Copper-Catalyzed [2 + 3] Cyclization of α-Hydroxyl Ketones and Arylacetonitriles: Access to Multisubstituted Butenolides and Oxazoles

Article abstract of DOI:10.1021/acs.joc.8b01822

A copper-catalyzed [2 + 3] formal cyclization reaction between α-hydroxyl ketones and arylacetonitriles has been developed. The reaction outcome was ultimately dependent on the structure of the α-hydroxy ketones employed. Tertiary α-hydroxy ketones gave 3,4,5,5-tetrasubstituted butenolides as the sole products, while secondary α-hydroxy ketones furnished 2,4,5-trisubstituted oxazoles selectively. This method has many advantages, such as the use of easily available substrates, broad substrate scope, good functional tolerance, and milder reaction conditions.

Full text of DOI:10.1021/acs.joc.8b01822

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Article
Copper-Catalyzed [2 + 3] Cyclization of #-Hydroxyl Ketones and
Arylacetonitriles: Access to Multisubstituted Butenolides and Oxazoles
Chaorong Qi, Youbin Peng, Lu Wang, Yanwei Ren, and Huanfeng Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01822 • Publication Date (Web): 03 Sep 2018
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Copper-Catalyzed [2 + 3] Cyclization of α-Hydroxyl Ketones and
Arylacetonitriles: Access to Multisubstituted Butenolides and
Oxazoles
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Chaorong Qi,*a,b Youbin Peng,a Lu Wang,a Yanwei Rena and Huanfeng Jiang*a
a Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and
Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China
b State Key Lab of Luminescent Materials and Devices, South China University of Technology, Guangzhou
510640, P. R. China
E-mail: crqi@scut.edu.cn or jianghf@scut.edu.cn
Abstract: A copper-catalyzed [2 + 3] formal cyclization reaction between α-hydroxyl
ketones and arylacetonitriles has been developed. The reaction outcome was
ultimately dependent on the structure of the α-hydroxy ketones employed. Tertiary
α-hydroxy ketones gave 3,4,5,5-tetrasubstituted butenolides as the sole products while
secondary α-hydroxy ketones furnished 2,4,5-trisubstituted oxazoles selectively. This
method has many advantages, such as the use of easily available substrates, broad
substrate scope, good functional tolerance and milder reaction conditions.
INTRODUCTION
Both butenolides and oxazoles are important five-membered heterocycles, which have
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been found as key structural units in a great number of biologically active natural
products and pharmaceutically important molecules.1,2 For example, both cadiolide
C1d and ramariolide A1e are butenolide-containing molecules, which exhibit significant
antibacterial activity and in vitro antimicrobial activity against Mycobacterium
smegmatis and Mycobacterium tuberculosis, respectively; ulapualide C bearing three
oxazole cycles was isolated from egg masses of the nudibranch Hexabranchus
sanguineus and was found to have potential cytotoxicity against select NCI cell lines
(Figure 1).2e Additionally, butenolides and oxazoles are also valuable synthetic
intermediates for the construction of a variety of important complex molecules.3,4
Therefore, the development of efficient methodologies for the synthesis of these
heteroaromatic compounds is of great importance in organic synthesis and medicinal
chemistry.
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Figure 1. Representative natural products containing butenolide or oxazole moiety.
Traditionally, multi-substituted butenolides and oxazoles were constructed
through transition metal-catalyzed or metal-free intramolecular cyclization
strategies.5,6 Recently, many elegant intermolecular cyclization reactions have been
developed for the synthesis of these heterocycles.7,8 For example, Shindo and
co-workers reported a Cu(II)-catalyzed tandem acylation-Wittig reaction of acyloins
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with a thiol ester leading to a one-pot synthesis of butenolides under neutral
conditions.7b Zhu et al. successfully developed a synergistic acid-promoted synthesis
of highly substituted butenolides via the annulation of keto acids and tertiary
alcohols.7eAnd very recently, Lin et al. reported a DBU-catalyzed [3 + 2] annulation
of cyclopropenones and β-ketoesters, providing a direct approach to highly
functionalized butenolides with a quaternary center.7f In regard to the synthesis of
oxozales, Xiao’s group reported a novel [3+2] cycloaddition/oxidative aromatization
of 2H-azirines and aldehydes via visible light-induced photoredox catalysis to
produce 2,4,5-trisubstituted oxazoles.8g Davies et al. have developed a gold-catalyzed
regioselective annulations of alkynyl thioethers with aminides to form densely
functionalized oxazoles.8i Although great progress have been made in these fields, the
development of new and facile procedures that allow the synthesis of structurally
diverse butenolides and oxazoles via intermolecular annulations strategies using
easily available substrates as the starting materials is still highly desirable.
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In 2016, we have developed a copper-catalyzed [4 + 1] annulations reaction
between α-hydroxy ketones and nitriles for the construction of a wide range of
3(2H)-furanone derivatives, in which the product structure relied on the nature of
nitriles (Scheme 1, a ).9a As part of our continuous interest in the use of α-hydroxyl
ketones and nitriles as versatile building blocks in the organic synthesis,9 herein, we
wish to report a copper-catalyzed [2 + 3] cyclization of α-hydroxyl ketones and
arylacetonitriles for the synthesis of a variety of highly substituted butenolides and
oxazoles (Scheme 1, b).
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Scheme 1. Annulation between α-hydroxy ketones and nitriles
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RESULTS AND DISCUSSION
Our initial efforts focused on the formal [2+3] annulation reaction of
2-hydroxy-2-methyl-1-phenylpropan-1-one (1a) and 2-phenylacetonitrile (2a) to
obtain 5,5-dimethyl-3,4-diphenylfuran-2(5H)-one (3aa), and the results were
summarized in Table 1. On the basis of our previous work,9a we performed the
reaction using CuI as the catalyst in the presence of 0.5 equiv of DBU in methanol at
o
80 C under N2 atmosphere, but no trace of the desired product 3aa was detected
(entry 1). The use of t-BuOK instead of DBU as the base did not give 3aa either
(entry 2). However, when the reaction was conducted in a mixed MeOH-H2O (1:1)
solvent, the target product 3aa was formed in 36% yield (entry 3), while the use of
neat water as the reaction media only led to a very low yield (entry 4). To our delight,
the yield of 3aa could be increased to 83% by increasing the amount of t-BuOK to 1
equiv and prolonging the reaction time to 24 h. These results prompted us to further
investigate other organic or inorganic base and it was showed that the nature of the
base has great influence on the transformation. In comparison with t-BuOK, NaOH
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was more efficient for the annulation but the use of other bases such as Et3N, DABCO,
DMAP, CH3ONa or Cs2CO3 would lead to no or lower yield of 3aa (entries 6-11).
Pleasingly, the yield of the desired product 3aa could be improved to 90% when 1.2
equivalent of NaOH was employed (entry 12). Two more control experiments showed
that both copper salt and base are necessary for the reaction to proceed smoothly
(entries 13 and 14). Other copper salts such as CuCl, CuBr, Cu(OAc)2 and Cu(OTf)2
were also examined and all of them could catalyze the reaction to give the desired
product albeit in slightly lower yields (entries 15-18). The results also showed that the
volume ratio of MeOH/H2O has influence on the reaction, and a MeOH/H2O ratio of
1:1 was found to be optimal (entries 12, 19 and 20). It should be noted that the
reaction could proceed smoothly to give 3aa in 82% yield even when the loading of
catalyst was reduced to 5 mol% (entry 21).
