Facile synthesis of benzo-fused 2,8-dioxabicyclo[3.3.1]nonane derivatives via a domino Knoevenagel condensation/hetero-Diels-Alder reaction sequence

Article abstract of DOI:10.1016/j.tet.2007.11.036

A facile two-step synthesis of a series of benzo-fused 2,8-dioxabicyclo[3.3.1]nonane derivatives is described, featuring a domino Knoevenagel condensation/intramolecular hetero-Diels-Alder reaction sequence.

Full text of DOI:10.1016/j.tet.2007.11.036

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Tetrahedron 64 (2008) 664e671
www.elsevier.com/locate/tet
Facile synthesis of benzo-fused 2,8-dioxabicyclo[3.3.1]nonane
derivatives via a domino Knoevenagel condensation/
hetero-DielseAlder reaction sequence
*
Ikyon Kim , Sun Gi Kim, Jihyun Choi, Ge Hyeong Lee
Center for Medicinal Chemistry, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea
Received 20 September 2007; received in revised form 9 November 2007; accepted 9 November 2007
Available online 17 November 2007
Abstract
A facile two-step synthesis of a series of benzo-fused 2,8-dioxabicyclo[3.3.1]nonane derivatives is described, featuring a domino Knoeve-
nagel condensation/intramolecular hetero-DielseAlder reaction sequence.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Knoevenagel condensation; Hetero-DielseAldercycloaddition; Domino reaction; Benzo-fused 2,8-dioxabicyclo[3.3.1]nonanes; Proline
1. Introduction
2. Results and discussion
The condensation reaction of carbonyl compounds with ac-
tive methylene compounds in the presence of amines, known
as the Knoevenagel condensation,1 represents one of the most
fundamental bond-forming reactions in organic chemistry.2 Par-
ticularly, due to the fact that the resulting a,b-unsaturated
dicarbonyl or related compounds are useful intermediates,
combination of this reaction with other reactions in a domino
fashion3 has been increasingly employed, thereby making for-
mation of multiple bonds possible.4 For example, Knoevenagel
condensation has been successfully combined with hetero-
DielseAlder reactions, Michael addition reactions, ene reac-
tions, and/or sigmatropic rearrangements for the synthesis of
highly functionalized molecules.5 In the course of our investiga-
tion directed toward the efficient synthesis of heterocycles,6 we
discovered a new route to benzo-fused 2,8-dioxabicyclo[3.3.1]-
nonane structures based upon Knoevenagel/hetero-DielseAl-
der cascade reactions. Herein, we wish to describe our findings.
As depicted in Scheme 1, domino Knoevenagel/hetero-
DielseAlder reactions have been extensively employed for
the synthesis of polycyclic compounds since the pioneering
work by Tietze. For instance, initial intermolecular Knoevena-
gel condensation of 1 with active methylene compounds gen-
erated a heterodiene 2, which underwent intramolecular
hetero-DielseAlder cycloaddition with inverse electron de-
mand to yield 3.7 As seen in (2), hetero-DielseAlder reaction
of the Knoevenagel product 5 with an enol ether moiety pro-
ceeded smoothly in an inter- or intramolecular fashion to fur-
nish a dihydropyran ring system 6.8 However, to the best of
our knowledge, no report on the Knoevenagel condensation/
hetero-DielseAlder cascade has been disclosed with substrate
7 where an enol ether functionality would act as a dienophile.
Particularly, due to the short tether length and orientation of
an enol ether group of 8, a different conformation for the
successful cycloaddition was envisaged as compared with 2
and 5.
As illustrated in Scheme 2, facile intermolecular Knoevena-
gel condensation between an aldehyde moiety in 7 and active
methylene compound was envisioned to set the stage for intra-
molecular hetero-DielseAlder cycloaddition to give rise to
* Corresponding author. Tel.: þ82 42 860 7177; fax: þ82 42 860 7160.
E-mail address: ikyon@krict.re.kr (I. Kim).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.036

I. Kim et al. / Tetrahedron 64 (2008) 664e671
665
domino Knoevenagel condensation/hetero-Diels-Alder reactions
O
O
R2
O
O
O
O
O
O
R2
R3
R2
R3
R2
(1)
(2)
n
R1
n
n
O
O
O
R1
R1
1
2
3
O
O
O
O
O
O
OMe
OMe
OMe
5
4
if n = 0
6
O
O
O
E
O
O
E
?
(this work)
O
R1
O
R1
7
8
Scheme 1.
initially assigned by NMR and mass spectroscopy but later un-
ambiguously established on the basis of an X-ray crystallo-
graphic analysis (Fig. 1).12
As expected, only one diastereomer was formed as con-
firmed by X-ray crystallographic, 1H, and 13C NMR data.
The other detectable side product was 14a as a result of direct
attack of another equivalent of cyclohexane-1,3-dione (11) to
an enedione unit in A (Eq. 1).
To optimize the reaction conditions, we screened several
solvents and catalysts (Table 1). Surprisingly, no desired prod-
uct was formed with pyrrolidine, which is commonly used for
Knoevenagel condensations (entry 3). Among the solvents ex-
amined, ethyl acetate provided the best yield.
