Inter- and intramolecular diels-alder reaction of ethenetricarboxylate derivatives

Article abstract of DOI:10.3987/COM-15-13394

Inter- and intramolecular [4+2] cycloaddition reactions of highly electron-deficient ethenetricarboxylates have been studied. Intermolecular Diels-Alder reaction of ethenetricarboxylate esters and cyclopentadiene proceeded at room temperature or -20 °C to give cycloadducts with 1:1.5-1.9 endo:exo ratio. Lewis acids such as EtAlCl2, Zn(OTf)2 and Cu(OTf)₂ catalyzed reaction at room temperature or -40 °C gave cycloadducts with 3.1-5.4:1 endo:exo ratio. Reaction of N-benzyl- or N-allyl-2-furylmethylamine and 1,1-diethyl 2-hydrogen ethenetricarboxylate in the presence of EDCI/HOBt/Et₃N at room temperature led directly to an intramolecular Diels-Alder adduct stereoselectively. The observed stereoselectivities were explained by the use of DFT calculations.

Full text of DOI:10.3987/COM-15-13394

HETEROCYCLES, Vol. 92, No. 3, 2016
485
HETEROCYCLES, Vol. 92, No. 3, 2016, pp. 485 - 510. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 11th December, 2015, Accepted, 20th January, 2016, Published online, 4th February, 2016
DOI: 10.3987/COM-15-13394
INTER- AND INTRAMOLECULAR DIELS-ALDER REACTION OF
ETHENETRICARBOXYLATE DERIVATIVES
Shoko Yamazaki,*a Hirotaka Sugiura,a Mamiko Niina,a Yuji Mikata,b and
Akiya Ogawac
aDepartment of Chemistry, Nara University of Education, Takabatake-cho, Nara
b
630-8528, Japan, KYOUSEI Science Center, Nara Women's University, Nara
c
630-8506, Japan, Department of Applied Chemistry, Graduate School of
Engineering, Osaka Prefecture University, Gakuen-cho 1-1, Nakaku, Sakai, Osaka
599-8531, Japan; E-mail: yamazaks@nara-edu.ac.jp
Abstract – Inter- and intramolecular [4+2] cycloaddition reactions of highly
electron-deficient ethenetricarboxylates have been studied. Intermolecular
Diels-Alder reaction of ethenetricarboxylate esters and cyclopentadiene proceeded
at room temperature or -20 °C to give cycloadducts with 1:1.5-1.9 endo:exo ratio.
Lewis acids such as EtAlCl2, Zn(OTf)2 and Cu(OTf)2 catalyzed reaction at room
temperature or -40 °C gave cycloadducts with 3.1-5.4:1 endo:exo ratio. Reaction
of N-benzyl- or N-allyl-2-furylmethylamine and 1,1-diethyl 2-hydrogen
ethenetricarboxylate in the presence of EDCI/HOBt/Et3N at room temperature led
directly to an intramolecular Diels-Alder adduct stereoselectively. The observed
stereoselectivities were explained by the use of DFT calculations.
INTRODUCTION
Diels-Alder reaction is one of the most widely used synthetic tools.1 The alkene component (dienophile)
is usually electron-deficient in normal electron-demand Diels-Alder reaction. In general, the greater the
number of electron-withdrawing substituents on the double bond, the more reactive is the dienophile,
owing to the lowering of the energy of the LUMO of the dienophile by the substituents.
Ethenetricarboxylate derivatives bearing three carbonyl groups have been employed as highly
electrophilic C=C components in various bond-forming reactions.2 Although an intramolecular inverse
electron demand hetero Diels-Alder reaction of 1-allylic 2,2-dimethyl esters of
ethene-1,2,2-tricarboxylate has been studied,3 only a few normal electron demand Diels-Alder reactions
of ethenetricarboxylate related compounds as electron-deficient dienophiles have been reported.4

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HETEROCYCLES, Vol. 92, No. 3, 2016
Ethenetricarboxylates allow for the facile derivatization at 2-carboxyl group. The electron-deficient
alkene moiety is expected to work as a reactive dienophile in the intramolecular Diels-Alder reaction.
The intramolecular Diels-Alder reaction of furans is used for facile formation of multicyclic skeletons.5
Furan derivatives can be obtained from renewable resources.6 The development of new synthetic methods
utilizing furans is of considerable interest.7 Lewis acid-catalyzed reaction of furan derivatives with
electron-deficient alkenes also gave Friedel-Crafts/conjugate addition products.8 The diversity of the
reactivity of furans is also of interest.
In this work, intermolecular and sequential intramolecular Diels-Alder reactions of ethenetricarboxylate
derivatives with dienes have been studied.
Intermolecular Diels-Alder
reaction
EtO2C
EtO2C
O
Y
O
RO2C
Y = OR
HN
EtO
O
OEt
Sequential intramolecular
Diels-Alder reaction
R1
EtO2C
CO2Et
O
EtO2C
O
O
EtO2C
O
H
O
HOBt
EDCI
Et3N
Y = OH
N
N
R1
R1
Scheme 1
RESULTS AND DISCUSSION
We have reported Lewis acid-catalyzed intermolecular reaction of ethenetricarboxylates with furan
derivatives to give Friedel-Crafts/ conjugate addition products.9 Both intermolecular Diels-Alder
reactions of methylenemalonates /alkylidenemalonates and dienes10 such as butadiene, cyclopentadiene or
1-methoxy-3-trimethylsiloxy-1,3-butadiene
and
intramolecular
Diels-Alder
reactions
of
alkylidenemalonates and dienes11 were reported previously. First, intermolecular Diels-Alder reaction of
ethenetricarboxylates and reactive dienes has been examined. The reaction of ethenetricarboxylate esters
1 and cyclopentadiene 2 proceeded at room temperature or -20 °C to give cycloadducts 3 with 1:1.5-1.9
endo:exo ratio (eq 1, Table 1). Endo and exo structures were assigned by observed NOEs between C3-H
and C5-H for endo and between C3-H and C7-HH for exo. Lewis acids such as Zn(OTf)2 and Cu(OTf)2
catalyzed reaction at room temperature gave cycloadducts 3 with 3.1-3.3:1 endo:exo ratio. EtAlCl2
catalyzed reaction at lower temperature increased endo:exo ratio. Thus, the uncatalyzed and Lewis
acid-catalyzed Diels-Alder reactions of ethenetricarboxylates 1 and cyclopentadiene 2 showed opposite

HETEROCYCLES, Vol. 92, No. 3, 2016
487
preference for stereoselectivity.
Treatment of cycloadduct 3b (1 : 1.8 endo:exo ratio) obtained by entry 8 reaction condition with
Zn(OTf)2 and Cu(OTf)2 at room temperature for 17 h resulted in very little change of the endo:exo ratio.
The possible epimerization of cycloadducts 3 by retro-[4+2]/[4+2]-cycloaddition10c may be very slow at
room temperature in the presence of these Lewis acids.
7
7
(Lewis
acid)
CO2Et
+
EtO2C
RO2C
1
6
1
6
2
2
CO2Et
CO2Et
CO2R
+
5
4
5
4
3
CH2Cl2
17 h
CO2Et
CO2R
3
CO2Et
1
2
(eq 1)
3-endo
3-exo
Table 1. Reactions of Ethenetricarboxylate Esters 1 and Cyclopentadine 2
Entry
R
Temp.
Lewis Acid Equiv. Product 3-endo:3-exo 3 Yield (%)
1
1
2
3
4
5
6
7
8
9
10
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Et
rt
-
1 : 1.5
1 : 1.9
3.1 : 1
3.2 : 1
96
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
3a
3a
3a
3a
-20 °C
-
62
rt
Zn(OTf)2
Cu(OTf)2
EtAlCl2
EtAlCl2
EtAlCl2
-
0.1
0.1
0.1
0.1
0.1
92
rt
88
rt
decomposed
-20 °C
-40 °C
rt
2.8 : 1
5.4 : 1
1 : 1.8
3.3 : 1
3.6 : 1
100
100
73
3a
3a
3b
3b
3b
Et
rt
Zn(OTf)2
EtAlCl2
0.1
0.1
97
Et
-40 °C
99
In order to explain the observed endo:exo preferences,12 the reaction mechanism was examined using
B3LYP/6-31G*13,14 calculations including the PCM15 solvent effect (solvent=CH2Cl2). TS geometry was
characterized by vibrational analysis, which checked whether the obtained geometry has single imaginary
frequencies (Q‡). From TSs, reaction paths were traced by the intrinsic reaction coordinate (IRC) method16
to obtain the energy-minimum geometries. Relative Gibbs free energies are of RB3LYP/6-31G* SCRF =
(PCM, solvent = CH2Cl2) (T = 298.15 K, P = 1 atm).
First, the conformations of compound 1 were calculated through the use of model compound trimethyl
ethenetricarboxylate 1m. Stable four conformations of 1m with respect to s-cis and s-trans of ester C=O
groups were obtained by geometry optimization. In the optimized structures, 1-syn ester group to 2-ester
is located almost perpendicularly to C=C plane. None of C=O of 1-syn ester on the C=C plane was
obtained, probably because of steric congestion. The energy differences of C=C−C=O s-cis and s-trans

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HETEROCYCLES, Vol. 92, No. 3, 2016
are small (within +1.73 kcal/mol) (Figure 1). Using the most stable conformation of 1m(cc) (cc =
1-anti-s-cis, 2-s-cis), the endo and exo transition states of the intermolecular Diels-Alder reaction of 1m
and cyclopendtadiene (2) were calculated (Figure 2). The activation energy 'G‡ of endo transition state
(TS) is 1.03 kcal/mol higher than that of exo TS. The exo preference is in accord with the experimental
results.
Although 1-syn ester group is perpendicular to C=C plane, it has still an electron-withdrawing effect. C-2
carbon may interact with diene first by the slight asynchronous approach (C2-C1' = 2.168 Å, C1-C4' =
2.327 Å for 2-ester exo TS, C2-C1' = 2.219 Å, C1-C4' = 2.291 Å for 2-ester endo TS). The exo approach
on 2-ester and 1-syn ester is considered to be endo approach on 1-anti ester group. The secondary orbital
interaction of 1-anti ester carbonyl carbon with diene carbon in 2-ester endo TS may be slightly more
effective than that of 2-ester carbonyl carbon in 2-ester endo TS (OC-C3' = 2.973 Å for 2-ester exo TS,
OC-C2' = 2.997 Å for 2-ester endo TS).
1-anti
O
O
O
O
H
O
H
H
O
1-syn
O
2
1
O
O
O
H
O
O
O
H
O
H
O
O
H
H
H
O
O
O
H
H
H
O
H
O
H
H
H
H
O
O
O
H
H
H
1m(cc)
[0 kcal/mol]
1m(tc)
[+0.60 kcal/mol]
O
H
O
H
O
H
O
O
O
O
H
O
O
H
O
O
O
H
O
O
H
O
O
H
H
O
O
H
H
O
O
H
H
H
O
O
H
H
O
O
H
H
H
H
1m(tt)
[+1.73 kcal/mol]
1m(ct)
[+1.21 kcal/mol]
Figure 1. RB3LYP/6-31G* SCRF = (PCM, solvent = CH2Cl2) optimized structures for conformational
isomers of trimethyl ethenetricarboxylate 1m. Gibbs free energies are relative to 1m(cc).

