A facile synthesis of bridged-tricyclic skeletons via intramolecular Diels-Alder reaction of cyclic 1,3-dienes containing an α,β- unsaturated ester

Article abstract of DOI:10.1002/jccs.200500057

Intramolecular Diels-Alder reaction (IMDA) precursors are easily available starting from addition of ester functionalized zinc-copper reagents to cyclohexadienyl- and cycloheptadienylirontricarbonyl cation salts. The resulting cyclic 1,3-dienes containing

Full text of DOI:10.1002/jccs.200500057

Journal of the Chinese Chemical Society, 2005, 52, 383-387
383
Note
A Facile Synthesis of Bridged-tricyclic Skeletons via Intramolecular
Diels-Alder Reaction of Cyclic 1,3-Dienes Containing an a,b-Unsaturated
Ester
Ming-Chang P. Yeh* (
Department of Chemistry, National Taiwan Normal University, Taipei 117, Taiwan, R.O.C.
), Wen-Cheng Tsao (
) and Ching-Jing Liu (
)
Intramolecular Diels-Alder reaction (IMDA) precursors are easily available starting from addition of es-
ter functionalized zinc-copper reagents to cyclohexadienyl- and cycloheptadienylirontricarbonyl cation salts.
The resulting cyclic 1,3-dienes containing an a,b-unsaturated ester functionality underwent smoothly IMDA
reaction to afford bridged tricyclic compounds. Bridged heterotricyclic skeletons were also available via
IMDA reaction of cyclic 1,3-dienes bearing an imine or aldehyde functionality.
Keywords: Cyclic 1,3-diene; Intramolecular Diels-Alder reaction; Bridged-tricyclic compound.
INTRODUCTION
Intramolecular Diels-Alder (IMDA) reaction has been
RESULTS AND DISCUSSION
Cyclohexa- and cyclohepta-1,3-dienes containing an
a,b-unsaturated ester can be synthesized using the method
developed in these laboratories. As shown in Scheme I, IMDA
reaction precursors, 2a-b, were prepared starting from addi-
tion of ester functionalized zinc-copper reagents RCu(CN)ZnI
to (h5-cyclohexadienyl)tricarbonyliron cation salt in THF ac-
cording to literature procedures.6 Decomplexation of the re-
sulting complexes with cerium ammonium nitrate (CAN) in
acetone followed by reduction with diisobutylaluminum hy-
dride (DIBAL) at -78 °C afforded cyclohexa-1,3-dienals 1a-
b. Treatment of the dienals with the Horner-Wadsworth-
Emmons reagent7 (Ph3PCHCO2Et) in CH2Cl2 at 30 °C for 4 h
furnished 2a-b, with an E stereochemistry at the double bond.
Cycloheptadiene analogs 2c-d were synthesized using a simi-
lar approach starting from cycloheptadienylirontricarbonyl
cation salt and ester functionalized zinc-copper reagents
(Scheme I).
widely utilized as one of the most powerful tools to construct
fairly complex carbocycles in organic synthesis.1 The 4+2 re-
action creates two new carbon-carbon bonds and generates
bicyclic compounds from a substrate having two separate
functional groups, diene and dienophile. Two types of IMDA
reaction are of great interest. When the diene and dienophile
are joined at the C-1 position of the diene, the reaction leads
to fused bicyclic compounds (type 1 IMDA),2 whereas the
type 2 variant of IMDA provides an access to bridged bi-
cyclic molecules in one step from the substrates with a di-
enophile at the C-2 position of the diene.3 These two types of
IMDA reactions can further be extended to the synthesis of
tricyclic skeletons by employing a system wherein a dieno-
phile is directly incorporated into a cyclic diene moiety. Sur-
prisingly, reports on the IMDA reaction of conjugated cyclic
dienes with a dienophile at the C-5 position of the rings are
rare.4,5 Herein we report that cyclohexa- and cyclohepta-1,3-
diene-tethered a,b-unsaturated esters undergo IMDA reac-
tion in refluxing n-butyl ether to give a variety of bridged
tricyclic skeletons. Moreover, IMDA reaction of cyclic 1,3-
dienes with an imine or aldehyde moiety furnished bridged
heterotricyclic compounds.
Our IMDA reaction study began with 2a. Substrate 2a
(0.33 g, 1.60 mmol) was added to a round-bottom flask con-
taining 100 mL of anhydrous n-butyl ether under nitrogen.
The dilute solution was stirred at 150 °C for 2 h and led to a
60% yield of tricyclo[4.3.1.03,7]dec-8-ene-2-carboxylic acid
ethyl ester (3) as the only stereoisomer isolated after chro-
* Corresponding author. E-mail: cheyeh@scc.ntnu.edu.tw

