Environmentally sustainable and chemo-selectively favorable synthesis of substituted 2H-Pyran-2-ones in water under MWI

Article abstract of DOI:10.1002/jccs.201300013

In this paper, a novel synthesis of diversely substituted 2H-pyran-2-ones via the tandem reaction of 3-hydroxyhexa-4,5-allenic esters in water under the promotion of MWI has been developed. Compared with those reactions carried out in organic solvents, wa

Full text of DOI:10.1002/jccs.201300013

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Environmentally Sustainable and Chemo-selectively Favorable Synthesis of
Substituted 2H-Pyran-2-ones in Water under MWI
Liang-Yan Cui,a Xin Wang,a,b Yan Hea and Xue-Sen Fana*
aSchool of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory for Environmental Pollution Control, Henan Normal University,
Xinxiang, Henan 453007, P. R. China
bXinyang Agricultural College, Xinyang, Henan 464000, P. R. China
(Received: Jan. 4, 2013; Accepted: Jun. 27, 2013; Published Online: Aug. 29, 2013; DOI: 10.1002/jccs.201300013)
In this paper, a novel synthesis of diversely substituted 2H-pyran-2-ones via the tandem reaction of 3-hy-
droxyhexa-4,5-allenic esters in water under the promotion of MWI has been developed. Compared with
those reactions carried out in organic solvents, water mediated synthesis of poly-substituted 2H-pyran-2-
ones is not only environmentally sustainable, but also chemo-selectively favorable.
Keywords: 2H-Pyran-2-ones; Functionalized allenes; Water; Microwave irradiation; Green chemis-
try.
INTRODUCTION
2H-Pyran-2-one scaffold has attracted considerable
Due to their importance, efficient methods for the
preparation of 2H-pyran-2-ones have been extensively in-
vestigated and numerous synthetic strategies starting from
different class of precursors have been established.9-12
While these literature methods are generally efficient and
reliable, some of them still suffer from difficult-to-obtain
starting materials, expensive catalysts and reagents, deli-
cate control of reaction conditions, or volatile and toxic
solvents.
interests since they are frequently found in a plethora of
natural products.1 Moreover, many 2H-pyran-2-ones ex-
hibit a broad range of biological activities.2 For example,
4-hydroxy-6-phenyl-3-(phenylthio)pyran-2-one (I, Figure
1) is an efficient HIV PR inhibitor with low micromolar af-
finity.3 Phomenin (II) is isolated from the phytopathogenic
fungus Phoma tracheiphila, which has remarkable phyto-
toxicity.4 In another example, 6-pentyl-2-pyrone (III) dem-
onstrates antimicrobial activity against Rhizoctonia cerealis,
Gaeumannomyces graminis and Botrytis cinerea.5 Bicyclic
radicinin (IV) has been proved as a potential inhibitor to
the germination of seeds of Lepidum sativum.6 3-Alkyl-6-
chloro-2-pyrone (V), on the other hand, is a selective inhib-
itor of pancreatic cholesterol esterase.7 The steroidal poae-
fusarin (VI) can prevent the germination of pea, beans and
barley seed.8
Nowadays, the development of environmentally
friendly synthetic methods is one of the main priorities for
modern chemistry. It has been well recognized that the vol-
atile molecular organic solvents represent the biggest pol-
lution problem in many synthetic processes. Therefore,
elimination or replacement of hazardous solvents with en-
vironmentally benign ones has been intensively pursued. In
this regard, water is considered as an ideal candidate since
it is nontoxic, nonflammable, readily available and envi-
ronmentally benign, thus providing unlimited opportuni-
ties for clean processing and pollution prevention.13 More-
over, many organic reactions mediated by water showed
unique properties compared with those carried out in hy-
drocarbon solvents.14 Therefore, to develop synthetic pro-
cedures accomplished in water is an important aim for sus-
tainable chemistry.15
Recently, we have developed an access toward di-
versely substituted 2H-pyran-2-ones through an acid pro-
moted domino reaction of 3-hydroxyhexa- 4,5-allenic es-
ters.16 While the reaction itself is generally efficient and
Fig. 1. 2H-Pyran-2-ones with remarkable biological
activities.
* Corresponding author. E-mail: xuesen.fan@htu.cn
J. Chin. Chem. Soc. 2014, 61, 233-239
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233

Article
Cui et al.
Table 1. Optimization study for the preparation of 2a in aqueous
mediaa
Ph
easy to perform, the solvent used therein, dichloromethane
(CH2Cl2), is highly volatile and potentially hazardous. In
addition, when the reaction was run in CH2Cl2, substrates
with substituent on the internal position of the allene moi-
ety afforded indenes as the major products, thus resulting in
poor yields of the corresponding 2H-pyran-2-ones. As a
continuation of our study with regard to water mediated or-
ganic reactions,17 and considering that hydration is pro-
posed as a key step in the formation of 2H-pyran-2-ones in
the above described process,16 we were curious if the selec-
tivity for the formation of substituted 2H-pyran-2-ones
could be improved in the presence of an excess amount of
water. Herein we would like to report our preliminary results
in this regard.