HETEROCYCLES, Vol. 92, No. 3, 2016
489
O
1-anti
O
O
CO2Me
2
1
O
O
CO2Me
CO2Me
O
CO2Me
CO2Me
O
H
H
1'
H
O
4'
H
H
H
H
H
H
2'
H
3'
O
H
O
H
H
O
O
O
O
H
O
O
H
H
H
O
H
2.219 Å
H
H
1
2
O
O
O
H
H
H
O
H
2.291 Å
H
O
1.591 Å
1.589 Å
H
H
O
3.460 Å
H
O
H
H
H
O
H
4.126 Å
H
H
H
O
H
H
4'
1'
2.997 Å
H
H
H
H
H
H
H
H
3'
H
2'
H
H
1m(cc)---2 endo
[+1.10 kcal/mol]
2-ester endo
(1-anti-ester exo) TS
3m-endo
[-4.99 kcal/mol]
[+23.80 kcal/mol]
Q‡ = 381.76i cm-1
O
O
1-anti
H
H
O
1
2
H
O
MeO2C
MeO2C
O
CO2Me
H
H
H
O
O
2'
CO2Me
3'
H
O
O
O
H
O
1'
H
H
H
O
MeO2C
O
4'
2.973 Å
H
O
H
H
O
H
H
H
H
O
1
2
O
O
H
H
H
H
O
H
H
H
O
O
H
H
H
O
1.585 Å
H
H
4.048 Å
H
O
O
H
2'
3'
1.588 Å
O
H
3.619 Å
H
O
H
2.327 Å
H
2.168 Å
H
H
H
H
H
H
1'
4'
H
H
H
H
H
H
1m(cc)---2 exo
[0 kcal/mol]
2-ester exo
3m-exo
[-6.03 kcal/mol]
(1-anti-ester endo) TS
[+22.77 kcal/mol]
Q‡ = 389.61i cm-1
Figure 2. RB3LYP/6-31G* SCRF = (PCM, solvent = CH2Cl2) optimized structures for endo:exo
Diels-Alder reaction paths of 1m(cc) and cyclopentadiene (2). Gibbs free energies are relative to
1m(cc)---2endo.
Next, Lewis acid-catalyzed Diels-Alder reaction of 1m and cyclopendtadiene (2) was examined using the
bidentate AlCl3-coordinated 1m shown in Figure 3 as a model system.17,18 In the initial AlCl3-1m and 2
complex, 2-ester group is located perpendicularly to C=C plane (1,1-diester C=O groups are both s-trans
to C=C). Stepwise mechanism with zwitterionic intermediates was obtained.19 Lewis acid-catalyzed
reaction lowers the activation energies. The activation energy 'G‡ of endo TS1 is 1.16 kcal/mol lower
than that of exo TS1. The endo preference is in accord with the experimental results. The endo preference
may arise from the steric congestion of 2-ester group and methylene hydrogen of cyclopentadiene in exo
TS. The endo preference in the kinetic product has also been reported in the TiCl4-catalyzed
cycloaddition reaction of dimethyl benzylidenemalonate and cyclopentadiene at -78 °C.10c

490
HETEROCYCLES, Vol. 92, No. 3, 2016
Cl
Cl
Cl
H
H
2.192 Å
2.235 Å
H
H
(+0.74)
H
H
(-0.55)
O
H
O
Al
2.069 Å
O
H
Al
O
Cl
Cl
Al
Cl
Cl
H
H
H
1.979 Å
O
O
H
Cl
H
O
H
O
Cl
H
O
1.880 Å
(-0.58)
O
O
H
O
H
2.185 Å
H
H
1.922 Å
H
H
H
H
O
H
O
H
O
H
H
O
O
H
H
H
3.473 Å
H
H
H
H
O
H
H
3.588 Å
H
AlCl3
3.274 Å
O
O
3.307 Å
H
H
O
H
2.411 Å
O
1.613 Å
H
H
H
(+0.21)
O
O
H
AlCl3
AlCl3
O
O
O
H
H
(+0.24)
MeO2C
O
H
MeO2C
H
O
2-ester endo TS1
[+5.52 kcal/mol]
Q‡ = 126.74i cm-1
O
MeO2C
AlCl3-1m---2 endo
[+1.31 kcal/mol]
2-ester endo Int
[-3.84 kcal/mol]
Cl
Cl
H
H
H
H
H
H
H
2.059 Å
H
O
H
O
Al
Al
O
OH
O
Cl
Cl
H
O
O
H
O
H
Cl
H
H
Cl
H
O
H
1.920 Å
O
H
O
H
1.681 Å
H
H
O
H
H
H
1.567 Å
OMe
O
1.604 Å
2.297 Å
H
H
AlCl3
O
O
O
H
H
H
H
H
H
MeO
MeO2C
AlCl3
O
O
MeO2C
2-ester endo TS2
[+0.55 kcal/mol]
Q‡ = 186.68i cm-1
AlCl3-3m-endo
[-4.77 kcal/mol]
Cl
Cl
Cl
H
H
2.191 Å
(+0.75)
H
2.054 Å
2.237 Å
H
(-0.56)
1.975 Å
H
Cl
Cl
Al
Al
Cl
O
H
Al
O
H
O
O
H
Cl
H
H
H
O
H
Cl
O
O
H
O
O
Cl
O
1.879 Å
O
H
H
O
H
(-0.58)
1.924 Å
3.508 Å
H
H
H
2.188 Å
H
O
H
H
H
H
O
O
O
H
H
H
H
H
H
H (+0.22)
2.327 Å
H
H
H
H
3.457 Å
3.293 Å
O
3.211 Å
H
O
H
H
H
H
(+0.21)
H
H
H
1.613 Å
AlCl3
O
O
O
H
O
H
AlCl3
O
O
O
O
O
AlCl3
H
MeO2C
H
O
O
O
MeO2C
H
MeO2C
AlCl3-1m---2 exo
2-ester exo TS1
[+6.68 kcal/mol]
Q‡ = 194.70i cm-1
2-ester exo Int
[-2.05 kcal/mol]
[0 kcal/mol]
Cl
H
H
H
Cl
H
H
H
O
H
2.051 Å
O
O
O
Al
H
Cl
Al
O
O
H
H
Cl
O
H
Cl
H
H
Cl
H
O
H
1.926 Å
O
H
1.608 Å
H
H
H
O
H
O
H
H
H
O
H
H
MeO
O
H
2.325 Å
H
H
H
AlCl3
O
O
O
O
1.572 Å
1.654 Å
H
H
MeO2C
Cl3Al
H
MeO2C
2-ester exo TS2
[2.02 kcal/mol]
Q‡ = 180.32i cm-1
O
OMe
AlCl3-3m-exo
[-4.79 kcal/mol]
Figure 3. RB3LYP/6-31G* SCRF = (PCM, solvent = CH2Cl2) optimized structures for endo:exo
Diels-Alder reaction paths of AlCl3-1m and cyclopentadiene (2). Gibbs free energies are relative to
AlCl3-1m---2exo. Values in parentheses are Mulliken charges with hydrogens summed into heavy atoms.
The reaction of 1b and Danishefsky's diene has also been carried out. The reaction of 1b and
1-methoxy-3-trimethylsiloxy-1,3-butadiene 4 in dichloromethane proceeded at room temperature to give
the crude adduct 5, which was hydrolyzed directly with 1 N HCl in THF to give the cyclohexenone 6 in
67% yield regioselectively.

HETEROCYCLES, Vol. 92, No. 3, 2016
491
OMe
OMe
3
CO2Et
+
EtO2C
2
EtO2C
EtO2C
EtO2C
rt
EtO2C
EtO2C
1H HCl
THF
4
(eq 2)
CH2Cl2
OSiMe3
EtO2C
1
O
5
OSiMe3
6
EtO2C
1b
6
4
5
(67%)
Thus, it was shown that ethenetricarboxylates 1 have high reactivity towards Diels-Alder reaction with
reactive dienes such as 2 and 4.
Next, intramolecular [4+2] cycloaddition reaction of ethenetricarboxylates has been examined. Reaction
of N-benzyl- or N-allyl-2-furylmethylamine 8a,b and 1,1-diethyl 2-hydrogen ethenetricarboxylate 7 in the
presence of EDCI/HOBt/Et3N at room temperature led directly to an intramolecular Diels-Alder adducts
9a,b in 65-82% yield (eq 3, Table 2). The possible intermediate 10 could not be observed under the
reaction conditions of amide formation (Scheme 2). The reaction of 7 and 8a in the absence of
condensation reagents only gave the mixture of the 7 and 8a, probably forming a salt. Treatment of the
mixture with condensation reagents led to the Diels-Alder adduct 9a in 75% yield.
The structure of 10-oxa-3-aza-tricyclo[5.2.1.01,5]dec-8-ene 9a was determined by X-ray analysis (Figure
4).20 The exo stereochemistry of Diels-Alder adducts 9a-e with respect to the amide group was also
determined by NOEs. NOEs between C5-H and C2-HH and/or between C5-H and C9-H were observed
(atom numbering is shown in eq 3.).
Figure 4. ORTEP drawing of 9a (thermal ellipsoids are drawn at 50% probability). The atom numbering
is different from that in eq 3.

