Palladium(II)-catalyzed tandem annulation reaction of o-alkynylbenzoates with methyl vinyl ketone for the synthesis of isocoumarins

Article abstract of DOI:10.1016/j.tet.2013.07.057

A palladium(II)-catalyzed highly regioselective tandem reactions of o-alkynylbenzoates with methyl vinyl ketone for the synthesis of isocoumarins was developed. It is a convenient, mild and environmentally benign reaction with moderate to high yield. The

Full text of DOI:10.1016/j.tet.2013.07.057

Tetrahedron 69 (2013) 8626e8631
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Palladium(II)-catalyzed tandem annulation reaction of
o-alkynylbenzoates with methyl vinyl ketone for the
synthesis of isocoumarins
*
*
Huan Wang, Xiuling Han , Xiyan Lu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu,
Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2013
Received in revised form 4 July 2013
Accepted 11 July 2013
Available online 31 July 2013
A palladium(II)-catalyzed highly regioselective tandem reactions of o-alkynylbenzoates with methyl
vinyl ketone for the synthesis of isocoumarins was developed. It is a convenient, mild and environ-
mentally benign reaction with moderate to high yield. The reaction is initiated by the Pd(II) species and
regenerate the Pd(II) species to complete the catalytic cycle without the necessity of a redox system.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Conjugate addition
Isocoumarin
Oxypalladation
Palladium(II)
Protonolysis
Tandem reaction
1. Introduction
cyclization of o-alkynylbenzoates.6 On the other hand, our group
has explored some palladium(II)-catalyzed conjugate reactions
Conjugate addition of organometallic reagents to
a
,
b
-un-
including the addition of arylboron reagents to enals or enones2eeg
and the tandem reaction initiated by nucleopalladation of alkynes.7
Considering the diverse activities of isocoumarins, we wonder
whether this kind of compounds could be obtained through Pd(II)-
catalyzed cyclization of o-alkynylbenzoates initiated by oxy-
palladation of alkynes and quenched by conjugate addition to an
enone. To the best of our knowledge, there are only few examples
for the synthesis of isocoumarins catalyzed by palladium(II) com-
plexes via tandem cyclization of o-alkynylbenzoate and enones.8
saturated carbonyl compounds is one of the basic methods for the
construction of CeC bonds. These addition reactions have been
used as key steps in the synthesis of numerous biologically active
compounds and show a broad scope in synthetic chemistry. The
widely employed nucleophiles are Grignard reagents, diorganozinc
compounds or organocopper reagents.1 In recent years the
transition-metal-catalyzed conjugate addition reaction is attracting
more and more attention for the advantage of no need for stoi-
chiometric amounts of organometallic reagents. Among them,
palladium is one of the most used transition-metal and many ex-
amples have been widely reported.2
2. Results and discussion
Isocoumarins represent one important class of naturally occur-
ring lactones,3 which are structural subunits in numerous natural
products that exhibit a wide range of biological activities, such as
antimicrobial, androgen-like, phytotoxic, antifungal and phero-
monal effects.4 Considerable efforts have been directed toward the
synthesis of isocoumarins either by traditional approaches or by
transition-metal-catalyzed reactions.5 Recently, a more convenient
way for the synthesis of isocoumarins was available from the
The first attempt for the annulation reaction was carried out by
the reaction of 1a and methyl vinyl ketone (2) under the catalysis of
Pd(II) salts in the presence of 4 equiv of LiCl.9 To our delight,
through initial screening of different catalysts, additives and sol-
vents, it was found that both Pd(OAc)2 and PdCl2 could make the
reaction proceed well to form six-membered-ring product (3a)10
regioselectively via 6-endo cyclization in excellent yield. No five-
membered-ring product was detected. The solvent played a cru-
cial role in the catalytic system. When dried HOAc, toluene or di-
oxane was used, the substrate 1a could not transform effectively
* Corresponding authors. E-mail address: xylu@mail.sioc.ac.cn (X. Lu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.057

H. Wang et al. / Tetrahedron 69 (2013) 8626e8631
8627
Table 2
and only trace amount of product was obtained (Table 1, entries
1e3). The substrate can transform completely when some water
was added to the reaction (Table 1, entries 4e7). However, some
amount of the byproduct, 3-oxobutyl acetate, produced from the
reaction of HOAc with 2 was also obtained, which was difficult to
remove from our product. In order to inhibit the formation of 3-
oxobutyl acetate, some mixed solvents were tried and it was re-
ally effective. Among which toluene/HOAc/H2O was the best
one and only trace of the byproduct could be detected (Table 1,
entries 8e14). When the additive LiBr was used instead of LiCl,
the product can be obtained in a similar yield together with
a large amount of byproducts. Thus, the optimal conditions for our
annulation reaction is: 0.15 mmol of 1, 8 equiv of 2, 5 mol % of
Pd(OAc)2 and 4 equiv of LiCl were stirred in HOAc/toluene/H2O
(1 mL/1 mL/0.05 mL) at room temperature for about 7e8 h.