384 J. Chin. Chem. Soc., Vol. 52, No. 2, 2005
Yeh et al.
Scheme I
(OC) Fe
3
(OC) Fe
3
IZn(CH ) E
DIBAL-H
2 m
Ce(NH ) (NO )
4 2
3 6
o
( )
- 78 C
n
( )
( )
CuCN • 2 LiCl
n
n
(CH ) CO Et
2 m
2
(CH ) CO Et
2 m
2
a : m = 2, n = 1
b : m = 3, n = 1
c : m = 2, n = 2
d : m = 3, n = 2
Ph P CHCO Et
3
2
( )
CO Et
( )
n
2
n
o
(CH ) CHO
(CH )
2 m
30
C
2 m
2
1
matographic purification (eq 1). Of particular note is the use
of a readily available C-5 functionalized cyclohexa-1,3-diene
derivative 2a to control the relative stereochemistry of the
five contiguous asymmetric centers. NMR studies provided
the initial evidence for support of the structural assignments.
The resonances of a multiplet at d 6.20 for 3 were due to vinyl
protons at C-8 and C-9. A quartet, centered at d 4.08 was as-
signed to the methylene protons at C-12; a multiplet, centered
at d 2.86 was assigned to the methine proton at C-1 and a
multiplet, centered at d 2.45 was assigned to the methine pro-
ton at C-7. The C-13 NMR spectrum exhibited a signal at d
174.7 assigned to C-11 (carbonyl); two signals at d 132.5 and
131.4 assigned to two vinyl carbons (C-8 and C-9); and a sig-
nal at d 60.2 assigned to C-12. The relative configuration of
five contiguous stereogenic centers as depicted is fixed by
syn-endo addition of the dienophile to the diene. This stereo-
chemistry is generally governed by the steric and/or orbital
requirements, as is often the case for the IMDA reaction.8 The
substrate with an additional methylene group at the tether, 2b,
also underwent IMDA reaction to afford tricyclo[5.3.1.03,8]-
undec-9-ene-2-carboxylic acid ethyl ester (4) as the only
stereomer in 47% isolated yield (eq 2). However, the IMDA
reaction of seven-membered ring substrate, 2c, was more
sluggish and led to a 64% yield of tricyclo[4.3.2,03,7]undec-
8-ene-2-carboxylic acid ethyl ester (5) after refluxing 2c in
n-butyl ether for 6 days (eq 3). Attempted IMDA reaction of
2d failed to provide the desired product 6 (eq 4).
In order to further utilize the above method for synthe-
sis of bridged heterotricyclic skeletons we set out to exam the
IMDA reaction of the benzylimine derivative of cyclodienal
4
3
O
2
12
5
n-butyl ether
CO2Et
7
11
O
(1)
8
13
(CH2)2
6
o
150 C, 2h
1
10
9
60%
2a
3
O
n-butyl ether
CO2Et
O
(2)
(CH2)3
o
150 C, 6h
47%
2b
4

Tricycles via Intramolecular Diels-Alder Reaction
J. Chin. Chem. Soc., Vol. 52, No. 2, 2005 385
O
n-butyl ether
CO Et
( )
2
O
(3)
2
(CH )
2 2
o
150 C, 7d
64%
2c
5
O
( )
2
CO Et
2
O
(4)
X
(CH )
2 3
2d
6
not formed
C H CH NH HCl
6
5
2
2
EtOH/H O
2
N
(5)
Ph
o
70 C, 24h
75%
(CH ) CHO
(CH ) CH NCH Ph
2 2
2 2
2
1a
7
O
THF
( )
(6)
2
o
65 C, 48 h
60%
(CH ) CHO
2 2
9
1c
1a by slow addition of 1a over 10 h to a 1.0 M solution of
benzylamine hydrochloride (excess) in water/ethanol (1:1) at
ca. 70 °C. The reaction was further stirred at 70 °C for 24 h to
produce 2-benzyl-2-azatricyclo[4.3.1.03,7]dec-8-ene (7) in
75% yield. The formation of 7 was derived from IMDA reac-
tion of the initially formed benzylimine with the cyclic 1,3-
diene (eq 5). The spectral data for 7 are similar to those of 8
found in the literature.5 Moreover, IMDA reaction of the
seven-membered ring substrate, 1c, also provided 2-oxatri-
cyclo[4.3.2.03,7]undec-8-ene (9) in 60% yield after refluxing
1c in THF at 65 °C for 48 h (eq 6).
reo-controlled manner to give bridged tricyclic skeletons.
This chemistry can be extended to bridged tricyclic amine
and ether derivatives by IMDA reaction of cyclic 1,3-dienes
with an imine and aldehyde functionality, respectively.
EXPERIMENTAL
All reactions were run under an argon atmosphere in
oven-dried glassware unless otherwise indicated. Complexes
2a-d were synthesized following the literature procedures.6
Anhydrous solvents or reaction mixtures were transferred via
an oven-dried syringe or cannula. Tetrahydrofuran (THF)
was predried by molecular sieves and then by passing through
an Al2O3 column.9 n-Butyl ether was distilled from CaH2
prior to use. Flash column chromatography, following the
method of Still, was carried out with E. Merck silica gel
(Kieselgel 60, 230-400 mesh) using the indicated solvents.10
1H nuclear magnetic resonance (NMR) spectra were obtained
IMDA reaction of cyclohexa- and cyclohepta-1,3-di-
enes with an a,b-unsaturated ester moiety proceeded in a ste-
Me
N
8

