Silver-Catalyzed Cyclization of Propargylic Amides to Oxazolines

Article abstract of DOI:10.1002/adsc.201500610

A ligand-accelerated effect is observed in the cyclization of propargylic amides catalyzed by bis(pyridyl)silver(I) complexes, with an unexpected reversal of electronic demand to the analogous NH addition reaction. The catalyst was found to be effective for internal alkyne substrates, offering exclusive selectivity for the 5-exo-dig product. Differences in selectivity profile between gold- and silver-catalyzed processes are highlighted and discussed.

Full text of DOI:10.1002/adsc.201500610

FULL PAPERS
DOI: 10.1002/adsc.201500610
Silver-Catalyzed Cyclization of Propargylic Amides to Oxazolines
Valerie H. L. Wong,a,b Andrew J. P. White,a T. S. (Andy) Hor,b
and King Kuok (Mimi) Hiia,*
a
Department of Chemistry, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, U.K.
E-mail: mimi.hii@imperial.ac.uk
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
b
Received: June 24, 2015; Revised: August 12, 2015; Published online: November 25, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500610.
Abstract: A ligand-accelerated effect is observed in selectivity for the 5-exo-dig product. Differences in
the cyclization of propargylic amides catalyzed by selectivity profile between gold- and silver-catalyzed
bis(pyridyl)silver(I) complexes, with an unexpected processes are highlighted and discussed.
À
reversal of electronic demand to the analogous N H
addition reaction. The catalyst was found to be effec- Keywords: cyclization; heterocycles; oxazolines;
tive for internal alkyne substrates, offering exclusive silver
Introduction
we revealed that the rate of this reaction is highly
sensitive to the ligandꢀs electronic properties; the re-
Previously, we have reported the catalytic activity of action rate was greatly enhanced by electron-with-
bis(pyridyl)silver(I) complexes for the intramolecular drawing groups on pyridine.[1b] These results encour-
cyclization of O-propargyl imidates 1 [Scheme 1, Eq. aged us to initiate a study to investigate the utility of
(1)].[1a] The cyclization proceeds exclusively with 5- these silver complexes in the cyclization of propargyl-
exo-dig selectivity, to generate 2-oxazolines containing ic amides 2, which is a highly complementary strategy,
a methylene unit at C-4. More recently in this journal, in that the heteroatoms on the acyclic substrate are
interchanged [Scheme 1, Eq. (2)], producing the het-
À
erocycle via a formal O H addition process.
A number of catalysts have been reported for this
type of cyclization, including simple acid, base and
non-precious metals.[2] However, the reaction condi-
tions are rather impractical, requiring very high cata-
lyst loadings, stoichiometric reagents, and/or elevated
temperatures. In terms of the coinage metals, simple
[4]
CuI[3] and AgSbF6 salts have been reported to medi-
ate 5-exo-dig cyclization reactions, but are only effec-
tive for substrates containing geminal substituents at
the propargylic position (R2 and R3 =alkyl); presuma-
bly assisted by the Thorpe–Ingold effect. In compari-
son, gold catalysts have a much wider scope, and ex-
hibit different selectivity profiles, depending on the
oxidation state and ligand. In the presence of AuCl3,
cyclization of terminal alkyne substrates (R4 =H)
gave aromatic oxazoles 4 as the primary product,[5]
while the use of cationic Au(I)-phosphine complexes
promoted the formation of oxazolines 3.[6]
In terms of substrate scope, cyclization of internal
alkynes (where R4 ¼ H) is rare. To date, this is only
refluxing toluene to afford oxazole 3,[2b] or by using
possible by using a stoichiometric amount of acid in
Scheme 1. Synthesis of 2-oxazolines by complementary in-
tramolecular N H or O H addition reactions.
À
À
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Valerie H. L. Wong et al.