Tandem annulation reaction of substituted o-alkynylbenzonates 1 with 2 under
optimal conditionsa
Entry
1
Yield (%)b
R1
R2
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
Ph (1a)
99 (3a)
75 (3b)
68 (3c)
97 (3d)
90 (3e)
92 (3f)
93 (3g)
72 (3h)
68 (3i)
74 (3j)
85 (3k)
56 (3l)
77 (3m)
95 (3n)
90 (3o)
88 (3p)
88 (3q)
89 (3r)
4-MeeC6H4 (1b)
4-MeOeC6H4 (1c)
4-FeC6H4 (1d)
4-CleC6H4 (1e)
4-BreC6H4 (1f)
4-O2NeC6H4 (1g)
nC4H9 (1h)
Table 1
Optimization of the reaction conditionsa
9
nC6H13 (1i)
10
11
12
13
14
15
16
17
18
Cle(CH2)3 (1j)
Cyclohexyl-CH2 (1k)
Cyclopropyl (1l)
tBu (1m)
Ph (1n)
Ph (1o)
Ph (1p)
Ph (1q)
Ph (1r)
H
5-O2N
5-Me
4-F
4-Cl
4-Br
Entry
Catalyst
Solvent
Time (h)
Yield (%)b
1
2
3
PdCl2
PdCl2
PdCl2
PdCl2
HOAc
Toluene
Dioxane
HOAc/H2O (2/0.025)
HOAc/H2O (2/0.025)
HOAc/H2O (2/0.05)
HOAc/H2O (1.5/0.5)
HOAc/dioxane/H2O (1/1/0.05)
HOAc/dioxane/H2O (1/1/0.5)
HOAc/toluene/H2O (1/1/0.05)
HOAc/DCE/H2O (1/1/0.05)
HOAc/CH2Cl2/H2O (1/1/0.05)
HOAc/THF/H2O (1/1/0.05)
HOAc/dioxane/H2O (1/1/0.05)
168
48
48
5
12
2
0.7
5
3.5
8
Trace
NR
NR
82
84
82
81
85
84
99
a
A mixture of 1 (0.15 mmol), 2 (1.2 mmol, 8 equiv), LiCl (4 equiv) and Pd(OAc)2
(5 mol %) was stirred in HOAc/toluene/H2O (1 mL/1 mL/0.05 mL) at room temper-
ature for about 7e8 h as monitored by TLC.
4c
5c
6c
7c
8
b
Isolated yields.
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
demonstrate a whole spectrum of bioactivity and have been
shown to be antifungal, antibiotic, cytotoxic, neurotoxic and phy-
totoxic.11 Considering the diverse bioactivities of 2-pyrones, we
wonder whether this kind of compounds could be obtained from
our new annulation reaction. Thus, substrates 1s and 1t were
synthesized and subjected to the same reaction conditions as Table
2. To our delight, the corresponding 5,6-disubstituted-2H-2-
pyrones were produced in good yields (Scheme 1).
9
10
11
12
13
14
24
24
4
72
100
84
3.5
90
a
A mixture of 1a (0.15 mmol), 2 (1.2 mmol, 8 equiv), LiCl (4 equiv) and the cat-
alyst (5 mol %) were stirred in solvent (2 mL) at room temperature as monitored by
TLC.
b
Isolated yields.
c
A byproduct 3-oxobutyl acetate can also be formed in the reaction.
To explore the generality of the annulation reaction, a variety of
o-alkynylbenzonates were then subjected to the optimal conditions
and the results were summarized in Table 2. The reactions pro-
ceeded smoothly with different substituents on the alkynes. Either
aryl or alkyl group could be tolerated and all gave six-membered-
ring products only. The substrates with electron-withdrawing
groups on the aryl groups (R2) would give better yields (Table 2,
entries 4e7). On the contrary, the existence of electron-donating
groups on R2 made the yields lower (Table 2, entries 2 and 3).
When R2 were the alkyl groups, the yields of the corresponding
products decreased slightly (Table 2, entries 8e13). There is no
obvious influence for the substituents (R1) on the benzene ring of o-
alkynylbenzonates. No matter they were electron-donating or
-withdrawing groups, all of them can give the corresponding
products in excellent yields (Table 2, entries 14 and 15). It should be
noted that the halogen atoms on the benzene ring could be toler-
ated in this annulation reaction (Table 2, entries 5, 6 and 16e18).
Recently, 2-pyrones have been shown to be potent HIV-1 pro-
Scheme 1. Synthesis of 2-pyrones 3s and 3t.
