An efficient synthesis of 3-arylmethyl-7,8-dihydro-6H-chromene-2,5-diones from Baylis-Hillman adduct acetates under solvent-free conditions

Article abstract of DOI:10.1016/j.tet.2008.04.003

A simple, efficient synthesis of 3-arylmethyl-7,8-dihydro-6H-chromene-2,5-dione 4 from Baylis-Hillman adduct acetates derived from aromatic aldehydes and cyclohexane-1,3-diones under solvent-free conditions is described. Interestingly, when Baylis-Hillman adducts derived from aliphatic aldehydes were tested under the similar conditions, the unexpected stereoisomers 5 and 6 were obtained in moderate yields. A plausible mechanism for the formation of 4-6 is proposed.

Full text of DOI:10.1016/j.tet.2008.04.003

Tetrahedron 64 (2008) 5491–5496
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An efficient synthesis of 3-arylmethyl-7,8-dihydro-6H-chromene-2,5-
diones from Baylis–Hillman adduct acetates under solvent-free conditions
*
Weihui Zhong, Yongzhi Zhao, Weike Su
College of Pharmaceutical Sciences, Zhejiang University of Technology, Zhejiang Key Laboratory of Pharmaceutical Engineering, Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient synthesis of 3-arylmethyl-7,8-dihydro-6H-chromene-2,5-dione 4 from Baylis–Hillman
adduct acetates derived from aromatic aldehydes and cyclohexane-1,3-diones under solvent-free
conditions is described. Interestingly, when Baylis–Hillman adducts derived from aliphatic aldehydes
were tested under the similar conditions, the unexpected stereoisomers 5 and 6 were obtained in
moderate yields. A plausible mechanism for the formation of 4–6 is proposed.
Received 23 October 2007
Received in revised form 31 March 2008
Accepted 1 April 2008
Available online 8 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Baylis–Hillman adducts
a
-Pyrone
Solvent free
1. Introduction
conditions, and provides an unique class of attractive densely
functionalized molecules, whose applications in many organic
The
a-pyrone moiety is an important structural unit present in
transformation methodologies have been well documented.15 Ow-
ing toits highlysynthetic versatility, Baylis–Hillman adducts are also
many biologically important molecules that show a broad range of
biological activities such as anti-HIV,1 antimicrobial,2 antifungal,3
phytotoxic,3b,4 anti-leukemic,5 anti-alzheimer,6 and anti-inflam-
employed as substrates for the preparation of
Kim and co-workers16 reported the synthesis of 3,5,6-trisubstituted
-pyrones from Baylis–Hillman adducts and ketones treated with
a-pyrone derivatives.
matory1b effects. Moreover a number of
a
-pyrone derivatives7 with
a
various biological activities were synthesized. Besides its biological
activities, -pyrone derivatives have been widely used as synthons
in organic synthesis.8 Many methods have been introduced for the
synthesis of -pyrone by traditional approaches or by a process
base and trifluoroacetic anhydride. Subsequently, they have also
described an attractive synthesis of 3-benzyl-7,8-dihydro-6H-
chromene derivatives by using Baylis–Hillman adduct acetates as
substrates.17 Despite its elegance, this method has some drawbacks,
firstly the reaction mixture should be treated with K2CO3 in DMF,
after extractive workup, the mixture in p-xylene was heated to
a
a
involving transition metal catalyzed reaction. In the past decades,
classical methods reported for their preparations are summarized
as follows: (1) palladium-catalyzed coupling of 3-halo-(2Z)-enoic
acids, 3-halo-(2Z)-enoates or 2-halobezoic acids with allenyl-
stannanes,9 alkynes10 or terminal alkynes11 and subsequent cycli-
zation; (2) lactonization reaction of various internal alkynes;12 (3)
K2CO3-catalyzed Michael addition–lactonization of 1,2-allenic
ketones with electron-withdrawing group substituted acetates;13
(4) nucleophilic addition of active methane compounds to 2-alky-
none in the presence of bases.14 The most disadvantages for some of
these methodologies are either low yielding or lacking regiose-
lectivity. As a result, development of simple, efficient and ‘green’
reflux for 6 h in the presence of DMAP (5.0 equiv) to give
derivatives thereafter.
a-pyrone
It occurred to us that it would be useful if we would directly
convert Baylis–Hillman adduct acetates into the desired 3-
substituted-7,8-dihydro-6H-chromene-2,5-diones by treatment
with an appropriate reagent, if possible under solvent-free condi-
tions. In our ongoing project aimed to synthesize some heterocyclic
molecules with Baylis–Hillman adduct acetates, we wish to report
a convenient, efficient and ‘green’ synthesis of 3-substituted-7,8-
dihydro-6H-chromene-2,5-diones by treatment of Baylis–Hillman
adducts and cyclohexane-1,3-diones in the presence of triethyl-
amine under solvent-free conditions.
methodologies for the synthesis of
highly desirable.
a-pyrone derivatives remains
The Baylis–Hillman reaction is a powerful carbon–carbon bond
formation reaction in organic synthesis, and has gained much
attention because of its atom economy, selectivity, mild reaction
2. Results and discussions
In our initial study, when we mixed Baylis–Hillman adduct
acetate (1a) and cyclohexane-1,3-dione (2a) in acetone using K2CO3
* Corresponding author. Tel./fax: þ86 571 88320752.
E-mail address: suweike@zjut.edu.cn (W. Su).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.003

5492
W. Zhong et al. / Tetrahedron 64 (2008) 5491–5496
O
O
R1
OMe
OH
OAc O
R1
O
O
O
cyclization
base
R1
OMe
+
R2
R2
O
R2
R2
O
R2
R2
3
1
2
4
Scheme 1.
as base at room temperature for 2 h (Scheme 1), the SN20 type
product 3a was obtained only in 50% yield (Table 1 entry 1), and no
desired product 4a was detected. However, if the similar reaction
was performed under refluxing acetone, the yield of product 3a
would be increased to 88% within 25 min (entry 2). When aceto-
nitrile and Et3N were used as a solvent and a base, respectively, the
corresponding product 3d was obtained in 82% yield (entry 5).
Under solvent-free condition, the reaction was completed within
15 min and afforded 3b with 89% yield (entry 7). In a word, within
a short time under refluxing condition, SN20 type products 3 were
formed with moderate to good yields. Fortunately, when the re-
action time was prolonged to 3 h under refluxing acetone, the de-
Table 2
Synthesis of 3-arylmethyl-7,8-hydro-6H-chromene-2,5-dione 4 from Baylis–Hill-
man adduct acetates under solvent-free conditionsa
Entry
R1
R2
R3
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Phenyl
Phenyl
3-Nitrophenyl
2-Chlorophenyl
2-Chloro-6-fluorophenyl
4-Fluorophenyl
Furan-2-yl
4-Methylthiazol-5-yl
Phenyl
Me
Et
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
2.5
6
2
80 (4a)
71 (4a)
91 (4b)
88 (4c)
82 (4d)
84 (4e)
80 (4f)
89 (4g)
79 (4h)
89 (4i)
85 (4i)
89 (4j)
82 (4j)
80 (4k)
82 (4l)
78 (4m)
90 (4n)
63 (4o)
Me
Me
Me
Me
Me
Me
Me
Me
Et
2
3.5
2.5
5
2.5
2
2
4.5
2
5
4
3
5.5
2.5
7
9
10
11
12
13
14
15
16
17
18
3-Nitrophenyl
3-Nitrophenyl
sired a-pyrone 4a was provided in 60% yield. But 3a could not be
converted completely into 4a even prolonging the reaction time or
increasing the amount of K2CO3.