À
À
N-heterocyclic carbene (NHC) complexes of Au, to ing steps operate in the N H and O H addition reac-
furnish either the oxazoline 3, or the 6-endo-dig prod- tions to alkynes catalyzed by silver. The optimization
uct 5, depending on the substituents present.[7] In this study concluded with an investigation of the counter
article, we report a ligand-assisted silver-catalyzed anion effect (entries 6–10),Àwhere the slightly coordi-
process for the intramolecular cyclization of propar- nating TfOÀ and CF3CO2 (entries 4 and 10) were
À
gylic amide substrates under ambient conditions, much less prodÀuctive than the non-coordinating PF6 ,
À
which offers exclusive selectivity for the 5-exo-dig BF4 and SbF6 counter anions, which afforded near
products 3.
quantitative yields of 3a (entries 9 and 10) at half the
catalyst loading.
Subsequently, the cyclization of sixteen substrates
containing different substituents at the amide (R1),
propargylic positions (R2 and R3) and alkyne (R4)
Results and Discussion
To avoid biases by Thorpe–Ingold and thermal effects, were examined (Figure 1). In all cases, only the non-
the optimization studies were performed at ambient aromatic 5-exo-dig products (3) were obtained. Alkyl,
temperature, using the simple, unsubstituted propar- aryl and crotonyl substituents were well tolerated as
gylic amide 2a in a solution of CH2Cl2 (selected exam- the amide substituent (R1), affording 3a–3d in good
ples presented in Table 1, see also Table S1 in the conversions. Vinyl (2e) and ethoxy (2f) substituents at
Supporting Information). Guided by our previous R1 afforded low conversions of unidentifiable prod-
study, the activity of electronically different silver(I) ucts, while no reaction was observed for the ester-sub-
bis(pyridyl) triflate complexes was assessed (en-
tries 1–5). In this case, an increase in catalyst efficien-
cy is associated with more electron-rich pyridyl li-
gands, with 4-methoxypyridine offering the best per-
formance (entry 4). Catalyst deactivation was indicat-
ed by the formation of insoluble white precipitates
during the reaction; this was most severe with the
DMAP complex, which is catalytically inactive
(entry 5). This result is surprising as the reverse trend
was observed in the previous study of the analogous
À
N H addition [Scheme 1, Eq. (1)]; where the most
electron-deficient 4-Ac-Py offered the highest catalyt-
ic activity.[1b] This implies that different turnover-limit-
Table 1. Initial reaction optimization.[a]
Entry [Cat]
mol% Time Yield[b]
[h]
[%]
1
2
3
4
5
6
7
8
9
10
[(Py)2Ag]OTf
10
10
10
10
10
10
6
6
6
6
6
6
6
24
24
24
8
[(4-Ac-Py)2Ag]OTf
[(4-Me-Py)2Ag]OTf
[(4-MeO-Py)2Ag]OTf
[(4-NMe2-Py)2Ag]OTf
[(4-MeO-Py)2Ag]ClO4
26
59
85
5
98
31
93
96
95
[(4-MeO-Py)2Ag][TFA] 10
[(4-MeO-Py)2Ag]BF4
[(4-MeO-Py)2Ag]PF6
[(4-MeO-Py)2Ag]SbF6
5
5
5
Figure 1. Reaction conditions:Substrate 2a–p (0.2 mmol),
catalyst [Ag(MeO-Py)2]PF6 (1–15 mol%), CH2Cl2 (0.5 mL),
238C. Conversions determined by 1H NMR spectroscopy
(1,3,5-trimethoxybenzene as internal standard). Isolated
yields after purification are indicated in parentheses.
[a]
Reaction conditions: substrate 2a (0.4 mmol), catalyst
(0.04 mmol, 10 mol%), 238C, solvent (1 mL).
[b]
1
Determined by H NMR spectroscopy, using 1,3,5-trime-
thoxybenzene as internal standard.