It was known that indole skeleton is also popular in natural
products and the compounds with indole moiety usually have wide
bioactivity.12 We wonder if our new annulation reaction can be
applied to the synthesis of indoles bearing a 2-pyrone skeleton. So
the substrate 1u was synthesized and reacted with 2. Un-
fortunately, the reaction did not occur at all. Then, we synthesized
substrate 1v, which contains a tosyl group on the nitrogen atom and
found that it can give the cyclization product 3v in 41% yield
(Scheme 2). These results show that the substituents on the ni-
trogen atom of indole are crucial for this reaction. For substrate 1u,
the lone pair electrons on the nitrogen may influence the electron
density of the alkyne making the reaction impossible. While the
tease inhibitors. The 2-pyrone ring (2H-pyran-2-one),
a six-
membered unsaturated cyclic ester, is biodiverse and found in
bacterial, microbial, plant, insect and animal systems. 2-Pyrones

8628
H. Wang et al. / Tetrahedron 69 (2013) 8626e8631
Scheme 2. The reaction of indoles 1u and 1v with methyl vinyl ketone.
tosyl group substituted indole 1v diminishes the effect of the lone
pair electrons making the reaction possible even in a moderate
yield.
In order to understand the mechanism of the reaction further,
the substrate 1w with a large steric hindrance (tBu) on the ester
group was synthesized and subjected to the standard conditions. It
was surprising that the reaction occurred faster (2 h) than the
methyl ester (1a, 8 h), although the yield was decreased a little
(Scheme 3). This result was similar to the literature, in which the
possible nucleophile for the oxypalladation in the cyclization re-
action was suggested as the carbonyl oxygen of o-alkynylbenzoates,
not the methoxy oxygen.6c,6i
Scheme 5. The proposed mechanism for the annulation reaction.
or Clꢀ gave intermediate C or the enolate C0, then protonolysis of C0
offered the corresponding product 3a in the presence of an acid
with regeneration of the palladium species to complete the cata-
lytic cycle. The key for the success of the reaction is the addition of
LiCl, which can inhibit the
b-H elimination reaction and promote
the conjugate addition.9
Scheme 3. The reaction of tert-butyl-o-phenylethynylbenzonate with methyl vinyl
ketone.
3. Conclusion
In the literature, o-alkynylbenzoic acids can also undergo the
similar oxypalladation as o-alkynylbenzonates.13 Thus, a question
arose as to whether the substrates used in our reaction hydrolyzed
to the corresponding o-alkynylbenzoic acids first and then reacted
with 2. To test this hypothesis, substrate 1a was stirred in the
standard reaction conditions and it was found that there was no o-
phenylethynylbenzoic acid formed at all in the presence or absence
of Pd(OAc)2 (Scheme 4), indicating that the nucleophile is an ester,
not an acid in our new reaction.
In summary, a palladium(II)-catalyzed highly regioselective
tandem reaction of o-alkynylbenzoates with methyl vinyl ketone
was developed. This methodology provides a convenient way for
the synthesis of substituted isocoumarins or 2-pyrones in excellent
yields. The biggest advantage of this reaction is that it has good
regioselectivity and only six-membered-ring products were given
without the formation of the corresponding five-membered-ring
lactones.
4. Experimental section
4.1. General methods
All reactions were performed in dried tube and monitored by
TLC to ensure the completion of the reaction. All solvents were
dried and distilled according to the standard methods before use.
Pd(OAc)2 and PdCl2 were purchased from Strem and Aldrich
Chemicals Co, respectively. Substrates 1aes were synthesized by
the Sonogashira coupling from o-iodobenzonates or iodoacrylate
with arylethynes according to the literature procedures.6c,6f
Scheme 4. Further control experiments.
4.2. Procedure for the synthesis of substrate 1v
Finally, in the view of the results of the above tests and the
literature,6i,7 a possible mechanism for the reaction was proposed
using 1a as the model substrate (Scheme 5). The carbonyl oxygen
atom of the substrate 1a attacked the triple bond under the ca-
talysis of Pd(OAc)2 to form intermediate A. Subsequently, conju-
gate addition of the vinylpalladium species in intermediate A to
the double bond of 2 occurred to yield B. Attack of B by the water
Under the N2 atmosphere, the substrate 1u14 (0.4 g, 1.45 mmol)
was added into the three-necked-bottle and the DMF (10 mL) was
used to dissolve it. Ice bath was used to cool the reaction system to
0 ꢁC and NaH (3 equiv) was added. Then TsCl (0.38 g, 1.4 equiv) was
added. Subsequently, the mixture was stirred and the reaction
system was warmed to room temperature. When the reaction was
completed as monitored by TLC, H2O was added carefully to quench

H. Wang et al. / Tetrahedron 69 (2013) 8626e8631
8629
the reaction. EtOAc was used for extraction. Then the organic phase
was combined, dried by Na2SO4, concentrated under reduced
pressure and purified by flash column chromatography on silica gel
using ethyl acetate and petroleum ether as the eluent to afford the
product 1v (63% yield).
112.6, 43.1, 29.9, 20.5; IR (KBr):
n
3073, 2997, 2975, 2913, 1732, 1712,
1624, 1599, 1507, 1364, 1231, 1097, 844, 768, 697 cmꢀ1; MS (m/z, EI):
310 (Mþ), 253, 225 (100), 196, 123, 95, 75, 43; Calcd for C19H15FO3:
C, 73.54%; H, 4.87%; Found: C, 73.41%; H, 4.92%.