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HETEROCYCLES, Vol. 92, No. 3, 2016
R3
7
HOBt
CO2Et
+
R2
HN
6
5
EtO2C
O
EtO2C
8
9
EDCI
R3
EtO2C
O
(eq 3)
O
H
O
R1
Et3N
1
2
R2
4 N
OH
R1
3
7
8
9
Table 2. Reactions of 1,1-Diethyl 2-hydrogen ethenetricarboxylate 7 and 2-Furylmethylamines 8
Entry
R1
R2 R3 Temp,Time solvent
Product Yield (%)
8
1
2
3
4
5
6
8
4
6
7
CH2CH=CH2
CH2Ph
CH2Ph
CHMePh
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
H
H
H
H
rt 17 h
rt 21 h
rt 20 h
rt 20 h
THF
THF
THF
THF
THF
THF
82
8a
8b
8c
8d
8e
8e
8e
8e
8b
8b
9a
9b
9c
9d
9e
9e
9e
9e
9b
9b
65
Me H
48 (dr=2:1)
H
H
H
H
H
H
H
H
43 (dr=1:1)
Br rt 20 h
Br rt 1 h
48
40
55
75
46
50
Br 60 ˚C, 20 h THF
Br 80 ˚C, 20 h CH2ClCH2Cla
H
H
60 ˚C, 20 h THF
80 ˚C, 20 h CH2ClCH2Cla
a The byproducts was removed by column chromatography.22
EtO2C
CO2Et
+
EtO2C
O
HOBt
EDCI
CO2Et
O
EtO2C
O
EtO2C
O
H
O
O
R1
Et3N
THF
rt
HN
OH
N
8
N
R1
R1
9
7
10
not detected
EtO2C
CO2Et
EtO2C
O
HOBt
EDCI
EtO2C
H
O
H
O
N
7 • 8a
+
THF
rt
O
Et3N
THF
N
OH
8a
75%
9a
7
Scheme 2
In order to explain the stereoselectivity of the intramolecular Diels-Alder reaction was examined by
B3LYP/6-31G* calculations including the PCM solvent effect (solvent=THF).
The endo and exo intramolecular Diels-Alder reactions from a model compound 10m as a possible

HETEROCYCLES, Vol. 92, No. 3, 2016
493
intermediate were calculated (Figure 5). The activation energy 'G‡ of endo TS (31.17 kcal/mol) is much
higher than that of exo TS (21.41 kcal/mol). The acid-catalyzed intramolecular Diels-Alder reactions of
10m were also calculated (Figure 6). The protonated six-membered ring intermediates with hydrogen
bonding
were
assumed.21
The
acid
in
situ,
possibly
generating
from
EDCI
(1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride) or starting material 7 may catalyze the
cycloaddition reactions. Stepwise mechanism with zwitterionic intermediates was obtained for the
H+-catalyzed reaction. The acid-catalyzed reaction lowers the activation energies compared to the
uncatalyzed reaction. The activation energy 'G‡ of the second bond formation TS (H+IM-exo-TS2)
(10.10 kcal/mol) is higher than that of the first TS (H+IM-exo-TS1) (1.51 kcal/mol) for exo addition. The
H+-catalyzed process accelerates the formation of the exo adduct 9.
The first bond formation TS (H+IM-endo-TS1) for endo addition was obtained, however the second bond
formation TS could not be obtained. Optimization of the initial structure of endo10m-H+ led to the
intermediate (H+IM- endo-Int). The endo TS and product are highly unstable probably because of the
steric constraint. Therefore, the exo adducts 9 produced stereoselectively.
MeO2C
MeO2C
H
O
MeO2C
CO2Me
O
MeO2C
O
H
H
MeO2C
O
H
O
H
H
H
H
O
H
H
H
N
N
O
O
O
O
N
H
O
O
H
H
H
O
O
H
O
O
O
H
H
H
H
H
O
O
H
1.597 Å
O
O
H
2.422 Å
3.471 Å
H
H
O
H
H
H
H
H
N
1.566 Å
N
1.685 Å
O
H
H
H
N
H
H
H
O
H
H
H
H
H
H
H
H
H
H
H
9m
exo10m
[0 kcal/mol]
IM-exo-TS
[+21.41 kcal/mol]
[+4.92 kcal/mol]
H
H
H
H
MeO2C
MeO2C
H
CO2Me
MeO2C
O
H
MeO2C
MeO2C
H
O
H
O
O
H
O
H
H
O
O
O
O
N
N
O
N
O
H
O
O
O
O
H
H
H
O
H
H
H
H
3.571 Å
2.220 Å
H
O
H
H
1.638 Å
H
H
O
H
H
H
H
O
O
O
H
N
H
H
H
H
N
O
N
H
1.614 Å
H
1.552 Å
O
H
H
H
H
H
H
H
H
H
H
H
O
H
endo9m
[+23.33 kcal/mol]
endo10m
[0.21 kcal/mol]
IM-endo-TS
[+31.17 kcal/mol]
Figure 5. RB3LYP/6-31G* SCRF = (PCM, solvent=THF) optimized structures for endo:exo
intramolecular Diels-Alder reaction paths of 10m.

494
HETEROCYCLES, Vol. 92, No. 3, 2016
H
H O
O
H O
OMe
O
O
OMe
O
O
OMe
O
MeO
O
MeO
O
MeO
O
O
H
H
H
H
H
N
N
H
H
N
H
1.036 Å
H
H
O
O
H
H
H
O
1.526 Å
O
H
O
O
O
O
H+
3.187 Å
O
O
H 3.323 Å
O
exo10m
H
O
H
2.140 Å
H
H
O
H
O
H
H
H
H
O
N
H
H
N
H
H
O
O
2.463 Å
H
O
H
H
(+0.48)
H
H
H
1.620 Å
N
3.131 Å
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
exo10m-H+
[0 kcal/mol]
H+IM-exo-Int
[-2.18 kcal/mol]
H+IM-exo-TS1
[+1.51 kcal/mol]
H O
O
OMe
O
H
O
H
O
H
OMe
O
O
H
H
O
O
H
H
H
MeO
O
H
MeO
O
H
O
H
O
-H+
H
1.690 Å
H
H
O
exo9m
N
H
O
O
N
H
O
O
H
H
H
H
O
H
H
H
H
1.993 Å
1.573 Å
1.600 Å
N
O
N
H
H
H
H
H
H
H
H
H
H
H
exo9m-H+
[+8.91 kcal/mol]
H+IM-exo-TS2
[+10.10 kcal/mol]
H O
O
OMe
H O
OMe
O
H
H
H
H
H
O
O
MeO
O
H
H
O
H
O
MeO
O
H
O
H
O
H
H
H
H
OMe
MeO
O
1.039 Å
O
N
O
H
O
O
N
O
1.517 Å
O
O
O
H
N
3.736 Å
O
H
O
H
H
H
3.481 Å
H
H
O
O
H
H
O
H
H+
H
3.494 Å
H
1.590 Å
H
H
H
(+0.50)
H
N
H
endo10m
O
H
H
H
H
N
N
H
H
2.694 Å
O
H
O
H
H
H
H
H
2.123 Å
O
H
H
H
H
H
H
H
H+IM-endo-Int
[-0.14 kcal/mol]
H+IM-endo-TS1
[+6.14 kcal/mol]
endo10m-H+
[+2.74 kcal/mol]
H
O
OMe
O
O
MeO
O
H
N
endo9m-H+
Figure 6. RB3LYP/6-31G* SCRF = (PCM, solvent=THF) optimized structures for endo:exo
acid-catalyzed intramolecular Diels-Alder reaction paths of 10m. Values in parentheses are Mulliken
charges with hydrogens summed into heavy atoms.
Reaction of 1-phenylethyl-2-furylmethylamine or benzyl-1-(2-furyl)ethylamine 8c,d gave Diels-Alder
adducts 9c,d with diastereomer ratios of 2:1-1:1 in 43-48% yield. Reaction of
N-benzyl-(5-bromofuran-2-yl)methylamine 8e gave Diels-Alder adduct 9e at room temperature in THF
forꢀ1 h in 40%, for 20 h in 48% and at 80 °C in CH2ClCH2Cl22 for 20 h in 75%. A small amount of

HETEROCYCLES, Vol. 92, No. 3, 2016
495
byproducts formed at room temperature possibly contain amine adducts at C=C bond. The reaction of 7
and 8b with DCC gave a complex mixture containing a small amount of DCU-incorporated byproducts.23
Next, formation and reaction of 3-substituted amide 12 was examined as a comparison. The 3-substituted
amide 12 may not undergo the intramolecular Diels-Alder reaction by the high strain. Although the main
objective of this study is to examine Diels-Alder reactions, examination of the selectivity of Diels-Alder
vs Friedel-Crafts/Michael addition for furans are also of interest.8,24 Reaction of
benzyl-3-furylmethylamine 11 and ethenetricarboxylate 7 in the presence of EDCI/HOBt/Et3N gave a
non-cyclized amide 12. Lewis acid-catalyzed reaction of the amide 12 gave the Friedel-Crafts cyclized
product 13 selectively in 74-76% yield (Scheme 3), similar to Lewis acid-catalyzed cyclization of
phenyl-substituted ethenetricarboxylate derivatives.25 The highly strained Diels-Alder adduct 14 with
10-oxa-7-aza-tricyclo[3.3.1.13,9]dec-4-ene system was not formed.
CO2Et
+
EtO2C
O
0.2 equiv.
Lewis acid
CO2Et
O
EtO2C
O
CO2Et
EtO2C
HOBt
EDCI
NH
7
1
6
7a
O
O
rt
Et3N
THF
2
CH2Cl2
OH
O
5 N
N
11
3a
3
AlCl3 74%
Sc(OTf)3 76%
51%
4
7
12
13
EtO2C
EtO2C
O
O
N
Ph
14
Scheme 3
Unlike 2-furylmethylamides of ethenetricarboxylate, 2-furylmethyl ester of ethenetricarboxylate 17 is a
stable compound at room temperature and the similar thermal or Lewis acid-catalyzed reaction did not
give [4+2] adduct (Scheme 4). The reaction of 3-furylmethyl ester of ethenetricarboxylate 19 under the
thermal or Lewis acid-catalyzed reaction only gave starting materials along with decomposed products.
The difference on reactivity between oxygen and nitrogen analogues (intermediate 10 vs 17, 12 vs 19) can
be explained, similar to the cyclization of other ethenetricarboxylate derivatives.26 Triesters may be more
stable in s-cis conformation of O=C−O−CH2furanyl bond, probably because of the steric repulsion. In
diester amides, the energy differences of s-cis and s-trans conformations of O=C−N−CH2furanyl may be
small. The facile intramolecular reactions of amides probably originates from higher ratio of the reactive
s-trans conformer.