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Silver-Catalyzed Cyclization of Propargylic Amides to Oxazolines
stituted 2g, even in refluxing DCE; presumably due
to reduced O-nucleophilicity:
As expected, the presence of gem-dimethyl groups
at the propargylic position afforded quantitative con-
version to the product 3i within an hour, using just
1 mol% of the catalyst. On the other hand, the intro-
duction of an aromatic (PMP=p-methoxyphenyl)
group at R2 (2j) also afforded good yields of the 3j in
30 min using 5 mol% of the catalyst. Encouraged by
these results, the cyclization of the challenging non-
terminal propargylic amides was examined, focussing
initially on substrates where R2 =PMP. We were de-
lighted to find that substrates containing cyclopropyl,
n-butyl, cyclohexenyl and phenyl cyclized smoothly to
afford the corresponding 5-exo-dig products 3k–3p in
mostly good to excellent yields. The preservation of
the cyclopropyl ring in 3k is noteworthy, as it suggests
that radical intermediates are unlikely to be involved
in these reactions. Within this subset of substrates,
mixtures of E/Z-isomers were obtained with alkyl
substituents at R4 (3k–3m), whereas only Z-isomer
Scheme 2. Rationalization of observed selectivities.
was obtained for phenyl-substituted substrates (3n– bias.[8a] In the presence of a basic pyridine, however,
3p), irrespective of substitution at the propargylic po- formation of the 5-membered heterocycle is favoured
sition (R2, R3), i.e., the observed stereochemistry is under silver catalysis. The formation of the E-isomer
likely to be (largely) associated with electronic, rather is explained by the greater Lewis acidity of the Ag
than steric, effects. In all cases, a long-range allylic catalyst than Au, so it could also coordinate to the
(4J) coupling of ca. 2.5 Hz for the alkenyl and methine amide functionality during the p-activation step, di-
protons is associated with the (Z)-configuration, con- recting a syn-addition across the triple bond (pathway
firmed by a NOESY experiment performed on 3m, c). Such a simultaneous binding to alkyne and oxygen
and an X-ray crystal structure obtained for 3n (Sup- has been previously shown by DFT calculations to be
porting Information).
energetically feasible in the Au-catalyzed reaction (al-
The different regio- and stereoselectivities exhibit- though the formation of the E-isomer was not ob-
ed by the silver- and gold-catalyzed reactions is partic- served using gold catalysts).[8a] Under silver catalysis,
ularly striking, and warrants further comment. For the this competitive pathway is prohibited when R4 =Ph
(NHC)Au-catalyzed reactions, competitive formation (as in compounds 3n and 3o), due to unfavourable al-
of the oxazine product 5 was observed for substrates lylic (A1,3) interactions[9] between substituents R2 and
containing an alkyl substituent at R4,[8] whereas the R4. This is supported further by the increasing Z/E
Ag catalyst only afforded the 5-membered heterocy- ratios obtained for products 3k–3m.
cle. Conversely, the Au-catalyzed reaction only af-
Previous work by Hashmi and co-workers has
forded Z-3, whereas the E-isomer was obtained as shown that the exo-methylene group in oxazolines 3
a minor product using the Ag catalyst. Control experi- may be oxidized using O2,[10] halogenated using
ments established that the E/Z-isomerization does not NXS,[11] or Alder-ene reactions,[12] to give added func-
occur in the presence of triflic acid or the 4-methoxy- tionalities for further elaboration. As compounds 3k–
pyridinium hexafluorophosphate salt. Furthermore, 3m decomposed on silica gel, we attempted to tele-
the formation of Z- and E-3 occurs simultaneously, scope the cyclization process with other reactions that
their relative concentrations did not vary during the can lead to stable products. The aromatization of un-
course of the reaction, suggesting that the two isomers substituted methylenic oxazolines (R4 =H, including
are formed via competitive pathways. Three different 3a) has been reported to proceed in the presence of
reaction routes are proposed to account for these ob- DBU at 508C.[13,14] During an attempt to reduce the
ꢀ
servations (Scheme 2). The principal mode of C C ac- C=C bond, however, we discovered that aromatiza-
tivation is by its coordination to the p-acidic metal tion of 3k also occurred in the presence of Pd/C, to
centre, whereupon 5-exo-dig cyclization is generally give the compound 6 in low yield (Scheme 3); with
favoured, to furnish a putative vinylmetallic inter- further optimization, this may offer a possible alterna-
mediate that affords the Z-isomer after protodemetal- tive to the synthesis of trisubstituted oxazoles.[15]
lation (pathway a). When R4 =alkyl group, 6-endo-dig
cyclization is favoured by a cationic Au-NHC catalyst
(pathway b), which was attributed to electronic
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Valerie H. L. Wong et al.
is abbreviated to s (singlet), br s (broad singlet), d (doublet),
t (triplet), q (quartet), sept (septet), and multiplet (m).