2-Chlorophenyl
2-Chlorophenyl
2-Chloro-6-fluorophenyl
4-Fluorophenyl
Furan-2-yl
Me
Et
Me
Me
Me
Me
Me
To optimize this reaction, the same reaction was carried out in
various solvents including ethanol, acetonitrile, and under solvent-
free conditions in the presence of several bases. The results are
summarized in Table 1. When DMAP was used as base in refluxing
acetone or under solvent-free condition, product 4 was obtained in
poor yield (entries 8 and 9). It was found that under refluxing
condition, ethanol resulted in poor yield (entry 16), acetonitrile
brought higher yield (entries 14 and 15), and the highest yield (80%)
was obtained under solvent-free condition (entries 17). The
solvent-free condition might be benefit to increasing the reaction
efficiency in two ways: (1) driving the reaction toward the desired
4-Methylthiazol-5-yl
3,4-(Methylenedioxy)phenyl
a
All reactions were carried out on a 1 mmol scale of Baylis–Hillman adduct
acetates with cyclic
b-diketone derivatives (1.2 mmol) in the presence of Et3N
(1.2 mmol) at 90 ꢀC under solvent-free conditions.
b
Isolated yield based on Baylis–Hillman adduct acetates.
O
a
-pyrone products by achieving high concentration of reactants; (2)
O
O
OAc O
R1
O
base
solvent-free, heat
removing the other volatile products like alcohols, and facilitating
OR2
R1
completion of the reaction.18
R3
R3
R3
R3
With the optimal reaction condition in hand, we then success-
fully transformed a representative class of Baylis–Hillman adduct
acetates into 3-substituted-7,8-hydro-6H-chromene-2,5-dione de-
rivatives and the full results are summarized in Table 2 (Scheme 2).
O
1
2
4
Scheme 2.
Table 1
Synthesis of (E)-methyl 2-((2-hydroxy-4,4-disubstituted-6-oxocyclohex-1-enyl)methyl)-3-arylmethylacrylate 3 and 3-benzyl-7,8-hydro-6H-chromene-2,5-dione (4a) from
Baylis–Hillman adduct acetate (1) and cyclohexane-1,3-diones (2) under various conditions
Entry
R1
R2
Conditions
Time
Yield of 3a (%)
Yield of 4a (%)
1
2
3
4
5
6
7
8
Phenyl
Phenyl
Phenyl
Furan-2-yl
Furan-2-yl
Ethyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
H
H
CH3
H
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
K2CO3 (0.6 equiv), acetone, rt
120 min
25 min
25 min
25 min
20 min
120 min
15 min
2.5 h
2 h
3 h
12 h
4 h
3.5 h
2.5 h
2.5 h
10.5 h
2.5 h
50 (3a)
88 (3a)
87 (3b)
80 (3c)
82 (3d)
78 (3e)
89 (3b)
60 (3b)
32 (3b)
20 (3a)
21 (3a)
23 (3a)
21 (3a)
12 (3a)
14 (3a)
34 (3a)
10 (3a)
d
K2CO3 (0.6 equiv), acetone, reflux
K2CO3 (0.6 equiv), acetone, reflux
K2CO3 (0.6 equiv), acetone, reflux
Et3N (1.2 equiv), acetonitrile, reflux
Et3N (1.2 equiv), solvent-free, 60 ꢀ
Et3N (1.2 equiv), solvent-free, 90 ꢀ
DMAP (1.2 equiv), acetone, reflux
DMAP (1.2 equiv), solvent-free, 90 ꢀ
K2CO3 (0.6 equiv), acetone, reflux
K2CO3 (0.6 equiv), acetone, reflux
K2CO3 (1.2 equiv), acetone, reflux
Et3N (1.2 equiv), acetone, reflux
d
d
d
d
C
C
d
d
11 (4b)
48 (4b)
60 (4a)
61 (4a)
62 (4a)
65 (4a)
78 (4a)
73 (4a)
43 (4a)
80 (4a)
9
C
10
11
12
13
14
15
16
17
K2CO3 (0.6 equiv), acetonitrile, reflux
Et3N (1.2 equiv), acetonitrile, reflux
Et3N (1.2 equiv), ethanol, reflux
Et3N (1.2 equiv), solvent-free, 90 ꢀ
C
a
Isolated yield.

W. Zhong et al. / Tetrahedron 64 (2008) 5491–5496
5493
large NOE
Ha
R1
O
Ha
1
R
O
O
Hb
OAc O
Hb
CO2Me
Me
Me
Et3N
90 °C, 10 h
R1
O
+
OMe
+
CO2Me
Me
Me
Me
O
O
Me
6a (R1 =Et)
5a (R1 =Et)
1
2b
Scheme 3.
As a result, the desired
a-pyrones were obtained in good to excel-
From the above results, a possible mechanism for the formation
lent yields. The presence of electron-withdrawing or electron-do-
nating groups has obviously influenced the rate and efficiency of
the reaction. The substrates with electron-donating groups resulted
in lower yield and needed longer reaction time (Table 2, entry 18),
while the substrates with electron-withdrawing groups (entries 3,
4, and 10–13) afforded the corresponding products in good yield.
On the other hand, ethyl ester in substrates 1 gave lower yields than
that of methyl ester probably due to higher steric effect of the
former (entries 1 and 2).
of compounds 4–6 from Baylis–Hillman adduct acetates and cyclic
b-diketone derivatives can be summarized as shown in Scheme 4.
The formation of compounds 5a and 6a might include two-step
successive reaction: SN20 substitution–cyclization and 1,4-addition.
Firstly, the reaction of Baylis–Hillman acetates 1 with cyclic
b
-diketone derivatives 2 in the presence of bases gives SN20 prod-
ucts 3, followed by 1,4-addition to the corresponding stereoisomers
5a and 6a.