4.3.5. Compound 3e. Solid; mp 143e144 ꢁC; 1H NMR (400 MHz,
4.2.1. Substrate 1v. Oil; 1H NMR (400 MHz, CDCl3):
d
8.06 (d,
CDCl3):
7.48e7.43 (m, 4H), 2.98 (t, J¼8.0 Hz, 2H), 2.71 (t, J¼8.4 Hz, 2H), 2.14
(s, 3H); 13C NMR (100 MHz, CDCl3):
206.7,161.9,150.8,136.9,135.7,
135.0, 131.4, 130.3, 130.2, 128.8, 128.3, 123.0, 121.2, 112.8, 43.1, 29.9,
d 8.40e8.37 (m, 1H), 7.82e7.79 (m, 1H), 7.59e7.55 (m, 2H),
J¼8.4 Hz, 1H), 7.88 (d, J¼8 Hz, 2H), 7.72 (d, J¼8 Hz, 1H), 7.55 (d,
J¼3.6 Hz, 2H), 7.44 (t, J¼7.6 Hz, 1H), 7.36e7.33 (m, 4H), 7.24 (s,
1H), 7.21 (s, 1H), 4.06 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz,
d
CDCl3):
d
161.9, 145.3, 136.0, 134.5, 132.6, 131.7, 129.7, 129.2, 128.8,
20.5; IR (KBr): n ;
3107, 2962, 1716, 1634, 1488, 1094, 772, 698 cmꢀ1
128.4, 127.3, 124.5, 122.5, 121.4, 115.0, 110.1, 97.3, 78.9, 53.0, 21.5;
MS (m/z, EI): 328 (37Cl, Mþ), 326 (35Cl, Mþ), 269, 241, 234 (100), 178,
139, 111, 75, 43; HRMS-EI Calcd for C19H15ClO3: 326.0710; Found:
326.0714.
IR (neat):
n 3054, 2950, 2220, 1731, 1596, 1374, 1264, 1177, 756,
663, 575, 539 cmꢀ1; MS (m/z, EI): 429 (Mþ), 274 (100), 244, 214,
189, 91, 65. HRMS-EI Calcd for C25H19NO4S: 429.1035; Found:
429.1038.
4.3.6. Compound 3f. Solid; mp 146e147 ꢁC; 1H NMR (400 MHz,
CDCl3):
d
8.39 (d, J¼8.0 Hz, 1H), 7.81 (t, J¼8.0 Hz, 1H), 7.62e7.56 (m,
4.3. General procedure for the tandem annulation reaction of
substituted o-alkynylbenzonates with methyl vinyl ketone
4H), 7.41e7.39 (m, 2H), 2.98 (t, J¼8.0 Hz, 2H), 2.71 (t, J¼8.4 Hz, 2H),
2.14 (d, J¼1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 206.6, 161.8,
150.9, 136.9, 135.0, 131.9, 131.8, 130.5, 130.2, 128.3, 124.0, 123.0,
The tube was charged with o-alkynylbenzonate (1) (0.15 mmol),
Pd(OAc)2 (5 mol %), LiCl (4 equiv), then the solvent HOAc (1 mL)/
toluene (1 mL)/H2O (0.05 mL) and another substrate methyl vinyl
ketone (2) (1.2 mmol, 8 equiv) was added. Subsequently, the re-
action mixture was stirred about 8e9 h at room temperature. Until
the completion of the reaction as monitored by TLC test, the mix-
ture was concentrated under reduced pressure and purified by flash
column chromatography on silica gel using ethyl acetate and pe-
troleum ether as the eluent to afford the product 3.
121.3, 112.8, 43.1, 29.9, 20.5; IR (KBr):
1487, 1366, 1094, 771, 697 cmꢀ1; MS (m/z, EI): 372 (81Br, Mþ), 370
79Br, Mþ), 285, 234 (100), 178, 115, 76, 43; HRMS-EI Calcd for
n 3071, 2962, 2919, 1717, 1634,
(
C19H15BrO3: 370.0205; Found: 370.0206.