Melting points were recorded using an Electrothermal Gal-
lenkamp apparatus, and are uncorrected. Mass spectra (MS)
were recorded at Imperial College London on Micromass
Autospec Premier, Micromass LCT Premier, or VG Plat-
form II spectrometers using EI, CI or ESI techniques. Infra-
red spectra were recorded using a Perkin–Elmer 100 series
FT-IR spectrometer, equipped with an ATR accessory.
Single crystal X-ray diffraction was performed at Imperial
College London using an Agilent Xcalibur 3 E diffractome-
ter. Elemental analyses were performed by the Analytical
Services at London Metropolitan University.
Scheme 3. Synthesis of tri-substituted oxazole by a telescop-
ed process.
The syntheses and characterization data of silver com-
plexes used in this work were described in our previous
work.[1] Preparation procedures for acyclic precursors 2 are
described in the Supporting Information. Characterization
data for new compounds are given in the Supporting Infor-
mation.
Conclusions
Ag-catalyzed cyclization of propargylic amides occurs
under mild conditions in the presence of electron-rich
pyridyl ligands to afford 5-exo-dig oxazoline products
exclusively. The different electronic demands ob-
served between the ligand-accelerated N H and O H
addition processes will require further investigations
by DFT calculations. Under silver catalysts, the reac-
tion is regioselective towards 5-exo-dig cyclization,
producing a mixture of E- and Z-isomers with inter-
nal alkynes, whereby the product distribution is de-
pendent on the pattern of substitution on the sub-
strate. This is in contrast to the gold-catalyzed pro-
À
À
Representative Procedure for the Ag(I)-Catalyzed
Conversion of 2 to 3
[(MeO-Py)2Ag]PF6 (1–15 mol%) was added to a solution of
the propargylic amide substrate 2a (2.0 mmol, 1 equiv.) in
CH2Cl2 (5.0 mL) at room temperature. After the prescribed
reaction time, the reaction mixture was filtered through
cess, where the regioselectivity is less well-defined, Celite, and the filtrate concentrated under vacuum. The resi-
due was purified by column chromatography (petroleum
yet produces only Z-isomers. Using this methdology,
the synthesis of a trisubstituted oxazole (6) was dem-
onstrated, including an alternative route to aromatize
the products to their corresponding oxazoles over
a heterogeneous Pd catalyst. This work has led us to
explore other silver catalysts with enhanced reactivi-
ties, and these results will be reported in due course.
1
ether/ethyl acetate). Copies of H and 13C NMR spectra are
provided in the Supporting Information.
2-Phenyl-5-methylene-4,5-dihydrooxazole (3a):[2d] Purified
by column chromatography (petroleum ether/ethyl acetate,
1
1:1); yield: 0.30 g (94%); yellow oil; H NMR (CDCl3): d=
8.05–7.91 (m, 2H), 7.56–7.47 (m, 1H), 7.48–7.40 (m, 2H),
4.82 (q, J=2.9 Hz, 1H), 4.65 (t, J=2.9 Hz, 2H), 4.36 (q, J=
2.6 Hz, 1H); 13C NMR (CDCl3): d=163.7, 158.8, 131.8,
128.5, 128.0, 126.7, 83.7, 57.7; HR-MS (ESI): m/z=160.0751,
calcd. for C10H9NO [M+H]+: 160.0757; IR: nmax =1692 (C=
C), 1647 cmÀ1 (C=N).
Experimental Section
2-Methyl-5-methylene-4,5-dihydrooxazole (3b): The reac-
tion was performed in CD2Cl2 and the product yield was cal-
culated in the presence of a known amount of added inter-
nal standard (1,3,5-trimethoxybenzene). The product is too
General
All reactions involving silver compounds were performed in
the dark by covering the reaction vessels with aluminium
foil. Catalytic reactions were carried out in parallel in a Rad-
leyꢀs 12-place reaction carousel, or in screw-cap vials. Sol-
vents were dried by passage through the columns of molecu-
lar sieves in a solvent purification system (Innovative Tech-
nology Inc.). Unless otherwise stated, materials obtained
from commercial suppliers were used without purification.