Interestingly, when the Baylis–Hillman adducts 1 (R1¼Et) de-
rived from propionaldehyde and methyl acrylate were used as the
substrates (Scheme 3), the unexpected products 5a and 6a were
obtained with the ratio of about 1:2, which were confirmed by their
spectroscopic data: 1H, 13C, DEPT, NOE, IR, HRMS, and MS experi-
ments. 1H NMR spectra showed two typical chemical shifts of Ha
(4.08 ppm) and Hb (2.94 ppm) in compound 6a. It was found that
large NOE existed between Ha and Hb in compound 6a (Scheme 3),
while in the case of 5a, no evident NOE was observed. Thus we
presumed that compound 6a should be cis-isomer while com-
pound 5a should be trans-isomer.19
3. Conclusion
We have developed a simple, efficient, and ‘green’ method for
the synthesis of various
acetates (derived from aromatic aldehydes and acrylate esters) and
cyclic -diketone derivatives under solvent-free conditions. The
a-pyrone derivatives from Baylis–Hillman
b
major advantages of the present process are solvent-free condi-
tions, simple experimental procedure, high yields, short reaction
time, and easy workup.
4. Experimental
4.1. General
And we also found that when other Baylis–Hillman adducts
derived from aliphatic aldehydes and methyl acrylate were used,
the similar results were obtained (Table 3).
Starting materials and solvents were purchased from common
commercial sources and were used without additional purification.
Melting points were determined with a Bu¨chi B-540 capillary
melting point apparatus and are uncorrected. IR spectra were
recorded on a Nicolet Aviatar-370 spectrometer using samples as
neat liquids or as KBr plates. Mass spectra were measured with
Thermo Finnigan LCQ-Advantage spectrometer. 1H and 13C NMR
Table 3
Synthesis of methyl 2-substituted-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro-2H-
chromene-3-carboxylates 5 and 6 from Baylis–Hillman adduct acetates under sol-
vent-free conditionsa
Entry
R1
Time (h)
Yield of 5a (%)
Yield of 6a (%)
spectra were recorded in CDCl3 with tetramethylsilane (TMS,
d
¼0)
19
20
21
Ethyl
n-Butyl
i-Butyl
10
4.5
4.5
12 (5a)
10 (5b)
11 (5c)
25 (6a)
21 (6b)
23 (6c)
as an internal standard at ambient temperature on a Varian-
400 MHz spectrometer at 400 and 100 MHz. Elemental analyses
were carried out on a Vario EL III instrument. High-resolution mass
a
Isolated yield.
O
O
O
O
O
R1
OR2
OH
OAc O
R1
OR2
O
R1
O
R3
R1 = aryl
base
AcOH
R1
OR2
+
R3
R3
R3
O
O
O
R3
R3
R3
R3
4
1
2
3
R
1 =Et, R2, R3 = Me
1,4-addition
base
Ha
Ha
O
Et
Et
Hb
CO2Me
Hb
CO2Me +
Et
OMe
O
O
cyclization
O
Me
Me
O
O
O
Me
Me
Me
Me
6a
5a
Scheme 4.

5494
W. Zhong et al. / Tetrahedron 64 (2008) 5491–5496
spectral (HRMS) analyses were measured on an APEX (Bruker) mass
III spectrometer using ESI (electrospray ionization) techniques.
(100 MHz, CDCl3): d 197.4, 172.4, 172.1, 149.5, 128.2, 111.9, 52.7, 50.7,
43.2, 31.3, 28.1 (CH3ꢂ2), 32.4, 19.3, 13.1; MS m/z (%) 265 (Mþꢁ1,
100), 264 (40), 233 (30). HRMS (ESI, m/z) calcd for C15H22O4
(MþH)þ 267.1598, found 267.1595.
4.2. General procedure for the preparation of (E)-methyl 2-
[(2,6-dioxocyclohexyl)methyl]-3-arylmethylacrylate (3)
4.3. General procedure for the preparation of 3-arylmethyl-
To a magnetically stirred solution of Baylis–Hillman adduct
7,8-dihydro-6H-4,5-dione derivatives
acetates (1 mmol) and cyclic
b-diketones (1.2 mmol) in acetone
(8 mL), K2CO3 (1.2 mmol) was added at room temperature. The
mixture was then heated under reflux, until TLC monitoring
indicated complete consumption of the Baylis–Hillman acetates.
The reaction mixture was then filtered and evaporated to furnish
the crude product, which was purified by column chromatography
(silica gel, 3:2/4:1 v/v hexane/ethyl acetate gradient elution) to
give the pure product.
A magnetically stirred mixture of Baylis–Hillman acetates
(1 mmol), cyclic b-diketones (1.2 mmol), and Et3N (1.2 mmol) was
heated at 80–90 ꢀC, and the reaction was monitored by TLC. The
reaction mixture was then cooled to room temperature, treated
with brine (10 mL) and dichloromethane (10 mL), and the separated
aqueous phase was extracted with dichloromethane (2ꢂ10 mL).
The combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure to give a yellow oil, which
was purified by column chromatography (silica gel, 2:1/6:1 v/v
hexane/ethyl acetate gradient elution) to give the pure product.
4.2.1. (E)-Methyl 2-((2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-
phenylacrylate (3a)17
White solid; mp 98–99 ꢀC; IR (KBr): nmax 1710, 1556, 1344, 1271,
1190 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
9.74 (br s, 1H), 7.75 (s, 1H),
4.3.1. 3-Benzyl-7,8-dihydro-6H-chromene-2,5-dione (4a)17
7.61 (d, J¼7.2 Hz, 2H), 7.44–7.34 (m, 3H), 3.86 (s, 3H), 3.51 (s, 2H),
Viscous oil; IR (film): nmax 1736, 1681, 1635, 1584, 1396 cmꢁ1; 1H
2.40–2.28 (m, 4H), 1.86–1.80 (m, 2H); 13C NMR (100 MHz, CDCl3):
NMR (400 MHz, CDCl3):
(m, 3H), 3.77 (s, 2H), 2.83 (t, J¼6.4 Hz, 2H), 2.52 (t, J¼6.4 Hz, 2H),
2.18–2.11 (m, 2H); 13C NMR (100 MHz, CDCl3):
194.0, 172.1, 161.1,
d 7.54 (s, 1H), 7.33–7.29 (m, 2H), 7.27–7.24
d
198.5, 172.4, 142.3, 135.4, 129.6, 129.5 (CHꢂ2), 128.6, 128.4, 128.3
(CHꢂ2), 113.0, 52.9, 39.7, 29.6, 20.2, 18.0; MS m/z (%) 286 (Mþ, 18),
254 (100). Anal. Calcd for C17H18O4: C, 71.31; H, 6.34. Found: C,
71.26; H, 6.40.
d
137.4, 135.4, 129.0 (CHꢂ2), 128.6 (CHꢂ2), 127.0, 126.8, 114.6, 36.5,
36.3, 27.7, 20.3; MS m/z (%) 225 (Mþþ1, 22), 254 (Mþ, 100). HRMS
(ESI, m/z) calcd for C16H14O3 (MþH)þ 255.1023, found 255.1026.