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Table 1. Optimization of the reaction a
Entry
Catalyst
CuI
Base (equiv)
DBU (0.5)
Solvent (v:v)
MeOH
Time (h) Yield (%) b
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n.d.
n.d.
36
CuI
t-BuOK (0.5)
t-BuOK (0.5)
t-BuOK (0.5)
t-BuOK (1)
Et3N (1)
MeOH
CuI
MeOH/H2O (1:1)
H2O
CuI
8
CuI
MeOH/H2O (1:1)
MeOH/H2O (1:1)
83
CuI
trace
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CuI
CuI
CuI
CuI
CuI
CuI
CuI
-
DABCO (1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
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n.d.
n.d.
47
8
DMAP (1)
Cs2CO3 (1)
CH3ONa (1)
NaOH (1)
NaOH (1.2)
-
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21c
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86
MeOH/H2O (1:1) 24
90 (88)
n.d.
51
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (1:1)
MeOH/H2O (3:1)
MeOH/H2O (1:3)
MeOH/H2O (1:1)
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NaOH (1.2)
NaOH (1.2)
NaOH (1.2)
CuCl
CuBr
85
87
Cu(OAc)2 NaOH (1.2)
Cu(OTf)2 NaOH (1.2)
86
83
CuI
CuI
CuI
NaOH (1.2)
NaOH (1.2)
NaOH (1.2)
80
73
82
a Reaction conditions: 1a (0.3 mmol), 2a(0.6 mmol), CuI (0.03 mmol), solvent (2 mL),
o
b
80 C, 24 h, N2 atmosphere. Yield were determined by GC-MS analysis with
n-dodecane as internal standard. Number in parentheses is the yield of isolated
product. c The reaction was performed in the presence of 0.015 mmol of CuI.
With the optimized reaction conditions in hand, the copper-catalyzed formal [2+3]
annulation was then applied to the reaction of 1a with various arylacetonitriles. As can
be seen from Table 2, a wide range of arylacetonitriles with different substitution
patterns could undergo the reaction to give the corresponding products (3aa-3aj) in
moderate to excellent yields. Both electron-donating and -withdrawing groups at the
para-position of the benzene ring, including halide (F, Cl, Br, I), alkyl (Me and tBu),
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Table 2. Scope of arylacetonitriles a
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a Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), CuI (0.03 mmol), NaOH (0.36
o
mmol), MeOH/H2O (v:v = 1:1, 2 mL), 80 C, 24 h, N2 atmosphere. Isolated yield
based on 1a. b The reaction was performed on a 5 mmol scale.
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methoxy, trifluoromethyl, and even nitro group were tolerated without any difficulty
under the reaction conditions, which would provide ample potential for further
transformations. The structure of the product 3ad was unambiguously confirmed by
means of X-ray crystallographic analysis (Figure S1).10 Moreover, it was found that
the steric hindrance has little influence on the transformation as ortho- or
meta-substituted substrates could furnish the corresponding products (3ak and 3al) in
high yields as well. In addition to mono-substituted arylacetonitriles, di- or
tri-substituted ones reacted well with 1a to afford the desired products (3am-3ao).
Moreover, product 3am could be obtained in a satisfactory yield (62%) when the
reaction was conducted on a 5 mmol scale, demonstrating the scalability of the
present reaction. To our delight, the nitriles containing heterocycles or fused aryl rings
(2p-2u) could be successfully transformed into the corresponding products 3ap-3au.
However, alkyl nitriles such as butyronitrile could not take part in the reaction, and
could be recovered unchanged after the experiment (not showed).
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Subsequently, the reactivity of various α-hydroxy ketones was examined (Table 3).
Gratifyingly, a range of aryl and heteroaryl-substituted tertiary α-hydroxy ketones
(1a-1e) could react with 2-phenylacetonitrile (2a) smoothly to generate the
corresponding products 3aa-3ea in moderate to high yields. The substrate 1b with a
2-hydroxyethoxy group at position 4 of the benzenyl ring could enter into the reaction
and gave the desired product carrying a free hydroxyl group (3ba) in a satisfactory
yield. Both cyclopentyl and cyclohexyl ring adjacent to the carbonyl group were
compatible with the transformation and the spirocyclic products 3ca and 3da were
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Table 3.Scope of α-hydroxyl ketonesa
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O
R1
R2
R2
R3
OH
CuI / NaOH
CN
R1
+
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MeOH/H2O (1:1)
80 oC, 24 h, N2
O
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O
1a-k
2a
3aa-3ka
HO
O
O
O
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O
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O
3ca
, 64%
3aa
, 88%
3ba,58%
N
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3da
, 62%
3ea
3fa, 63%
, 80%
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O
O
O
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O
3ia
, 50%
3ga, 73%
3ha
, 40%
O
O
O
O
Ph
3ka,76%
3ja, 73%
a Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), CuI (0.03 mmol), NaOH (0.36
o
mmol), MeOH/H2O (v:v = 1:1, 2 mL), 80 C, 24 h, N2 atmosphere. Isolated yield
based on 1.
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obtained in 64% and 62% yields, respectively. Moreover, the catalytic protocol could
be applied to a variety of methyl ketones with different R2 and R3 substituents
including alkyl and aryl groups, furnishing the corresponding products (3fa-3ja) in
synthetically useful yields. It was notable that 2-hydroxy-2-phenylcyclohexan-1-one
(1k) was also a good substrate for the reaction and afforded the desired product (3ka)
with a fused-ring system in a high yield.
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To our surprise, when benzoin (1m), which is a secondary α-hydroxy ketone,
was used as the substrate to react with 2a under the standard reaction conditions, no
trace of desired butenolide product was detected. However, a 2,4,5-trisubstituted
oxazole derivative, 2-benzyl-4,5-diphenyloxazole (4ma), was obtained in 28% yield
upon isolation. This result indicated that the gem-disubstituent effect play a crucial
role in the formation of butenolide products,11 and oxazole ring would be more easy to
formed when secondary α-hydroxy ketones were employed for the reaction.
Considering that the reaction might provide a straightforward method for the
construction of 2-benzyl-substituted oxazoles, which are difficult to be synthesized by
previously reported methods,6,8 we decided to further optimize the reaction.
Fortunately, when the reaction media was switched to MeOH and 2 equivalents of
NaOH was added as the base, the yield of 4ma could be dramatically increased to
75%.
Encouraged by this result, the scope of the transformation was then investigated. As
can be seen from Table 4, both electron-rich and electron-deficient 2-arylacetonitriles
could work well with 1m to deliver the desired oxazoles in moderate to excellent
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Table 4: Synthesis of 2,4,5-trisubstituted oxazoles a
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a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), CuI (0.03 mmol), NaOH (0.6
o
mmol), MeOH (1 mL), 80 C, 24 h, N2 atmosphere. Isolated yield based on 1.b The
reaction was carried out with 0.36 mmol of NaOH in a mixed MeOH/H2O (v:v = 1:1,
2 mL) solvent. c n.d. = not detected.