Column chromatography was performed on silica gel (Kie-
selgel 60) or neutral alumina. Preparative TLC was per-
formed on 20”20 cm2 glass plates with a 1.5 mm thick layer
of silica gel 60 F254 (Analtech). TLCs were performed using
silica gel 60 F254 aluminium sheets and visualized with
KMnO4 solution or exposure to UV light (l=254 nm).
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were
recorded at 258C on Bruker Avanceꢂ 400 spectrometers.
Residual protic solvents were used as an internal standard
and 13C resonances were referenced to the deuterated
carbon. Chemical shifts (d) are reported in ppm. Multiplicity
1
volatile to be isolated. H NMR (CD2Cl2): d=4.73–4.71 (m,
1H), 4.47–4.44 (m, 2H), 4.34–4.33 (m, 1H), 2.12 (t, J=
1.5 Hz, 3H).
2-tert-Butyl-5-methylene-4,5-dihydrooxazole (3c):[11] The
reaction was performed in CD2Cl2 and the product yield was
calculated in the presence of a known amount of added in-
ternal standard (1,3,5-trimethoxybenzene). The product is
1
too volatile to be isolated. H NMR (CD2Cl2): d=4.52 (dt,
J=3.0, 2.4 Hz, 1H), 4.29 (t, J=2.9 Hz, 2H), 4.14 (dt, J=3.0,
2.4 Hz, 1H), 1.13 (s, 9H).
(E)-5-Methylene-2-styryl-4,5-dihydrooxazole (3d):[11] Puri-
fied by column chromatography (petroleum ether/ethyl ace-
tate, 2:1); yield: 0.31 g (84%); white solid; 1H NMR
(CDCl3): d=7.60–7.30 (m, 6H), 6.63 (d, J=16.3 Hz, 1H),
4.76 (q, J=2.9 Hz, 1H), 4.58 (t, J=2.8 Hz, 2H), 4.32 (q, J=
2.7 Hz, 1H); 13C NMR (CDCl3): d=163.5, 158.5, 140.8,
134.9, 129.7, 128.9, 127.6, 114.1, 83.3, 57.7; HR-MS (ESI): m/
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Silver-Catalyzed Cyclization of Propargylic Amides to Oxazolines
z=186.0916, calcd. for C12H11NO [M+H]+: 186.0913; IR:
nmax =1687 (C=C), 1656 cmÀ1 (C=N).
(CDCl3): d=8.07–8.04 (m, 2H), 7.48–7.39 (m, 3H), 7.32–
7.28 (m, 2H), 6.91–6.88 (m, 2H), 6.49 (t, J=4.0 Hz, 1H),
5.27 (d, J=3.4 Hz, 1H), 5.08 (d, J=3.4 Hz, 1H), 3.80 (s,
3H), 2.27–2.21 (m, 2H), 2.20–2.12 (m, 2H), 1.75–1.62 (m,
4H).
Ethyl-(5-methylene-4,5-dihydro-1,3-oxazol-2-yl)acetate
(3h):[11] This compound was not isolated due to the low yield
of this compound (ca. 10% by NMR) and difficulties in sep-
1
(5Z)-5-(1-cyclohexenylmethylene)-4-(4-methoxyphenyl)-2-
phenyl-4,5-dihydro-1,3-oxazole (Z-3m): Purified by prepara-
tive TLC (petroleum ether/ethyl acetate, 4:1); yield: 0.34 g
aration from unreacted starting material. H NMR (CDCl3):
d=4.70 (q, J=3.0 Hz, 1H), 4.46 (td, J=2.8, 1.4 Hz, 2H),
4.30 (q, J=2.7 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 3.43 (s,
2H), 1.28 (t, J=7.1 Hz, 3H).