4.2.2. (E)-Methyl 2-((2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-
enyl)methyl)-3-phenylacrylate (3b)
4.3.2. 3-(3-Nitrobenzyl)-7,8-dihydro-6H-chromene-2,5-dione (4b)
White solid; mp 143–144 ꢀC; IR (KBr): nmax 1730, 1715, 1667,
White solid; mp 138–140 ꢀC; IR (KBr): nmax 1709, 1562, 1351,
1313, 1251, 1204 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
9.68 (br s, 1H),
1633, 1579, 1528, 1400, 1352 cmꢁ1 1H NMR (400 MHz, CDCl3):
;
7.71 (s, 1H), 7.59 (d, J¼8.0 Hz, 2H), 7.42–7.33 (m, 3H), 3.84 (s, 3H),
d
8.11 (d, J¼7.2 Hz, 1H), 8.10 (s, 1H), 7.65 (s, 1H), 7.63 (d, J¼7.2 Hz,
3.54 (s, 2H), 2.24–2.16 (m, 4H), 0.95 (s, 6H); 13C NMR (100 MHz,
1H), 7.51–7.47 (m, 1H), 3.88 (s, 2H), 2.86 (t, J¼6.4 Hz, 2H), 2.56 (t,
CDCl3):
d
204.0, 172.3, 141.9, 135.2, 129.5, 129.2 (CHꢂ2), 128.6, 128.2
J¼6.4 Hz, 2H), 2.18–2.15 (m, 2H); 13C NMR (100 MHz, CDCl3):
(CHꢂ2), 127.9, 111.8, 52.8, 50.5, 43.5, 31.2, 28.1 (CH3ꢂ2), 20.5; MS
d 193.9, 172.9, 160.7, 148.3, 139.5, 136.4, 135.3, 129.5, 125.3, 123.7,
m/z (%) 315 (Mþþ1, 30), 314 (Mþ, 19), 282 (100). Anal. Calcd for
122.0, 114.5, 36.4, 36.2, 27.7, 20.2; MS m/z (%) 299 (Mþ, 48), 282
(100). Anal. Calcd for C16H13NO5: C, 64.21; H, 4.38; N, 4.68. Found:
C, 64.24; H, 4.55; 4.77.
C
19H22O4: C, 72.59; H, 7.05. Found: C, 72.48; H, 7.18.
4.2.3. (E)-Methyl 3-(furan-2-yl)-2-((2-hydroxy-6-oxocyclohex-1-
enyl)methyl)acrylate (3c)
4.3.3. 3-(2-Chlorobenzyl)-7,8-dihydro-6H-chromene-
2,5-dione (4c)
White solid; mp 142–143 ꢀC; IR (KBr): nmax 1717, 1620, 1542,
1378, 1253 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
9.99 (br s, 1H), 7.59
Viscous oil; IR (film): nmax 1732, 1682, 1635, 1584, 1396 cmꢁ1; 1H
(d, J¼1.6 Hz, 1H), 7.50 (s, 1H), 7.16 (d, J¼3.2 Hz, 1H), 6.55 (dd, J¼3.2,
NMR (400 MHz, CDCl3): d 7.42–7.37 (m, 2H), 7.33–7.31 (m, 1H),
1.6 Hz, 1H), 3.84 (s, 3H), 3.67 (s, 2H), 2.48–2.40 (m, 2H), 2.36–2.30
7.24–7.22 (m, 2H), 3.90 (s, 2H), 2.84 (t, J¼6.4 Hz, 2H), 2.51 (t,
(m, 2H), 1.91–1.85 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 198.5,
J¼6.4 Hz, 2H), 2.17–2.12 (m, 2H); 13C NMR (100 MHz, CDCl3):
174.0, 172.6, 150.7, 144.6, 128.6, 124.5, 117.2, 113.1, 112.4, 52.9, 36.9,
d 193.8, 172.1, 160.9, 135.5, 134.7, 134.2, 131.5, 129.6, 128.5, 127.0,
29.7, 21.5, 20.2; MS m/z (%) 276 (Mþ, 22), 244 (100). Anal. Calcd for
124.9, 114.5, 36.4, 33.7, 27.6, 20.1; MS m/z (%) 289 (Mþþ1, 30), 287
(Mþꢁ1, 100). HRMS (ESI, m/z) calcd for C16H13ClO3 (MþH)þ
289.0633, found 289.0632.
C
15H16O5: C, 65.21; H, 5.84. Found: C, 65.18; H, 5.80.
4.2.4. (E)-Methyl 3-(furan-2-yl)-2-((2-hydroxy-4,4-dimethyl-6-
oxocyclohex-1-enyl)methyl)acrylate (3d)
4.3.4. 3-(2-Chloro-6-fluorobenzyl)-7,8-dihydro-6H-chromene-
2,5-dione (4d)
White solid; mp 163–164 ꢀC; IR (KBr): nmax 1716, 1628, 1548,
1370, 1350, 1250 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
9.89 (br s, 1H),
White solid; mp 86–87 ꢀC; IR (KBr): nmax 1737, 1682, 1638, 1584,
7.59 (d, J¼1.6 Hz, 1H), 7.49 (s, 1H), 7.18 (d, J¼3.2 Hz, 1H), 6.54 (dd,
1396 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 7.28–7.25 (m, 2H), 7.17 (s,
J¼3.2, 1.6 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 2H), 2.35–2.27 (m, 2H), 2.17–
1H), 7.07–7.02 (m, 1H), 3.95 (s, 2H), 2.86 (t, J¼6.4 Hz, 2H), 2.52 (t,
2.09 (m, 2H), 1.01 (s, 6H); 13C NMR (100 MHz, CDCl3):
d 204.9, 172.6,
J¼6.4 Hz, 2H), 2.17–2.10 (m, 2H); 13C NMR (100 MHz, CDCl3):
169.2, 150.6, 144.6, 128.5, 124.6, 117.2, 112.5, 111.9, 52.9, 50.6, 43.3,
31.2, 28.2 (CH3ꢂ2), 21.2; MS m/z (%) 304 (Mþ, 18), 272 (100). Anal.
Calcd for C17H20O5: C, 67.09; H, 6.62. Found: C, 67.01; H, 6.58.
d
193.8, 171.9, 161.6 (d, J¼247.9 Hz), 160.8, 135.8, 134.2, 129.2 (d,
J¼9.1 Hz), 125.6, 124.1, 123.0 (d, J¼18.2 Hz), 114.6, 114.3 (d,
J¼22.0 Hz), 36.5, 27.8, 26.7, 20.3; MS m/z (%) 307 (Mþþ1, 7), 271
(100). Anal. Calcd for C16H12ClFO3: C, 62.65; H, 3.94. Found: C,
62.58; H, 3.87.