O
O
O
O
E
H
O
O
E
E
catalyst
H
O
O
O
O
R1
R1
R1
H
7
8
9
Scheme 2.
a benzo-fused 2,8-dioxabicyclo[3.3.1]nonane system 9.9 Nota-
bly, one diastereomer was anticipated from this step due to the
restricted conformation of 8.
To validate this hypothesis, 10a10 and 11 were chosen for
the Knoevenagel condensation partners and with proline as
the catalyst (Scheme 3).11
O
HO
O
11
11
HO
O
O
O
O
O
O
CO2Me
ð1Þ
CO2Me
O
O
O
O
A
10a
14a
CO2Me
Due to the formation of 14a, one more equivalent of cyclo-
hexane-1,3-dione (11) was added to the reaction mixture for
the reaction with the remaining 10a after no detection of 11
was confirmed by TLC (after 6 h), which resulted in increased
yield of the desired product (entry 7). Mild heating at 50 ꢀC
was also found to be beneficial (entries 11 and 12). At this
point, the following procedure gave the best result. A mixture
of 10a (0.48 mmol), cyclohexane-1,3-dione (11) (0.96 mmol),
and D-proline (0.14 mmol) in ethyl acetate (3 mL) was stirred
at 50 ꢀC for 24 h. After the completion of reaction, the solvent
was evaporated in vacuo and the resulting residue was directly
purified by silica gel column chromatography (hexanes/ethyl
acetate¼10:1) to give 13a in 89% yield.
R2
O
O
O
6
3
R2
CO2Me
H
1
2
CO2Me
D-proline
5
4
+
R2
H
O
O
O
O
R1
R2
11: R2 = H
12: R2 = Me
R1
H
13
10
Scheme 3.
We were pleased to find that the reaction of 10a and 11 in
CH3CN in the presence of D-proline (Table 1, entry 1) gave an
approximately 45% yield of 13a, the structure of which was

666
I. Kim et al. / Tetrahedron 64 (2008) 664e671
Me
O
O
O
H
O
O
13a
Figure 1. Crystal structure of 13a.
exposure of 10a and Meldrum’s acid (17) to our reaction condi-
tions delivered 18 instead of 19. The formation of 18 can be ex-
plained by the sequence depicted in Scheme 5.15
Table 1
O
H
O
O
Thus, the expected product 19 was indeed produced as
a consequence of the domino Knoevenagel/hetero-Dielse
Alder reaction. However, 19 would lose acetone via a retro-
DielseAlder reaction to give ketene 20. Hydrolysis of the
unstable ketene 20 followed by decarboxylation of the inter-
mediate carboxylic acid 21 would result in lactone 18.
However, the expected domino sequence did not occur when
cyclopentane-1,3-dione was subjected to our conditions. Only
22 was isolated as a major product (Fig. 2). Acyclic active meth-
ylene compounds such as pentane-2,4-dione and dimethyl malo-
nate were also examined. Unfortunately, only Knoevenagel
condensation took place from 10a and pentane-2,4-dione under
our conditions, delivering adduct 23 in low yield while reaction
with dimethyl malonate yielded a complex mixture of products.
Certainly, the rigid conformation and the bond angles of the het-
erodiene group in Knoevenagel adducts derived from cyclic ac-
tive methylene compounds seemed crucial for the subsequent
hetero-DielseAlder reaction (see the lower box of Fig. 2).
CO2Me
conditions
+
CO2Me
H
O
O
O
O
H
13a
10a
11
Entry Equiv of 11 Catalyst (equiv)
Solvent
Time (h) Yield of
13a (%)
1
1
D-Proline (0.3)
DBU (1.0)
Pyrrolidine (1.0) CH3CN
CH3CN
CH3CN
5
5
45
d
d
2
1
3
1
5
4
1
D-Proline (0.3)
D-Proline (1.0)
D-Proline (1.0)
D-Proline (0.3)
D-Proline (0.3)
D-Proline (1.0)
D-Proline (0.3)
D-Proline (0.3)
D-Proline (0.3)
DMSO
DMF
EtOH
5
6.8
5
1þ1a
1þ1a
1þ1a
1þ1a
1þ1a
1þ1a
1þ1a
2
24
24
24
24
25
22
60
58
57
77
85
89
6
7
CH3CN
CHCl3
8
9
Benzene 24
10
11
12
a
EtOAc
EtOAcb
EtOAcb
24
24
24
One more equivalent of 11 was added after 6 h.
The reaction temperature was 50 ꢀC.
b
3. Conclusions
Having the optimal conditions in hand, other benzalde-
hydes were tested with 11 or 12 as summarized in Table 2.
Overall, the highly functionalized benzo-fused 2,8-dioxabi-
cyclo[3.3.1]nonanes13 were obtained in good yields. When
benzaldehyde bearing an electron-donating group such as me-
thoxyl at the C4 position was used, modest yields of the cor-
responding 2,8-dioxabicyclo[3.3.1]nonanes were obtained
(entries 2 and 7). Substrate 10e derived from naphthaldehyde
also provided 13e and 13j in acceptable yields (entries 4 and
9). It should be mentioned that coupling with 12 gave better
yields of the products 13 than that with 11.