1
(49%); white solid; mp 116–1208C; H NMR (CDCl3): d=
8.09–8.02 (m, 2H), 7.59–7.51 (m, 1H), 7.50–7.44 (m, 2H),
7.26–7.21 (m, 2H), 6.93–6.86 (m, 2H), 5.77 (br s, 1H), 5.71
(br s, 1H), 5.05 (br s, 1H), 3.80 (s, 2H), 2.54 (s, 2H), 2.12 (s,
2H), 1.78–1.67 (m, 2H), 1.64–1.56 (m, 2H); 13C NMR
(CDCl3): d=162.7, 159.3, 152.4, 133.3, 133.2, 131.9, 128.5,
128.3, 126.9, 126.8, 114.2, 106.1, 73.2, 55.3, 27.8, 25.9, 23.0,
22.0; HR-MS (ESI): m/z=346.1807, calcd. for C23H23NO2
[M+H]+: 346.1818; IR: nmax =1686 (C=C), 1646 cmÀ1 (C=
N). anal. calcd. for C23H23NO2: C 79.97, H 6.71, N 4.05%;
found: C 79.92, H, 6.64, N 4.03%.
(5Z)-5-Benzylidene-4-(4-methoxyphenyl)-2-phenyl-4,5-di-
hydro-1,3-oxazole (Z-3n): Purified by column chromatogra-
phy (petroleum ether/ethyl acetate, 4:1); yield: 0.56 g
(82%); white solid. X-ray diffraction quality single crystals
were grown from CH2Cl2/hexane at À208C; mp 160–1638C;
1H NMR (CDCl3): d=8.17–8.15 (m, 2H), 7.62–7.54 (m,
3H), 7.54–7.52 (m, 2H), 7.40–7.38 (m, 2H), 7.31–7.28 (m,
2H), 6.94–6.90 (m, 1H), 6.94–6.90 (m, 2H), 5.93 (d, J=
2.4 Hz, 1H), 5.52 (d, J=2.4 Hz, 1H), 3.81 (s, 3H); 13C NMR
(CDCl3): d=162.6, 159.5, 155.7, 134.8, 132.5, 132.2, 128.9,
128.6, 128.5, 128.4, 128.0, 127.0, 126.4, 114.3, 102.8, 73.7,
55.3; HR-MS (ESI): m/z=342.1500, calcd. for C23H19NO2
[M+H]+: 342.1494; IR: nmax =1692 (C=C), 1650 cmÀ1 (C=
N); anal. calcd. for C23H19NO2: C 80.92, H 5.61, N 4.10%;
found: C 81.13, H 5.56, N 4.05%. Crystal data for (Z)-3n
have been deposited at the Cambridge Crystallographic Da-
tabase, reference code: CCDC 1053097. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
4,4-Dimethyl-5-methylene-2-phenyl-4,5-dihydrooxazole
(3i):[2c] Purified by column chromatography (petroleum
ether/ethyl acetate, 6:1); yield: 0.36 g (96%); colourless oil;
1H NMR (CDCl3): d=8.00–7.98 (m, 2H), 7.54–7.47 (m,
1H), 7.47–7.40 (m, 2H), 4.74 (d, J=2.8 Hz, 1H), 4.25 (d, J=
2.9 Hz, 1H), 1.45 (s, 6H); 13C NMR (CDCl3): d=167.9,
159.8, 131.6, 128.4, 128.1, 127.0, 82.3, 69.1, 29.7; HR-MS
(ESI): m/z=188.1074, calcd. for C12H13NO [M+H]+:
188.1070; IR: nmax =1694 (C=C), 1645 cmÀ1 (C=N).
4-(4-Methoxyphenyl)-5-methylene-2-phenyl-4,5-dihydro-
1,3-oxazole (3j): Purified by column chromatography (petro-
leum ether/ethyl acetate, 4:1); yield: 0.48 g (90%); white
solid; mp 75–818C; 1H NMR (CDCl3): d=8.10–8.03 (m,
2H), 7.58–7.51 (m, 1H), 7.50–7.42 (m, 2H), 7.29–7.23 (m,
2H), 6.94–6.87 (m, 2H), 5.74 (t, J=2.8 Hz, 1H), 4.91 (t, J=
2.9 Hz, 1H), 4.27 (t, J=2.7 Hz, 1H), 3.80 (s, 3H); 13C NMR
(CDCl3): d=162.7, 162.6, 159.3, 132.7, 132.0, 128.5, 128.5,
128.3, 126.6, 114.2, 85.0, 71.8, 55.3; HR-MS (ESI): m/z=
266.1174, calcd. for C17H15NO2 [M+H]+: 266.1181; IR:
nmax =1695 (C=C), 1645 cmÀ1 (C=N); anal. calcd. for
C17H15NO2: C 76.96, H 5.70, N 5.28%; found: C 76.80, H
5.64, N, 5.20%.