4.2.5. (E)-Methyl 2-((2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-
enyl)methyl)pent-2-enoate (3e)
Viscous oil; IR (film): nmax 2959, 2873, 1716, 1672, 1611, 1439,
4.3.5. 3-(4-Fluorobenzyl)-7,8-dihydro-6H-chromene-
2,5-dione (4e)
1375, 1297 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 10.26 (br s, 1H), 6.87
(t, J¼8.0 Hz, 1H), 3.80 (s, 3H), 3.27 (s, 2H), 2.56 (td, J¼8.0, 6.0 Hz,
White solid; mp 135–136 ꢀC; IR (KBr): nmax 1731, 1677, 1639,
2H), 2.32 (s, 2H), 2.19 (s, 2H), 1.03 (t, J¼6.0 Hz, 9H); 13C NMR
1591, 1507, 1395 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 7.54 (s, 1H),

W. Zhong et al. / Tetrahedron 64 (2008) 5491–5496
5495
7.23–7.20 (m, 2H), 7.01–6.97 (m, 2H), 3.74 (s, 2H), 2.84 (t, J¼6.4 Hz,
2H), 2.53 (t, J¼6.4 Hz, 2H), 2.17–2.12 (m, 2H); 13C NMR (100 MHz,
J¼248.0 Hz), 161.2, 135.8, 133.9, 129.2 (d, J¼9.9 Hz), 125.5, 123.9,
122.9 (d, J¼19.0 Hz), 114.2 (d, J¼22.8 Hz), 113.5, 50.4, 41.4, 32.6, 28.2
(CH3ꢂ2), 26.6; MS m/z (%) 335 (Mþþ1, 4), 299 (100). Anal. Calcd for
CDCl3):
d
194.0, 172.3, 161.8 (d, J¼243.4 Hz), 161.0, 135.4, 133.1, 130.5
(d, J¼8.3 Hz, CHꢂ2), 126.8, 115.5 (d, J¼21.2 Hz, CHꢂ2), 114.6, 36.5,
35.6, 27.7, 20.3; MS m/z (%) 271 (Mþꢁ1, 100), 243 (78). Anal. Calcd
for C16H13FO3: C, 70.58; H, 4.81. Found: C, 70.53; H, 4.87.
C18H16ClFO3: C, 64.58; H, 4.82. Found: C, 64.53; H, 4.76.
4.3.12. 3-(4-Fluorobenzyl)-7,7-dimethyl-7,8-dihydro-6H-
chromene-2,5-dione (4l)
4.3.6. 3-(Furan-2-ylmethyl)-7,8-dihydro-6H-chromene-
2,5-dione (4f)
White solid; mp 138–139 ꢀC; IR (KBr): nmax 1713, 1676, 1634,
1582, 1508, 1399; 1H NMR (400 MHz, CDCl3):
d
7.51 (s, 1H), 7.24–
7.21 (m, 2H), 7.02–6.98 (m, 2H), 3.74 (s, 2H), 2.69 (s, 2H), 2.39 (s,
2H), 1.12 (s, 6H); 13C NMR (100 MHz, CDCl3):
193.9, 170.9, 161.8 (d,
Viscous oil; IR (film): nmax 1736, 1682, 1635, 1584, 1397 cmꢁ1; 1H
NMR (400 MHz, CDCl3):
d
7.59 (s, 1H), 7.33 (d, J¼1.6 Hz, 1H), 6.31
d
(dd, J¼3.2, 1.6 Hz, 1H,), 6.17 (d, J¼3.2 Hz, 1H), 3.79 (s, 2H), 2.84 (t,
J¼243.4 Hz), 161.3, 135.2, 133.0, 130.6 (d, J¼8.0 Hz, CHꢂ2), 126.7,
115.5 (d, J¼21.2 Hz, CHꢂ2), 113.6, 50.4, 41.4, 35.6, 32.7, 28.3
(CH3ꢂ2); MS m/z (%) 300 (Mþ, 15), 299 (Mþꢁ1, 100). Anal. Calcd for
J¼6.4 Hz, 2H), 2.53 (t, J¼6.4 Hz, 2H), 2.17–2.11 (m, 2H); 13C NMR
(100 MHz, CDCl3):
d 193.8, 172.3, 160.7, 150.5, 141.9, 135.8, 123.9,
114.5, 110.4, 107.5, 36.4, 28.5, 27.7, 20.2; MS m/z (%) 245 (Mþþ1, 27),
244 (Mþ, 100). HRMS (ESI, m/z) calcd for C14H12O4 (MþH)þ
245.0816, found 245.0817.
C18H17FO3: C, 71.99; H, 5.71. Found: C, 71.90; H, 5.65.
4.3.13. 3-(Furan-2-ylmethyl)-7,7-dimethyl-7,8-dihydro-6H-
chromene-2,5-dione (4m)
4.3.7. 3-((4-Methylthiazol-5-yl)methyl)-7,8-dihydro-6H-
chromene-2,5-dione (4g)
Viscous oil; IR (film): nmax 1731, 1675, 1643, 1398 cmꢁ1; 1H NMR
(400 MHz, CDCl3)
0.8 Hz, 1H,), 6.19 (d, J¼3.2 Hz, 1H), 3.81 (s, 2H), 2.71 (s, 2H), 2.40 (s,
2H), 1.14 (s, 6H); 13C NMR (100 MHz, CDCl3):
193.9, 171.0, 161.2,
d
7.57 (s,1H), 7.35 (d, J¼0.8 Hz,1H), 6.33 (dd, J¼3.2,
White solid; mp 118–119 ꢀC; IR (KBr): nmax 1737, 1713, 1673,
1638, 1585, 1397, 1372; 1H NMR (400 MHz, CDCl3):
d
8.64 (s, 1H),
7.53 (s, 1H), 3.92 (s, 2H), 2.86 (t, J¼6.4 Hz, 2H), 2.54 (t, J¼6.4 Hz, 2H),
2.43 (s, 3H), 2.17–2.14 (m, 2H); 13C NMR (100 MHz, CDCl3):
193.8,
d
150.4, 150.3, 142.0, 135.6, 123.8, 113.6, 110.5, 107.7, 50.4, 41.4, 32.7,
28.6, 28.2 (CH3ꢂ2); MS m/z (%) 273 (Mþþ1, 23), 272 (Mþ,100). HRMS
(ESI, m/z) calcd for C16H16O4 (MþH)þ 273.1129, found 273.1126.
d
172.5, 160.7, 150.6, 150.5, 135.5, 126.2, 125.3, 114.6, 36.5, 27.8, 26.8,
20.3, 14.9. MS m/z (%) 275 (Mþþ1, 40), 177 (100). Anal. Calcd for
C
14H13NO3S: C, 61.07; H, 4.76; N, 5.09. Found: C, 61.05; H, 4.82; N,
4.3.14. 7,7-Dimethyl-3-((4-methylthiazol-5-yl)methyl)-7,8-
dihydro-6H-chromene-2,5-dione (4n)
5.01.