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yields (4ma-4ml). It was also found that ortho-substituted substrate 2l exhibited lower
reactivity than its para- and meta-substituted analogues, which might be due to the
steric hindrance effect. Substrate 2o having three methoxy group on its benzene ring
afforded the desired product 4mo in 71% yield. Pleasingly, the nitriles containing a
heterocycle could also be successfully transformed into the desired products (4ms and
4mu). Notably, when 2,2-diphenylacetonitrile (2w) was applied as the reaction partner,
excellent yield of 4mw was obtained. By contrast, benzonitriles showed much lower
reactivity to the reaction, as exemplified by 4-bromobenzonitrile (2x), which gave the
desired product 4mx in only 23% yield. Other benzoins such as 1n and 1o could also
react with 2a efficiently to give the desired products 4na and 4oa in 82% and 93%
yields, respectively. However, the acyloin 1p failed to take part in the cyclization
reaction but led to the formation of large amount of unidentified products. Alkyl
nitriles such as butyronitrile and pentanenitrile also failed to undergo the reaction to
give the corresponding oxazole derivatives, and the raw materials could be recovered.
To demonstrate the synthetic utility of the new method, the products derived from
this method were employed for further transformations to prepare other functional
molecules. As shown in Scheme 2, compound 3am could enter into Scholl-type
oxidative cyclization reaction in the presence of 1.1 equivalents of phenyliodine(III)
bis(trifluoroacetate) (PIFA), giving rise to a phenanthrene-fused butenolide derivative
5, albeit in a low yield.12 Moreover, compound 3ae having an iodo-substituted
aromatic ring could efficiently undergo Suzuki–Miyaura cross-coupling with
phenylboronic acid, furnishing product 6 in 81% yield upon isolation.
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Scheme 2. The synthetic utility
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To obtain more insight into the mechanism of the transformation, a series of control
experiments were performed. When phenylacetic acid (7) was employed to react with
1a under the standard reaction conditions, no trace of 3aa was observed (Scheme 3, a).
Moreover, phenylacetamide (8) could not undergo the reaction with 1a or 1m under
the standard conditions to give the desired product 3aa or 4ma (Scheme 3, b and c).
These results revealed that neither phenylacetic acid nor phenylacetamide is the
18
intermediate of the reaction. Finally, when H2 O was used in the reaction of 1a and
2a under the optimized conditions, the 18O-isotopologue 3aa′ was obtained in 76%
yield and in 87% isotopic purity (Scheme 3, d). This isotope labeled experiment
revealed that water also acted as a reaction participant and the carbonyl oxygen atom
of products 3 was mainly originated from water.
On the basis of the above results and previous literatures,9a, 10 a plausible
mechanism is illustrated in Scheme 4. Initially, under the action of base, α-hydroxy
ketones 1 generates an oxy anion species A, which would undergo a nucleophilic
attack to nitrile 2 activated by copper salt to give intermediate B. In the case where
neither R2 nor R3 is hydrogen atom, intermediate B will undergo an intramolecular
Knoevenagel reaction to give intermediate D via C due to the Thorpe-Ingold effect.
Then, the hydrolyzation of D will give the butenolide product 3 (Path A). However,
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when R3 is a hydrogen atom, intermediate B will undergo an intramolecular
cyclization to give intermediate E instead of C. The subsequent dehydration of E will
give rise to the oxazole product 4 (Path B).
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Scheme 3. Mechanism studies
O
CuI (10 mol%)
NaOH (1.2 equiv)
COOH
(a)
+
OH
1a
MeOH/H2O (v:v = 1:1)
80 oC, 24 h, N2
O
O
7
3aa
1a
CuI (10 mol%)
NaOH (1.2 equiv)
CONH2
+
(b)
(c)
3aa
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80 oC, 24 h, N2
8
O
CuI (10 mol%)
NaOH (2 equiv)
Ph
Ph
Ph
N
Ph
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8
OH
1m
MeOH
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O
4ma
CuI (10 mol%)
NaOH (1.2 equiv)
CN
(d)
+
1a
MeOH/H218O (v:v = 1:1)
80 oC, 24 h, N2
O18
O
2a
3aa', 76%
(87% 18O, 13% 16O)
Scheme 4. Plausible mechanism for the reaction
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CONCLUSION
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In conclusion, we have successfully developed a copper catalyzed [2 + 3]
cyclization reaction between α-hydroxy ketones and arylacetonitriles. The outcome of
the reaction was dependent on the structure of α-hydroxy ketones: tertiary α-hydroxy
ketones afforded the highly substituted butenolide products while the secondary ones
selectively gave rise to oxazole derivatives. The protocol features mild reaction
conditions, high yields, the use of easily available substrates, a broad substrate scope
and good functional group tolerance.
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EXPERIMENTAL SECTION
1
General method. H and 13C NMR spectra were recorded using a 400 MHz NMR
spectrometer using CDCl3 as solvent and TMS as an internal standard. The chemical
shifts are referenced to signals at 7.26 and 77.0 ppm, respectively. GC analyses were
performed on a gas chromatograph with an FID and equipped with an AT.SE-30
capillary column (internal diameter: 0.32 mm, length: 30 m). Mass spectra were
recorded on a gas chromatograph-mass spectrometer at an ionization voltage of 70 eV
and equipped with a DB-WAX capillary column (internal diameter: 0.25 mm, length:
30 m). The data of HRMS was carried out on a high-resolution mass spectrometer
(LCMS-IT-TOF). IR spectra were obtained either as potassium bromide pellets or as
liquid films between two potassium bromide pellets with an infrared spectrometer.
Melting points were determined with a digital melting point measuring instrument.
The α-hydroxy ketones were prepared according to previous literature procedures.13
Other compounds and solvents were commercially purchased and used without
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further purification.
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General procedure for the preparation of butenolides 3. To a 25 mL dried Schlenk
tube was added the mixture of NaOH (0.36 mmol), CuI (0.03 mmol), tertiary
α-hydroxy ketones 1 (0.3 mmol), arylacetonitriles 2 (0.6 mmol), MeOH (1 mL) and
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o
H2O (1 mL) successively. The mixture was then stirred at 80 C for 24 h under N2
atomsphere. After the reaction was completed, the mixture was cooled to room
temperature, diluted with saturated brine water (15 mL), and extracted with EtOAc
(10 mL×3). The organic phase was washed with H2O (10 mL×3), dried over
anhydrous Na2SO4, and then filtered. After removing the solvent under vacuum, the
crude product was purified by column chromatography on silica gel using petroleum
ether/ethyl acetate (20:1 to 10:1) as the eluent to give the desired product 3.
