
Efforts to lower the Cu loading and achieve catalytic turnover
were not successful, despite the use of aerobic (ambient air) con-
ditions in these reactions (entries 11 and 12). Nevertheless, the
use of an air atmosphere is beneficial to the reaction. The
product yield diminished to 54% when the reaction was
performed under anaerobic (N2) conditions, and the use of pure
O2 (1 atm) also led to a lower yield (50%). The latter result
correlates with an increase in the formation of unidentified side-
products in the reaction.
The optimized conditions were employed with a number of
different substrates to explore the reaction scope (Table 2). The
Ru-catalyzed hydroamidation protocol of Goossen et al. enabled
ð4Þ
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Experimental section
General
All commercially available compounds were purchased form
Sigma-Aldrich, and used as received unless otherwise indicated.
Solvents were dried over alumina columns prior to use; anhy-
drous 1,4-dioxane was used as received. 1H and 13C NMR
spectra were recorded on Bruker AC-300 MHz, Varian Mercury-
300 MHz, or Varian INOVA 500 MHz spectrometers. Chemical
shift values are given in parts per million relative to residual
solvent peaks or TMS internal standard. Exact mass measure-
ments were obtained by the mass spectrometry facility at the
University of Wisconsin. Melting points were taken on a Mel-
Temp II melting point apparatus. Gas chromatography was done
on a Shimadzu GC-17A using Shimadzu RTX-5MS (15 m)
column and referenced to an internal standard (trimethoxy-
benzene). Flash chromatography was performed using SilicaFlash
P60 (Silicycle, particle size 40–63 μm, 230–400 mesh) from
Sigma Aldrich.
Scheme 2 Proposed mechanism for oxazole synthesis.
Substrates were varied at both the amide- or alkyne-derived
portion of the molecule. In general, good yields were obtained
with substrates bearing aromatic substituents, particularly elec-
tron-rich groups (Table 2, entries 1–6 and 8–10). A modest
reduction in yield was observed for substrates bearing electron-
deficient aromatic substituents (entries 5 and 8).
Poor yields were obtained with substrates derived from alkyl-
substituted amides. For example, the pivalamide derivative
(entry 7) led to only 29% yield of the oxazole, and no desired
product was obtained with the corresponding iPr derivative (not
shown). In contrast, a β-nBu-enamide derived from 1-hexyne
underwent cyclization in moderate yield (58%, entry 12).
The β-cyclohexyl enamide 3 underwent cyclization to the
desired oxazole 4 in 38% yield (eqn (5)); however, a significant
amount of the vinylic chlorination product 5 was observed as a
side product (41% yield). Vinylic chlorination is not a significant
side-reaction with the other substrates in Table 2. Chlorination of
the β C–H bond of 3 resembles CuCl2-mediated chlorination of
electron-rich arene C–H bonds, which are believed to be initiated
by single-electron transfer from the arene to CuII.1b,11 By
analogy, we speculate that the present reactions involve initial
CuII-mediated one-electron oxidation of the enamide. Addition
of the amide oxygen to the radical-cation intermediate, followed
by loss of two protons and another electron, affords the oxazole
product (Scheme 2). This mechanism seems more plausible than
an organometallic pathway involving directed C–H activation.12
Single-electron-transfer mechanisms have also been proposed in
another CuII-mediated arene annulation reaction.3e Partial
support for this hypothesis was obtained from the observation
that the β-deuterated enamide 1-d1 exhibits an identical time
course relative to the reaction of 1, KIE = 1.0 ( 0.2).13
Typical procedure for oxazole formation
All products were synthesized in the following manner from
either (Z) or (E) enamides: In a 6 dram vial equipped with a stir
bar were added 1.0 equiv Z or E enamide and 2.0 equiv CuCl2.
1,4-Dioxane was added to achieve 0.1 M substrate concentration,
followed by 2.0 equiv NMI under an air atmosphere. The vial
threadings were lined with Teflon tape and a Teflon cap was
securely fastened. The sealed vial was allowed to stir at 140 °C
behind a blast shield for 20 h, after which time the vial was
removed from the bath and allowed to cool. The contents of the
vial were concentrated, and then chromatographed directly –
typically in 1 : 10 or 1 : 5 EtOAc–hexanes.