496
HETEROCYCLES, Vol. 92, No. 3, 2016
CO2Et
EtO2C
'
PPh3
O
benzene
68%
EtO2C
CO2Et
or Lewis acid
O
O
No cyclized
products
+
O
O
O
15
16
O
17
CO2Et
EtO2C
benzene
'
or Lewis acid
PPh3
EtO2C
CO2Et
No cyclized
products
O
+
O
O
26%
O
O
O
15
18
19
O
'
Scheme 4
On the other hand, in the reaction of diethyl ketomalonate 15 with (2E,4E)-hexa-2,4-dien-1-yl
(triphenylphosphoranylidne)acetate (20) in benzene at room temperature or at 80 °C, tandem Wittig
reaction/intramolecular Diels-Alder reaction proceeded to give 22 in 42 and 59% yields, respectively
(Scheme 5). Intermediate 21 could not be isolated. The corresponding intermolecular Diels-Alder reaction
of ester 1b and (2E,4E)-hexa-2,4-dien-1-ol 23 in CH2Cl2 at room temperature for 20 h did not proceed.
The reaction at 80 °C (in 1,2-dichloroethane) or 110 °C (in toluene) caused decomposition of the
substrates and did not give the Diels-Alder product.
5
EtO2C
CO2Et
EtO2C
EtO2C
4
PPh3
O
6
7
EtO2C
CO2Et
3a
7a
+
O
H
O
O
O
O
15
benzene
rt 42%
80 °C 59%
3
H
O
1
20
2
22
21
EtO2C
EtO2C
CO2Et
EtO2C
EtO2C
+
EtO2C
1b
HO
23
OH
24
Scheme 5
In summary, inter- and intramolecular [4+2] cycloaddition reactions of ethenetricarboxylates have been
studied. Intermolecular Diels-Alder reaction of ethenetricarboxylate esters and cyclopentadiene

HETEROCYCLES, Vol. 92, No. 3, 2016
497
proceeded at room temperature or -20 °C to give cycloadducts with 1:1.5-1.9 endo:exo ratio. Lewis acids
such as EtAlCl2, Zn(OTf)2 and Cu(OTf)2 catalyzed reaction at room temperature or -40 °C gave
cycloadducts with 3.1-5.4:1 endo:exo ratio. Reaction of benzyl- or allyl-2-furylmethylamine and
1,1-diethyl 2-hydrogen ethenetricarboxylate in the presence of EDCI/HOBt/Et3N at room temperature led
directly to intramolecular Diels-Alder adducts stereoselectively. On the other hand, reaction of benzyl
3-furylmethylamine and 1,1-diethyl 2-hydrogen ethenetricarboxylate under the condensation reaction
conditions gave a non-cyclized amide. Lewis acid-catalyzed reaction of the amide gave the Friedel-Crafts
cyclized product selectively. The highly functionalized cyclic compounds obtained in this study should be
useful synthetic intermediates.
EXPERIMENTAL
1
General Methods. H Chemical shifts are reported in ppm relative to Me4Si. 13C Chemical shifts are
13
reported in ppm relative to CDCl3 (77.1 ppm). C mutiplicities were determined by DEPT and HSQC.
Peak assignments are made by 2D COSY, HSQC, NOESY, and HMBC spectra. Mass analyzer type used
for EI is double-focusing in the HRMS measurements. Column chromatography was performed on silica
gel (75-150 Pm).
Ethenetricarboxylates 1a,b were prepared according to the literature.27
Typical experimental procedure (eq 1, entry 3). A solution of 1a (272 mg, 1.0 mmol) in CH2Cl2 (2
mL) was cooled to 0 °C. Zn(OTf)2 (36 mg, 0.1 mmol) was added to the solution, followed by
cyclopentadiene (66 mg, 83 PL, 1.0 mmol; distilled prior to use). The mixture was allowed to warm to
room temperature and stirred for 17 h. The reaction mixture was quenched by water and then saturated
aqueous NaHCO3. The mixture was extracted with CH2Cl2 and the organic phase was dried (Na2SO4),
and evaporated in vacuo. The residue was purified by column chromatography over silica gel with
hexane-Et2O (2 : 1) as eluent to give 3a (312 mg, 92%, 3a-endo:3a-exo = 3.1 : 1) as an inseparable
endo:exo mixture.
2,2-Diethyl 3-tert-butyl bicyclo[2.2.1]hept-5-ene-2,2,3-tricarboxylate (3a; endo:exo = 1 : 11): 3a
(endo:exo = 1 : 11) was obtained by recrystallization of endo:exo = 1 : 1.5 mixture (entry 1). (3a;
1
endo:exo = 1 : 11): Rf = 0.6 (hexane-Et2O = 2 : 1); colorless crystals; mp 58-62 qC (EtOAc); H NMR
(400 MHz, CDCl3) G (ppm) 1.22 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 1.44 (s, 9H), 1.56 (dddd, J =
9.2, 1.8, 1.8, 1.8 Hz, 1H), 2.31 (ddd, J = 9.2, 1.6, 1.6 Hz, 1H), 2.98 (bs, 1H), 3.22 (d, J = 2.0 Hz, 1H),
3.45 (bs, 1H), 3.96-4.04 (m, 1H), 4.07-4.21 (m, 2H), 4.24-4.33 (m, 1H), 5.99 (dd, J = 5.5, 2.8 Hz, 1H),
6.33 (dd, J = 5.5, 3.1 Hz, 1H). Selected NOEs are between G 3.22 (C3-H) and G 6.33 (C5-H), 2.98

498
HETEROCYCLES, Vol. 92, No. 3, 2016
(C4-H). Atom numbering is shown in eq 1.; 13C NMR (100.6 MHz, CDCl3) G (ppm) 13.97 (q), 14.14 (q),
28.01 (q), 47.27 (t), 47.74 (d), 50.10 (d), 51.80 (d), 61.43 (t), 61.52 (t), 63.57 (s), 80.92 (s), 135.13 (d),
139.97 (d), 170.08 (s), 170.42 (s), 172.21 (s). Selected HMBC correlations are between G 2.31 (C7-HH)
and G 47.74 (C4), 50.10 (C1), 135.13 (C6), 139.97 (C5), and between G 3.22 (C3-H) and G 47.74 (C4),
63.57 (C2), 135.13 (C6).; IR (neat) 2984, 1735, 1458, 1392, 1365, 1251, 1228, 1191, 1153, 1118, 1063,
1018 cm-1; MS (EI) m/z 338 (M+, 2.7), 282 (14), 264 (54), 237 (47), 217 (81), 171 (100%); HRMS (EI)
M+ 338.1729 (calcd for C18H26O6 338.1729).
1
(3a; endo:exo = 3.2 : 1); Rf = 0.6 (hexane-Et2O = 2 : 1); colorless oil; H NMR (400 MHz, CDCl3) For
3a-endo, G (ppm) 1.18 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.41 (s, 9H), 1.41 (bs, 2H), 3.15 (bs,
1H), 3.37 (bs, 1H), 3.88 (d, J = 3.5 Hz, 1H), 3.96-4.04 (m, 1H), 4.09-4.31 (m, 3H), 6.16 (dd, J = 5.5, 2.9
Hz, 1H), 6.54 (dd, J = 5.5, 3.1 Hz, 1H). Selected NOEs are between G 3.88 (C3-H) and G 3.15 (C4-H),
13
1.41 (C7-HH, overlapped).; C NMR (100.6 MHz, CDCl3) For 3a-endo, G (ppm) 13.93 (q), 14.03 (q),
28.01 (q), 46.64 (t), 47.29 (d), 51.48 (d), 52.78 (d), 60.94 (t), 61.87 (t), 65.21 (s), 80.57 (s), 135.25 (d),
136.47 (d), 169.55 (s), 171.10 (s), 171.33 (s). Selected HMBC correlations are between G 1.41 (C7-HH)
and G 52.78 (C3), 65.21 (C2), 135.25 (C5), 134.67 (C6) and between G 3.88 (C3-H) and G 47.29 (C4),
65.21 (C2), 135.25 (C5).; IR (neat) 2980, 1732, 1456, 1392, 1366, 1335, 1253, 1152, 1093, 1047 cm-1;
MS (EI) m/z 338 (M+, 1.4), 282 (23), 264 (85), 237 (59), 217 (66), 171 (100%); HRMS (EI) M+ 338.1733
(calcd for C18H26O6 338.1729).
2,2,3-Triethyl bicyclo[2.2.1]hept-5-ene-2,2,3-tricarboxylate (3b; endo:exo = 1 : 1.8); Rf = 0.7
1
(hexane-Et2O = 1 : 2); colorless oil; H NMR (400 MHz, CDCl3) For a major isomer 3b-exo, G (ppm)
1.21 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.59 (dddd, J = 9.2, 1.8, 1.8, 1.8
Hz, 1H), 2.33 (ddd, J = 9.2, 1.6, 1.6 Hz, 1H), 3.03 (bs, 1H), 3.31 (d, J = 2.2 Hz, 1H), 3.47 (bs, 1H),
3.98-4.31 (m, 6H), 6.02 (dd, J = 5.7, 2.8 Hz, 1H), 6.33 (dd, J = 5.7, 3.1 Hz, 1H). Selected NOEs are
13
between G 3.31 (C3-H) and G 6.33 (C5-H), 3.03 (C4-H).; C NMR (100.6 MHz, CDCl3) For a major
isomer 3b-exo, G (ppm) 13.96 (q), 14.12 (q), 14.21(q), 47.38 (d), 47.56 (t), 50.02 (d), 50.94 (d), 60.92 (t),
61.59 (t), 61.65 (t), 64.03 (s), 135.25 (d), 139.90 (d), 169.91 (s), 170.18 (s), 173.08 (s). Selected HMBC
correlations are between G 2.33 (C7-HH) and G 135.25 (C6), 139.90 (C5), and between G 3.31 (C3-H) and
G 47.56 (C7), 139.90 (C5).; IR (neat) 2983, 1735, 1465, 1372, 1254, 1200, 1119, 1096, 1034 cm-1; MS
(EI) m/z 310 (M+, 6.8), 264 (11), 199 (27), 91 (51), 66 (100%); HRMS (EI) M+ 310.1415 (calcd for
C16H22O6 310.1416); Anal. Calcd for C16H22O6: C, 61.92; H, 7.15. Found: C, 61.75; H, 7.39.
(3b; endo:exo = 3.3 : 1); Rf = 0.7 (hexane-Et2O = 1 : 2); colorless oil; 1H NMR (400 MHz, CDCl3) For a
major isomer 3b-endo, G (ppm) 1.19 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H),