OH
•
conditions
Ph
CO2Me
O
O
CH3
1a
2a
Yield
(%)b
Entry Catalyst
Solvent
H2O
T (ºC) t (h)
1
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
TsOH
H2SO4
H2SO4
r.t.
r.t.
r.t.
40
10
10
10
10
10
10
10
10
0.5
0.5
trace
trace
trace
26
2
H2O/CH3CN (5:1)
3
H2O/THF (5:1)
H2O
4
5
H2O
60
52
6
H2O
80
78
7
H2O
100
80
78
8
H2O
52
9
H2O
80
83c
65c
10
H2O
60
RESULTS AND DISCUSSION
a Reaction conditions: 0.5 mmol of 1a, 0.05 mmol of catalyst, 5
mL of solvent; b Isolated yields; c Under MWI.
Initially, 3-hydroxy-3-phenylhexa-4,5-dienoate (1a)
was chosen as model substrate to study its reactivity in
aqueous media. Thus, a suspension of 1a in water in the
presence of 10 mol% of H2SO4 was stirred at room temper-
ature for 10 h, but the desired product, 6-methyl-4-phenyl-
2H-pyran-2-one (2a), was only formed in trace amount
(Table 1, entry 1). Mixed solvents did not improve the reac-
tion obviously (entries 2-3). In further studies, we were
pleased to find that the reaction could be improved signifi-
cantly at increased temperatures (entries 3-7). When the re-
action was run at 80 ºC for 10 h, 2a could be obtained in a
yield of 78% (entry 6). Under similar conditions, using
TsOH as a catalyst gave much lower yield (entry 8). Fur-
thermore, considering that many organic reactions prog-
ress much faster under microwave irradiation (MWI) than
with conventional heating,18 especially for reactions car-
ried out in solvents with high dielectric constants such as
water and alcohols, the reaction of 1a in water was then run
under the promotion of MWI. Inspiringly, with MWI, the
period for a complete reaction shortened from 10 h to 0.5 h
and the yield of 2a amounted to 83% (entry 9). Based on the
above results, the optimal conditions were identified as:
treating 1a with 10 mol% of H2SO4 in H2O at 80 °C under
MWI for 0.5 h. Under such conditions, 2a was obtained in a
yield of 83%.
tuted allenic ketones with various substituents on the aryl
ring, but also compatible with substrates prepared from
diaryl or alkyl, aryl disubstituted allenic ketones to give
4,6-disubstituted 2H-pyran-2-ones with good efficiency
(Table 2, entries 1-16). Various functional groups such as
methyl, methoxy, halides and cyano are well tolerated with
the reaction conditions. In addition, from substrates pre-
pared from 1,2-allenic ketones and 2-bromo-propanoate,
3,4,6-trisubstituted 2H-pyran-2-ones could also be obtained
in good yields (Table 2, entries 17-19).
Furthermore, as mentioned previously, substrate with
a substituent on the internal position of the allene moiety
such as 1t (Scheme I), afforded the corresponding 2H-py-
ran-2-one (2t) in low yield (25%) upon treatment with
H2SO4 in CH2Cl2.16 This is mainly due to the formation of
substituted indene (3a, 61%). When 1t was treated with
H2SO4 in water under MWI, however, the formation of 3a
was suppressed and the yield of 2t was remarkably in-
Scheme I Reaction of 1t in different solvents
With the optimized reaction conditions in hand, the
scope of this transformation was studied. For this purpose,
a series of 3-hydroxyhexa-4,5-dienoates (2) with different
substitution patterns were treated with H2SO4 in water un-
der MWI (Table 2). It turns out that this tandem reaction is
not only suitable for substrates prepared from aryl substi-
234
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Synthesis of 2H-pyran-2-ones in Water under MWI
Table 2. Synthesis of 2H-pyran-2-ones (2a-2s) in watera
Table 3. Synthesis of diversely substituted 2H-pyran-2-ones (2t-
2ac) in watera
R1
R2
H2SO4 (10 mol%) R3
3
OH
R1
•
R
R4
OH
H
R3
O
R4
R2
H2O, MWI
O
3
R1
CO2Me
CH3
•
R
H2SO4 (10 mol%)
H2O, MWI
R
O
+
R1
CO2Me
1
2
O
CH3
CO2Me
3
2
1
Yield
(%)b
Entry
R1
Ph
R2
R3 Product
Yield (%)b
Entry
R1
Ph
R3
R4
1
H
H
H
2a
2b
2c
2d
2e
2f
83
85
85
80
75
88
78
77
80
71
77
72
81
82
73
72
82
83
88
2
3
2
p-Cl-C6H4
p-Br-C6H4
p-CH3-C6H4
p-CH3O-C6H4
p-NC-C6H4
o-F-C6H4
o-Cl-C6H4
o-Br-C6H4
o-CH3O-C6H4
m-F-C6H4
m-CH3-C6H4
Ph
H
1
H
H
H
H
CH3 2t, 72 (25)c 3a, 12 (61)c
CH3 2u, 80 (22)c 3b, 9 (63)c
CH3 2v, 75 (31)c 3c, 11 (56)c
CH3 2w, 78 (28)c 3d, 12 (55)c
CH3 2x, 65 (23)c 3e, 15 (62)c
CH3 2y, 62 (24)c 3f, 18 (59)c
CH3 2z, 82 (27)c 3g, 8 (53)c
C2H5 2aa, 75 (27)c 3h, 13 (58)c
C2H5 2ab, 73 (25)c 3i, 10 (61)c
3
H
H
2
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
4
H
H
3
5
H
H
4
6
H
H
5
p-CH3-C6H4
p-CH3O-C6H4
p-NC-C6H4
p-Cl-C6H4
H
H
H
H
H
7
H
H
2g
2h
2i
6
8
H
H
7
9
H
H
8
10
11
12
13
14
15
16
17
18
19
H
H
2j
9
p-Br-C6H4
H
H
2k
2l
10
p-Cl-C6H4
CH3 CH3 2ac, 68 (26)c 3j, 8 (41)c
H
H
a Reaction conditions: 1 (0.5 mmol), H2SO4 (0.05 mmol), H2O (5
mL), 80 ºC, MWI, 1 h. b Isolated yields. c Yields of reactions run
in CH2Cl2.