In summary, we describe here for the first time the stereo-
selective construction of the bridged and fused 2,8-dioxabicy-
clo[3.3.1]nonane ring system in two steps from commercially
available 2-hydroxybenzaldehydes, utilizing a domino Knoe-
venagel condensation/hetero-DielseAlder process as a key
step. Currently, efforts are being made to apply this protocol
to the synthesis of other novel heterocycles and will be re-
ported in due course.
4. Experimental
To expand the reaction scope, reactions with other active
methylene compounds were attempted (Scheme 4). The reac-
tion of 10awith the unsymmetrical activemethylene compound,
4-hydroxycoumarin (15),14 proceeded well to afford two penta-
cyclic compounds, 16a and 16b, in a 2:1 ratio. Interestingly,
4.1. General procedure
Thin layer chromatography was carried out with E. Merck
(Darmstadt) TLC plates precoated with silica gel 60 F254
.

I. Kim et al. / Tetrahedron 64 (2008) 664e671
667
Table 2
Entry
10
11 or 12
13
Yield (%)
O
O
O
H
CO2Me
CO2Me
1
10b
11
13b
77
H
O
O
H
OMe
OMe
O
O
H
CO2Me
2
3
4
10c
10d
10e
11
11
11
CO2Me
13c
13d
13e
52
76
40
H
O
O
MeO
MeO
O
O
MeO
MeO
H
O
H
CO2Me
CO2Me
H
O
O
O
H
O
O
H
CO2Me
CO2Me
H
O
O
O
H
Me
O
O
Me
H
CO2Me
CO2Me
5
6
10a
10b
12
12
13f
90
95
CO2Me
H
O
O
O
O
H
Me
O
Me
H
CO2Me
13g
H
O
O
O
OMe
H
OMe
Me
O
O
Me
H
CO2Me
7
8
10c
10d
12
12
13h
13i
54
76
CO2Me
Me
H
O
O
MeO
MeO
O
O
MeO
MeO
H
O
Me
H
CO2Me
CO2Me
H
O
O
O
H
Me
Me
CO2Me
O
O
H
CO2Me
9
10e
12
13j
46
H
O
O
O
H
Visualization was accomplished using a UV lamp, iodine va-
pors, and/or a p-anisaldehyde (PAA) stain. Flash column chro-
matography was accomplished with Silicycle silica gel 60
(230e400 mesh). Proton nuclear magnetic resonance spectra
were recorded in deuterated solvents on a VARIAN systems-
300 (300 MHz) instrument. Chemical shifts are reported in
parts per million (ppm, d) relative to tetramethylsilane
(TMS, d 0.00). Carbon nuclear magnetic resonance spectra
were recorded in deuterated solvents on a VARIAN systems-
300 (75 MHz) instrument. Infrared spectra were measured
on a Mattson Polaris FT-IR spectrometer, and signals are
recorded in wavenumbers. High resolution mass spectra
(HRMS) using electron ionization (EI) were measured on a
Micromass mass spectrometer.

668
I. Kim et al. / Tetrahedron 64 (2008) 664e671
O
O
O
O
O
O
H
H
O
O
CO2Me
15
OH
CO2Me
CO2Me
H
O
H
O
O
O
+
proline
H
H
10a
16a (43%)
16b (20%)
Me
O
O
Me
O
Me
O
Me
O
O
H
H
O
O
CO2Me
17
CO2Me
CO2Me
H
O
O
H
O
O
O
O
proline
H
H
10a
18 (72%)
19
Scheme 4.
Me
O
Me
O
O
H
O
17
CO2Me
CO2Me
H
O
O
O
O
10a
O
proline
H
18
H2O
Me
O
O
O
H
O
O
O
H
Me
H
H
O
O
O
CO2Me
CO2Me
CO2Me
H
O
O
H
O
H
O
O
H
H
H
19
20
21
Scheme 5.
4.2. General procedure for the synthesis of 10
(ddd, J¼9.3, 7.5, 2.1 Hz, 1H), 7.33 (t, J¼7.5 Hz, 1H), 7.16
(dd, J¼8.1, 0.9 Hz, 1H), 5.66 (d, J¼12.0 Hz, 1H), 3.75 (s,
3H); 13C NMR (75 MHz, CDCl3) d 188.3, 167.1, 158.3,
157.7, 136.2, 129.2, 126.7, 125.6, 118.4, 104.0, 51.7; IR
(KBr) 3100, 1705, 1648, 1598, 1482, 1303 cmꢁ1; HRMS
(EI) calcd for [C11H10O4]þ: m/z 206.0579, found 206.0575.
To a stirred solution of 2-hydroxybenzaldehyde (5.0 mmol) in
CH2Cl2 (9 mL) were added N-methylmorpholine (1.2 equiv) and
methyl propiolate (1.2 equiv) at rt. After being stirred at rt over-
night, the reaction mixture was concentrated invacuo. The result-
ing residue was purified by silica gel column chromatography
(hexanes/ethyl acetate/dichloromethane¼10:1:2) to afford 10.