HETEROCYCLES, Vol. 92, No. 3, 2016
499
1.43 (ddd, J = 9.0, 1.7, 1.7 Hz, 1H), 1.47 (ddd, J = 9.0, 1.6, 1.6 Hz, 1H), 3.17 (bs, 1H), 3.40 (bs, 1H), 3.90
(d, J = 3.5 Hz, 1H), 4.00-4.30 (m, 6H), 6.24 (dd, J = 5.5, 3.0 Hz, 1H), 6.47 (dd, J = 5.5, 3.1 Hz, 1H).
13
Selected NOEs are between G 3.90 (C3-H) and G 3.17 (C4-H), 1.47 (C7-HH).; C NMR (100.6 MHz,
CDCl3) For a major isomer 3b-endo, G (ppm) 13.96 (q), 14.05 (q), 14.21 (q), 46.81 (t), 46.88 (d), 51.46
(d), 52.25 (d), 60.57 (t), 61.15 (t), 62.00 (t), 65.54 (s), 135.97 (d), 136.19 (d), 169.30 (s), 171.26 (s),
172.00 (s). Selected HMBC correlations are between G 1.43, 1.47 (C7-H2) and G 51.46 (C1), 52.25 (C3),
135.97 (C5), 136.19 (C6) and between G 3.90 (C3-H) and G 46.88 (C4), 65.54 (C2), 135.97 (C5).; IR
(neat) 2982, 1733, 1446, 1368, 1335, 1255, 1219, 1094, 1034 cm-1; MS (EI) m/z 310 (M+, 6.8), 264 (47),
237 (50), 199 (58), 91 (62), 66 (100%); HRMS (EI) M+ 310.1417 (calcd for C16H22O6 310.1416).
Triethyl 5-oxocyclohex-3-ene-1,2,2-tricarboxylate (6) (eq 2): To a solution of 1b (244 mg, 1 mmol) in
CH2Cl2 (2 mL) was added 1-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (4) (0.19 mL, 172.3 mg, 1
mmol). The mixture was stirred at room temperature for 22 h. The reaction mixture was concentrated
under reduced pressure. To the residue was added THF (1 mL) containing a drop of 1N HCl and the
mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under
reduced pressure. The residue was purified by column chromatography over silica gel with hexane-Et2O
(1 : 2) as eluent to give 6 (209 mg, 67%).
6: Rf = 0.6 (hexane-Et2O = 1 : 2); colorless oil; 1H NMR (400 MHz, CDCl3) G (ppm) 1.23 (t, J = 7.1 Hz,
3H), 1.287 (t, J = 7.1 Hz, 3H), 1.293 (t, J = 7.1 Hz, 3H), 2.84 (ddd, J = 17.6, 6.1, 0.4 Hz, 1H), 2.99 (dd, J
= 17.6, 5.5 Hz, 1H), 3.91 (ddd, J = 6.1, 5.5, 1.1 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 4.22-4.30 (m, 4H), 6.11
(dd, J = 10.3, 0.4 Hz, 1H), 7.21 (dd, J = 10.3, 1.1 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) G (ppm) 13.93
(q), 13.98 (q), 37.16 (t), 45.41 (d), 57.08 (s), 61.65 (t), 62.60 (t), 62.94 (t), 129.68 (d), 143.65 (d), 167.32
(s), 170.99 (s), 195.26 (s). Selected HMBC correlations are between G 2.84, 2.99 (C6-H2) and G 195.26
(C5), 57.08 (C2), 170.99 (CHCO2Et), between G 6.11 (C4-H) and G 37.16 (C6), 57.08 (C2) and between G
7.21 (C3-H) and G 195.26 (C5), 45.41 (C1), 167.32 (C(CO2Et)2). Atom numbering is shown in eq 2.; IR
(neat) 2984, 1738, 1695, 1466, 1446, 1385, 1369, 1277, 1257, 1201, 1097, 1064, 1027 cm-1; MS (EI) m/z
312 (M+, 35), 267 (57), 167 (100%); HRMS (EI) M+ 312.1208 (calcd for C15H20O7 312.1209).
N-Allyl-furfurylamine (8a) was prepared by reaction of furfurylamine (2 equiv) with allyl bromide in
Et2O according to the literature procedure.28
8a: (5.9 mmol scale, 266 mg, 33%): Rf = 0.4 (hexane-Et2O = 1 : 4); pale yellow oil; 1H NMR (400 MHz,
CDCl3) G (ppm) 1.74 (bs, 1H), 3.26 (ddd, J = 6.0, 1.6, 1.3 Hz, 2H), 3.79 (s, 2H), 5.12 (ddt, J = 10.3, 1.8,
1.3 Hz, 1H), 5.19 (ddt, J = 17.2, 1.8, 1.6 Hz, 1H), 5.90 (ddt, J = 17.2, 10.3, 6.0 Hz, 1H), 6.18 (ddt, J =

500
HETEROCYCLES, Vol. 92, No. 3, 2016
13
3.3, 0.9, 0.7 Hz, 1H), 6.31 (dd, J = 3.3, 1.8 Hz, 1H), 7.36 (dd, J = 1.8, 0.9 Hz, 1H); C NMR (100.6
MHz, CDCl3) G (ppm) 45.35 (t), 51.41 (t), 107.09 (d), 110.15 (d), 116.46 (t), 136.36 (d), 141.89 (d),
153.71 (s); IR (neat) 3324, 3078, 2919, 2824, 1644, 1506, 1458, 1148, 1009, 921 cm-1; MS (EI) m/z 137
(M+, 62), 136 (100%); HRMS (EI) M+ 137.0830 (calcd for C8H11NO 137.0841).
N-Benzyl-furfurylamines 8b-e and 11 were prepared by reductive amination according to the literature
procedure.29
N-Benzyl-furfurylamine (8b): (8.9 mmol scale, 1.62 g, 97%). 8b was also prepared by reaction of
furfurylamine (2 equiv) with benzyl bromide in Et2O (5.0 mmol scale, 449 mg, 47%) according to the
literature procedure.28
1H and 13C NMR of 8b were in accord with the reported data.29b
8b: Rf = 0.2 (hexane-Et2O = 1 : 1); pale yellow oil; 1H NMR (400 MHz, CDCl3) G (ppm) 1.85 (bs, 1H),
3.78 (s, 4H), 6.18 (bd, J = 3.3 Hz, 1H), 6.31 (dd, J = 3.3, 1.8 Hz, 1H), 7.22-7.28 (m, 1H), 7.29-7.34 (m,
13
4H), 7.36 (dd, J = 1.8, 0.7 Hz, 1H); C NMR (100.6 MHz, CDCl3) G (ppm) 45.37 (t), 52.81 (t), 107.12
(d), 110.15 (d), 127.08 (d), 128.32 (d), 128.46 (d), 139.86 (s), 141.88 (d), 153.80 (s).
N-Benzyl-1-(furan-2-yl)ethylamine (8c): (8.9 mmol scale, 976 mg, 54%): Rf = 0.5 (hexane-Et2O = 1 :
1); pale yellow oil; 1H NMR (400 MHz, CDCl3) G (ppm) 1.43 (d, J = 6.8 Hz, 3H), 1.75 (bs, 1H), 3.66 (d,
J = 13.1 Hz, 1H), 3.74 (d, J = 13.1 Hz, 1H), 3.88 (q, J = 6.8 Hz, 1H), 6.16 (ddd, J = 3.1, 0.8, 0.6 Hz, 1H),
13
6.32 (dd, J = 3.1, 1.8 Hz, 1H), 7.21-7.26 (m, 1H), 7.29-7.33 (m, 4H), 7.36 (dd, J = 1.8, 0.8 Hz, 1H); C
NMR (100.6 MHz, CDCl3) G (ppm) 20.51 (q), 50.60 (d), 51.21 (t), 105.54 (d), 109.95 (d), 126.99 (d),
128.28 (d), 128.46 (d), 140.34 (s), 141.47 (d), 157.85 (s); IR (neat) 3330, 3028, 2972, 2930, 1603, 1505,
1495, 1454, 1371, 1315, 1225, 1150, 1121, 1010 cm-1; MS (EI) m/z 201 (M+, 8.9), 186 (100), 91 (92%);
HRMS (EI) M+ 201.1134 (calcd for C13H15NO 201.1154).
N-Furfuryl-1-phenylethylamine (8d): (8.9 mmol scale, 1.66 g, 93%): Rf = 0.5 (hexane-Et2O = 1 : 1);
pale yellow oil; 1H NMR (400 MHz, CDCl3) G (ppm) 1.36 (d, J = 6.6 Hz, 3H), 1.77 (bs, 1H), 3.58 (d, J =
14.5 Hz, 1H), 3.66 (d, J = 14.5 Hz, 1H), 3.78 (q, J = 6.6 Hz, 1H), 6.10 (dddd, J = 3.1, 0.8, 0.6, 0.6 Hz,
1H), 6.29 (dd, J = 3.1, 1.8 Hz, 1H), 7.23-7.28 (m, 1H), 7.31-7.36 (m, 5H); 13C NMR (100.6 MHz, CDCl3)
G (ppm) 24.30 (q), 44.05 (t), 57.15 (d), 106.90 (d), 110.13 (d), 126.85 (d), 127.12 (d), 128.57 (d), 141.82
(d), 145.08 (s), 154.03 (s); IR (neat) 3331, 3026, 2963, 2925, 1602, 1505, 1492, 1451, 1370, 1147, 1117,
1011 cm-1; MS (EI) m/z 201 (M+, 6.4), 186 (73), 81 (100%); HRMS (EI) M+ 201.1138 (calcd for
C13H15NO 201.1154).
N-Benzyl-(5-bromofuran-2-yl)methylamine (8e): (9.0 mmol scale, 2.14 g, 89%): Rf = 0.3 (hexane-Et2O
1
= 1 : 1); pale yellow oil; H NMR (400 MHz, CDCl3) G (ppm) 1.75 (bs, 1H), 3.71 (s, 2H), 3.75 (s, 2H),
6.13 (d, J = 3.2 Hz, 1H), 6.20 (d, J = 3.2 Hz, 1H), 7.21-7.26 (m, 1H), 7.28-7.33 (m, 4H); 13C NMR (100.6