Ph
H
2m
2n
2o
2p
2q
2r
2s
Ph
p-F-C6H4
H
CH3
Ph
H
CH3
p-F-C6H4
H
Ph
H
H
H
CH3
CH3
CH3
tion A. Subsequent hydration of C gives an enol (D).
Intramolecular transesterification of D affords 2t. On the
other hand, the formation of 3a is most likely through an
intramolecular Friedel–Crafts reaction of carbocation B.
The presence of a methyl group makes this alternative route
possible since it can stabilize B and E due to the formation
of a tetrasubstituted C-C double bond. When the reaction is
run in CH2Cl2 as reported in our previous communica-
tion,16 the relative stability of the cation intermediates (B
and E) dominates the selectivity of the reaction and under
this circumstance substituted indene 3a is formed as a ma-
jor product. When the reaction is run in water as described
herein, on the other hand, the hydration of intemediate C is
greatly facilited due to the presence of an excess amount of
water. Therefore, the reaction mainly proceeds via interme-
diate D. In this case, the reaction gives substituted 2H-py-
ran-2-one (2t) as a major product.
p-CH3O-C6H4
p-NC-C6H4
a Reaction conditions: 1 (0.5 mmol), H2SO4 (0.05 mmol), H2O (5
mL), 80 ºC, MWI, 0.5 h. b Isolated yields.
creased from 25% to 72%. This is a promising result with
regard to the much improved chemoselectivity toward the
formation of 4,5,6-trisubstituted 2H-pyran-2-one.
The above results might be explained by a plausible
mechanism shown in Scheme II.16 Initially, acid promoted
dehydration of 1t affords 2,4,5-trienoate (C) via carboca-
Plausible pathways for the reaction of 1t
Scheme II
run in different solvents
The generality of the above process was demon-
strated with a series of substrates (Table 3). This methodol-
ogy allows efficient preparation of 4,5,6-tri-substituted or
3,4,5,6-tetrasubstituted 2H-pyran-2-ones bearing various
functional groups. It is worth to be noted that in all cases
2H-pyran-2-ones (2) were obtained as major products
rather than the corresponding indenes (3), thus resulting in
a general, selective and mild synthetic protocol for synthe-
sis of poly-substituted 2H-pyran-2-ones.
J. Chin. Chem. Soc. 2014, 61, 233-239
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235

Article
Cui et al.
CONCLUSIONS
CDCl3) d: 2.31 (s, 3H), 6.25 (s, 1H), 6.30 (s, 1H), 7.43 (d, J = 8.4
Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) d:
20.2, 103.1, 108.2, 127.9, 129.4, 134.2, 136.8, 154.2, 162.5,
163.1. MS: m/z 221 [MH]+. 4-(4-Bromophenyl)-6-methyl-2H-
pyran-2-one (2c):16 Yield (85%), 1H NMR (400 MHz, CDCl3) d:
2.32 (s, 3H), 6.24 (s, 1H, CH), 6.32 (s, 1H, CH), 7.42 (d, J = 8.0
Hz, 2H,), 7.60 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3) d:
20.2, 103.0, 108.2, 125.1, 128.1, 132.4, 134.7, 154.3, 162.5,
163.1. MS: m/z 265 [MH]+. 4-(4-Methylphenyl)-6-methyl-2H-
pyran-2-one (2d):8 Yield (80%), 1H NMR (400 MHz, CDCl3) d:
2.30 (s, 3H), 2.39 (s, 3H), 6.29 (s, 1H), 6.32 (s, 1H), 7.26 (d, J =
8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H). 13C NMR (100 MHz,
CDCl3) d: 20.1, 21.3, 103.3, 107.3, 126.5, 129.8, 132.8, 141.1,
155.3, 161.9, 163.5. MS: m/z 201 [MH]+. 4-(4-Methoxyphenyl)-
In summary, we have developed a novel synthesis of
diversely substituted 2H-pyran-2-ones in water under MWI.