4.2.2. Compound 10b
1H NMR (300 MHz, CDCl3) d 10.24 (d, J¼0.9 Hz, 1H),
7.80 (d, J¼12.3 Hz, 1H), 7.49 (dd, J¼6.0, 1.5 Hz, 1H), 7.32
(dt, J¼8.2, 0.7 Hz, 1H), 7.25 (dd, J¼8.2, 1.6 Hz, 1H), 5.31 (d,
J¼12.3 Hz, 1H), 3.90 (s, 3H), 3.72 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 188.5, 167.5, 161.7, 151.5, 146.1, 129.2,
127.0, 120.0, 118.6, 101.0, 56.6, 51.6; IR (KBr) 3011, 1700,
1650, 1530, 1455, 1320 cmꢁ1; HRMS (EI) calcd for
[C12H12O5]þ: m/z 236.0685, found 236.0686.
4.2.1. Compound 10a
1H NMR (300 MHz, CDCl3) d 10.37 (d, J¼0.6 Hz, 1H),
7.94 (dd, J¼7.8, 1.8 Hz, 1H), 7.86 (d, J¼12.3 Hz, 1H), 7.65
O
O
O
HO
HO
CO2Me
O
O
O
22
23
4.2.3. Compound 10c
CO2Me
1H NMR (300 MHz, CDCl3) d 10.21 (s, 1H), 7.89 (d,
J¼9.0 Hz, 1H), 7.82 (d, J¼12.3 Hz, 1H), 6.82 (dd, J¼8.7,
2.1 Hz, 1H), 6.59 (d, J¼2.1 Hz, 1H), 5.68 (d, J¼12.3 Hz, 1H),
3.90 (s, 3H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 188.1, 167.3, 159.8, 157.3, 151.8, 127.5, 123.6, 120.7,
111.0. 103.0, 56.1, 51.7; IR (KBr) 3051, 1705, 1626, 1520,
1400, 1330 cmꢁ1; HRMS (EI) calcd for [C12H12O5]þ: m/z
236.0685, found 236.0688.
O
O
E
E
O
O
O
O
Inappropriate orbital interactions
between heterodiene and dienophile
Rotable bonds
Figure 2.

I. Kim et al. / Tetrahedron 64 (2008) 664e671
669
4.2.4. Compound 10d
118.1, 115.5, 108.2, 101.9, 92.1, 55.6, 52.7, 40.7, 36.5, 27.6,
25.0, 20.8; IR (KBr) 3003, 2975, 1752, 1678, 1455,
1356 cmꢁ1; HRMS (EI) calcd for [C18H18O6]þ: m/z 330.1103,
found 330.1108.
1H NMR (300 MHz, CDCl3) d 10.28 (d, 9.0 Hz, 1H), 7.81
(d, J¼12.3 Hz, 1H), 7.38 (d, J¼3.0 Hz, 1H), 7.18 (dd, J¼9.0,
3.1 Hz, 1H), 7.08 (d, J¼9.0 Hz, 1H), 5.52 (d, J¼12.3 Hz, 1H),
3.85 (s, 3H), 3.74 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 187.0, 167.2, 166.1, 160.0, 158.1, 131.0, 120.0, 111.4,
104.1, 103.8, 56.2, 51.8; IR (KBr) 3023, 1736, 1658, 1511,
1456, 1345 cmꢁ1; HRMS (EI) calcd for [C12H12O5]þ: m/z
236.0685, found 236.0683.
4.3.4. Compound 13d
1H NMR (300 MHz, CDCl3) d 6.86 (d, J¼3.0 Hz, 1H), 6.79
(d, J¼8.7 Hz, 1H), 6.64 (dd, J¼8.7, 3.0 Hz, 1H), 6.22 (t,
J¼1.8 Hz, 1H), 4.45 (t, J¼2.1 Hz, 1H), 3.70 (s, 3H), 3.68 (s,
3H), 3.07 (t, J¼2.3 Hz, 1H), 2.39e2.35 (m, 2H), 2.32e2.25
(m, 2H), 1.91e1.82 (m, 2H); 13C NMR (75 MHz, CDCl3)
d 195.8, 168.9, 154.6, 144.0, 126.2, 117.0, 114.8, 114.6, 112.7,
92.2, 55.9, 52.7, 40.4, 36.5, 27.6, 25.9, 20.8; IR (KBr) 2980,
1726, 1653, 1467, 1326, 1252 cmꢁ1; HRMS (EI) calcd for
[C18H18O6]þ: m/z 330.1103, found 330.1101.
4.2.5. Compound 10e
1H NMR (300 MHz, CDCl3) d 10.77 (s, 1H), 9.26 (dd,
J¼8.7, 0.5 Hz, 1H), 8.14 (d, J¼9.0 Hz, 1H), 7.92 (d, J¼
12.3 Hz, 1H), 7.87 (d, J¼8.1 Hz, 1H), 7.71 (dt, J¼6.9,
1.4 Hz, 1H), 7.56 (dt, J¼6.9, 1.3 Hz, 1H), 7.29 (d, J¼9.0 Hz,
1H), 5.64 (d, J¼12.0 Hz, 1H), 3.76 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 190.7, 167.1, 159.4, 158.8, 137.9, 131.3,
131.2, 130.5, 128.7, 126.8, 125.8, 120.0, 117.8, 104.2, 51.8; IR
(KBr) 3048, 1721, 1648, 1566, 1422, 1372 cmꢁ1; HRMS (EI)
calcd for [C15H12O4]þ: m/z 256.0736, found 256.0739.