5,5-Dimethyl-3,4-diphenylfuran-2(5H)-one (3aa).14 Colorless solid (75.8 mg, 88%),
mp: 159–161 oC. 1H NMR (400 MHz, CDCl3): δ = 7.39 (m, 5H), 7.25 – 7.17 (m, 5H),
13
1.60 (s, 6H). C NMR (100 MHz, CDCl3): δ = 171.2, 166.1, 132.5, 129.7, 129.1(3),
129.1(0), 128.9, 128.4, 128.1, 127.8, 126.2, 85.8, 25.3. IR (KBr): 2988, 2927, 1752,
1652, 1495, 1447, 1363, 1281, 1195, 1130, 1015, 964, 756, 700 cm-1. HRMS-ESI
(m/z): calcd for C18H16NaO2 [M + Na]+: 287.1043; found: 287.1046.
3-(4-Fluorophenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3ab). Colorless solid
o
1
(57.5 mg, 68%), mp: 164–166 C. H NMR (400 MHz, CDCl3): δ = 7.42 – 7.37 (m,
5H), 7.25 – 7.16 (m, 2H), 6.91 (t, J = 8.1 Hz, 2H), 1.59 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ = 171.1, 165.9, 162.6 (d, J = 247.6 Hz), 132.4, 131.0 (d, J = 8.2 Hz), 129.3,
129.1, 127.7, 125.7 (d, J = 3.4 Hz), 125.2, 115.2 (d, J = 21.4 Hz), 85.9, 25.2. IR (KBr):
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3072, 2988, 2936, 1758, 1599, 1511, 1285, 1225, 1131, 1020, 965, 839, 755, 706 cm-1.
HRMS-ESI (m/z): calcd for C18H15FNaO2 [M + Na]+: 305.0948; found: 305.0951.
3-(4-Chlorophenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3ac). Colorless solid
(69.7 mg, 78%), mp: 139–141 oC. 1H NMR (400 MHz, CDCl3): δ = 7.42 (s, 3H), 7.33
(d, J = 7.2 Hz, 2H), 7.19 (d, J = 6.8 Hz, 4H), 1.59 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ = 170.8, 166.5, 134.4, 132.2, 130.4, 129.3, 129.1, 128.4, 128.1, 127.6,
125.1, 85.9, 25.2. IR (KBr): 2984, 2923, 1750, 1560, 1943, 1281, 1195, 1131, 1095,
1016, 964, 828, 757, 703 cm-1. HRMS-ESI (m/z): calcd for C18H15ClNaO2 [M + Na]+:
321.0653; found: 321.0658.
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3-(4-Bromophenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3ad). Colorless solid
o
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(72.9 mg, 80%), mp: 133–135 C. H NMR (400 MHz, CDCl3): δ = 7.44 – 7.39 (m,
3H), 7.35 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 7.22 – 7.17 (m, 2H), 1.59 (s,
6H). 13C NMR (100 MHz, CDCl3): δ = 170.8, 166.6, 132.2, 131.3, 130.7, 129.3,
129.1, 128.6, 127.6, 125.2, 122.8, 85.9, 25.2. IR (KBr): 2982, 2923, 1746, 1583, 1488,
1276, 1190, 1012, 960, 886, 821, 753, 702 cm-1. HRMS-ESI (m/z): calcd for
C18H15BrNaO2 [M + Na]+: 365.0148; found: 365.0153.
3-(4-Iodophenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3ae). Yellow solid (71.4
mg, 61%), mp: 128–130 oC. 1H NMR (400 MHz, CDCl3): δ = 7.55 (d, J = 7.6 Hz, 2H),
13
7.44 – 7.38 (m, 3H), 7.22 – 7.16 (m, 2H), 7.12 (d, J = 7.6 Hz, 2H), 1.59 (s, 6H). C
NMR (100 MHz, CDCl3): δ = 170.7, 166.7, 137.3, 132.1, 130.8, 129.3, 129.1(3),
129.0(9), 127.6, 125.2, 94.7, 85.9, 25.2. IR (KBr): 2981, 2930, 1751, 1485, 1213,
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1130, 1012, 964, 823, 758, 702 cm-1. HRMS-ESI (m/z): calcd for C18H15INaO2 [M +
Na]+: 413.0009; found: 413.0012.
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5,5-Dimethyl-4-phenyl-3-(p-tolyl)furan-2(5H)-one (3af). Colorless solid (75.0 mg,
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90%), mp: 166–168 C. H NMR (400 MHz, CDCl3): δ = 7.39 (s, 3H), 7.28 (d, J =
13
7.6 Hz, 2H), 7.21 (br, 2H), 7.03 (d, J = 7.6 Hz, 2H), 2.27 (s, 3H), 1.59 (s, 6H). C
NMR (100 MHz, CDCl3): δ = 171.3, 165.3, 138.3, 132.7, 130.0, 129.0, 128.9, 128.8,
127.8, 126.7, 126.0, 85.6, 25.3, 21.2. IR (KBr): 2983, 1744, 1445, 1281, 1189, 1127,
1016, 962, 820, 752, 702 cm-1. HRMS-ESI (m/z): calcd for C19H18NaO2 [M + Na]+:
301.1199; found: 301.1203.
3-(4-(Tert-butyl)phenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3ag). Colorless
solid (78.7 mg, 82%), mp: 152–154 oC. 1H NMR (400 MHz, CDCl3): δ = 7.44 – 7.38
(m, 3H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 – 7.21 (m, 4H), 1.58 (s, 6H), 1.25 (s, 9H). 13C
NMR (100 MHz, CDCl3): δ = 171.4, 165.2, 151.4, 132.7, 129.0, 128.9, 128.7, 127.8,
126.6, 125.8, 125.0, 34.5, 31.1, 25.2. IR (KBr): 2955, 2845, 1741, 1509, 1456, 1277,
1190, 1107, 1017, 968, 837, 751, 696 2982, 2935, 2840, 1750, 1607, 1458, 1287,
1252, 1132, 965, 890, 837, 757, 702 cm-1. HRMS-ESI (m/z): calcd for C22H25O2 [M +
H]+: 321.1849; found: 321.1846.
3-(4-Methoxyphenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3ah).15 Yellow solid
(69.7 mg, 79%), mp: 88–90 oC. 1H NMR (400 MHz, CDCl3): δ = 7.42 – 7.36 (m, 3H),
7.35 (d, J = 7.6 Hz, 2H), 7.23 – 7.19 (m, 2H), 6.74 (d, J = 7.6 Hz, 2H), 3.73 (s, 3H),
1.57 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 171.4, 164.3, 159.5, 132.8, 130.4,
128.9, 127.8, 125.4, 122.0, 113.5, 85.6, 55.1, 25.3. IR (KBr): 2982, 2935, 2840, 1750,
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1607, 1458, 1287, 1252, 1132, 965, 890, 837, 757, 702 cm-1. HRMS-ESI (m/z): calcd
for C19H18NaO3 [M + Na]+: 317.1148; found: 317.1152.