2,5-Diphenyl-1,3-oxazole, (Table 2, entry 1).8g Isolated as a
white solid, mp = 65–66 C;1H NMR (300 MHz, CDCl3): δ 8.11
(m, 2H), 7.72 (m, 2H), 7.30–7.53 (m, 7H); 13C NMR
(300 MHz, CDCl3): δ 161.38, 151.49, 130.54, 129.15, 129.04,
128.65, 128.27, 127.71, 126.51, 124.42, 123.70; EMM (ESI)
m/z calc for C15H11NO [M + H]+: 222.0914, meas: 222.0911.
2-(4-Methoxyphenyl)-5-phenyl-1,3-oxazole (Table 2, entry
2).8g Isolated as a white solid, mp = 94–96 °C; 1H NMR
(300 MHz, CDCl3): δ 8.05 (dt, 2H, J = 9, 2.1 Hz), 7.71
(complex d, 2H, J = 7.2 Hz), 7.45 (t, 2H, J = 7.5 Hz), 7.41
(s, 1H), 7.34 (t, 1H, J = 6.6 Hz), 7.00 (dt, 1H, J = 9, 1.8Hz); 13
C
NMR (300 MHz, CDCl3): δ 160.58, 159.84, 151.32, 130.09,
128.78, 127.60, 126.15, 125.76, 121.98, 120.91, 114.42, 55.38;
EMM (ESI) m/z calc for C16H13NO2 [M + H]+: 252.1020, meas:
252.1025.
ð5Þ
5-(4-Methoxyphenyl)-2-phenyl-1,3-oxazole (Table 2, entry
3).8g Isolated as a white solid, mp = 63–66 °C; 1H NMR
(300 MHz, CDCl3): δ 8.10 (m, 2H), (dt, 2H, J = 8.7, 1.8 Hz),
7.43–7.53 (m, 3H), 7.326 (s, 1H), 6.98 (dt, 2H, J = 9, 2.1 Hz);
13C NMR (300 MHz, CDCl3): δ 160.80, 160.05, 151.54,
130.32, 128.99, 127.82, 126.37, 125.97, 122.18, 121.13, 114.64,
55.59. EMM (ESI) m/z calc for C16H13NO2 [M + H]+:
252.1020, meas: 252.1015.
Conclusion
In summary, we have developed an efficient route for the prep-
aration of 2,5-disubstituted oxazoles from simple alkyne and
amide precursors. These methods, based on oxidative cyclization
of enamides, complement the growing collection of CuII-based
methods for heterofunctionalization of C–H bonds.
3868 | Org. Biomol. Chem., 2012, 10, 3866–3870
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2,5-Bis(4-methoxyphenyl)-1,3-oxazole (Table 2, entry 4).14a
Isolated as a cream-colored solid, mp = 139–141 °C; H NMR
(300 MHz, CDCl3): δ 7.72 (m, 2H), 7.55 (m, 3H), 7.10–7.48
(m, 7H), 7.00 (d, 1H, J = 16.5 Hz); 13C NMR (300 MHz,
CDCl3): δ 166.66, 161.32, 151.13, 136.06, 135.82, 129.38,
129.16, 128.69, 128.17, 127.41, 124.45, 123.94, 114.147; EMM
(ESI) m/z calc for C17H13NO [M + H]+: 248.1070, meas:
248.1073.
1
(300 MHz, CDCl3): δ 8.02 (d, 2H, J = 8.7 Hz), 7.63 (d, 2H, J =
8.7 Hz), 7.27 (s, 1H), 6.95–7.00 (m, 4H), 3.87 (s, 3H), 3.81 (s,
3H); 13C NMR (300 MHz, CDCl3): δ 161.42, 160.91, 159.89,
150.99, 128.02, 125.82, 121.98, 121.30, 120.68, 114.59, 114.42,
55.58; EMM (EI) m/z calc for C17H15NO3 [M]+: 281.1047,
meas: 281.1046.