4.3.7. Compound 3g. Solid; mp 196e197 ꢁC; 1H NMR (400 MHz,
CDCl3):
d
8.42 (dd, J¼8.0 and 1.2 Hz, 1H), 8.35 (d, J¼8.8 Hz, 2H),
7.87e7.83 (m, 1H), 7.75 (s, 1H), 7.73 (s, 1H), 7.65e7.60 (m, 2H), 3.02
(t, J¼8.0 Hz, 2H), 2.76 (t, J¼8.0 Hz, 2H), 2.15 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 206.3, 161.4, 149.4, 148.1, 139.1, 136.5, 135.2,
4.3.1. Compound 3a. Solid; mp 104e106 ꢁC; 1H NMR (400 MHz,
130.4, 130.1, 128.9, 123.8, 123.3, 121.4, 114.2, 43.0, 30.0, 20.4; IR
CDCl3):
7H), 3.01e2.97 (m, 2H), 2.73e2.69 (m, 2H), 2.12 (s, 3H); 13C NMR
(100 MHz, CDCl3): 206.9, 162.1, 152.1, 137.2, 134.9, 133.0, 130.2,
129.6, 128.9, 128.5, 128.1, 122.9, 121.2, 112.4, 43.3, 29.8, 20.6; IR
d
8.39 (d, J¼8.0 Hz, 1H), 7.82e7.78 (m, 1H), 7.58e7.44 (m,
(KBr): n 3107, 3075, 2936, 1743, 1701, 1598, 1513, 1350, 773,
694 cmꢀ1; MS (m/z, EI): 337 (Mþ), 320, 278, 234 (100), 178, 150, 115,
104, 76, 43; HRMS-EI Calcd for C19H15NO5: 337.0950; Found:
337.0948.
d
(KBr):
n 3057, 2971, 2924, 1727, 1701, 1638, 1600, 1486, 765,
710 cmꢀ1; MS (m/z, EI): 292 (Mþ), 235, 207 (100), 178, 105, 77, 43;
Calcd for C19H16O3, C, 78.06%; H, 5.52%; Found: C, 78.20%; H,
5.26%.
4.3.8. Compound 3h. Oil; 1H NMR (400 MHz, CDCl3):
d 8.32 (d,
J¼8.0 Hz, 1H), 7.74 (t, J¼8.0 Hz, 1H), 7.49 (d, J¼8.0 Hz, 1H), 7.46 (d,
J¼8.0 Hz, 1H), 2.92 (t, J¼8.0 Hz, 2H), 2.70 (t, J¼8.0 Hz, 2H), 2.60 (t,
J¼8.0 Hz, 2H), 2.20 (s, 3H), 1.72e1.65 (m, 2H), 1.46e1.38 (m, 2H),
4.3.2. Compound 3b. Solid; mp 117e118 ꢁC; 1H NMR (400 MHz,
CDCl3):
0.95 (t, J¼8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 207.2, 162.6,
d
8.39e8.37 (m, 1H), 7.81e7.76 (m, 1H), 7.56e7.52 (m, 2H),
154.8, 137.3, 134.8, 130.0, 127.3, 122.1, 120.7, 110.7, 43.0, 30.5, 30.1,
7.40 (d, J¼8 Hz, 2H), 7.26 (d, J¼8 Hz, 2H), 3.01e2.97 (m, 2H),
29.9, 22.4, 19.8, 13.8; IR (neat): n 3070, 2959, 2827, 1716, 1642, 1488,
2.73e2.69 (m, 2H), 2.41 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz,
1364, 1091, 770, 732, 700 cmꢀ1; MS (m/z, EI): 272 (Mþ), 214 (100),
185, 173, 145, 131, 115, 57, 43, 41; HRMS-EI Calcd for C17H20O3:
272.1412; Found: 272.1413.
CDCl3):
d 207.0, 162.2, 152.2, 139.7, 137.3, 134.9, 130.1, 129.1, 128.8,
127.9, 122.8, 121.1, 112.1, 43.3, 29.9, 21.4, 20.6. IR (KBr): n 3038, 2995,
2920, 1726, 1712, 1615, 1508, 1107, 765, 691 cmꢀ1; MS (m/z, EI): 306
(Mþ), 278, 249, 221, 178, 119, 91, 71, 65, 43 (100); Calcd for C20H18O3,
C, 78.41%; H, 5.92%; Found: C, 78.26%; H, 6.09%.
4.3.9. Compound 3i. Oil; 1H NMR (400 MHz, CDCl3):
d 8.32 (d,
J¼8.0 Hz, 1H), 7.74 (t, J¼8.0 Hz, 1H), 7.50e7.45 (m, 2H), 2.92 (t,
J¼8.0 Hz, 2H), 2.70 (t, J¼8.0 Hz, 2H), 2.60 (t, J¼8.0 Hz, 2H), 2.20 (s,
3H), 1.73e1.66 (m, 2H), 1.39e1.26 (m, 6H), 0.89 (t, J¼6.4 Hz, 3H); 13C
4.3.3. Compound 3c. Solid; mp 122e124 ꢁC; 1H NMR (400 MHz,
CDCl3):
d
8.39e8.37 (m, 1H), 7.81e7.76 (m, 1H), 7.56e7.52 (m, 2H),
NMR (100 MHz, CDCl3): d 207.2, 162.6, 154.8, 137.3, 134.7, 130.0,
7.40 (d, J¼8 Hz, 2H), 7.26 (d, J¼8 Hz, 2H), 3.01e2.97 (m, 2H),
127.3, 122.1, 120.8, 110.7, 43.0, 31.5, 30.8, 30.0, 29.0, 27.8, 22.5, 19.8,
2.73e2.69 (m, 2H), 2.41 (s, 3H), 2.13 (s, 3H); 13C NMR (100 MHz,
14.0; IR (neat):
n 3070, 2956, 2928, 2857, 1716, 1641, 1605, 1566,
CDCl3):
d
207.0, 162.3, 160.5, 152.1, 137.4, 134.9, 130.4, 130.1, 127.8,
1364, 1091, 770, 700 cmꢀ1; MS (m/z, EI): 300 (Mþ), 242, 185, 173,
145, 131, 115, 43 (100), 41; HRMS-EI Calcd for C19H24O3: 300.1725;
Found: 300.1723.