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5,5-Dimethyl-4-phenyl-3-(4-(trifluoromethyl)phenyl)furan-2(5H)-one (3ai). White
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solid (81.7 mg, 82%), mp: 89–91 C. H NMR (400 MHz, CDCl3): δ = 7.49 (q, J =
13
8.0 Hz, 4H), 7.45 – 7.38 (m, 3H), 7.20 (d, J = 4.80 Hz, 2H), 1.61 (s, 6H). C NMR
(100 MHz, CDCl3): δ = 170.6, 168.0, 133.3, 131.9, 130.2 (q, J = 32.5 Hz), 129.5,
129.3 (d, J = 26.0 Hz), 127.6, 125.1 (d. J = 1.8 Hz), 125.0 (d, J = 3.8 Hz), 124.9,
123.9 (d, J = 270.5 Hz), 86.1, 25.1. IR (KBr): 3062, 2986, 2936, 2872, 1753, 1492,
1325, 1282, 1121, 1068, 1016, 964, 890, 850, 757, 698 cm-1. HRMS-ESI (m/z): calcd
for C19H15F3NaO2 [M + Na]+: 355.0916; found: 355.0922.
5,5-Dimethyl-3-(4-nitrophenyl)-4-phenylfuran-2(5H)-one (3aj). Brick red solid
o
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(46.4 mg, 50%), mp: 116–118 C. H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 8.8
Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.48 – 7.42 (m, 3H), 7.21 – 7.17 (m, 2H), 1.63 (s,
6H). 13C NMR (100 MHz, CDCl3): δ = 170.2, 169.3, 147.4, 136.2, 131.6, 130.0,
129.8, 129.4, 127.5, 124.6, 123.3, 86.4, 25.1. IR (KBr): 2923, 2853, 1750, 1646, 1518,
1347, 1017, 964, 857, 756, 698 cm-1. HRMS-ESI (m/z): calcd for C18H15NNaO4 [M +
Na]+: 332.0893; found: 332.0900.
3-(3-Methoxyphenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-ono (3ak). Yellow solid
o
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(77.6 mg, 88%), mp: 113–114 C. H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 4.4
Hz, 3H), 7.25 – 7.18 (m, 2H), 7.13 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.91
(s, 1H), 6.78 (d, J = 8.4 Hz, 1H), 3.59 (s, 3H), 1.59 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ = 171.0, 166.2, 159.1, 132.5, 130.8, 129.0, 128.9, 127.7, 125.9, 121.5,
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114.8, 113.9, 85.6, 54.9, 25.2. IR (KBr): 3063, 2981, 2934, 2837, 1750, 1598, 1460,
1244, 1127, 1018, 963, 890, 755, 697 cm-1. HRMS-ESI (m/z): calcd for C19H18NaO3
[M + Na]+: 317.1148; found: 317.1152.
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3-(2-Methoxyphenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3al). White solid
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(75.0 mg, 85%), mp: 113–115 C. H NMR (400 MHz, CDCl3): δ = 7.25 – 7.15 (m,
4H), 7.15 – 7.07 (m, 3H), 6.81 (t, J = 7.6 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 3.44 (s,
3H), 1.57 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 171.3, 167.3, 157.1, 132.9, 131.0,
129.9, 128.8, 128.3, 127.3, 124.9, 120.4, 119.3, 111.1, 86.2, 55.1, 25.7. IR (KBr):
3067, 2981, 2929, 2841, 1751, 1645, 1492, 1459, 1278, 11247, 1108, 1013, 963, 794,
754, 698 cm-1. HRMS-ESI (m/z): calcd for C19H18NaO3 [M + Na]+: 317.1148; found:
317.1151.
3-(3,4-Dimethoxyphenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3am). White
solid (69.0 mg, 71%), mp: 110–112 oC. 1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J =
6.8 Hz, 3H), 7.21 (d, J = 7.2 Hz, 2H), 7.17 (d, J = 8.4 Hz, 1H), 6.82 (s, 1H), 6.72 (d, J
13
= 8.4 Hz, 1H), 3.80 (s, 3H), 3.51 (s, 3H), 1.56 (s, 6H). C NMR (100 MHz, CDCl3):
δ = 171.2, 164.3, 149.0, 148.1, 133.0, 129.0, 128.9, 127.8, 125.2, 122.1, 121.9, 111.9,
110.6, 85.4, 55.6, 55.3, 25.1. IR (KBr): 3057, 2927, 2843, 1748, 1516, 1459, 1258,
1126, 1021, 856, 815, 755, 702 cm-1. HRMS-ESI (m/z): calcd for C20H21O4 [M + H]+:
325.1434; found: 325.1432.
3-(3,5-Dimethoxyphenyl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3an). Yellow
solid (71.9 mg, 74%), mp: 163–165 oC. 1H NMR (400 MHz, CDCl3): δ = 7.41 (d, J =
5.6 Hz, 3H), 7.25 – 7.17 (m, 2H), 6.57 (s, 2H), 6.34 (s, 1H), 3.58 (s, 6H), 1.59 (s, 6H).
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13C NMR (100 MHz, CDCl3): δ = 170.8, 166.4, 160.3, 132.6, 131.2, 129.1, 129.0,
127.7, 125.9, 106.9, 101.5, 85.5, 55.1, 25.2. IR (KBr): 2932, 2843, 1746, 1600, 1459,
1365, 1273, 1203, 1160, 1071, 1026, 844, 744, 696 cm-1. HRMS-ESI (m/z): calcd for
C20H20NaO4 [M + Na]+: 347.1254; found: 347.1259.
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5,5-Dimethyl-4-phenyl-3-(3,4,5-trimethoxyphenyl)furan-2(5H)-one (3ao). Pale
yellow solid (53.1 mg, 50%), mp: 177–179 oC. 1H NMR (400 MHz, CDCl3): δ = 7.40
– 7.32 (m, 3H), 7.20 – 7.14 (m, 2H), 6.64 (s, 2H), 3.72 (s, 3H), 3.52 (s, 6H), 1.52 (s,
6H). 13C NMR (100 MHz, CDCl3): δ = 171.1, 165.5, 152.7, 138.2, 133.1, 129.1,
129.0, 127.8, 125.3, 124.8, 106.3, 85.5, 60.8, 55.7, 25.2. IR (KBr): 3059, 2925, 2847,
1744, 1636, 1581, 1512, 1460, 1361, 1276, 1127, 1000, 903, 726, 644 cm-1.
HRMS-ESI (m/z): calcd for C21H22NaO5 [M + Na]+: 377.1359; found: 377.1364.
3-(Benzo[d][1,3]dioxol-5-yl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3ap). White
solid (68.4 mg, 74%), mp: 138-140 oC. 1H NMR (400 MHz, CDCl3): δ = 7.40 (s, 3H),
7.20 (d, J = 4.0 Hz, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.66 (d, J = 8.0 Hz,
1H), 5.87 (s, 2H), 1.57 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 171.2, 164.8, 147.6,
147.3, 132.5, 129.1, 129.0, 127.7, 125.5, 123.5, 123.4, 109.3, 108.1, 101.0, 85.6, 25.2.
IR (KBr): 3085, 3045, 2989, 2924, 1745, 1484, 1436, 1365, 1240, 1031, 967, 873,
754, 752, 696, 642 cm-1. HRMS-ESI (m/z): calcd for C19H16NaO4 [M + Na]+:
331.0941; found: 331.0945.