Notable features of the above process include: 1) combina-
tion of water as an environmentally benign solvent for
chemical transformations with the use of microwave irradi-
ation as an efficient heating method; 2) enhanced chemo-
selectivity toward the formation of substituted 2H-pyran-
2-ones in aqueous medium. With advantages such as high
efficiency, favorable chemoselectivity and environmental
benigncy, the synthetic method developed in this paper are
expected to be used as valuable alternative protocol for the
preparation of diversely substituted 2H-pyran-2-ones.
1
EXPERIMENTAL
6-methyl-2H-pyran-2-one (2e):8 Yield (75%), H NMR (400
1
General methods: The H, 13C NMR spectra were re-
MHz, CDCl3) d: 2.21 (s, 3H), 3.74 (s, 3H), 6.19 (s, 1H), 6.23 (s,
1H), 6.89 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H). 13C NMR
(100 MHz, CDCl3) d: 20.0, 55.4, 103.0, 106.1, 114.5, 127.5,
128.1, 154.7, 161.7, 161.8, 163.6. MS: m/z 217 [MH]+. 4-(4-
Cyanophenyl)-6-methyl-2H-pyran-2-one (2f):16 Yield (88%),
1H NMR (400 MHz, CDCl3) d: 2.30 (s, 3H), 6.25 (s, 1H), 6.32 (s,
1H), 7.64 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H). 13C NMR
(100 MHz, CDCl3) d: 20.2, 102.8, 109.7, 126.0, 127.4, 132.1,
132.9, 140.2, 153.5, 162.6, 163.1. MS: m/z 212 [MH]+. 4-(2-
Fluorophenyl)-6-methyl-2H-pyran-2-one (2g):16 Yield (78%),
1H NMR (400 MHz, CDCl3) d: 2.19 (s, 3H), 6.17 (s, 1H), 6.21 (s,
1H), 7.05-7.16 (m, 2H), 7.31-7.36 (m, 2H). 13C NMR (100 MHz,
CDCl3) d: 19.9, 104.7, 111.0, 116.4, 116.6, 124.7, 124.8, 129.4,
131.9, 132.0, 151.1, 158.5, 161.0, 161.6, 162.8. MS: m/z 205
[MH]+. 4-(2-Chlorophenyl)-6-methyl-2H-pyran-2-one (2h):16
Yield (77%), 1H NMR (400 MHz, CDCl3) d: 2.25 (s, 3H), 6.11 (s,
corded at 400 MHz or 100 MHz, respectively. Chemical shifts
were reported in ppm from tetramethylsilane (TMS) as internal
standard in CDCl3 solution. Multiplicity was indicated as fol-
lows: s (singlet); d (doublet); t (triplet); m (multiplet); dd (doublet
of doublets), etc. and coupling constants were given in Hz. High
resolution mass spectra (HRMS) were performed on a
time-of-flight (microTOF) mass spectrometer. The conversion of
starting materials were monitored by thin layer chromatography
(TLC) using silica gel plates (silica gel 60 F254 0.25 mm) and
components were visualized by observation under UV light (254
and 365 nm). Microwave assisted reactions were performed in a
commercial microwave reactor (XH-100A).
General procedure for the preparation of 2H-pyran-2-
one (2): To a round-bottom flask containing 3-hydroxyhexa-
4,5-dienoate (1, 0.5 mmol) in H2O (5 mL) were added H2SO4
(0.05 mmol). The flask was put into the cavity of the microwave
synthesis apparatus and irradiated at 300 W at 80 °C. Upon com-
pletion, it was cooled to room temperature and quenched with
aqueous NaHCO3. The mixture was extracted with ethyl acetate
(5 mL × 3). The combined organic phases were dried, filtered and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel eluenting with ethyl acetate/hexane
(1:10) to give 2H-pyran-2-one (2a-2ac, Table 2 and Table 3).
From substrates 1t-1ac, substituted indenes (3a-3j) were also ob-
tained as minor products (Table 3).