125.4, 122.8, 121.1, 113.9, 111.9, 55.3, 43.3, 29.9, 20.7; IR (KBr):
n
3050, 2960, 2937, 2893, 1709, 1616, 1600, 1514, 1258, 1180, 1104,
833, 773, 695 cmꢀ1; MS (m/z, EI): 322 (Mþ), 294, 265, 237 (100),
194, 165, 135, 107, 77, 57, 49, 43; HRMS-EI Calcd for C20H18O4:
322.1205; Found: 322.1208.
4.3.10. Compound 3j. Oil; 1H NMR (400 MHz, CDCl3):
d 8.32 (d,
J¼8.0 Hz, 1H), 7.76 (t, J¼8.0 Hz, 1H), 7.52e7.48 (m, 2H), 3.62 (d,
J¼8.0 Hz, 2H), 2.96 (t, J¼8.0 Hz, 2H), 2.83 (t, J¼8.0 Hz, 2H), 2.73 (t,
J¼8.0 Hz, 2H), 2.24e2.18 (m, 2H), 2.19 (s, 3H); 13C NMR (100 MHz,
4.3.4. Compound 3d. Solid; mp 118e119 ꢁC; 1H NMR (400 MHz,
CDCl3):
7.16 (t, J¼8.2 Hz, 2H), 2.98 (t, J¼8.0 Hz, 2H), 2.71 (t, J¼8.4 Hz, 2H),
2.14 (s, 3H); 13C NMR (100 MHz, CDCl3):
206.7, 164.5, 162.0, 151.0,
137.0, 135.0, 131.1, 131.0, 130.2, 129.1, 128.2, 122.9, 121.2, 115.8, 115.6,
d
8.39 (d, J¼8 Hz,1H), 7.81 (t, J¼8 Hz,1H), 7.58e7.50 (m, 4H),
CDCl3): d 207.0, 162.3, 152.6, 137.0, 134.9, 130.1, 127.6, 122.3, 120.8,
111.9, 44.1, 42.8, 30.1, 30.0, 27.7, 19.8; IR (neat):
n 3017, 2961, 1716,
d
1643, 1488, 1363, 1093, 1055, 771, 695 cmꢀ1; MS (m/z, EI): 294 (37Cl,
Mþ), 292 (35Cl, Mþ), 235, 185, 172, 145, 131, 115, 102, 89, 77, 63, 43

8630
H. Wang et al. / Tetrahedron 69 (2013) 8626e8631
(100), 41; HRMS-EI Calcd for C16H17ClO3: 292.0866; Found:
292.0863.
129.9, 128.9, 128.6, 122.8, 119.5, 111.7, 43.0, 29.9, 20.5; IR (KBr): n
3077, 2917, 1726, 1707, 1601, 1090, 779, 703, 691 cmꢀ1; MS (m/z, EI):
328 (37Cl, Mþ), 326 (35Cl, Mþ), 273, 271 (37Cl), 269 (35Cl), 243 (37Cl),
241 (35Cl, 100), 178, 105, 77, 51, 43; HRMS-EI Calcd for C19H15ClO3:
326.0710; Found: 326.0711.
4.3.11. Compound 3k. Oil; 1H NMR (400 MHz, CDCl3):
d 8.32 (d,
J¼8.0 Hz, 1H), 7.74 (t, J¼8.0 Hz, 1H), 7.50 (s, 1H), 7.46 (t, J¼8.0 Hz,
1H), 2.92 (t, J¼8.0 Hz, 2H), 2.69 (t, J¼8.0 Hz, 2H), 2.48 (d, J¼8.0 Hz,
2H), 2.19 (s, 3H), 1.88e1.83 (m, 1H), 1.74e1.68 (m, 5H), 1.26e1.14 (m,
4.3.18. Compound 3r. Solid; mp 152e153 ꢁC; 1H NMR (400 MHz,
3H), 1.06e0.96 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
207.2, 162.6,
CDCl3):
2.97e2.93 (m, 2H), 2.71e2.67 (m, 2H), 2.14 (s, 3H); 13C NMR
(100 MHz, CDCl3): 206.7, 160.8, 152.5, 138.0, 136.0, 132.7, 129.8,
128.9, 128.6, 124.8, 122.7, 121.8, 112.1, 43.1, 29.9, 20.5; IR (KBr):
d
8.32 (dd, J¼8 and 0.8 Hz, 1H), 7.53e7.46 (m, 7H),
153.6, 137.2, 134.8, 130.0, 127.3, 122.2, 120.7, 111.6, 42.9, 38.2, 36.6,
33.1, 30.0, 26.2, 26.1, 19.9; IR (neat):
n
3071, 2923, 2850, 1773, 1716,
d
1640, 1364, 1092, 769, 698 cmꢀ1; MS (m/z, EI): 312 (100, Mþ), 254,
230, 187, 173, 145, 115, 43, 41; HRMS-EI Calcd for C20H24O3:
312.1725; Found: 312.1724.