5,5-Dimethyl-3-(naphthalen-2-yl)-4-phenylfuran-2(5H)-one (3aq). Colorless solid
(76.3 mg, 81%), mp: 133–135 oC. 1H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1H), 7.72
(t, J = 8.0 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.43 – 7.35 (m, 5H), 7.28 (d, J = 8.4 Hz,
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1H), 7.23 (d, J = 4.8 Hz, 2H), 1.62 (s, 6H). C NMR (100 MHz, CDCl3): δ = 171.2,
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166.2, 132.9, 132.8, 132.4, 129.2, 129.1, 128.9, 128.4, 127.8, 127.5, 127.4, 127.1,
126.5, 126.2, 126.0, 85.8, 25.3. IR (KBr): 3057, 2982, 2932, 1749, 1212, 1076, 1019,
791, 751, 700 cm-1. HRMS-ESI (m/z): calcd for C22H18NaO2 [M + Na]+: 337.1199;
found: 337.1204.
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5,5-Dimethyl-4-phenyl-3-(pyridin-2-yl)furan-2(5H)-one (3ar). Colorless solid
o
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(73.9 mg, 93%), mp: 149–151 C. H NMR (400 MHz, CDCl3): δ = 8.42 (d, J = 4.4
Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 4.8 Hz, 3H),
7.18 (d, J = 4.8 Hz, 2H), 7.13 – 7.07 (m, 1H), 1.59 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ = 170.3, 169.3, 149.5, 149.4, 136.0, 131.9, 128.9, 128.4, 127.6, 126.1,
124.4, 122.8, 86.0, 25.1. IR (KBr): 3078, 2982, 2930, 1757, 1581, 1464, 1438, 1358,
1280, 1212, 1015, 807, 754, 703 cm-1. HRMS-ESI (m/z): calcd for C17H15NNaO2 [M +
Na]+: 288.0995; found: 288.0999.
5,5-Dimethyl-4-phenyl-3-(thiophen-2-yl)furan-2(5H)-one (3as).15 Colorless solid
o
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(70.5 mg, 87%), mp: 154–156 C. H NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 5.2
Hz, 4H), 7.25 (d, J = 5.2 Hz, 2H), 7.20 (d, J = 4.8 Hz, 1H), 6.91 (t, J = 4.8 Hz, 1H),
1.55 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 170.1, 162.2, 132.2, 131.3, 129.4,
129.3, 128.2, 127.6, 127.3, 126.7, 120.7, 86.0, 24.9. IR (KBr): 3100, 2982, 2927,
1746, 1440, 1361, 1279, 1231, 1118, 1052, 1005, 742, 699 cm-1. HRMS-ESI (m/z):
calcd for C16H14NaO2S [M + Na]+: 293.0607; found: 293.0610.
3-(Benzo[b]thiophen-3-yl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3at). White
solid (67.2 mg, 70%), mp: 141–143 oC. 1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J =
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8.0 Hz, 1H), 7.54 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.25 – 7.18 (m, 6H), 7.11 (t, J =
7.6 Hz, 1H), 1.71 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 171.0, 166.8, 139.8,
136.6, 131.9, 129.6, 128.8, 128.7, 127.8, 125.5, 124.3, 123.9, 123.0, 122.5, 122.2,
86.5, 26.1. IR (KBr): 3062, 2981, 2929, 2856, 1750, 1274, 1186, 1056, 1007, 729,
649 cm-1. HRMS-ESI (m/z): calcd for C20H16NaO2S [M + Na]+: 343.0763; found:
343.0766.
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3-(Benzofuran-2-yl)-5,5-dimethyl-4-phenylfuran-2(5H)-one (3au). White solid
(51.1 mg, 56%), mp: 143–145 oC. 1H NMR (400 MHz, CDCl3): δ = 8.14 (s, 1H), 7.52
– 7.29 (m, 6H), 7.18 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 8.0 Hz,
1H), 1.68 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 170.9, 164.2, 155.0, 146.6, 132.5,
129.6, 128.9, 128.0, 124.8, 124.3, 122.5, 121.7, 119.2, 111.3, 110.9, 86.7, 25.8. IR
(KBr): 2982, 2927, 2854, 1750, 1649, 1451, 1255, 1114, 1077, 942, 749, 699 cm-1.
HRMS-ESI (m/z): calcd for C20H16NaO3 [M + Na]+: 327.0992; found: 327.0996.
4-(4-(2-Hydroxyethoxy)phenyl)-5,5-dimethyl-3-phenylfuran-2(5H)-one
(3ba).
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Pale yellow oil (66.1 mg, 58%). H NMR (400 MHz, CDCl3): δ = 7.38 (dd, J = 6.8,
3.2 Hz, 2H), 7.25 (dd, J = 6.0, 3.2 Hz, 3H), 7.16 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.8
Hz, 2H), 4.12 – 4.06 (m, 2H), 4.01 – 3.93 (m, 2H), 1.61 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ = 171.4, 165.8, 159.3, 130.0, 129.5, 129.2, 128.3, 128.2, 125.8, 124.7,
115.0, 85.8, 69.2, 61.3, 25.5. IR (KBr): 3060, 2981, 2934, 2875, 1746, 1572, 1512,
1453, 1354, 1285, 1251, 1079, 1043, 964, 891, 799, 752, 697 cm-1. HRMS-ESI (m/z):
calcd for C20H20NaO4 [M + Na]+: 347.1254; found: 347.1257.
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3,4-Diphenyl-1-oxaspiro[4.4]non-3-en-2-one (3ca).5e White solid (55.7 mg, 64%);
mp: 154–156 oC. 1H NMR (400 MHz, CDCl3): δ = 7.39 (br, 5H), 7.24 – 7.18 (m, 5H),
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2.14 – 1.95 (m, 5H), 1.75 (br, 2H). C NMR (100 MHz, CDCl3): δ = 171.3, 163.2,
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132.5, 129.8, 129.1, 129.0, 128.9, 128.3, 128.2, 128.1, 127.3, 96.1, 36.2, 24.5. IR
(KBr): 3022, 2959, 2926, 2876, 2851, 1743, 1440, 1355, 1156, 1124, 1073, 922, 798,
698, 640 cm-1. HRMS-ESI (m/z): calcd for C20H18NaO2 [M + Na]+: 313.1199; found:
313.1202.
3,4-Diphenyl-1-oxaspiro[4.5]dec-3-en-2-one (3da).5c White solid (56.5 mg, 62%),
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mp: 182–184 oC. H NMR (400 MHz, CDCl3): δ = 7.42 – 7.34 (m, 5H), 7.23 – 7.14
(m, 5H), 1.89 – 1.69 (m, 10H). 13C NMR (100 MHz, CDCl3): δ = 171.5, 166.8, 132.8,
129.7, 129.1, 128.8, 128.3, 128.0, 127.9, 126.5, 87.4, 33.6, 24.4, 22.0. IR (KBr): 3071,
2938, 2857, 1741, 1560, 1493, 1445, 1352, 1274, 1186, 1121, 982, 764, 704, 643 cm-1.
HRMS-ESI (m/z): calcd for C21H20NaO2 [M + Na]+: 327.1356; found: 327.1359.