1H), 6.13 (s, 1H), 7.23-7.34 (m, 3H), 7.41 (d, J = 7.6 Hz, 1H). 13
C
NMR (100 MHz, CDCl3) d: 20.0, 105.7, 112.0, 127.3, 129.7,
130.4, 130.6, 131.6, 135.9, 155.0, 161.4, 162.8. MS: m/z 221
[MH]+. 4-(2-Bromophenyl)-6-methyl-2H-pyran-2-one (2i):16
Yield (80%), 1H NMR (400 MHz, CDCl3) d: 2.29 (s, 3H), 6.10 (s,
1H), 6.14 (s, 1H), 7.24-7.29 (m, 2H), 7.38 (t, J = 7.2 Hz, 1H), 7.64
(d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) d: 20.0, 105.9,
112.1, 120.8, 127.8, 129.7, 130.7, 133.6, 138.1, 156.5, 161.4,
162.8. MS: m/z 265 [MH]+. 4-(2-Methoxyphenyl)-6-methyl-
2H-pyran-2-one (2j):16 Yield (71%), 1H NMR (400 MHz,
CDCl3) d: 2.25 (s, 3H), 3.82 (s, 3H), 6.25 (s, 1H), 6.28 (s, 1H),
6.95-6.99 (m, 2H), 7.26-7.38 (m, 2H). 13C NMR (100 MHz,
CDCl3) d: 20.0, 55.5, 105.9, 111.0, 111.4, 121.0, 125.5, 129.5,
131.4, 154.5, 156.7, 160.4, 163.6. MS: m/z 217 [MH]+. 4-(3-
Fluorophenyl)-6-methyl-2H-pyran-2-one (2k):16 Yield (77%),
1H NMR (400 MHz, CDCl3) d: 2.29 (s, 3H), 6.24 (s, 1H), 6.28 (s,
6-Methyl-4-phenyl-2H-pyran-2-one (2a):8 Yield (83%),
1H NMR (400 MHz, CDCl3) d: 2.32 (s, 3H), 6.30 (s, 1H), 6.36 (s,
1H), 7.45-7.47 (m, 3H), 7.55-7.58 (m, 2H). 13C NMR (100 MHz,
CDCl3) d: 20.2, 103.5, 108.1, 126.6, 129.1, 130.6, 135.8, 155.5,
162.1, 163.4. MS: m/z 187 [MH]+. 4-(4-Chlorophenyl)-6-meth-
yl-2H-pyran-2-one (2b):8 Yield (85%), H NMR (400 MHz,
1
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Synthesis of 2H-pyran-2-ones in Water under MWI
1H), 7.11-7.16 (m, 1H), 7.22 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H),
7.38-7.42 (m, 1H). 13C NMR (100 MHz, CDCl3) d: 20.1, 103.1,
108.5, 113.5, 113.7, 117.3, 117.5, 122.3, 122.4, 130.8, 130.9,
137.9, 137.9, 154.1, 161.7, 162.5, 163.0, 164.2. MS: m/z 205
[MH]+. 4-(3-Methylphenyl)-6-methyl-2H-pyran-2-one (2l):16
Yield (72%), 1H NMR (400 MHz, CDCl3) d: 2.24 (s, 3H), 2.35 (s,
3H), 6.25 (s, 2H), 7.22-7.29 (m, 4H). 13C NMR (100 MHz,
CDCl3) d: 20.0, 21.3, 103.5, 107.8, 123.7, 127.2, 129.0, 131.3,
135.6, 138.8, 155.6, 162.0, 163.3. MS: m/z 201 [MH]+. 6-
Benzyl-4-phenyl-2H-pyran-2-one (2m):11a Yield (81%), 1H
NMR (400 MHz, CDCl3) d: 3.86 (s, 2H), 6.22 (s, 1H), 6.35 (s,
1H), 7.26-7.38 (m, 5H), 7.44-7.55 (m, 5H). 13C NMR (100 MHz,
CDCl3) d: 40.3, 103.5, 108.6, 126.7, 127.4, 128.9, 129.1, 129.3,
130.6, 135.1, 135.7, 155.3, 163.1, 164.4. MS: m/z 263 [MH]+.
6-(4-Fluorobenzyl)-4-phenyl-2H-pyran-2-one (2n):16 Yield
(82%), 1H NMR (400 MHz, CDCl3) d: 3.84 (s, 2H), 6.20 (s, 1H),
6.36 (s, 1H), 7.04 (t, J = 8.0 Hz, 2H), 7.27-7.29 (m, 2H), 7.45-7.52
(m, 5H). 13C NMR (100 MHz, CDCl3) d: 39.4, 103.5, 108.7,
115.7, 115.9, 126.6, 129.1, 130.7, 130.75, 130.82, 135.7, 155.3,
163.0, 164.0. MS: m/z 281 [MH]+. 6-Benzyl-4-methyl-2H-
pyran-2-one (2o):16 Yield (73%), 1H NMR (400 MHz, CDCl3) d:
2.05 (s, 3H), 3.74 (s, 2H), 5.72 (s, 1H), 5.92 (s, 1H), 7.24-7.34 (m,
5H). 13C NMR (100 MHz, CDCl3) d: 21.4, 39.9, 106.4, 110.9,
127.3, 128.8, 129.2, 135.2, 156.2, 162.9, 163.4. MS: m/z 201
[MH]+. 6-(4-Fluorobenzyl)-4-methyl-2H-pyran-2-one (2p):16
Yield (72%), 1H NMR (400 MHz, CDCl3) d: 2.07 (s, 3H), 3.72 (s,
2H), 5.72 (s, 1H), 5.92 (s, 1H), 6.98-7.02 (m, 2H), 7.19-7.26 (m,
2H). 13C NMR (100 MHz, CDCl3) d: 21.4, 39.0, 106.3, 111.0,
115.5, 115.8, 130.7, 130.8, 130.9, 156.1, 162.7, 163.1. MS: m/z
219 [MH]+. 3,6-Dimethyl-4-phenyl-2H-pyran-2-one (2q):16
Yield (82%), 1H NMR (400 MHz, CDCl3) d: 2.03 (s, 3H), 2.25 (s,
3H), 5.97 (s, 1H), 7.27-7.44 (m, 5H). 13C NMR (100 MHz,
CDCl3) d: 13.8, 19.6, 106.6, 118.1, 127.8, 128.5, 128.7, 137.7,
152.0, 157.8, 164.8. MS: m/z 201 [MH]+. 4-(4-Methoxyphen-
yl)-3,6-dimethyl-2H-pyran-2-one (2r):16 Yield (83%), 1H NMR
(400 MHz, CDCl3) d: 2.04 (s, 3H), 2.22 (s, 3H), 3.83 (s, 3H), 5.96
(s, 1H), 6.94 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H). 13C
NMR (100 MHz, CDCl3) d: 13.9, 19.6, 55.3, 106.7, 113.9, 117.4,
129.5, 129.9, 151.7, 157.5, 159.9, 165.0. MS: m/z 231 [MH]+.