4.3.5. Compound 13e
1H NMR (300 MHz, CDCl3) d 8.81 (d, J¼8.4 Hz, 1H), 7.73
(td, J¼8.0, 0.6 Hz, 1H), 7.66 (d, J¼8.8 Hz, 1H), 7.58 (ddd,
J¼9.9, 6.9, 1.2 Hz, 1H), 7.37 (ddd, J¼8.1, 6.9, 1.2 Hz, 1H),
7.13 (d, J¼8.8 Hz, 1H), 6.35 (t, J¼1.8 Hz, 1H), 5.29 (t, J¼
2.4 Hz, 1H), 3.74 (s, 3H), 3.19 (t, J¼2.3 Hz, 2H), 2.43 (t,
J¼5.9 Hz, 2H), 2.28e2.34 (m, 2H), 1.76e1.93 (m, 2H); 13C
NMR (75 MHz, CDCl3) d 196.1, 170.4, 169.1, 148.1, 131.6,
129.9, 129.1, 128.2, 127.2, 124.6, 118.4, 117.8, 114.8, 91.7,
52.8, 40.8, 36.7, 28.0, 22.0, 20.4; IR (KBr) 3056, 2981, 1755,
1645, 1488, 1356 cmꢁ1; HRMS (EI) calcd for [C21H18O5]þ:
m/z 350.1154, found 350.1149.
4.3. General procedure for the synthesis of 13
To a stirred solution of 10 (0.48 mmol) and 11 or 12 (2 equiv)
in ethyl acetate (3 mL) was added D-proline (0.3 equiv) at rt.
After being stirred at 50 ꢀC for 24 h, the reaction mixture was
concentrated invacuo. The residuewas purified by silica gel col-
umn chromatography (hexanes/ethyl acetate¼10:1) to give 13.
4.3.1. Compound 13a
4.3.6. Compound 13f
1H NMR (300 MHz, CDCl3) d 7.36 (dd, J¼7.8, 1.8 Hz,
1H), 7.13 (dt, J¼8.2, 1.8 Hz, 1H), 6.93e6.88 (m, 2H), 6.30
(t, J¼2.1 Hz, 1H), 4.54 (t, J¼2.4 Hz, 1H), 3.72 (s, 3H), 3.12
(t, J¼2.3 Hz, 1H), 2.43e2.38 (m, 2H), 2.35e2.27 (m, 2H),
1.94e1.85 (m, 2H); 13C NMR (75 MHz, CDCl3) d 195.8,
168.9, 168.6, 150.3, 128.7, 128.2, 125.7, 122.1, 116.3, 115.0,
92.1, 52.7, 40.3, 36.5, 27.6, 25.6, 20.8; IR (KBr) 2953, 1741,
1628, 1482, 1388, 1231 cmꢁ1; HRMS (EI) calcd for
[C17H16O5]þ: m/z 300.0998, found 300.0995.
1H NMR (300 MHz, CDCl3) d 7.33 (d, J¼7.5 Hz, 1H), 7.10
(t, J¼8.4 Hz, 1H), 6.91e6.86 (m, 2H), 6.30 (d, J¼0.6 Hz, 1H),
4.53 (s, 1H), 3.71 (s, 3H), 3.12 (s, 1H), 2.35e2.03 (m, 4H),
0.98 (s, 3H), 0.95 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 195.5, 168.9, 166.9, 150.3, 128.5, 128.2, 125.5, 122.1, 116.3,
114.1, 92.4, 52.6, 50.4, 41.3, 40.2, 32.7, 29.5, 27.0, 25.5; IR
(KBr) 3063, 2985, 1753, 1655, 1485, 1326 cmꢁ1; HRMS
(EI) calcd for [C19H20O5]þ: m/z 328.1311, found 328.1315.
4.3.7. Compound 13g
4.3.2. Compound 13b
1H NMR (300 MHz, CDCl3) d 6.96 (d, J¼7.8 Hz, 1H), 7.86
(dt, J¼7.8, 0.9 Hz, 1H), 6.74 (d, J¼8.4 Hz, 1H), 6.41 (t,
J¼1.5 Hz, 1H), 4.55 (s, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 3.14
(t, J¼1.2 Hz, 1H), 2.36e2.04 (m, 4H), 0.98 (s, 3H), 0.95 (s,
3H); 13C NMR (75 MHz, CDCl3) d 195.5, 168.8, 167.1,
147.9, 139.4, 126.5, 122.1, 120.3, 113.9, 110.4, 92.2, 56.0, 52.6,
50.3, 41.2, 40.1, 32.6, 29.4, 27.0, 25.3; IR (KBr) 3025, 2866,
1H NMR (300 MHz, CDCl3) d 6.98 (dd, J¼7.6, 1.5 Hz,
1H), 6.86 (t, J¼7.7 Hz, 1H), 6.75 (dd, J¼8.1, 1.5 Hz, 1H),
6.39 (t, J¼2.1 Hz, 1H), 4.54 (t, J¼2.1 Hz, 1H), 3.87 (s, 3H),
3.72 (s, 3H), 3.13 (t, J¼2.2 Hz, 1H), 2.43e2.39 (m, 2H),
2.34e2.27 (m, 2H), 1.93e1.83 (m, 2H); 13C NMR (75 MHz,
CDCl3) d 195.8, 168.8, 147.9, 139.5, 126.7, 122.1, 120.5,
114.9, 110.4, 92.0, 56.1, 52.7, 40.2, 36.5, 27.5, 25.5, 20.7; IR
(KBr) 2945, 1750, 1645, 1436, 1385, 1226 cmꢁ1; HRMS (EI)
calcd for [C18H18O6]þ: m/z 330.1103, found 330.1105.