(5E)-5-(Cyclopropylmethylene)-4-(4-methoxyphenyl)-2-
phenyl-4,5-dihydro-1,3-oxazole (E-3k): This compound de-
1
composes on silica and was not isolated. H NMR (CDCl3):
d=7.95–7.93 (m, 2H), 7.43–7.36 (m, 3H), 7.29–7.27 (m,
2H), 6.90–6.88 (m, 2H), 5.19 (d, J=3.0 Hz, 1H), 4.91 (d, J=
3.0 Hz, 1H), 3.79 (s, 3H), 1.58–1.51 (m, 1H), 0.90–0.86 (m,
2H), 0.78–0.72 (m, 2H).
(5Z)-5-(Cyclopropylmethylene)-4-(4-methoxyphenyl)-2-
phenyl-4,5-dihydro-1,3-oxazole (Z-3k): This compound de-
(5Z)-5-Benzylidene-2-phenyl-4,5-dihydro-1,3-oxazole (Z-
3o):[8b] Purified by column chromatography (petroleum
ether/ethyl acetate, 6:1); yield: 0.19 g (40%); white solid;
1H NMR (CDCl3): d=8.11–8.02 (m, 4H), 7.66–7.16 (m,
6H), 5.66 (t, J=2.6 Hz, 1H), 4.81 (d, J=2.6 Hz, 2H);
13C NMR (CDCl3): d=164.1, 151.8, 134.9, 132.2, 130.8,
128.8, 128.7, 128.3, 128.0, 126.4, 100.9, 59.5; HR-MS (ESI):
m/z=236.1076, calcd. for C16H14NO [M+H]+: 236.1075.
(Z)-5-Benzylidene-4,4-dimethyl-2-phenyl-4,5-dihydrooxa-
zole (Z-3p):[16] Purified by column chromatography (petrole-
um ether/ethyl acetate, 6:1); yield: 0.48 g (92%); white
1
composes on silica and was not isolated. H NMR (CDCl3):
d=8.10–8.08 (m, 2H), 7.55–7.51 (m, 1H), 7.47–7.43 (m,
2H), 7.24–7.22 (m, 2H), 6.90–6.87 (m, 2H), 5.70 (d, J=
2.4 Hz, 1H), 4.07 (dd, J=9.5, 2.4 Hz, 1H), 3.79 (s, 3H),
1.85–1.76 (m, 1H), 0.84–0.73 (m, 2H), 0.42–0.32 (m, 2H).
(5E)-5-Pentylidene-4-(4-methoxyphenyl)-2-phenyl-4,5-di-
hydro-1,3-oxazole (E-3l): This compound decomposes on
1
silica and was not isolated. H NMR (CDCl3): d=8.01–7.99
(m, 2H), 7.42–7.37 (m, 3H), 7.30–7.27 (m, 2H), 6.90–6.88
(m, 2H), 5.19 (d, J=2.8 Hz, 1H), 4.84 (d, J=2.8 Hz, 1H),
3.80 (s, 3H), 2.23 (t, J=7.5 Hz, 2H), 1.63–1.56 (m, 2H),
1.50–1.43 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).
1
solid; H NMR (CDCl3): d=8.11M–8.09 (m, 2H), 7.66–7.65
(m, 2H), 7.58–7.48 (m, 3H), 7.40 (t, J=7.8 Hz, 2H), 7.24–
7.21 (m, 1H), 5.55 (s, 1H), 1.54 (s, 6H); 13C NMR (CDCl3):
d=160.7, 159.9, 135.0, 131.9, 128.6, 128.5, 128.3, 127.9, 126.9,
126.2, 99.4, 70.9, 29.7. HR-MS (ESI): m/z=264.1396, calcd.
for C18H18NO [M+H]+: 264.1388.