White solid; mp 123–124 ꢀC; IR (KBr): nmax 1725, 1679, 1633,
4.3.8. 3-Benzyl-7,7-dimethyl-7,8-dihydro-6H-
chromene-2,5-dione (4h)17
1581,1397,1369 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d
8.64 (s,1H), 7.50
(s,1H), 3.92 (s, 2H), 2.72 (s, 2H), 2.43 (s, 3H), 2.41 (s, 2H),1.14 (s, 6H);
13C NMR (100 MHz, CDCl3):
193.6, 171.1, 160.9, 150.4, 150.3, 135.0,
White solid; mp 141–143 ꢀC; IR (KBr): nmax 1717, 1675, 1633,
d
1583, 1400 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
7.51 (s, 1H), 7.31–
7.25 (m, 5H), 3.76 (s, 2H), 2.68 (s, 2H), 2.38 (s, 2H), 1.12 (s, 6H); 13
NMR (100 MHz, CDCl3): 193.9, 170.8, 161.4, 137.4, 135.1, 129.1
125.9, 124.8, 113.3, 50.2, 41.2, 32.5, 28.1 (CH3ꢂ2), 26.6, 14.8; MS m/z
(%) 304 (Mþþ1, 40), 205 (100), 149 (41). Anal. Calcd for C16H17NO3S:
C, 63.34; H, 5.65; N, 4.62. Found: C, 63.36; H, 5.87; N, 4.66.
C
d
(CHꢂ3), 128.7 (CHꢂ2), 126.8, 113.6, 50.4, 41.4, 36.3, 32.6, 28.2
(CH3ꢂ2); MS m/z (%) 281 (Mþꢁ1, 42), 265 (100). Anal. Calcd for
4.3.15. 3-(Benzo[d][1,3]dioxol-5-ylmethyl)-7,7-dimethyl-7,8-
dihydro-6H-chromene-2,5-dione (4o)
C
18H18O3: C, 76.57; H, 6.43. Found: C, 76.51; H, 6.38.
White solid; mp 109–110 ꢀC; IR (KBr): nmax 1726, 1675, 1636,
4.3.9. 3-(3-Nitrobenzyl)-7,7-dimethyl-7,8-dihydro-6H-
chromene-2,5-dione (4i)
1588, 1499, 1487, 1397 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
7.49 (s,
1H), 6.76–6.69 (m, 3H), 5.94 (s, 2H), 3.68 (s, 2H), 2.69 (s, 2H), 2.38 (s,
2H), 1.13 (s, 6H); 13C NMR (100 MHz, CDCl3):
194.0, 170.8, 161.4,
White solid; mp 150–152 ꢀC; IR (KBr): nmax 1737, 1670, 1633,
d
1584,1530,1398,1353 cmꢁ1; 1H NMR (400 Hz, CDCl3:)
d
8.12 (s, 1H),
147.8, 146.4, 135.0, 130.9, 127.0, 122.2, 113.6, 109.5, 108.4, 100.9, 50.4,
41.4, 36.0, 32.6, 28.3 (CH3ꢂ2); MS m/z (100%) 327 (Mþþ1, 21), 326
(Mþ, 100). Anal. Calcd for C19H18O5: C, 69.93; H, 5.56. Found: C,
67.79; H, 5.60.
8.11 (d, J¼6.4 Hz, 1H), 7.63 (d, J¼6.4 Hz, 1H), 7.62 (s, 1H), 7.52–7.48
(m, 1H), 3.88 (s, 2H), 2.72 (s, 2H), 2.41 (s, 2H), 1.14 (s, 6H); 13C NMR
(100 MHz, CDCl3):
d 193.8, 171.5, 161.0, 148.2, 139.4, 135.9, 135.3,
129.4, 125.1, 123.7, 121.9, 113.4, 50.2, 41.3, 36.1, 32.6, 28.1 (CHꢂ2);
MS m/z (%) 326 (Mþꢁ1, 50), 294 (100). Anal. Calcd for C18H17NO5: C,
66.05; H, 5.23; N, 4.28. Found: C, 66.01; H, 5.19; N, 4.20.
4.3.16. Methyl 2-ethyl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro-
2H-chromene-3-carboxylate (5a)
Viscous oil; IR (film): nmax 2957, 2880, 1737, 1631, 1437, 1396,
4.3.10. 3-(2-Chlorobenzyl)-7,7-dimethyl-7,8-dihydro-6H-
chromene-2,5-dione (4j)
1224, 1167, 754 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 4.10–4.05 (m,
1H), 3.71 (s, 3H), 2.64–2.56 (m, 2H), 2.49–2.39 (m, 1H), 2.29–2.19
White solid; mp 107–108 ꢀC; IR (KBr): nmax 1738, 1682, 1589,
(m, 4H), 1.73–1.58 (m, 2H), 1.07 (s, 6H), 1.03 (t, J¼8.4 Hz, 3H); 13C
1397 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
7.39–7.38 (m, 2H), 7.34–
7.32 (m, 1H), 7.25–7.23 (m, 2H), 3.90 (s, 2H), 2.71 (s, 2H), 2.38 (s,
2H), 1.13 (s, 6H); 13C NMR (100 MHz, CDCl3):
193.8, 170.7, 161.4,
NMR (100 MHz, CDCl3): d 197.4, 173.3, 168.8, 108.5, 78.3, 52.0, 50.4,
42.0, 41.9, 32.1, 28.2, 27.8, 25.9, 21.0, 9.2; MS m/z (100%) 265 (Mþꢁ1,
30), 264 (68), 233 (100), 189 (30). HRMS (ESI, m/z) calcd for
d
135.3, 134.8, 134.4, 131.7, 129.8, 128.6, 127.3, 124.9, 113.6, 50.4, 41.4,
33.8, 32.6, 28.3 (CH3ꢂ2); MS m/z (%) 317 (Mþþ1, 7), 281 (100). Anal.
Calcd for C18H17ClO3: C, 68.25; H, 5.41. Found: C, 68.20; H, 5.35.
C
15H22O4 (MþH)þ 267.1598, found 267.1596.
4.3.17. Methyl 2-ethyl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro-
2H-chromene-3-carboxylate (6a)
4.3.11. 3-(2-Chloro-6-fluorobenzyl)-7,7-dimethyl-7,8-dihydro-6H-
chromene-2,5-dione (4k)
Viscous oil; IR (film): nmax 2957, 2880, 1738, 1628, 1437, 1396,
1217, 1165, 732 cmꢁ1 1H NMR (400 MHz, CDCl3):
; d 4.22–4.18 (m,
White solid; mp 130–131 ꢀC; IR (KBr): nmax 1740, 1684, 1584,
1H), 3.69 (s, 3H), 2.97–2.92 (m, 1H), 2.50–2.48 (m, 2H), 2.29–2.22
(m, 4H), 1.69–1.63 (m, 1H), 1.55–1.50 (m, 1H), 1.07 (s, 6H), 1.02 (t,
1390, 1369 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
7.27–7.24 (m, 2H),
7.14 (s, 1H), 7.07–7.04 (m, 1H), 3.96 (s, 2H), 2.72 (s, 2H), 2.37 (s, 2H),
1.13 (s, 6H); 13C NMR (100 MHz, CDCl3):
193.9, 170.6, 161.6 (d,
J¼7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 197.5, 171.6, 168.6,
108.4, 78.0, 51.7, 50.4, 42.1, 40.2, 32.1, 28.5, 27.7, 23.8, 18.8, 10.2; MS
d

5496
W. Zhong et al. / Tetrahedron 64 (2008) 5491–5496
m/z (100%) 265 (Mþꢁ1, 36), 233 (100), 217 (50), 189 (80). HRMS
(ESI, m/z) calcd for C15H22O4 (MþH)þ 267.1598, found 267.1595.