1732, 1676, 1385, 1216 cmꢁ1
; HRMS (EI) calcd for
[C20H22O6]þ: m/z 358.1416, found 358.1412.
4.3.8. Compound 13h
4.3.3. Compound 13c
1H NMR (300 MHz, CDCl3) d 7.23 (d, J¼9.3 Hz, 1H),
6.48e6.45 (m, 2H), 6.41 (dd, J¼1.8, 1.2 Hz, 1H), 4.47 (s,
1H), 3.73 (s, 3H), 3.70 (s, 3H), 3.11 (t, J¼1.8 Hz, 1H),
2.35e2.04 (m, 4H), 1.00 (s, 3H), 0.96 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 195.6, 169.0, 166.7, 159.7, 151.1, 128.9,
117.9, 114.6, 108.2, 101.9, 92.3, 55.6, 52.6, 50.4, 41.3, 40.6,
1H NMR (300 MHz, CDCl3) d 7.25 (d, J¼8.6 Hz, 1H), 6.50e
6.46 (m, 2H), 6.27 (t, J¼1.8 Hz, 1H), 4.47 (t, J¼2.4 Hz, 1H),
3.74 (s, 3H), 3.71 (s, 3H), 3.10 (t, J¼2.3 Hz, 1H), 2.42e2.38
(m, 2H), 2.35e2.27 (m, 2H), 1.93e1.85 (m, 2H); 13C NMR
(75 MHz, CDCl3) d 195.9, 169.0, 168.4, 159.8, 151.1, 129.1,

670
I. Kim et al. / Tetrahedron 64 (2008) 664e671
32.7, 29.5, 27.0, 24.8; IR (KBr) 3055, 2980, 1752, 1686, 1495,
1336 cmꢁ1; HRMS (EI) calcd for [C20H22O6]þ: m/z 358.1416,
found 358.1420.
(KBr) 3004, 2980, 1740, 1434, 1360, 1221 cmꢁ1; HRMS (EI)
calcd for [C13H12O5]þ: m/z 248.0685, found 248.0689.
Acknowledgements
4.3.9. Compound 13i
1H NMR (300 MHz, CDCl3) d 6.88e6.80 (m, 2H), 6.67
(dd, J¼9.0, 3.0 Hz, 1H), 6.27 (t, J¼1.5 Hz, 1H), 4.49 (s,
1H), 3.73 (s, 3H), 3.71 (s, 3H), 3.11 (t, J¼1.8 Hz, 1H),
2.35e2.04 (m, 4H), 0.98 (s, 3H), 0.96 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 195.4, 168.9, 167.2, 154.5, 144.0, 126.0,
116.9, 114.5, 113.8, 112.5, 92.4, 55.8, 52.6, 50.3, 41.3, 40.2,
32.7, 29.5, 26.9, 25.7; IR (KBr) 3035, 2875, 1782, 1698,
1461, 1308 cmꢁ1; HRMS (EI) calcd for [C20H22O6]þ: m/z
358.1416, found 358.1415.
We thank the Center for Biological Modulators and Korea
Research Institute of Chemical Technology for generous finan-
cial support.
Supplementary data
1
Copies of H and 13C NMR spectra for 10, 13, 16, and 18.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.11.036.
References and notes
4.3.10. Compound 13j
1H NMR (300 MHz, CDCl3) d 8.79 (d, J¼8.7 Hz, 1H), 7.72
(d, J¼8.4 Hz, 1H), 7.64 (d, J¼9.0 Hz, 1H), 7.58 (t, J¼7.8 Hz,
1H), 7.36 (t, J¼7.5 Hz, 1H), 7.12 (d, J¼8.7 Hz, 1H), 6.38 (t,
J¼1.8 Hz, 1H), 5.28 (s, 1H), 3.74 (s, 3H), 3.18 (t, J¼1.8 Hz,
1H), 2.39e2.04 (m, 4H), 0.97 (s, 3H), 0.93 (s, 3H); 13C
NMR (75 MHz, CDCl3) d 196.0, 169.1, 168.6, 148.2, 131.5,
129.9, 129.1, 128.1, 127.2, 124.5, 118.3, 117.7, 113.8, 91.9,
52.7, 50.8, 41.7, 40.7, 33.0, 29.6, 26.9, 21.8; IR (KBr) 3077,
3015, 2936, 1746, 1685, 1456 cmꢁ1; HRMS (EI) calcd for
[C23H22O5]þ: m/z 378.1467, found 378.1469.
1. (a) Knoevenagel, E. Chem. Ber. 1896, 29, 172; (b) Knoevenagel, E. Chem.
Ber. 1894, 27, 2345.