386 J. Chin. Chem. Soc., Vol. 52, No. 2, 2005
Yeh et al.
with Bruker-AC 400 (400 MHz) and Varian G-200 (200
MHz) spectrometers. The chemical shifts are reported in
parts per million with either tetramethylsilane (0.00 ppm) or
CDCl3 (7.26 ppm) as internal standard. 13C NMR spectra
were recorded with Bruker-AC 400 (100.4 MHz) spectrome-
ter with CDCl3 (77.0 ppm) as the internal standard. Infrared
(IR) spectra were recorded with a JASCO IR-700 spectrome-
ter. Mass spectra were acquired on a JEOL JMS-D 100 spec-
trometer at an ionization potential of 70 eV and are reported
as mass/charge (m/e) with percent relative abundance. High-
resolution mass spectra were obtained with an AEI MS-9
double-focusing mass spectrometer and a JEOL JMS-HX
110 spectrometer at the Department of Chemistry, Central In-
strument Center, Taichung, Taiwan.
2H), 1.43 (m, 5H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
100 MHz): d 175.50, 136.59, 131.99, 60.13, 47.68, 38.49,
34.60, 32.33, 30.32, 29.53, 29.04, 14.86, 14.24; IR (CH2Cl2):
3049, 2986, 2929, 2685, 2410, 2305, 1422, 1264 cm-1; MS
(20 ev) m/e: 220 (M+), 174, 130, 91, 79, 77; HRMS (EI) m/e
calcd for C14H20O2 220.1463, found 220.1459.
Tricyclo[4.3.2.03,7]undec-8-ene-2-carboxylic acid ethyl es-
ter (5)
The crude mixture from IMDA reaction of 2c (0.23 mg,
1.05 mmol) was purified via flash column chromatography
(silica gel, hexanes/ethyl acetate = 40/1) to give 5 (0.14 g,
0.79 mmol, 64%). 1H-NMR (CDCl3, 400 MHz): d 6.03 (dd, J
= 11, 8.5 Hz, 1H), 5.89 (t, J = 9.0 Hz, 1H), 4.03 (q, J = 5.9 Hz,
2H), 2.77 (t, J = 9.3 Hz, 1H), 2.46 (m, 2H), 2.16 (m, 1H), 2.08
(m, 1H), 1.80 (m, 2H), 1.53 (m, 3H), 1.40 (m, 3H), 1.15 (t, J =
5.9 Hz, 3H); 13C NMR (CDCl3, 100 MHz): d 176.20, 130.67,
128.40, 60.25, 55.50, 43.75, 42.23, 36.26, 35.53, 33.73,
27.60, 27.29, 25.41, 14.25; IR (CH2Cl2): 3055, 2975, 2928,
2358, 1717, 1605, 1558, 1317 cm-1; MS (20 ev) m/e: 220
(M+), 201.2, 191.2, 174.2, 149, 117.1, 114.1, 105.1, 91.1,
79.1, 77.1; HRMS (EI) m/e calcd for C14H20O2 220.1463,
found 220.1459.
General Procedure I: IMDA Reaction of Cyclic
1,3-Dienes Containing an a,b-Unsaturated Ester Moiety
A solution of 2a (0.33 mg, 1.60 mmol) in 100 mL of dry
n-butyl ether was refluxed under nitrogen. The reaction was
1
terminated until substrate 2a was no longer detected on H
NMR.
Tricyclo[4.3.1.03,7]dec-8-ene-2-carboxylic acid ethyl ester
(3)
The crude mixture from IMDA reaction of 2a (0.33 mg,
1.60 mmol) was purified via flash column chromatography
(silica gel, hexanes/ethyl acetate = 40/1) to give 3 (0.20 g,
2-Benzyl-2-azatricyclo[4.3.1.03,7]dec-8-ene (7)