5-Butyl-2-phenyl-1,3-oxazole (Table 2, entry 12).14e Isolated
as a clear oil; 1H NMR (300 MHz, CDCl3): δ 7.99 (m, 2H), 7.42
(m, 3H), 6.85 (t, 1H, J = 0.9 Hz), 2.72 (td, 2H, J = 8.1 Hz, J =
0.9 Hz), 1.67 (p, 2H, J = 7.5 Hz), 1.43 (m, 2H), 0.97 (t, 3H, J =
7.5 Hz); 13C NMR (300 MHz, CDCl3) δ 160.80, 153.45,
130.04, 128.90, 128.09, 126.18, 123.75, 29.95, 25.54, 22.41,
13.95; EMM (EI) m/z calc for C13H15NO [M]+: 201.1149, meas:
201.1149.
5-(4-Methoxyphenyl)-2-(4-nitrophenyl)-1,3-oxazole (Table 2,
entry 5).14a Isolated as a yellow solid, mp = 205–206 °C with
1
decomposition; H NMR (300 MHz, CDCl3): δ 8.34 (d, 2H, J =
9 Hz), 8.24 (d, 2H, J = 8.7 Hz), 7.68 (d, 2H, 8.7 Hz), 7.41 (s,
1H), 7.00 (d, 2H, J = 9 Hz), 3.87 (s, 3H); 13C NMR (300 MHz,
CDCl3): δ 159.37, 157.34, 151.92, 147.36, 131.94, 125.66,
125.09, 123.22, 121.86, 119.10, 113.56, 54.41; EMM (ESI) m/z
calc for C16H12N2O4 [M + H]+: 297.0870, meas: 297.0880.
N-[(Z)-2-Chloro-2-cyclohexylethenyl]benzamide, 5. Assign-
ment of (Z)-isomer made based on NOE observed between vinyl
proton and cyclohexyl methine proton (500 MHz, CDCl3): NOE
of 4.42%, mix: 1.26 ms. 1H NMR (300 MHz, CDCl3) δ 8.00 (br
d, 1H, J = 9.6 Hz), 7.83 (d, 2H, J = 8.1 Hz), 7.46–7.58 (m, 3H),
7.18 (d, 1H, J = 10.5 Hz), 2.26 (m, 1H), 1.21–1.92 (m, 10H);
13C NMR (300 MHz, CDCl3) δ 164.24, 133.52, 132.43, 129.04,
127.35, 125.00, 116.81, 44.64, 31.69, 26.22, 26.09; EMM (ESI)
m/z calc for C15H18ClNO [M]+: 263.1072, meas: 263.1084.
5-(3,4-Dimethoxyphenyl)-2-phenyl-1,3-oxazole (Table 2, entry
6).14b Isolated as a white solid, mp = 95–97 °C; 1H NMR
(300 MHz, CDCl3): δ 8.10 (m, 2H), 7.48 (m, 3H), 7.45 (s, 1H),
7.33 (dd, 1H, J = 8.4, 2.1 Hz), 7.20 (d, 1H, 2.1 Hz), 3.99 (s, 3H)
3.93 (s, 3H); 13C NMR (300 MHz, CDCl3): δ 160.88, 151.51,
149.69, 149.59, 130.38, 129.01, 127.77, 126.39, 122.49, 121.31,
117.50, 111.74, 107.71, 56.26, 56.23; EMM (ESI) m/z calc for
C17H15NO3 [M]+: 281.1047, meas: 281.1059.
2-tert-Butyl-5-phenyl-1,3-oxazole (Table 2, entry 7).14c Iso-
lated as a yellow oil; H NMR (300 MHz, CDCl3): δ 7.63 (m,
1
Acknowledgements
2H), 7.40 (t, 2H, J = 7.8 Hz), 7.30 (m, 1H), 7.202 (s, 1H), 1.445
(s, 9H); 13C NMR (300 MHz, CDCl3): δ 171.05, 150.82,
129.02, 128.62, 128.26, 124.19, 121.70, 34.05, 28.83; EMM
(ESI) m/z calc for C13H15NO [M]+: Calc: 201.1149, meas:
201.1158.
We thank the U.S. Department of Energy (DE-FG02-
05ER15690) for financial support of this work. Analytical instru-
mentation was partially funded by the NSF (CHE-9208463,
CHE-0342998, CHE-9629688, CHE-9974839).