5,5-Dimethyl-3-phenyl-4-(pyridin-2-yl)furan-2(5H)-one (3ea). White solid (63.6
mg, 80%), mp: 114–116 oC. 1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 4.4 Hz, 1H),
7.52 (td, J = 7.6, 1.6 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.36 – 7.31 (m, 3H), 7.28 – 7.22
(m, 1H), 7.13 (d, J = 7.6 Hz, 1H), 1.77 (s, 6H). 13C NMR (100 MHz, CDCl3): δ =
171.3, 163.0, 151.3, 149.7, 136.1, 130.0, 129.3, 128.8, 128.5, 127.8, 125.2, 123.7,
86.7, 25.9. IR (KBr): 3058, 2980, 2931, 2859, 1749, 1580, 1460, 1356, 1286, 1212,
1131, 1097, 1015, 967, 922, 889, 749, 698 cm-1. HRMS-ESI (m/z): calcd for
C17H15NNaO2 [M + Na]+: 288.0995; found: 288.0998.
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4,5,5-Trimethyl-3-phenylfuran-2(5H)-one (3fa). White solid (38.2 mg, 63%), mp:
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94–96 oC. H NMR (400 MHz, CDCl3): δ = 7.49 – 7.39 (m, 4H), 7.35 (t, J = 7.2 Hz,
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1H), 2.12 (s, 3H), 1.52 (s, 6H). 13C NMR (100 MHz, CDCl3): δ = 171.5, 165.0, 130.2,
128.9, 128.4, 128.3, 125.6, 85.3, 24.7, 12.0. IR (KBr): 3058, 2981, 2927, 2855, 1748,
1664, 1442, 1381, 1292, 1221, 1166, 1081, 981, 937, 793, 751, 698, 635 cm-1.
HRMS-ESI (m/z): calcd for C13H14NaO2 [M + Na]+: 225.0886; found: 225.0889.
5-Ethyl-4,5-dimethyl-3-phenylfuran-2(5H)-one (3ga). White solid (38.2 mg, 73%),
mp: 68–70 oC. 1H NMR (400 MHz, CDCl3): δ = 7.50 – 7.40 (m, 4H), 7.39 – 7.34 (m,
1H), 2.07 (s, 3H), 2.02 – 1.92 (m, 1H), 1.80 – 1.71 (m, 1H), 1.51 (s, 3H), 0.84 (t, J =
7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ = 171.9, 163.6, 130.2, 129.0, 128.4,
128.3, 127.0, 87.7, 30.1, 23.5, 12.1, 7.4. IR (KBr): 3182, 3149, 2927, 2853, 1728,
1582, 1149, 756, 648 cm-1. HRMS-ESI (m/z): calcd for C14H16NaO2 [M + Na]+:
239.1043; found: 239.1044.
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5-Isobutyl-4,5-dimethyl-3-phenylfuran-2(5H)-one (3ha). Colorless oil (29.3 mg,
40%). 1H NMR (400 MHz, CDCl3): δ = 7.50 – 7.40 (m, 4H), 7.37 (d, J = 6.0 Hz, 1H),
2.10 (s, 3H), 1.88 (d, J = 10.0 Hz, 1H), 1.62 (d, J = 11.2 Hz, 2H), 1.49 (s, 3H), 0.94
13
(dd, J = 12.0, 5.2 Hz, 6H). C NMR (100 MHz, CDCl3): δ = 171.8, 164.4, 130.3,
128.9, 128.4, 128.3, 126.6, 45.6, 24.6, 24.3, 24.1, 23.9, 12.5. IR (KBr): 2957, 2926,
2873, 1750, 1590, 1459, 1382, 1307, 1206, 934, 793, 749, 699 cm-1. HRMS-ESI (m/z):
calcd for C16H20NaO2 [M + Na]+: 267.1356; found: 267.1357.
5-Hexyl-4,5-dimethyl-3-phenylfuran-2(5H)-one (3ia). White solid (40.8 mg, 50%),
mp: 54–56 oC. 1H NMR (400 MHz, CDCl3): δ = 7.51 – 7.40 (m, 4H), 7.38 – 7.34 (m,
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1H), 2.08 (s, 3H), 1.95 – 1.86 (m, 1H), 1.74 – 1.65 (m, 1H), 1.50 (s, 3H), 1.32 – 1.06
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(m, 8H), 0.87 (t, J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl3): δ = 171.9, 164.0,
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130.3, 129.0, 128.4, 128.3, 126.7, 87.5, 37.2, 31.6, 29.2, 23.8, 22.9, 22.5, 14.0, 12.2.
IR (KBr): 3058, 2927, 2857, 1749, 1663, 1454, 1379, 1216, 1171, 980, 793, 750, 698
cm-1. HRMS-ESI (m/z): calcd for C18H24NaO2 [M + Na]+: 295.1669; found: 295.1673.
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4,5-Dimethyl-3,5-diphenylfuran-2(5H)-one (3ja). Colorless oil (57.8 mg, 73%). H
NMR (400 MHz, CDCl3): δ = 7.52 (d, J = 7.6 Hz, 2H), 7.48 – 7.35 (m, 8H), 2.00 (s,
3H), 1.95 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 172.2, 165.0, 138.4, 130.0, 129.0
128.8, 128.5, 128.4, 125.4(2), 125.3(5), 87.6, 22.9, 12.4. IR (KBr): 3060, 2989, 1752,
1573, 1446, 1380, 1128, 1066, 1026, 918, 792, 749, 697, 665 cm-1. HRMS-ESI (m/z):
calcd for C18H16NaO2 [M + Na]+: 287.1043; found: 287.1047.
3,7a-Diphenyl-5,6,7,7a-tetrahydrobenzofuran-2(4H)-one (3ka). White solid (66.1
mg, 76%), mp: 98–100 oC. 1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 7.2 Hz, 2H),
7.48 (t, J = 7.6 Hz, 2H), 7.43 – 7.32 (m, 6H), 3.18 (t, J = 14.0 Hz, 2H), 2.38 – 2.22 (m,
13
1H), 2.03 – 1.86 (m, 2H), 1.80 (td, J = 13.2, 3.6 Hz, 1H), 1.59 – 1.38 (m, 2H). C
NMR (100 MHz, CDCl3): δ = 171.6, 166.3, 136.7, 129.9, 129.0, 128.9, 128.5(0),
128.4(6), 126.9, 125.4, 86.6, 37.7, 27.6, 26.7, 22.4. IR (KBr): 3059, 2944, 2863, 1748,
1598, 1495, 1449, 1179, 1020, 984, 944, 789, 749, 696 cm-1. HRMS-ESI (m/z): calcd
for C20H18NaO2 [M + Na]+: 313.1199; found: 313.1202.
General procedure for preparation of oxazoles 4. To a 25 mL dried Schlenk tube
was added the mixture of NaOH (0.6 mmol), CuI (0.03 mmol), secondary α-hydroxy
ketones 1 (0.3 mmol), nitriles 2 (0.6 mmol), MeOH (1 mL) successively. The mixture
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was then stirred at 80 C for 24 h under N2 atomsphere. After the reaction was
completed, the mixture was cooled to room temperature and diluted with saturated
brine water (15 mL), and extracted with EtOAc (10 mL×3). The organic phase was
washed with H2O (10 mL×3), dried over anhydrous Na2SO4, and then filtered. After
removing the solvent under vacuum, the crude product was purified by column
chromatography on a silica gel column using petroleum ether/ethyl acetate (30:1 to
4:1) as eluent to give the desired product 4.