Benzylaminehydrochloride (0.95 g, 7.25 mmol) was
added to a 25-mL round-bottom flask containing 3.3 mL of
50% EtOH/H2O. Dienal 1a (0.2 g, 1.50 mmol) in 3.3 mL of
50% EtOH/H2O was added slowly to the reaction mixture.
The reaction was stirred for 40 h at 70 °C. The reaction was
quenched with saturated NaHCO3 solution and was extracted
with ethyl acetate (ca. 30 mL). The resultant solution was
washed with water, brine and dried with anhydrous MgSO4.
The solution was filtered and concentrated on a rotary evapo-
rator to give the crude mixture. The crude mixture was puri-
fied by flash column chromatography (silica gel, hexanes/
ethyl acetate = 40/1) to give 7 (0.25 g, 1.11 mmol, 75%). 1H-
NMR (CDCl3, 400 MHz): d 7.36 (d, J = 7.4 Hz, 2H), 7.30 (t, J
= 7.4 Hz, 2H), 7.22 (t, J = 7.1 Hz, 1H), 6.37 (m, 2H), 3.68 (d, J
= 13.6 Hz, 1H), 3.36 (d, J = 13.4 Hz, 1H), 3.30 (m, 1H), 2.47
(m, 1H), 2.41 (m, 1H), 1.74 (m, 4H), 1.50 (m, 3H); 13C NMR
(CDCl3, 100 MHz): d 140.54, 133.95, 129.76, 128.90, 128.03,
126.55, 63.17, 60.83, 50.62, 42.13, 38.59, 32.97, 32.68,
31.44; IR (CH2Cl2): 3055, 2985, 2685, 2305, 1733, 1423,
1674, 1258 cm-1; MS (20 ev) m/e: 226 (M+1), 201.2, 174.2,
149.0, 117.1, 114.1, 105.1, 91.1, 79.1, 77.1; HRMS (EI) m/e
1
0.96 mmol, 60%). H-NMR (CDCl3, 400 MHz): d 6.20 (m,
2H), 4.08 (q, J = 7.2 Hz, 2H), 2.86 (m, 1H), 2.45 (m, 1H), 2.36
(m, 1H), 2.17 (dd, J = 5.3, 2.7 Hz, 1H), 1.88 (m, 2H), 1.46 (m,
3H), 1.24 (t, 7.2 Hz, 3H), 0.98 (m, 1H); 13C-NMR (CDCl3,
100 MHz): d 174.73, 132.54, 131.43, 60.20, 54.19, 41.93,
39.27, 37.46, 34.17, 32.05, 31.85, 31.36, 14.29; IR (CH2Cl2):
3055, 2985, 2685, 2305, 1733, 1423, 1674, 1258 cm-1; MS
(20 ev) m/e: 206 (M+), 160, 133, 104, 91, 79, 77; HRMS (EI)
m/e calcd for C13H18O2 206.1307, found 206.1304.
Tricyclo[5.3.1.03,8]undec-9-ene-2-carboxylic acid ethyl es-
ter (4)
The crude mixture from IMDA reaction of 2b (0.37 mg,
1.68 mmol) was purified via flash column chromatography
(silica gel, hexanes/ethyl acetate = 40/1) to give 4 (0.17 g,
0.79 mmol, 47%). 1H-NMR (CDCl3, 400 MHz): d 6.37 (t, J =
7.1 Hz, 1H), 6.18 (t, J = 6.9 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H),
2.89 (d, J = 3.1 Hz, 1H), 2.32 (dd, J = 4.6, 2.5 Hz, 1H), 2.12
(dt, J = 6.4, 2.7 Hz, 1H), 2.05 (m, 1H), 1.68 (m, 2H), 1.56 (m,

Tricycles via Intramolecular Diels-Alder Reaction
calcd for C16H19N 225.1517, found 225.1523.
J. Chin. Chem. Soc., Vol. 52, No. 2, 2005 387
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ACKNOWLEDGEMENTS
This work was supported by grants from the National
Science Council (NSC 92-2113-M-003-009).
Received November 30, 2004.