4-(3,6-Dimethyl-2-oxo-2H-pyran-4-yl)benzonitrile (2s):16
Yield (88%), 1H NMR (400 MHz, CDCl3) d: 2.01 (s, 3H), 2.27 (s,
3H), 5.91 (s, 1H, CH), 7.41 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz,
2H). 13C NMR (100 MHz, CDCl3) d: 13.7, 19.6, 105.5, 112.7,
117.5, 119.0, 128.7, 132.4, 142.2, 148.5, 158.6, 164.1. MS: m/z
226 [MH]+. 5,6-Dimethyl-4-phenyl-2H-pyran-2-one (2t):11a
Yield (72%), 1H NMR (400 MHz, CDCl3) d: 1.83 (s, 3H), 2.29 (s,
3H), 6.06 (s, 1H), 7.21-7.24 (m, 2H), 7.40-7.42 (m, 3H). 13C NMR
(100 MHz, CDCl3) d: 13.8, 18.1, 110.2, 112.1, 127.6, 128.5,
128.9, 158.3, 160.2, 162.6. MS: m/z 201 [MH]+. 4-(4-Fluoro-
1
phenyl)-5,6-dimethyl-2H-pyran-2-one (2u): Yield (80%), H
NMR (400 MHz, CDCl3) d: 1.83 (s, 3H), 2.29 (s, 3H), 6.05 (s,
1H), 7.10-7.14 (m, 2H), 7.21-7.24 (m, 2H). 13C NMR (100 MHz,
CDCl3) d: 13.9, 18.2, 110.1, 112.4, 115.6, 115.8, 129.5, 129.6,
133.3, 133.4, 158.6, 159.2, 161.8, 162.5, 164.3. MS: m/z 219
[MH]+. HRMS calcd for C13H12FO2: 219.0821 [M+H], found:
219.0825. 4-(4-Chlorophenyl)-5,6-dimethyl-2H-pyran-2-one
(2v):16 Yield (75%), 1H NMR (400 MHz, CDCl3) d: 1.81 (s, 3H),
2.28 (s, 3H), 6.02 (s, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4
Hz, 2H). 13C NMR (100 MHz, CDCl3) d: 13.8, 18.1, 109.9, 112.2,
128.8, 129.0, 135.1, 135.7, 158.6, 158.9, 162.3. MS: m/z 235
[MH]+. 4-(4-Bromophenyl)-5,6-dimethyl-2H-pyran-2-one
(2w):16 Yield (78%), 1H NMR (400 MHz, CDCl3) d: 1.82 (s, 3H),
2.29 (s, 3H), 6.03 (s, 1H), 7.11 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0
Hz, 2H). 13C NMR (100 MHz, CDCl3) d: 13.8, 18.2, 109.8, 112.2,
123.3, 129.3, 129.3, 131.8, 136.1, 158.7, 158.9, 162.3. MS: m/z
279 [MH]+. 5,6-Dimethyl-4-p-tolyl-2H-pyran-2-one (2x):16
Yield (65%), 1H NMR (400 MHz, CDCl3) d: 1.83 (s, 3H), 2.27 (s,
3H), 2.37 (s, 3H), 6.03 (s, 1H), 7.12 (d, J = 7.6 Hz, 2H), 7.21 (d, J
= 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) d: 13.9, 18.1, 21.2,
110.3, 111.9, 127.6, 129.1, 134.4, 138.9, 158.2, 160.2, 162.7. MS:
m/z 215 [MH]+. 4-(4-Methoxyphenyl)-5,6-dimethyl-2H-py-
ran-2-one (2y): Yield (62%), 1H NMR (400 MHz, CDCl3) d: 1.
88 (s, 3H), 2.30 (s, 3H), 3.85 (s, 3H), 6.06 (s, 1H), 6.94-6.96 (m,
2H), 7.19-7.21 (m, 2H). 13C NMR (100 MHz, CDCl3) d: 14.1,
18.2, 55.4, 110.4, 111.9, 113.9, 129.2, 129.6, 158.3, 159.9, 160.2,
162.9. MS: m/z 231 [MH]+. HRMS calcd for C14H15O3: 231.1021
[M+H], found: 231.1018. 4-(5,6-Dimethyl-2-oxo-2H-pyran-
4-yl)benzonitrile (2z):16 Yield (82%), 1H NMR (400 MHz,
CDCl3) d: 1.80 (s, 3H), 2.30 (s, 3H), 6.04 (s, 1H), 7.37 (d, J = 8.0
Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) d:
13.7, 18.2, 109.3, 112.6, 112.9, 118.1, 128.4, 132.4, 141.8, 158.0,
159.2, 161.9. MS: m/z 226 [MH]+. 4-(4-Chlorophenyl)-5-ethyl-
1
6-methyl-2H-pyran-2-one (2aa): Yield (75%), H NMR (400
MHz, CDCl3) d: 0.84 (t, J = 7.2 Hz, 3H), 2.24 (q, J = 7.6 Hz, 2H),
2.30 (s, 3H), 6.00 (s, 1H), 7.16-7.19 (m, 2H), 7.39-7.41 (m, 2H).