(5Z)-5-Pentylidene-4-(4-methoxyphenyl)-2-phenyl-4,5-di-
hydro-1,3-oxazole (Z-3l): This compound decomposes on
1
silica and was not isolated. H NMR (CDCl3): d=8.08–8.06
(m, 2H), 7.47–7.44 (m, 3H), 7.25–7.23 (m, 2H), 6.90–6.88
(m, 2H), 5.68 (d, J=2.5 Hz, 1H), 4.54 (td, J=7.5, 2.5 Hz,
1H), 3.80 (s, 3H), 2.32–2.17 (m, 2H), 1.40–1.33 (m, 4H),
0.91 (t, J=7.1 Hz, 3H).
Procedure for the Synthesis of 6 (Unoptimized)
(5E)-5-(1-Cyclohexenylmethylene)-4-(4-methoxyphenyl)-
2-phenyl-4,5-dihydro-1,3-oxazole (E-3m): This compound
decomposes on silica and was not isolated. 1H NMR
[(Ac-Py)2Ag]PF6 (0.1 mmol, 47.1 mg, 0.1 equiv.) was added
to
a solution of the substrate 2k (1.0 mmol, 0.31 g,
1.0 equiv,) in CH2Cl2 (2.5 mL) in a 10-mL round-bottomed
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FULL PAPERS
Valerie H. L. Wong et al.
flask. The reaction mixture was stirred at room temperature
for 12 h, before it was filtered through basic alumina and
evaporated under vacuum. Absolute ethanol (4 mL) and Pd/
C (10 mol% Pd) were then added to the residue and the re-
sulting mixture was heated at 508C for 2 h. After cooling,
the solvent was evaporated and the resulting oily residue pu-
rified by column chromatography on silica (petroleum
ether:ethyl acetate, 6:1) to afford the oxazole product as
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1
a white solid; yield: 91.6 mg (30%). H NMR (CDCl3): d=
[6] Au(I) catalysts containing other ligands have also been
reported, but have limited scope/afforded mixtures of
products: a) iminophosphoranes: D. Aguilar, M.
Contel, R. Navarro, T. Soler, E. P. Urriolabeitia, J. Or-
ganomet. Chem. 2009, 694, 486–493; b) H. V. Wachen-
feldt, P. Rose, F. Paulsen, N. Loganathan, D. Strand,
Chem. Eur. J. 2013, 19, 7982–7988; c) S. Doherty, J. G.
Knight, A. S. K. Hashmi, C. H. Smyth, N. A. B. Ward,
K. J. Robson, S. Tweedley, R. W. Harrington, W. Clegg,
Organometallics 2010, 29, 4139–4147.
8.10–8.08 (m, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.46–7.44 (m,
3H), 6.98 (d, J=8.8 Hz, 2H), 3.85 (s, 3H), 2.87 (d, J=
6.6 Hz, 2H), 1.19–1.12 (m, 1H), 0.58–0.55 (m, 2H), 0.32–
0.30 (m, 2H); 13C NMR (CDCl3): d=159.0, 146.5, 135.8,
129.9, 129.2, 128.6, 128.3, 127.8, 126.2, 125.0, 114.0, 55.3,
30.3, 9.8, 4.4; HR-MS (ESI): m/z=306.1375, calcd. for
C20H20NO2 [M+H]+: 306.1494.
[7] A. S. K. Hashmi, C. Lothschutz, K. Graf, T. Haffner, A.
Schuster, F. Rominger, Adv. Synth. Catal. 2011, 353,
1407–1412.
Acknowledgements
[8] a) A. S. K. Hashmi, A. M. Schuster, S. Gaillard, L. Cav-
allo, A. Poater, S. P. Nolan, Organometallics 2011, 30,
6328–6337; b) A. S. K. Hashmi, A. M. Schuster, M.
Schmuck, F. Rominger, Eur. J. Org. Chem. 2011, 4595–
4602.
We thank the National University of Singapore for a Research
Scholarship to VHLW.
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3948
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Adv. Synth. Catal. 2015, 357, 3943 – 3948