2. For general reviews, see: (a) Tietze, L. F.; Beifuss, U. Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New
York, NY, 1991; Vol. 2, p 341; (b) Jones, G. Org. React. 1967, 15, 204.
3. For selected books and reviews on domino or tandem reactions, see: (a)
Chapman, C. J.; Frost, C. G. Synthesis 2007, 1; (b) Pellissier, H. Tetra-
hedron 2006, 62, 2143; (c) Domino Reactions in Organic Synthesis; Tietze,
L. F., Brasche, G., Gericke, K. M., Eds.; Wiley-VCH: Weinheim, Germany,
2006; (d) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (e)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551;
(f) Tietze, L. F. Chem. Rev. 1996, 96, 115; (g) Tietze, L. F.; Beifuss, U.
Angew. Chem., Int. Ed. Engl. 1993, 32, 131; (h) Ho, T.-L. Tandem Organic
Reactions; John Wiley and Sons: New York, NY, 1992.
4. For reviews on domino sequence initiated by Knoevenagel condensations,
see: (a) Tietze, L. F.; Rackelmann, N. Multicomponent Reactions; Zhu, J.,
Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; p 121; (b)
Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967; (c)
Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304; (d) Tietze, L. F.; Kett-
schau, G.; Gewart, J. A.; Schuffenhauer, A. Curr. Org. Chem. 1998, 2, 19.
5. For recent domino reactions triggered by Knoevenagel condensations,
see: (a) Ramachary, D. B.; Kishor, M. J. Org. Chem. 2007, 72, 5056; (b)
Ramachary, D. B.; Ramakumar, K.; Narayana, V. V. J. Org. Chem. 2007,
72, 1458; (c) Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946; (d) Sa-
bitha, G.; Fatima, N.; Reddy, E. V.; Yadav, J. S. Adv. Synth. Catal. 2005, 347,
1353; (e) Ramachary, D. B.; Anebouselvy, K.; Chowdari, N. S.; Barbas,
C. F., III. J. Org. Chem. 2004, 69, 5838; (f) Sabitha, G.; Reddy,
G. S. K. K.; Rajkumar, M.; Yadav, J. S.; Ramakrishna, K. V. S.; Kunwar,
A. C. Tetrahedron Lett. 2003, 44, 7455; (g) Clarke, P. A.; Martin,
W. H. C. Org. Lett. 2002, 4, 4527; (h) Tratrat, C.; Giorgi-Renault, S.;
4.3.11. Compound 16a
1H NMR (300 MHz, CDCl3) d 7.81 (dd, J¼8.7, 1.8 Hz,
1H), 7.53e7.45 (m, 2H), 7.26e7.14 (m, 3H), 6.99e6.94 (m,
2H), 6.12 (t, J¼1.8 Hz, 1H), 4.70 (t, J¼2.1 Hz, 1H), 3.72 (s,
3H), 3.35 (t, J¼2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 168.3, 161.4, 157.5, 152.5, 150.3, 132.4, 129.0, 128.7, 124.5,
124.3, 123.2, 122.7, 116.9, 116.6, 114.7, 104.8, 92.6,
53.0, 40.4, 27.5; IR (KBr) 2953, 1714, 1635, 1488, 1402,
1222 cmꢁ1
;
HRMS (EI) calcd for [C20H14O6]þ: m/z
350.0790, found 350.0793.
4.3.12. Compound 16b
1H NMR (300 MHz, CDCl3) d 8.14 (dd, J¼8.4, 1.8 Hz,
1H), 7.61e7.51 (m, 2H), 7.38e7.33 (m, 2H), 7.15 (ddd,
J¼9.0, 7.8, 1.8 Hz, 1H), 6.97e6.93 (m, 2H), 6.59 (t, J¼
1.5 Hz, 1H), 4.89 (t, J¼2.1 Hz, 1H), 3.72 (s, 3H), 3.36 (t, J¼
2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 175.9, 168.3,
162.6, 153.1, 149.9, 133.5, 128.8, 128.6, 126.0, 125.6, 125.5,
122.9, 122.8, 117.7, 116.6, 99.5, 94.9, 53.1, 40.6, 26.3; IR
(KBr) 2935, 1741, 1626, 1567, 1426, 1218 cmꢁ1; HRMS
(EI) calcd for [C20H14O6]þ: m/z 350.0790, found 350.0789.
´
´
Husson, H.-P. Org. Lett. 2002, 4, 3187; (i) Marchalın, S.; Cvopova, K.;
´
€
Pham-Huu, D.-P.; Chudık, M.; Kozisek, J.; Svoboda, I.; Daıch, A. Tetra-
hedron Lett. 2001, 42, 5663; (j) Betancort, J. M.; Sakthivel, K.; Thayumana-
van, R.; Barbas, C. F., III. Tetrahedron Lett. 2001, 42, 4441; (k) Tietze, L. F.;
Zhou, Y. Angew. Chem., Int. Ed. 1999, 38, 2045; (l) Ye, J.-H.; Ling, K.-Q.;
Zhang, Y.; Li, N.; Xu, J.-H. J. Chem. Soc., Perkin Trans. 1 1999, 2017; (m)
Sartori, G.; Maggi, R.; Bigi, F.; Porta, C.; Tao, X.; Bernardi, G. L.; Ianelli, S.;
Nardelli, M. Tetrahedron 1995, 51, 12179; (n) Miyano, M.; Stealey, M. A.