13C NMR (100 MHz, CDCl3) d: 14.2, 17.7, 20.2, 113.0, 116.5,
128.81, 128.82, 134.9, 135.8, 158.92, 158.94, 162.3. MS: m/z 249
[MH]+. HRMS calcd for C14H14ClO2: 249.0682 [M+H], found:
249.0688. 4-(4-Bromophenyl)-5-ethyl-6-methyl-2H-pyran-2-
one (2ab): Yield (73%), 1H NMR (400 MHz, CDCl3) d: 0.85 (t, J
= 7.6 Hz, 3H), 2.25 (q, J = 7.6 Hz, 2H), 2.32 (s, 3H), 6.02 (s, 1H),
7.11-7.13 (m, 2H), 7.56-7.58 (m, 2H). 13C NMR (100 MHz,
CDCl3) d: 14.2, 17.7, 20.2, 112.9, 116.5, 123.1, 129.1, 131.8,
136.3, 158.92, 158.94, 162.2. MS: m/z 293 [MH]+. HRMS calcd
J. Chin. Chem. Soc. 2014, 61, 233-239
© 2014 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Article
Cui et al.
for C14H14BrO2: 293.0177 [M+H], found: 293.0196. 4-(4-
Chlorophenyl)-3,5,6-trimethyl-2H-pyran-2-one (2ac):16 Yield
(68%), 1H NMR (400 MHz, CDCl3) d: 1.61 (s, 3H), 1.80 (s, 3H),
Yield (8%), 1H NMR (400 MHz, CDCl3) d: 2.15 (s, 3H), 3.57 (s,
2H), 3.67 (s, 3H), 5.84 (s, 1H), 6.08 (s, 1H), 7.24 (d, J = 8.0 Hz,
1H), 7.52 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H). 13C NMR (100 MHz,
CDCl3) d: 10.1, 31.3, 52.2, 107.7, 113.7, 118.6, 119.8, 122.3,
132.4, 133.0, 136.0, 139.2, 146.2, 146.9, 170.4. MS: m/z 240
[MH]+. Methyl 2-(6-chloro-2-ethyl-1-methylene-1H-inden-
3-yl)acetate (3h): Yield (13%), 1H NMR (400 MHz, CDCl3) d:
1.16 (t, J = 7.6 Hz, 3H), 2.55 (q, J = 8.0 Hz, 2H), 3.56 (s, 2H), 3.68
(s, 3H), 5.74 (s, 1H), 6.01 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.21
2.25 (s, 3H), 7.05 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H). 13
C
NMR (100 MHz, CDCl3) d: 14.2, 14.4, 17.7, 110.4, 119.9, 128.8,
129.1, 134.1, 135.5, 154.1, 154.4, 163.9. MS: m/z 249 [MH]+.
Methyl
2-(2-methyl-1-methylene-1H-inden-3-yl)acetate
(3a):16 Yield (12%), 1H NMR (400 MHz, CDCl3) d: 2.13 (s, 3H),
3.58 (s, 2H), 3.68 (s, 3H), 5.70 (s, 1H), 6.01 (s, 1H), 7.14-7.26 (m,
3H) 7.53 (d, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) d: 9.9,
31.6, 52.1, 110.5, 118.0, 119.2, 124.8, 128.1, 133.2, 134.9, 135.6,
143.0, 148.0, 171.0. MS: m/z 215 [MH]+. Methyl 2-(6-fluoro-2-
methyl-1-methylene-1H-inden-3-yl) acetate (3b): Yield (9%),
1H NMR (400 MHz, CDCl3) d: 2.09 (s, 3H), 3.54 (s, 2H), 3.67 (s,
3H), 5.70 (s, 1H), 5.95 (s, 1H), 6.90-6.95 (m, 1H), 7.08-7.11 (m,
1H), 7.19-7.22 (m, 1H). 13C NMR (100 MHz, CDCl3) d: 9.9, 31.7,
52.2, 107.2, 107.5, 111.5, 114.1, 114.3, 118.7, 118.8, 132.8,
134.76, 134.80, 137.7, 137.8, 138.9, 147.3, 160.6, 163.0, 170.9.