HETEROCYCLES, Vol. 92, No. 3, 2016
501
MHz, CDCl3) G (ppm) 45.28 (t), 52.60 (t), 109.86 (d), 111.72 (d), 120.57 (s), 127.06 (d), 128.20 (d),
128.41 (d), 139.62 (s), 155.94 (s); IR (neat) 3329, 3027, 2917, 2830, 1602, 1505, 1453, 1200, 1125, 1010
cm-1; MS (EI) m/z 267 (M+, 12), 265 (M+, 12), 186 (11), 161 (21), 159 (22), 106 (23), 91 (100%); HRMS
(EI) M+ 265.0099, 267.0045 (calcd for C12H12BrNO 265.0102, 267.0082).
N-Benzyl-furan-3-ylmethylamine (11): (9.2 mmol scale, 1.70 g, 99%): Rf = 0.6 (hexane-Et2O = 1 : 2);
pale yellow oil; 1H NMR (400 MHz, CDCl3) G (ppm) 1.64 (bs, 1H), 3.65 (dd, J = 0.6, 0.4 Hz, 2H), 5.80
(s, 2H), 6.39 (dd, J = 1.8, 0.8 Hz, 1H), 7.22-7.28 (m, 1H), 7.30-7.34 (m, 4H), 7.35 (ddd, J = 1.6, 0.8, 0.6
13
Hz, 1H), 7.38 (dd, J = 1.8, 1.6 Hz, 1H); C NMR (100.6 MHz, CDCl3) G (ppm) 43.61 (t), 53.21 (t),
110.51 (d), 127.06 (d), 128.24 (d), 128.46 (s), 128.48 (d), 139.93 (d), 140.17 (s), 143.17 (d); IR (neat)
3315, 3027, 2921, 2823, 1602, 1496, 1453, 1362, 1158, 1108, 1065, 1021, 874 cm-1; MS (EI) m/z 187
(M+, 7.0), 186 (18), 106 (100), 91 (76), 81 (77%); HRMS (EI) M+ 187.0977 (calcd for C12H13NO
187.0997).
Typical experimental procedure for eq 3 and preparation of 12 in Scheme 3 (eq 3, Table 2, entry 1).
To a solution of 1,1-diethyl 2-hydrogen ethenetricarboxylate (7) (313 mg, 1.45 mmol) (prepared from
1,1-diethyl 2-tert-butyl ethenetricarboxylate (1a) upon treatment with CF3CO2H)25 in THF (0.5 mL) were
added N-allyl-furfurylamine (8a) (176 mg, 1.28 mmol) in THF (1.5 mL), Et3N (0.25 mL, 179 mg, 1.77
mmol),
HOBt
(1-hydroxybenzotriazole)
(430
mg,
3.18
mmol)
and
EDCI
(1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride) (292 mg, 1.52 mmol) at 0 °C. The
reaction mixture was stirred for 1 h at 0 °C, and was allowed to warm to room temperature and stirred for
17 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with
CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 solution, 2M aqueous citric
acid, saturated aqueous NaHCO3 and water, dried (Na2SO4), and evaporated in vacuo. The residue was
purified by column chromatography over silica gel eluting with hexane-Et2O to give 9a (350 mg, 82%).
Diethyl 3-allyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.01,5]dec-8-ene-6,6-dicarboxylate (9a): Rf = 0.3
(hexane-Et2O = 1 : 2); colorless crystals; mp 100-103 qC (EtOAc); 1H NMR (400 MHz, CDCl3) G (ppm)
1.27 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 3.44 (s, 1H), 3.67 (d, J = 11.7 Hz, 1H), 3.88 (dddd, J =
15.6, 5.6, 1.5, 1.5 Hz, 1H), 3.94 (d, J = 11.7 Hz, 1H), 3.97 (dd, J = 15.6, 5.6 Hz, 1H), 4.11-4.37 (m, 4H),
5.20 (dddd, J = 10.1, 1.5, 1.3, 1.3 Hz, 1H), 5.23 (dddd, J = 17.0, 1.5, 1.3, 1.3 Hz, 1H), 5.36 (d, J = 1.6 Hz,
1H), 5.72 (dddd, J = 17.0, 10.1, 5.6, 5.6 Hz, 1H), 6.33 (dd, J = 5.7, 1.6 Hz, 1H), 6.61 (d, J = 5.7 Hz, 1H).
Selected NOEs are between G 3.44 (C5-H) and G 3.94 (C2-HH), 6.61 (C9-H), between G 3.94 (C2-HH)
and G 6.61 (C9-H), and between G 6.33 (C8-H) and Gꢀ5.36 (C7-H), 6.61 (C9-H). Atom numbering is
13
shown in eq 3.; C NMR (100.6 MHz, CDCl3) G (ppm) 13.72 (q), 13.77 (q), 44.87 (t), 47.92 (t), 54.34

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(d), 61.60 (t), 61.75 (t), 62.04 (s), 83.20 (d), 89.36 (s), 117.58 (t), 131.43 (d), 135.26 (d), 136.89 (d),
167.86 (s), 168.52 (s), 169.49 (s). Selected HMBC correlations are between G 3.44 (C5-H), 3.94 (C2-HH),
5.36 (C7-H), 6.33 (C8-H) and G 136.89 (C9), between G 3.94 (C2-HH), 5.36 (C7-H), 6.33 (C8-H) and G
89.36 (C1) and between G 3.44 (C5-H), 6.61 (C9-H), 6.33 (C8-H) and G 83.20 (C7).; IR (KBr) 2997,
1730, 1691, 1480, 1365, 1266, 1107, 1066, 1039, 1000 cm-1; MS (EI) m/z 335 (M+); HRMS (EI)
335.1358 (calcd for C17H21NO6 M+ 335.1369); Anal. Calcd for C17H21NO6: C, 60.89; H, 6.31; N, 4.18.
Found: C, 60.93; H, 6.08; N, 4.17.
9b: (2.35 mmol scale, 590 mg, 65%): Rf = 0.8 (CH2Cl2-Et2O = 1 : 1); colorless crystals; mp 138-140 qC
(EtOAc); 1H NMR (400 MHz, CDCl3) G (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz, 3H), 3.47 (s,
1H), 3.59 (d, J = 11.9 Hz, 1H), 3.65 (d, J = 11.9 Hz, 1H), 4.11-4.40 (m, 5H), 4.68 (d, J = 15.0 Hz, 1H),
5.37 (d, J = 1.6 Hz, 1H), 6.32 (dd, J = 5.7, 1.6 Hz, 1H), 6.54 (d, J = 5.7 Hz, 1H), 7.23-7.36 (m, 5H).
Selected NOEs are between G 3.47 (C5-H) and G 3.65 (C2-HH), 6.54 (C9-H), between G 3.65 (C2-HH)
and G 3.47 (C5-H), and between G 6.32 (C8-H) and Gꢀ5.37 (C7-H), 6.54 (C9-H).; 13C NMR (100.6 MHz,
CDCl3) G (ppm) 14.07 (q), 14.09 (q), 46.76 (t), 48.13 (t), 54.69 (d), 61.99 (t), 62.23 (t), 62.38 (t), 83.58
(d), 89.49 (s), 127.74 (d), 128.00 (d), 128.88 (d), 135.73 (d), 135.89 (d), 136.96 (d), 168.20 (s), 168.86
(s), 170.01 (s). Selected HMBC correlations are between G 3.59 (C2-HH), 3.65 (C2-HH), 5.37 (C7-H) and
G 136.96 (C9), between G 3.59 (C2-HH), 6.54 (C9-H), 5.37 (C7-H), 6.32 (C8-H) and G 89.49 (C1) and
between G 3.47 (C5-H), 6.54 (C9-H), 6.32 (C8-H) and G 83.58 (C7).; IR (KBr) 2984, 1756, 1734, 1690,
1478, 1368, 1266, 1192, 1117, 1046 cm-1; MS (EI) m/z 385 (M+, 1.9), 340 (9.4), 295 (11), 248 (19), 221
(25), 200 (40), 186 (100%); HRMS (EI) 385.1521 (calcd for C21H23NO6 M+ 385.1525); Anal. Calcd for
C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 65.50; H, 6.06; N, 3.76.
9c: (2 mmol scale, 381 mg, 48%, diastereomer ratio 2 : 1): Rf = 0.5 (hexane-Et2O = 1 : 3); pale yellow oil;
1H NMR (400 MHz, CDCl3) G (ppm) 1.25-1.34 (m, 9H), 3.43 (s, 1H×0.33), 3.53 (s, 1H×0.67), 3.77 (q, J
= 6.8 Hz, 1H×0.67), 3.97 (d, J = 15.2 Hz, 1H×0.33), 4.00 (q, J = 6.5 Hz, 1H×0.33), 4.10-4.41 (m,
4H+1H×0.67), 4.92 (d, J = 15.6, 1H×0.67), 5.06 (d, J = 15.2 Hz, 1H×0.33), 5.37 (d, J = 1.8 Hz,
1H×0.67), 5.39 (d, J = 1.8 Hz, 1H×0.33), 6.33 (dd, J = 5.7, 1.8 Hz, 1H×0.33), 6.34 (dd, J = 5.9, 1.8 Hz,
1H×0.67), 6.49 (d, J = 5.7 Hz, 1H×0.33), 6.59 (d, J = 5.9 Hz, 1H×0.67), 7.22-7.35 (m, 5H). Selected
NOEs are between G 3.43 (C5i-H) and G 6.49 (C9i-H), between G 3.53 (C5-H) and G 6.59 (C9-H),
1.25-1.34 (C2-CH3, overlapped) and between G 6.33, 6.34 (C8i,8-H) and Gꢀ5.37, 5.39 (C7,7i-H). Atom
13
numberings Cx and Cxi denote those of major and minor diastereomers, respectively.; C NMR (100.6
MHz, CDCl3) G (ppm) 12.97 (q), 14.06 (q), 14.09 (q), 15.77 (q), 43.70 (t), 44.45 (t), 52.52 (d), 53.08 (d),
54.17 (d), 54.48 (d), 61.95 (t), 61.98 (t), 62.18 (t), 62.61 (s), 62.78 (s), 83.35 (d), 83.53 (d), 92.41 (s),
93.29 (s), 127.49 (d), 127.60 (d), 127.89 (d), 128.76 (d), 128.83 (d), 135.55 (d), 135.96 (d), 136.10 (s),