5. (a) Kikuchi, H.; Sasaki, K.; Sekiya, J.; Moeda, Y.; Amagai, A.; Kubohara, Y.;
Oshma, Y. Bioorg. Med. Chem. 2004, 12, 3203; (b) Kamano, Y.; Nogawa, T.;
Yamashita, A.; Hayashi, M.; Inoue, M. J. Nat. Prod. 2002, 65, 1001.
6. Hua, D. H.; Huang, X.; Tamura, M.; Chen, Y.; Woltkamp, M.; Jin, L.-W.;
Perchellet, E. M.; Perchellet, J.-P.; Chiang, P. K.; Namatame, I.; Tomoda, H.
Tetrahedron 2003, 59, 4795.
4.3.18. Methyl 2-butyl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro-
2H-chromene-3-carboxylate (5b)
7. (a) Lee, Y. S.; Kim, S. N.; Lee, Y. S.; Lee, J. Y.; Lee, C.-K.; Kim, H. S.; Park, H. Arch. Pharm.
Pharm. Med. Chem. 2000, 333, 319; (b) Shi, X. W.; Leal, W. S.; Liu, Z.; Schrader, E.;
Meinwald, J. Tetrahedron Lett. 1995, 36, 71; (c) Hagen, S. E.; Vara Prasad, J. V. N.;
Boyer, F. E.; Domagala, J. M.; Ellsworth, E. L.; Gajda, C.; Hamilton, H. W.; Markoski, L.
J.; Steinbaugh, B. A.; Tait, B. D.; Lunney, E. A.; Tummino, P. J.; Ferguson, D.; Hupe, D.;
Nouhan, C.; Gracheck, S. J.; Saunders, J. M.; VanderRoest, S. J. Med. Chem. 1997, 40,
3707; (d) Puerta, D. T.; Mongan, J.; Tran, B. L.; McCammon, J. A.; Cohen, S. M. J. Am.
Chem. Soc. 2005, 127, 14148; (e) Thaisrivongs, S.; Watenpaugh, K. D.; Howe, W. J.;
Tomich, P. K.; Dolak, L. A.; Chong, K.-T.; Tomich, C.-S. C.; Tomasselli, A. G.; Turner, S.
R.; Strohbach, J. W.; Mulichak, A. M.; Janakiraman, M. N.; Moon, J. B.; Lynn, J. C.;
Horng, M.-M.; Hinshaw, R. R.; Curry, K. A.; Rothrock, D. J. J. Med. Chem. 1995, 38,
3624; (f) Griutas, W. C.; Stanga, M. A.; Brubaker, M. J.; Huang, T. L.; Moi, M. K.;
Carroll, R. T. J. Med. Chem. 1985, 28, 1106; (g) Thaisrivongs, S.; Romero, D. L.;
Tommasi, R. A.; Janakiraman, M. N.; Strohbach, J. W.; Turner, S. R.; Biles, C.; Morge,
R. R.; Johnson, P. D.; Aristoff, P. A.; Tomich, P. K.; Lynn, J. C.; Horng, M.-M.; Chong,
K.-T.;Hinshaw, R. R.; Howe, W. J.; Finzel, B. C.; Watenpaugh, K. D. J. Med. Chem.1996,
39, 4630; (h) Thaisrivings, S.; Skulnick, H. I.; Tunner, S. R.; Strohbach, J. W.;
Tommasi, R. A.;Johnson, P. D.;Aristoff,P. A.;Judge, T. M.; Gammill, R. B.; Morris, J. K.;
Romines, K. R.; Chrusciel, R. A.; Hinshaw, R. R.; Chong, K. T.; Tarpley, W. G.; Poppe,
S. M.; Slade, D. E.; Lynn, J. C.; Horng, M.-M.; Tomich, P. K.; Seest, E. P.; Dolak, L. A.;
Howe, W. J.; Howard, G. M.; Schwende, F. J.; Toth, L. N.; Padbury, G. E.; Wilson, G. J.;
Shiou, L.; Zipp, G. L.; Wilkinson, K. F.; Rush, B. D.; Ruwart, M. J.; Koeplinger, K. A.;
Zhao, Z. Y.; Cole, S.; Zaya, R. M.; Kakuk, T. J.; Janakiraman, M. N.; Watenpaugh, K. D.
J. Med. Chem.1996, 39, 4349; (i) Deck, L. M.; Baca, M. L.; Salas, S. L.; Hunsaker, L. A.;
Vander Jagt, D. L. J. Med. Chem.1999, 42, 4250; (j) Posner, G. H.; Lee, J. K.; White, M.
C.; Hutchings, R. H.; Dai, H.; Kachinski, J. L.; Dolan, P.; Kensler, T. W. J. Org. Chem.
1997, 62, 3299.
Viscous oil; IR (film): nmax 2958, 2881, 1737, 1632, 1437,
1396 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 4.15–4.11 (m, 1H), 3.71 (s,
3H), 2.63–2.55 (m, 2H), 2.44–2.41 (m, 1H), 2.27–2.23 (m, 4H), 1.62–
1.58 (m, 2H), 1.51–1.50 (m, 1H), 1.39–1.32 (m, 3H), 1.07 (s, 6H), 0.91
(t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 197.4, 173.6, 168.6,
108.5, 76.8, 52.0, 50.5, 42.4, 42.1, 32.6, 32.1, 28.7, 27.9, 27.1, 22.4, 21.0,
13.9; MS m/z (100%) 295 (Mþþ1, 100). HRMS (ESI, m/z) calcd for
C
17H26O4 (MþH)þ 295.1911, found 295.1913.
4.3.19. Methyl 2-butyl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydro-
2H-chromene-3-carboxylate (6b)
Viscous oil; IR (film): nmax 2957, 2881, 1737, 1627, 1436,
1396 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 4.31–4.28 (m, 1H), 3.69 (s,
3H), 2.94–2.90 (m, 1H), 2.50–2.48 (m, 2H), 2.28–2.23 (m, 4H), 1.63–
1.61 (m, 1H), 1.46–1.44 (m, 2H), 1.39–1.32 (m, 3H), 1.07 (s, 6H), 0.91
(t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 197.6, 171.8, 168.5,
108.5, 74.7, 51.8, 50.5, 42.2, 40.8, 39.2, 32.3, 28.5, 27.9, 24.8, 23.2,
21.8, 18.6; MS m/z (100%) 295 (Mþþ1, 100). HRMS (ESI, m/z) calcd
for C17H26O4 (MþH)þ 295.1911, found 295.1913.