n
3100, 3074, 2993, 2920, 1728, 1706, 1614, 1483, 1114, 847, 748,
696 cmꢀ1; MS (m/z, EI): 372 (81Br, Mþ), 370 (79Br, Mþ), 315, 313, 287,
285, 206, 178, 105 (100), 77, 43; HRMS-EI Calcd for C19H15BrO3:
370.0205; Found: 370.0208.
4.3.12. Compound 3l. Oil; 1H NMR (400 MHz, CDCl3):
d 8.28 (d,
J¼8.0 Hz, 1H), 7.75e7.71 (m, 1H), 7.46e7.41 (m, 2H), 3.07e3.03 (m,
2H), 2.78e2.74 (m, 2H), 2.20 (s, 3H), 2.05e2.00 (m, 1H), 1.19e1.15
4.3.19. Compound 3s. Oil; 1H NMR (400 MHz, CDCl3):
d 7.22 (d,
(m, 2H), 0.97e0.92 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
207.5,
J¼9.6 Hz, 1H), 6.14 (d, J¼9.6 Hz, 1H), 2.66e2.63 (m, 2H), 2.60e2.57
(m, 2H), 2.52 (t, J¼8 Hz, 2H), 2.17 (s, 3H), 1.68e1.61 (m, 2H),
1.41e1.35 (m, 2H), 0.94 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
162.1, 153.7, 137.6, 134.8, 130.0, 126.8, 121.6, 120.3, 110.2, 42.8, 30.1,
19.5, 10.8, 7.2; IR (neat): n 3016, 2975, 2926, 1723, 1709, 1634, 1487,
1098, 768, 697 cmꢀ1; MS (m/z, EI): 256 (100, Mþ), 199, 171, 143, 128,
115, 77, 69, 43, 41; HRMS-EI Calcd for C16H16O3: 256.1099; Found:
256.1101.
d 206.7, 162.5, 162.4, 146.7, 113.7, 113.3, 43.4, 30.5, 30.0, 29.6, 22.8,
22.3, 13.7; IR (neat):
n 3050, 2957, 2932, 2872, 1720, 1638, 1552,
1369, 1163, 1084, 822 cmꢀ1; MS (m/z, EI): 222 (Mþ), 179, 136, 109,
95, 57, 43 (100), 41; HRMS-EI Calcd for C13H18O3: 222.1256; Found:
222.1261.
4.3.13. Compound 3m. Oil; 1H NMR (400 MHz, CDCl3):
d 8.32 (dd,
J¼8.0 and 1.6 Hz, 1H), 7.74 (td, J¼8.0 and 1.6 Hz, 1H), 7.50e7.47 (m,
2H), 3.13 (t, J¼8.0 Hz, 2H), 2.74 (t, J¼8.0 Hz, 2H), 2.22 (s, 3H),1.45 (s,
4.3.20. Compound 3t. oil; 1H NMR (400 MHz, CDCl3):
d 7.53e7.49
9H); 13C NMR (100 MHz, CDCl3):
d
207.2, 162.2, 159.9, 138.5, 134.7,
(m, 2H), 7.47e7.45 (m, 3H), 7.36 (d, J¼9.6 Hz, 1H), 6.29 (d, J¼9.6 Hz,
129.7,127.4,122.3,120.7,110.9, 43.6, 37.8, 30.1, 30.0,19.7; IR (neat):
n
1H), 2.76e2.71 (m, 2H), 2.66e2.61 (m, 2H), 2.12 (s, 3H); 13C NMR
3017, 2961, 1715, 1615, 1486, 1364, 1162, 1111, 771, 707 cmꢀ1; MS (m/
z, EI): 272 (Mþ), 215, 199, 173, 145, 115, 57, 43 (100), 41; HRMS-EI
Calcd for C17H20O3: 272.1412; Found: 272.1411.
(100 MHz, CDCl3): d 206.7, 161.8, 158.4, 146.8, 132.1, 130.0, 128.5,
114.8, 114.7, 43.3, 29.8, 23.2; IR (neat):
n 3060, 2890, 1716, 1632,
1545, 1491, 1164, 1101, 733, 699 cmꢀ1; MS (m/z, EI): 242 (Mþ), 214,
199, 185, 171, 151, 128, 105 (100), 77, 51, 43; HRMS-EI Calcd for
C15H14O3: 242.0943; Found: 242.0942.