J. Org. Chem. 1982, 47, 3184.
4.3.13. Compound 18
6. (a) Kim, I.; Lee, G. H.; No, Z. S. Bull. Korean Chem. Soc. 2007, 28, 685;
(b) Kim, I.; Choi, J.; Won, H. K.; Lee, G. H. Tetrahedron Lett. 2007, 48,
6863; (c) Kim, I.; Won, H. K.; Choi, J.; Lee, G. H. Tetrahedron 2007, 63,
12954; (d) Kim, I.; Kim, S. G.; Kim, J. Y.; Lee, G. H. Tetrahedron Lett.
2007, 48, 8976.
7. (a) Devi, I.; Bhuyan, P. J. Tetrahedron Lett. 2004, 45, 7727; (b) Davion,
Y.; Joseph, B.; Beneteau, V.; Leger, J.-M.; Jarry, C.; Merour, J.-Y. Helv.
Chim. Acta 2003, 86, 2687; (c) Tietze, L. F.; Brumby, T.; Pretor, M.;
Remberg, G. J. Org. Chem. 1988, 53, 810; (d) Tietze, L. F.; Brand, S.;
1H NMR (300 MHz, CDCl3) d 7.24 (ddd, J¼9.3, 8.1, 0.6 Hz,
1H), 7.11 (dd, J¼7.8, 1.8 Hz, 1H), 7.02 (dt, J¼7.2, 0.9 Hz, 1H),
6.94 (d, J¼8.1 Hz, 1H), 6.39 (t, J¼1.8 Hz, 1H), 3.85 (s, 3H),
3.61 (dd, J¼3.3, 1.8 Hz, 1H), 3.25 (dd, J¼3.3, 1.5 Hz, 1H),
3.10 (dd, J¼18.3, 5.4 Hz, 1H), 2.72 (td, J¼18.6, 1.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 168.8, 167.1, 149.0, 130.0,
128.7, 124.2, 123.3, 117.9, 95.0, 53.2, 40.7, 36.2, 30.0; IR

I. Kim et al. / Tetrahedron 64 (2008) 664e671
671
Pfeiffer, T.; Antel, J.; Harms, K.; Sheldrick, G. M. J. Am. Chem. Soc.
1987, 109, 921; (e) Tietze, L. F.; von Kiedrowski, G.; Harms, K.; Clegg,
W.; Sheldrick, G. Angew. Chem., Int. Ed. Engl. 1980, 19, 134.
10. For the synthesis of 10, see Section 4. Also see: Ciganek, E. Synthesis
1995, 1311.
11. For the use of proline as a catalyst in the Knoevenagel condensations, see
Refs. 5a,c,d,e.
8. (a) Tietze, L. F.; Denzer, H.; Holdgrun, X.; Neumann, M. Angew. Chem.,
¨
Int. Ed. Engl. 1987, 26, 1295; (b) Tietze, L. F. Angew. Chem., Int. Ed.
12. CCDC 656410 contains the supplementary crystallographic data of
compound 13a. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Engl. 1983, 22, 828; (c) Tietze, L. F.; Glusenkamp, K.-H.; Holla, W.
¨
Angew. Chem., Int. Ed. Engl. 1982, 21, 793.
9. To the best of our knowledge, this cascade reaction has never been used for
the construction of bridged and fused ring system 9 although the synthesis
of the similar fused ring structure (shown below) was reported by Tietze.
See: Tietze, L. F.; Ott, C.; Haunert, F. Can. J. Chem. 2001, 79, 1511.
13. For other approaches to benzo-fused 2,8-dioxabicyclo[3.3.1]nonanes,
see: (a) Selenski, C.; Pettus, T. R. R. Tetrahedron 2006, 62, 5298;
(b) Chen, D.-U.; Kuo, P.-Y.; Yang, D.-Y. Bioorg. Med. Chem. Lett.
2005, 15, 2665.
O
14. For the use of 4-hydroxycoumarin in domino Knoevenagel condensation/
hetero-DielseAlder reactions, see: (a) Manian, R. D. R. S.; Jayashan-
karan, J.; Raghunathan, R. Tetrahedron Lett. 2007, 48, 1385; (b) Yadav,
J. S.; Reddy, B. V. S.; Naveenkumar, V.; Srinivasa Rao, R.; Nagaiah, K.
Synthesis 2004, 1783; (c) Shanmugasundaram, M.; Manikandan, S.;
Raghunathan, R. Tetrahedron 2002, 58, 997; (d) Cravotto, G.; Nano,
G. M.; Palmisano, G.; Pilati, T.; Tagliapietra, S. J. Heterocycl. Chem.
2001, 38, 965.
Me
O
Me
O
Me
N
N
N
O
O
O
N
Me
EDDA, MeOH
rt, 69%
O
O
Me
Me
O
Me
N
N
N
15. See Ref. 5d. Also, see: Tietze, L. F.; Rackelmann, N.; Muller, I. Chem.d
Eur. J. 2004, 10, 2722.
¨
O
O
O
O
H
H
N
Me
EDDA, MeOH
rt
n = 1 43%
n = 2 67%
n
O
n