4.3.20. Methyl 2-isobutyl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-3-carboxylate (5c)
8. (a) Shin, J.-T.; Shin, S. H.; Cho, C.-G. Tetrahedron Lett. 2004, 45, 5857; (b) Shi-
mizu, H.; Okamura, H.; Yamashita, N.; Iwagawa, T.; Nakatani, M. Tetrahedron
Lett. 2001, 42, 8649; (c) Chung, S.-I.; Seo, J.; Cho, C.-G. J. Org. Chem. 2006, 71,
6701; (d) Hong, B.-C.; Jiang, Y.-F.; Kumar, E. S. Bioorg. Med. Chem. Lett. 2001, 11,
1981; (e) Shin, I.-J.; Choi, E.-S.; Cho, C.-G. Angew. Chem., Int. Ed. 2007, 46, 2303;
(f) Afarinkia, K.; Posner, G. H. Tetrahedron Lett. 1992, 33, 7839; (g) Hsung, R. P.;
Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen, S. J.; Yao, L. J. J. Org. Chem. 1999,
64, 690; (h) Chen, C.-H.; Liao, C.-C. Org. Lett. 2000, 2, 2049; (i) Bellina, F.;
Carpita, A.; Mannocci, L.; Rossi, R. Eur. J. Org. Chem. 2004, 2610.
Viscous oil; IR (film): nmax 2957, 2882, 1736, 1625, 1438,
1397 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 4.25–4.21 (m, 1H), 3.71 (s,
3H), 2.57–2.53 (m, 2H), 2.48–243 (m, 1H), 2.30–2.20 (m, 4H), 1.91–
1.86 (m, 1H), 1.62–1.56 (m, 1H), 1.33–1.25 (m, 1H), 1.05 (d, J¼11.5 Hz,
6H), 0.94 (t, J¼6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d 197.4,
ˆ
9. (a) Riusset, S.; Abarbri, M.; Thibonnet, J.; Duchene, A.; Parrain, J.-L. Chem.
ˆne, A.;
173.3, 168.6, 108.5, 75.6, 52.0, 50.5, 42.8, 42.1, 32.1, 28.7, 27.9, 24.4,
23.4, 21.6, 20.8; MS m/z (100%) 295 (Mþþ1, 100). HRMS (ESI, m/z)
calcd for C17H26O4 (MþH)þ 295.1911, found 295.1909.
Commun. 2000, 1987; (b) Cherry, K.; Parrain, J.-L.; Thibonnet, J.; Duche
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Wang, Y.; Burton, D. J. J. Org. Chem. 2006, 71, 3859.
4.3.21. Methyl 2-isobutyl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-
hexahydro-2H-chromene-3-carboxylate (6c)
12. (a) Yao, T.; Larcok, R. C. Tetrahedron Lett. 2002, 43, 7401; (b) Biagetti, M.; Bellina,
F.; Carpita, A.; Viel, S.; Mannina, L.; Rossi, R. Eur. J. Org. Chem. 2002, 1063; (c)
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J. Org. Chem. 2003, 68, 8996.
Viscous oil; IR (film): nmax 2958, 2880, 1737, 1627, 1436,
1396 cmꢁ1; 1H NMR (400 MHz, CDCl3):
d 4.45–4.41 (m, 1H), 3.70 (s,
3H), 2.91–2.87 (m, 1H), 2.52–2.44 (m, 2H), 2.27–2.23 (m, 4H), 1.82–
1.80 (m, 1H), 1.60–1.54 (m, 1H), 1.22–1.17 (m, 1H), 1.06 (s, 6H), 0.94
(t, J¼5.5 Hz, 6H); 13C NMR (100 MHz, CDCl3):
d 197.6, 171.8, 168.5,
108.5, 74.7, 51.8, 50.5, 42.2, 40.8, 39.2, 32.3, 28.5, 27.9, 24.8, 23.2,
21.8, 18.6; MS m/z (100%) 295 (Mþþ1, 100). HRMS (ESI, m/z) calcd
for C17H26O4 (MþH)þ 295.1911, found 295.1910.
14. (a) Hachiya, I.; Shibuya, H.; Shimizu, M. Tetrahedron Lett. 2003, 44, 2061; (b)
Akye´-Ge´du, R.; He´nichart, J.-P.; Couturier, D.; Rigo, B. Tetrahedron Lett. 2004, 45,
9197.
15. (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811; (b)
Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001; (c) Kim, J. N.;
Lee, K. Y. Curr. Org. Chem. 2002, 6, 627; (d) Lee, K. Y.; Gowrisankai, S.; Kim, J. N.
Bull. Korean Chem. Soc. 2005, 26, 1481; (e) Shi, M.; Jiang, J.-K.; Li, C.-J. Tetrahe-
dron Lett. 2002, 43, 127; (f) Shi, M.; Li, C.-J.; Jiang, J.-K. Chem. Commun. 2001,
833; (g) Shi, M.; Li, C.-J.; Jiang, J.-K. Helv. Chim. Acta 2002, 85, 1051.
16. Kim, S. J.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48, 1069.
17. Kim, S. J.; Lee, H. S.; Kim, J. N. Bull. Korean Chem. Soc. 2007, 28, 147.
18. Du, W.; Truong, Q.; Qi, H.; Guo, Y.; Chobanian, H. R.; Hagmann, W. K.; Hale, J. J.
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (No. 20476098 and No. 20676123) for financial support.
References and notes
19. Kim, J. N.; Kim, J. M.; Lee, K. Y.; Gowrisankar, S. Bull. Korean Chem. Soc. 2004, 25,
1733. The detailed NOE experimental results were shown as follows:
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2. (a) Sitachitta, N.; Gadepalli, M.; Davidson, B. S. Tetrahedron 1996, 52, 8073; (b)
NOE
CH3
H2C
CH3
H2C
NOE
H
H
H
H
O
O
CO2Me
CO2Me
´
Barrero, A. F.; Oltra, J. E.; Herrador, M. M.; Cabrera, E.; Sanchez, J. F.; Quılez, J. F.;
H
H
Rojas, F. J.; Reyes, J. F. Tetrahedron 1993, 49, 141; (c) Pereda-Miranda, R.; Her-
na´ndez, L.; Villavicencio, M. J.; Novelo, M.; Ibarra, P. J. Nat. Prod. 1993, 56, 583.
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Evidente, A.; Visconti, A. J. Agric. Food Chem. 2004, 52, 2997.
H
H
Me
Me
Me
Me
O
O
5a
6a
Representative NOE effects observed during the NMR
investigation of the two isomeric products 5a and 6a.
4. (a) Pedras, M. S. C.; Chumala, B. Phytochemistry 2005, 66, 81; (b) Jenkins, K. M.;
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