5-(4-Chlorophenyl)-2-phenyl-1,3-oxazole (Table 2, entry 8).8g
Isolated as an off-white solid, mp = 102–104 °C; 1H NMR
(300 MHz, CDCl3): δ 8.10 (m, 2H), 7.65 (dt, 2H, J = 8.7, 1.8
Hz), 7.49 (m, 6H); 13C NMR (300 MHz, CDCl3): δ 161.61,
150.48, 134.40, 130.71, 129.43, 129.07, 127.50, 126.74, 126.55,
125.63, 124.08; EMM (ESI) m/z calc for C15H10ClNO [M]+:
255.0446, meas: 255.0442.
Notes and references
1 For leading references in this area, see: (a) X. Li, J. B. Hewgley,
C. A. Mulrooney, J. Yang and M. C. Kozlowski, J. Org. Chem., 2003,
68, 5500; (b) L. Menini and E. V. Gusevskaya, Chem. Commun., 2006,
209; (c) X. Chen, X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem.
Soc., 2006, 128, 6790; (d) T. Hamada, X. Ye and S. S. Stahl, J. Am.
Chem. Soc., 2008, 130, 833; (e) H.-Q. Do and O. Daugulis, J. Am.
Chem. Soc., 2009, 131, 17052; (f) C. Zhang and N. Jiao, J. Am. Chem.
Soc., 2010, 132, 28.
5-(4-Methylphenyl)-2-phenyl-1,3-oxazole (Table 2, entry 9).8g
1
2 For recent reviews, see: (a) A. E. Wendlandt, A. M. Suess and S.
S. Stahl, Angew. Chem., Int. Ed., 2011, 50, 11062; (b) T. Punniyamurthy
and L. Rout, Coord. Chem. Rev., 2008, 252, 134.
Isolated as a white solid, mp = 77–78 °C; H NMR (300 MHz,
CDCl3): δ 8.10 (m, 2H), 7.61 (d, 2H, J = 8.1 Hz), 7.47 (m, 3H),
7.39 (s, 1H), 7.25 (d, 2H overlaps with CHCl3, J = 8.1 Hz), 2.38
(s, 3H); 13C NMR (300 MHz, CDCl3): δ 161.05, 151.70,
138.71, 130.40, 129.84, 129.00, 127.79, 126.44, 125.53, 124.40,
123.04, 21.59; EMM (ESI) m/z calc for C16H13NO [M + H]+:
236.1070, meas: 236.1080.
3 For representative examples, see: (a) G. Brasche and S. L. Buchwald,
Angew. Chem., Int. Ed., 2008, 47, 1932; (b) S. Ueda and H. Nagasawa,
Angew. Chem., Int. Ed., 2008, 47, 6411; (c) S. Ueda and H. Nagasawa,
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D. Liang, L. Liu, J. Zhang and Q. Zhu, Angew. Chem., Int. Ed., 2011, 50,
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3694.
5-(4-tert-Butylphenyl)-2-phenyl-1,3-oxazole (Table 2, entry
1
10).14d Isolated as an oil; H NMR (300 MHz, CDCl3): δ 8.11
(m, 2H), 7.65 (m, 2H), 7.47 (m, 4H), 7.39 (s, 1H), 1.34 (s, 9H);
13C NMR (300 MHz, CDCl3): δ 161.12, 151.95, 151.66,
130.41, 129.02, 127.82, 126.45, 126.08, 125.51, 124.29, 123.17,
34.99, 31.44; EMM (ESI) m/z calc for C19H19NO [M + H]+:
278.1540, meas: 278.1551.
5-Phenyl-2-[(E)-2-phenylethenyl]-1,3-oxazole (Table 2, entry
11).8e Isolated as a white solid, mp = 97–100 °C; 1H NMR
This journal is © The Royal Society of Chemistry 2012
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4 For reviews, see: (a) V. Kotov, C. C. Scarborough and S. S. Stahl, Inorg.
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5 See, for example: (a) D. C. Palmer and E. C. Taylor, The Chemistry of
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3870 | Org. Biomol. Chem., 2012, 10, 3866–3870
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