HETEROCYCLES, Vol. 92, No. 3, 2016
503
136.21 (d), 136.46 (s), 136.63 (d), 168.25 (s), 168.39 (s), 168.91 (s), 168.94 (s), 169.93 (s), 170.46 (s).
Selected HMBC correlations are between G 5.37, 5.39 (C7,7i-H) and G 135.55, 136.63 (C9,9i), between G
5.37, 5.39 (C7,7i-H), 6.33, 6.34 (C8i,8-H), 6.49, 6.59 (C9i,9-H), 1.25-1.34 (C2,2i-CH3, overlapped) and G
92.41, 93.29 (C1i,1) and between G 6.33, 6.34 (C8i,8-H), 6.49, 6.59 (C9i,9-H) and G 83.35, 83.53
(C7i,7).; IR (neat) 2979, 1732, 1695, 1496, 1418, 1367, 1262, 1197, 1112, 1068, 1039 cm-1; MS (EI) m/z
399 (M+, 1.3), 304 (24), 200 (100%); HRMS (EI) 399.1689 (calcd for C22H25NO6 M+ 399.1682).
9d: (2 mmol scale, 340 mg, 43%, diastereomer ratio 1 : 1): Rf = 0.2 (hexane-Et2O = 1 : 2); pale yellow
viscous oil; 1H NMR (400 MHz, CDCl3) G (ppm) 1.26 (t, 7.1 Hz, 3H×0.5), 1.28 (t, J = 7.1 Hz, 3H×0.5),
1.30 (t, J = 7.1 Hz, 3H×0.5), 1.33 (t, J = 7.1 Hz, 3H×0.5), 1.53 (d, J = 7.0 Hz, 3H×0.5), 1.57 (d, J =
3H×0.5), 3.37 (d, J = 11.7 Hz, 1H×0.5), 3.41 (s, 1H×0,5), 3.44 (d, J = 11.7 Hz, 1H×0.5), 3.49 (s,
1H×0.5), 3.61 (d, J = 11.7 Hz, 1H×0.5), 3.82 (d, J = 11.7 Hz, 1H×0.5), 4.09-4.42 (m, 4H), 5.34 (d, J = 1.8
Hz, 1H×0.5), 5.35 (d, J = 1.8 Hz, 1H×0.5), 5.50 (q, J = 7.0 Hz, 1H×0.5), 5.53 (q, J = 7.0 Hz, 1H×0.5),
6.29 (dd, J = 5.7, 1.6 Hz, 1H×0.5), 6.31 (dd, J = 5.7, 1.6 Hz, 1H×0.5), 6.49 (d, J = 5.7 Hz, 1H×0.5), 6.56
(d, J = 5.7 Hz, 1H×0.5), 7.22-7.38 (m, 5H). Selected NOEs are between G 3.41 (C5-H) and G 6.49 (C9-H),
between G 3.49 (C5i-H) and G 6.56 (C9i-H), between G 3.37 (C2-HH) and G 6.49 (C9-H), between G 3.44
(C2i-HH) and G 6.56 (C9i-H), and between G 6.29, 6.31 (C8,8i-H) and Gꢀ5.34, 5.35 (C7,7i-H), 6.49, 6.56
(C9,9i-H). Atom numberings Cx and Cxi denote those of two diastereomers, respectively.; 13C NMR
(100.6 MHz, CDCl3) G (ppm) 14.01 (q), 14.05 (q), 15.82 (q), 16.74 (q), 44.02 (t), 44.05 (t), 48.70 (d),
49.30 (d), 55.03 (d), 55.11 (d), 61.91 (t), 62.09 (t), 62.35 (s), 62.49 (s), 83.43 (d), 83.50 (d), 89.28 (s),
89.47 (s), 126.77 (d), 127.25 (d), 127.35 (d), 127.76 (d), 128.63 (d), 128.76 (d), 135.69 (d), 135.79 (d),
136.93 (d), 136.98 (d), 139.36 (s), 139.67 (s), 168.17 (s), 168.31 (s), 168.77 (s), 169.49 (s), 169.71 (s).
Selected HMBC correlations are between G 5.34, 5.35 (C7,7'-H) and G 136.93, 136.98 (C9,9'), between G
5.34, 5.35 (C7,7'-H), 6.49, 6.56 (C9,9'-H), 6.29, 6.32 (C8,8'-H) and G 89.28, 89.47 (C1,1') and between G
3.41, 3.49 (C5,5'-H), 6.49, 6.56 (C9,9'-H), 6.29, 6.32 (C8,8'-H) and G 83.43, 83.50 (C7,7').; IR (neat)
2980, 1736, 1691, 1496, 1469, 1450, 1423, 1364, 1302, 1261, 1189, 1110, 1064, 1041 cm-1; MS (EI) m/z
399 (M+, 2.2), 354 (7.6), 294 (56), 200 (100%); HRMS (EI) 399.1685 (calcd for C22H25NO6 M+
399.1682).
9e: (1 mmol scale, 227 mg, 48%): Rf = 0.1 (hexane-Et2O = 1 : 4); pale yellow crystals; mp 127-127.5 qC
(EtOAc-Et2O = 1 : 1); 1H NMR (400 MHz, CDCl3) G (ppm) 1.32 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.1 Hz,
3H), 3.54 (s, 1H), 3.66 (d, J = 11.9 Hz, 1H), 3.78 (d, J = 11.9 Hz, 1H), 4.24-4.41 (m, 4H), 4.43 (d, J =
15.0 Hz, 1H), 4.61 (d, J = 15.0 Hz, 1H), 6.41 (d, J = 5.5 Hz, 1H), 6.54 (d, J = 5.5 Hz, 1H), 7.25-7.30 (m,
3H), 7.33-7.37 (m, 2H). Selected NOEs are between G 3.54 (C5-H) and G 6.54 (C9-H), between G 3.78
(C2-HH) and G 6.54 (C9-H), and between G 6.41 (C8-H) and Gꢀ6.54 (C9-H).; 13C NMR (100.6 MHz,

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CDCl3) G (ppm) 13.96 (q), 14.05 (q), 46.77 (t), 48.09 (t), 57.80 (d), 62.42 (t), 62.56 (t), 66.86 (s), 87.69
(s), 91.14 (s), 127.86 (d), 128.02 (d), 128.94 (d), 135.50 (s), 137.23 (d), 140.81 (d), 166.06 (s), 167.52 (s),
169.23 (s). Selected HMBC correlations are between G 3.78 (C2-HH) and G 137.23 (C9), between G 3.66
(C2-HH), 6.54 (C9-H), 6.41 (C8-H) and G 87.69 (C1) and between G 3.54 (C5-H), 6.54 (C9-H), 6.41
(C8-H) and G 91.14 (C7).; IR (KBr) 2980, 1745, 1718, 1687, 1475, 1440, 1359, 1311, 1288, 1264, 1240,
1213, 1199, 1083, 1037 cm-1; MS (EI) m/z 465 (M+, 0.6), 463 (M+, 0.6), 438 (4.5), 436 (4.6), 266 (92),
264 (100%); HRMS (EI) 463.0648, 465.0623 (calcd for C21H22BrNO6 M+ 463.0631, 465.0610); Anal.
Calcd for C21H22BrNO6: C, 54.32; H, 4.78; N, 3.02. Found: C, 54.22; H, 4.68; N, 3.05.
1
12: (3 mmol scale, 598 mg, 51%): Rf = 0.5 (hexane-Et2O = 1 : 3); pale yellow oil; H NMR (400 MHz,
CDCl3) (2 rotamers, ratio 1.3 : 1) G (ppm) 1.27-1.35 (m, 6H), 4.23-4.38 (m, 4H), 4.28 (s, 2H×0.4, minor
rotamer), 4.40 (s, 2H×0.6, major rotamer), 4.49 (s, 2H×0.6), 4.62 (s, 2H×0.4), 6.29 (d, J = 0.8 Hz,
1H×0.4), 6.35 (d, J = 0.8 Hz, 1H×0.6), 7.19-7.43 (m, 8H); 13C NMR (100.6 MHz, CDCl3) G (ppm) 13.98
(q), 14.02 (q), 14.04 (q), 38.86 (t), 42.17 (t), 47.49 (t), 50.54 (t), 62.00 (t), 62.22 (t), 62.27 (t), 109.68 (d),
110.93 (d), 120.14 (s), 120.35 (s), 127.10 (d), 127.79 (d), 128.14 (d), 128.49 (d), 128.76 (d), 129.10 (d),
134.57 (d), 134.73 (d), 135.25 (s), 135.28 (s), 135.56 (s), 136.30 (s), 140.57 (d), 141.26 (d), 143.49 (d),
144.17 (d), 162.92 (s), 162.97 (s), 164.36 (s), 164.45 (s), 164.47 (s), 164.62 (s); IR (neat) 2983, 1730,
1651, 1497, 1465, 1446, 1374, 1256, 1202, 1069, 1021 cm-1; MS (EI) m/z 385 (M+, 2.5), 340 (9.4), 248
(11), 200 (42), 186 (100%); HRMS (EI) 385.1514 (calcd for C21H23NO6 M+ 385.1525).
Diethyl 2-(5-benzyl-4,5,6,7-tetrahydro-6-oxofuro[3,2-c]pyridin-7-yl)malonate (13). To a solution of
12 (187 mg, 0.49 mmol) in CH2Cl2 (1 mL) was added Sc(OTf)3 (50 mg, 0.1 mmol). The mixture was
stirred at room temperature overnight. The reaction mixture was quenched by water and then saturated
aqueous NaHCO3. The mixture was extracted with CH2Cl2 and the organic phase was dried (Na2SO4),
and evaporated in vacuo. The residue was purified by column chromatography over silica gel with
hexane-Et2O (1 : 1) as eluent to give 13 (142 mg, 76%).
13: Rf = 0.3 (hexane-Et2O = 1 : 1); pale yellow oil; 1H NMR (400 MHz, CDCl3) G (ppm) 1.21 (t, J = 7.1
Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 4.15-4.30 (m, 6H), 4.33 (d, J = 3.9 Hz, 1H), 4.45 (ddd, J = 3.9, 3.9, 3.9
Hz, 1H), 4.75 (d, J = 14.8 Hz, 1H), 4.77 (d, J = 14.8 Hz, 1H), 6.20 (d, J = 1.8 Hz, 1H), 7.24-7.34 (m, 6H);
13C NMR (100.6 MHz, CDCl3) G (ppm) 13.98 (q), 14.01 (q), 41.40 (d), 44.89 (t), 50.89 (t), 52.52 (d),
61.57 (t), 61.66 (t), 107.68 (d), 112.65 (s), 127.60 (d), 128.18 (d), 128.66 (d), 136.61 (s), 143.10 (d),
144.65 (s), 166.99 (s), 167.63 (s), 167.79 (s). Selected HMBC correlations are between G 4.33
(CH(CO2Et)2), 6.20 (C3-H) and G 144.65 (C7a), between G 4.33 (CH(CO2Et)2) and G 41.40 (C7), and
between G 6.20 (C3-H) and G 112.65 (C3a). Atom numberings are shown in Scheme 8.; IR (neat) 2981,