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2-Benzyl-4,5-diphenyloxazole (4ma).16 White solid (70.0 mg, 75%), mp: 85–87 C.
1H NMR (400 MHz, CDCl3): δ = 7.75 – 7.69 (m, 2H), 7.64 – 7.58 (m, 2H), 7.46 (d, J
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= 7.2 Hz, 2H), 7.43 – 7.29 (m, 9H), 4.25 (s, 2H). C NMR (100 MHz, CDCl3): δ =
161.5, 145.6, 135.4, 135.2, 132.4, 128.9, 128.8, 128.6, 128.5(0), 128.4(6), 128.3,
128.0, 127.9, 127.0, 126.4, 34.7. IR (KBr): 3061, 3031, 2925, 2855, 1570, 1497, 1448,
1369, 1219, 1061, 1025, 988, 962, 765, 731, 695 cm-1.
2-(4-Fluorobenzyl)-4,5-diphenyloxazole (4mb). White solid (79.9 mg, 81%), mp:
o
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110–112 C. H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 7.6 Hz, 2H), 7.54 (d, J =
13
7.2 Hz, 2H), 7.40 – 7.27 (m, 8H), 7.02 (t, J = 8.4 Hz, 2H), 4.15 (s, 2H). C NMR
(100 MHz, CDCl3): δ = 161.9 (d, J = 243.9 Hz), 161.3, 145.7, 135.2, 132.3, 131.1 (d,
J = 3.3 Hz), 130.4 (d, J = 8.0 Hz), 128.8, 128.5 (d, J = 5.9 Hz), 128.4, 128.1, 127.9,
126.4, 115.5 (d, J = 21.3 Hz), 33.9. IR (KBr): 3059, 2927, 1601, 1572, 1509, 1445,
1158, 1096, 1060, 989, 915, 841, 763, 695 cm-1. HRMS-ESI (m/z): calcd for
C22H17FNO [M + H]+: 330.1289; found: 330.1286.
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2-(4-Chlorobenzyl)-4,5-diphenyloxazole (4mc). Pale yellow solid (89.0 mg, 86%),
mp: 75–77 oC. 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.0 Hz, 2H), 7.56 (d, J =
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7.6 Hz, 2H), 7.41 – 7.29 (m, 10H), 4.18 (s, 2H). C NMR (100 MHz, CDCl3): δ =
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161.0, 145.8, 135.2, 133.9, 133.0, 132.3, 130.2, 128.8(3), 128.7(9), 128.6, 128.5(4),
128.5(0), 128.1, 127.9, 126.5, 34.1. IR (KBr): 3058, 2925, 2857, 1581, 1493, 1444,
1218, 1091, 1016, 772, 696 cm-1. HRMS-ESI (m/z): calcd for C22H16ClNNaO [M +
Na]+: 368.0813; found: 368.0811.
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2-(4-Bromobenzyl)-4,5-diphenyloxazole (4md). Yellow oil (81.7 mg, 70%). H
NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.2 Hz, 2H), 7.46
(d, J = 8.0 Hz, 2H), 7.39 – 7.23 (m, 8H), 4.14 (s, 2H). 13C NMR (100 MHz, CDCl3): δ
= 160.9, 145.8, 135.2, 134.4, 132.3, 131.8, 130.6, 128.8, 128.6, 128.5(3), 128.4(9),
128.1, 127.9, 126.5, 121.1, 34.1. IR (KBr): 3057, 2926, 1569, 1488, 1445, 1368, 1218,
1013, 961, 914, 844, 763, 693 cm-1. HRMS-ESI (m/z): calcd for C22H16BrNNaO [M +
Na]+: 412.0307; found: 412.0307.
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2-(4-Iodobenzyl)-4,5-diphenyloxazole (4me). Yellow oil (73.4 mg, 56%). H NMR
(400 MHz, CDCl3): δ = 7.67 (t, J = 8.4 Hz, 4H), 7.59 – 7.54 (m, 2H), 7.41 – 7.31 (m,
13
6H), 7.17 (d, J = 8.0 Hz, 2H), 4.15 (s, 2H). C NMR (100 MHz, CDCl3): δ = 160.9,
145.8, 137.7, 135.3, 135.0, 132.3, 130.9, 128.8, 128.6, 128.5(1), 128.4(8), 128.1,
127.9, 126.5, 92.5, 34.2. IR (KBr): 3058, 2925, 1585, 1488, 1445, 1217, 1063, 1007,
772, 699 cm-1. HRMS-ESI (m/z): calcd for C22H17INO [M + H]+: 438.0349; found:
438.0351.
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2-(4-Methylbenzyl)-4,5-diphenyloxazole (4mf). Yellow oil (89.7 mg, 92%). H
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MHz, CDCl3): δ = 161.8, 145.6, 136.6, 135.2, 132.5, 132.4, 129.4, 129.0, 128.7,
128.5(2), 128.4(8) 128.3, 128.0, 127.9, 126.4, 34.3, 21.0. IR (KBr): 3061, 2924, 1577,
1444, 1373, 1271, 1219, 1062, 979, 915, 769, 698 cm-1. HRMS-ESI (m/z): calcd for
C23H20NO [M + H]+: 326.1539; found: 326.1540.
2-(4-Methoxybenzyl)-4,5-diphenyloxazole (4mh). White solid (85.9 mg, 84%), mp:
86–88 oC. 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6
Hz, 2H), 7.41 – 7.29 (m, 8H), 6.90 (d, J = 8.4 Hz, 2H), 4.16 (s, 2H), 3.80 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ = 162.0, 158.6, 145.6, 135.1, 132.4, 129.9, 128.9, 128.6,
128.5, 128.4, 128.0, 127.9, 127.4, 126.4, 114.1, 55.2, 33.8. IR (KBr): 3056, 2929,
2839, 1603, 1509, 1449, 1249, 1175, 1034, 915, 834, 770, 698 cm-1. HRMS-ESI (m/z):
calcd for C23H20NO2 [M + H]+: 342.1489; found: 342.1486.
4,5-Diphenyl-2-(4-(trifluoromethyl)benzyl)oxazole (4mi). Yellow solid (68.4 mg,
o
1
69%), mp: 102–104 C. H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.0 Hz, 2H),
7.63 (d, J = 8.0 Hz, 2H), 7.56 (dd, J = 12.0, 8.0 Hz, 4H), 7.41 – 7.32 (m, 6H), 4.28 (s,
13
2H). C NMR (100 MHz, CDCl3): δ = 160.6, 146.0, 139.4 (d, J = 1.2 Hz), 135.3,
132.2, 129.5 (d, J = 32.4 Hz), 129.2, 128.7, 128.6(2), 128.5(6), 128.2, 127.9, 126.5,
125.7 (q, J = 3.7 Hz), 124.1 (d, J = 270.3 Hz), 34.5. IR (KBr): 3063, 2927, 1585, 1499,
1443, 1325, 1167, 1123, 1066, 1019, 766, 696 cm-1. HRMS-ESI (m/z): calcd for
C23H17F3NO [M + H]+: 380.1257; found: 380.1258.
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