4.3.14. Compound 3n. Yellow solid; mp 153e154 ꢁC; 1H NMR
(400 MHz, CDCl3):
d
9.18 (d, J¼2.4 Hz, 1H), 8.57 (dd, J¼9.6 and
2.4 Hz, 1H), 7.76 (d, J¼8.8 Hz, 1H), 7.55e7.51 (m, 5H), 3.05 (t,
4.3.21. Compound 3v. Solid; mp 202e203 ꢁC; 1H NMR (400 MHz,
J¼8.0 Hz, 2H), 2.71 (t, J¼8.0 Hz, 2H), 2.15 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d
8.60 (d, J¼8.4 Hz, 1H), 8.12 (d, J¼8.4 Hz, 2H), 7.88 (d,
CDCl3):
d
206.3, 160.2, 155.6, 146.7, 142.4, 132.1, 130.4, 128.9, 128.8,
J¼8 Hz, 1H), 7.67 (t, J¼7.6 Hz, 1H), 7.48e7.43 (m, 6H), 7.32 (d,
J¼8.4 Hz, 2H), 3.20 (t, J¼8 Hz, 2H), 2.76 (t, J¼8 Hz, 2H), 2.41 (s, 3H),
128.7, 125.9, 124.7, 121.7, 112.1, 42.9, 29.9, 20.5; IR (KBr):
n 3095,
2098, 1738, 1712, 1612, 1568, 1524, 1344, 1104, 784, 698 cmꢀ1; MS
(m/z, EI): 337 (Mþ), 307, 280, 252, 206, 178, 105, 77 (100), 51, 43;
HRMS-EI Calcd for C19H15NO5: 337.0950; Found: 337.0947.
2.13 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 206.8, 154.3, 153.6, 145.1,
141.1, 136.5, 132.7, 132.1, 129.7, 129.5, 129.0, 128.5, 128.1, 124.5, 123.1,
122.6, 121.5, 116.4, 111.5, 43.2, 30.0, 21.7, 21.6; IR (KBr): 3059, 2985,
n
2750, 1735, 1713, 1621, 1596, 1372, 1177, 1097, 754, 662, 574 cmꢀ1
;
4.3.15. Compound 3o. Solid; mp 143e144 ꢁC; 1H NMR (400 MHz,
MS (m/z, EI): 485 (Mþ), 421, 330, 265, 105 (100), 91, 77, 65, 51, 43;
CDCl3):
d
8.18 (s, 1H), 7.60 (d, J¼7.6 Hz, 1H), 7.51e7.44 (m, 6H), 2.97
HRMS-EI Calcd for C28H23NO5S: 485.1297; Found: 485.1301.
(t, J¼7.6 Hz, 2H), 2.71 (t, J¼7.6 Hz, 2H), 2.48 (s, 3H), 2.12 (s, 3H); 13C
NMR (100 MHz, CDCl3):
133.0, 129.8, 129.4, 128.9, 128.4, 122.9, 121.0, 112.3, 43.3, 29.8, 21.1,
d 206.9, 162.2, 151.1, 138.3, 136.1, 134.6,
Acknowledgements
20.5; IR (KBr): n 3072, 3035, 2995, 2952, 1703, 1615, 1502, 1113, 772,
We thank the National Basic Research Program of China
(2011CB808706), National Natural Science Foundation of China
(21232006, 21272249) and Chinese Academy of Sciences for fi-
nancial support.
695 cmꢀ1; MS (m/z, EI): 306 (Mþ, 100), 249, 221, 178, 115, 105, 77,
43; HRMS-EI Calcd for C20H18O3: 306.1256; Found: 306.1255.
4.3.16. Compound 3p. Solid; mp 128e129 ꢁC; 1H NMR (400 MHz,
CDCl3):
2.96e2.93 (m, 2H), 2.72e2.68 (m, 2H), 2.13 (s, 3H); 13C NMR
(100 MHz, CDCl3): 206.6, 168.2, 165.7, 161.1, 153.4, 140.3, 140.1,
133.5, 133.4, 132.7, 129.8, 128.8, 128.5, 117.6, 116.4, 116.1, 112.0, 109.3,
d 8.43e8.38 (m, 1H), 7.52e7.46 (m, 5H), 7.27e7.19 (m, 2H),
Supplementary data
d
Copies of 1H NMR and 13C NMR spectra of compounds 1v and
3aev. X-ray crystallography data for compound 3a. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2013.07.057.
42.9, 29.8, 20.6; IR (KBr):
n 3063, 2922, 1725, 1708, 1615, 1568,
1484, 777, 698, 670 cmꢀ1; MS (m/z, EI): 310 (Mþ), 253, 225 (100),
196, 105, 77, 51, 43; HRMS-EI Calcd for C19H15FO3: 310.1005; Found:
310.1004.
References and notes
4.3.17. Compound 3q. Solid; mp 139e140 ꢁC; 1H NMR (400 MHz,
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