MS: m/z 233 [MH]+. HRMS calcd for C14H14FO2: 233.0978
[M+H], found: 233.0979. Methyl 2-(6-chloro-2-methyl-1-
methylene-1H-inden-3-yl) acetate (3c):16 Yield (11%), 1H NMR
(400 MHz, CDCl3) d: 2.09 (s, 3H), 3.53 (s, 2H), 3.67 (s, 3H), 5.70
(d, J = 2.0 Hz, 1H), 5.96 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 7.6 Hz,
1H)), 7.19-7.20 (m, 1H), 7.45 (s, 1H). 13C NMR (100 MHz,
CDCl3) d: 9.9, 31.5, 52.1, 111.8, 118.9, 119.8, 127.7, 130.8,
132.8, 135.3, 137.3, 141.4, 147.1, 170.7. MS: m/z 249 [MH]+.
Methyl 2-(6-bromo-2-methyl-1-methylene-1H-inden-3-yl) ac-
etate (3d):16 Yield (12%), 1H NMR (400 MHz, CDCl3) d: 2.10 (s,
3H), 3.55 (s, 2H), 3.67 (s, 3H), 5.73 (s, 1H), 5.99 (s, 1H), 7.05 (d, J
= 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 1.2 Hz, 1H).
13C NMR (100 MHz, CDCl3) d: 9.9, 31.6, 52.2, 111.9, 118.8,
119.4, 122.6, 130.6, 132.8, 135.3, 137.6, 141.8, 147.1, 170.8. MS:
m/z 293 [MH]+. Methyl 2-(2,6-dimethyl-1-methylene-1H-
(dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H). 13
C
NMR (100 MHz, CDCl3) d: 15.4, 18.1, 31.6, 52.2, 111.9, 119.2,
119.9, 127.8, 130.9, 132.2, 137.4, 141.3, 141.4, 145.7, 170.9. MS:
m/z 263 [MH]+. HRMS calcd for C15H16ClO2: 263.0839 [M+H],
found: 263.0843. Methyl 2-(6-bromo-2-ethyl-1-methylene-
1H-inden-3-yl) acetate (3i): Yield (10%), 1H NMR (400 MHz,
CDCl3) d: 1.15 (t, J = 7.6 Hz, 3H), 2.55 (q, J = 7.6 Hz, 2H), 3.55
(s, 2H), 3.67 (s, 3H), 5.75 (s, 1H), 6.02 (s, 1H), 7.08 (d, J = 7.6 Hz,
1H), 7.35-7.38 (m, 1H), 7.62 (s, 1H). 13C NMR (100 MHz,
CDCl3) d: 15.3, 18.0, 31.6, 52.2, 112.0, 118.9, 119.7, 122.7,
130.9, 132.3, 137.7, 141.4, 141.7, 145.7, 170.9. MS: m/z 307
[MH]+. HRMS calcd for C15H16BrO2: 307.0333 [M+H], found:
307.0346. Ethyl 2-(6-chloro-2-methyl-1-methylene-1H-inden-
3-yl) propanoate (3j):16 Yield (8%), 1H NMR (400 MHz, CDCl3)
d: 1.65 (t, J = 7.2 Hz, 3H), 1.47 (d, J = 7.2 Hz, 3H), 2.09 (s, 3H),
3.85-3.88 (m, 1H), 4.11-4.16 (m, 2H), 5.70 (s, 1H), 5.96 (s, 1H),
7.14-7.16 (m, 2H), 7.47 (s, 1H). 13C NMR (100 MHz, CDCl3) d:
9.8, 14.1, 15.3, 37.4, 60.9, 111.4, 119.7, 119.8, 127.5, 130.6,
133.4, 137.8, 138.8, 140.1, 147.1, 173.7. MS: m/z 277 [MH]+.
ACKNOWLEDGEMENT
We are grateful to the National Natural Science Foun-
dation of China (21172057, 21272058), and The Research
Fund for the Doctoral Program of Higher Education
(20114104110005) for financial support.
1
inden-3-yl)acetate (3e):16 Yield (15%), H NMR (400 MHz,
CDCl3) d: 2.16 (s, 3H), 2.44 (s, 3H), 3.60 (s, 2H), 3.71 (s, 3H),
5.68 (s, 1H), 6.00 (s, 1H), 7.11-7.17 (m, 2H), 7.40 (s, 1H). 13C
NMR (100 MHz, CDCl3) d: 9.8, 21.5, 31.7, 52.0, 109.9, 117.8,
120.3, 128.6, 133.3, 134.0, 136.0, 140.6, 148.2, 171.0. MS: m/z
229 [MH]+. Methyl 2-(6-methoxy-2-methyl-1-methylene-
1H-inden-3-yl) acetate (3f): Yield (18%), 1H NMR (400 MHz,
CDCl3) d: 2.08 (s, 3H), 3.54 (s, 2H), 3.67 (s, 3H), 3.83 (s, 3H),
5.64 (s, 1H), 5.95 (s, 1H), 6.75-6.78 (m, 1H), 7.08 (d, J = 8.0 Hz,
1H), 7.12 (d, J = 2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) d: 9.9,
31.8, 52.2, 55.7, 106.8, 110.1, 112.4, 118.5, 133.1, 133.2, 136.2,
137.5, 148.0, 158.2, 171.1. MS: m/z 245 [MH]+. HRMS calcd for
C15H17O3: 245.1177 [M+H], found: 245.1190. Methyl 2-(6-
cyano-2-methyl-1-methylene-1H-inden-3-yl) acetate (3g):16
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