HETEROCYCLES, Vol. 92, No. 3, 2016
505
1738, 1645, 1507, 1483, 1454, 1372, 1347, 1263, 1176, 1034 cm-1; MS (EI) m/z 385 (M+, 64), 340 (22),
293 (64), 266 (82), 91 (100%); HRMS (EI) M+ 385.1531 (calcd for C21H23NO6 385.1525).
Ethenetricarboxylates 17 and 19 were prepared by the reaction of diethyl ketomalonate with the
corresponding (triphenylphosphoranylidne)acetate according to the literature procedure.27,30 The
(triphenylphosphoranylidne)acetate esters for 17 and 19, and ylide 20 were prepared by the corresponding
chloroacetates and triphenylphosphine in benezene and subsequent treatment with NaOH. The
chloroacetates were preprared by the reaction of the corresponding alcohols (1 equiv) and chloroacetyl
chloride (1 equiv) in the presence of pyridine (1 equiv) in Et2O at 0 °C. Data of chloroacetates for the
(triphenylphosphoranylidne) acetate esters and ethenetricarboxylates 17, 19 are shown below.
1
(Furan-2-yl)methyl 2-chloroacetate: (30.4 mmol scale, 5.31 g, 100%); pale yellow oil; H NMR (400
MHz, CDCl3) G (ppm) 4.08 (s, 2H), 5.17 (s, 2H), 6.38 (dd, J = 3.3, 2.0 Hz, 1H), 6.46 (d, J = 3.3 Hz, 1H),
13
7.43 (dd, J = 2.0, 0.9 Hz, 1H); C NMR (100.6 MHz, CDCl3) G (ppm) 40.82 (t), 59.55 (t), 110.77 (d),
111.55 (d), 143.70 (d), 148.53 (s), 167.07 (s); IR (neat) 3126, 2958, 1760, 1501, 1411, 1369, 1309, 1284,
1167, 1079, 1017, 964 cm-1; MS (EI) m/z 176 (M+, 11), 174 (M+, 34), 98 (19), 81 (100%); HRMS (EI) M+
174.0065, 176.0070 (calcd for C7H7ClO3 M+ 174.0083, 176.0054).
1
(Furan-3-yl)methyl 2-chloroacetate: (30.4 mmol scale, 5.27 g, 99%); pale yellow oil; H NMR (400
MHz, CDCl3) G (ppm) 4.07 (s, 2H), 5.10 (s, 2H), 6.44 (dd, J = 1.8, 0.8 Hz, 1H), 7.41 (dd, J = 1.8, 1.8 Hz,
13
1H), 7.51 (ddd, J = 1.8, 0.8, 0.8 Hz, 1H); C NMR (100.6 MHz, CDCl3) G (ppm) 40.92 (t), 59.39 (t),
110.63 (d), 119.62 (s), 142.15 (d), 143.67 (d), 167.28 (s); IR (neat) 3137, 2959, 1752, 1505, 1412, 1312,
1289, 1159, 1076, 1021, 956, 875 cm-1; MS (EI) m/z 176 (M+, 8.8), 174 (M+, 27), 98 (100), 81 (63%);
HRMS (EI) M+ 174.0064, 176.0070 (calcd for C7H7ClO3 M+ 174.0084, 176.0054); Anal. Calcd for
C7H7ClO3: C, 48.16; H, 4.04. Found: C, 48.11; H, 3.79.
(2E,4E)-Hexa-2,4-dienyl 2-chloroacetate: (15.2 mmol scale, 2.55 g, 96%); colorless oil; bp
1
78-80 °C/3.6 mmHg; H NMR (400 MHz, CDCl3) G (ppm) 1.77 (bd, J = 6.6 Hz, 3H), 4.07 (s, 2H), 4.68
(d, J = 6.6 Hz, 2H), 5.62 (dt, J = 15.2, 6.6 Hz, 1H), 5.78 (dq, J = 15.0, 6.6 Hz, 1H), 6.06 (ddq, J = 15.0,
13
10.5, 1.6 Hz, 1H), 6.29 (dd, J = 15.2, 10.5 Hz, 1H); C NMR (100.6 MHz, CDCl3) G (ppm) 18.16 (q),
40.93 (t), 66.69 (t), 122.48 (d), 130.23 (d), 132.10 (d), 136.08 (d), 167.11 (s); IR (neat) 3024, 2959, 1762,
1737, 1661, 1446, 1413, 1380, 1309, 1168, 990 cm-1; MS (EI) m/z 176 (M+, 13), 174 (M+, 39), 98 (37),
97 (37), 81 (79), 79 (100%); HRMS (EI) M+ 174.0431, 176.0431 (calcd for C8H11ClO2 M+ 174.0448,
176.0418).
1,1-Diethyl 2-(furan-2-yl)methyl ethene-1,1,2-tricarboxylate (17): (19.2 mmol scale, 3.85 g, 68%); Rf

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HETEROCYCLES, Vol. 92, No. 3, 2016
1
= 0.6 (hexane-Et2O = 1 : 1); pale yellow oil; H NMR (400 MHz, CDCl3) G (ppm) 1.31 (t, J = 7.1 Hz,
3H), 1.32 (t, J = 7.1 Hz, 3H), 4.29 (q, J = 7.1 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 5.17 (s, 2H), 6.37 (dd, J =
3.3, 1.8 Hz, 1H), 6.45 (bd, J = 3.3 Hz, 1H), 6.88 (s, 1H), 7.44 (dd, J = 1.8, 0.9 Hz, 1H); 13C NMR (100.6
MHz, CDCl3) G (ppm) 13.91 (q), 13.99 (q), 59.11 (t), 62.18 (t), 62.58 (t), 110.77 (d), 111.52 (d), 129.42
(d), 139.47 (s), 143.66 (d), 148.38 (s), 162.20 (s), 163.18 (s), 164.14 (s); IR (neat) 2984, 1781, 1732,
1650, 1502, 1467, 1446, 1377, 1344, 1261, 1177, 1067, 1018 cm-1; MS (EI) m/z 296 (M+, 1.3), 200 (61),
154 (81), 126 (56), 81 (100%); HRMS (EI) M+ 296.0891 (calcd for C14H16O7 M+ 296.0896).
1,1-Diethyl 2-(furan-3-yl)methyl ethene-1,1,2-tricarboxylate (19): (16.4 mmol scale, 1.25 g, 26%); Rf
= 0.6 (hexane-Et2O = 1 : 1); colorless oil; 1H NMR (400 MHz, CDCl3) G (ppm) 1.311 (t, J = 7.1 Hz, 3H),
1.314 (t, J = 7.1 Hz, 3H), 4.29 (q, J = 7.1 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 5.09 (s, 2H), 6.43 (dd, J =
13
1.8, 0.8 Hz, 1H), 6.87 (s, 1H), 7.41 (dd, J = 1.8, 1.6 Hz, 1H), 7.50 (ddd, J = 1.6, 0.8, 0.8 Hz, 1H); C
NMR (100.6 MHz, CDCl3) G (ppm) 13.89 (q), 13.97 (q), 58.95 (t), 62.12 (t), 62.57 (t), 110.62 (d), 119.50
(s), 129.65 (d), 139.29 (s), 142.04 (d), 143.63 (d), 162.23 (s), 163.43 (s), 164.18 (s); IR (neat) 2984, 1737,
1651, 1505, 1466, 1447, 1372, 1345, 1257, 1179, 1067, 1023 cm-1; MS (EI) m/z 296 (M+, 3.8), 199 (83),
143 (72), 126 (64), 81 (100%); HRMS (EI) M+ 296.0880 (calcd for C14H16O7 M+ 290.0896).
Diethyl 1,3,3a,7a-tetrahydro-5-methyl-3-oxoisobenzofuran-4,4(5H)-dicarboxylate (22). To an
ice-water-cooled solution of (2E,4E)-hexa-2,4-dien-1-yl (triphenylphosphoranylidene)acetate (20) (2.63
g, 6.57 mmol) in 13 mL of benzene was added diethyl ketomalonate (1.0 mL, 1.14 g, 6.57 mmol). The
mixture was stirred for 1 h at 0 °C and then allowed to warm to room temperature and stirred overnight.
The benzene was evaporated, and Et2O was added. The precipitated triphenylphosphine oxide was
removed by filtration. The filtrate was concentrated, and the residue was purified by column
chromatography over silica gel with hexane-Et2O (2 : 1) as eluent to give 22 (821 mg, 42%) as an isolable
product.
22: Rf = 0.1 (hexane-Et2O = 2 : 1); colorless oil; 1H NMR (400 MHz, CDCl3) G (ppm) 1.03 (d, J = 7.3 Hz,
3H), 1.25 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 2.69-2.80 (m, 2H), 3.40 (qdd, J = 7.3, 2.6, 2.2 Hz,
1H), 3.83-3.88 (m, 1H), 4.19-4.36 (m, 4H), 4.43-4.46 (m, 1H), 5.72 (bs, 2H); 13C NMR (100.6 MHz,
CDCl3) G (ppm) 13.72 (q), 13.88 (q), 17.72 (q), 36.37 (d), 38.00 (d), 42.65 (d), 57.38 (s), 61.61 (t), 61.88
1
(t), 69.20 (t), 121.65 (d), 134.73 (d), 167.48 (s), 168.55 (s), 171.52 (s); H NMR (400 MHz, C6D6) G
(ppm) 0.860 (d, J = 7.5 Hz, 3H), 0.956 (t, J = 7.1 Hz, 3H), 0.998 (t, J = 7.1 Hz, 3H), 2.46 (m, 1H), 2.58
(d, J = 13.9 Hz, 1H), 3.04 (dd, J = 11.1, 8.0 Hz, 1H), 3.51 (m, 1H), 3.68 (dd, J = 8.0, 6.7 Hz, 1H),
3.93-4.10 (m, 4H), 5.11 (ddd, J = 9.9, 1.7, 1.7 Hz, 1H), 5.32 (ddd, J = 9.9, 3.8, 2.7 Hz, 1H). Selected
NOEs are between G 0.860 (C5-CH3) and G 2.58 (C3a-H), 5.32 (C6-H), between G 2.46 (C7a-H) and G

HETEROCYCLES, Vol. 92, No. 3, 2016
507
3.68 (C1-HH), and between G 2.58 (C3a-H) and G 3.04 (C1-HH). Atom numbering is shown in Scheme
10.; 13C NMR (100.6 MHz, C6D6) G (ppm) 13.83 (q), 13.99 (q), 18.01 (q), 36.89 (d), 38.25 (d), 43.22 (d),
57.92 (s), 61.61 (t), 61.82 (t), 68.68 (t), 121.99 (d), 134.85 (d), 167.93 (s), 168.81 (s), 170.95 (s). Selected
HMBC correlations are between G 3.04, 3.68 (C1-H2) and G 121.99 (C7), 38.25 (C7a), 43.22 (C3a),
between G 2.58 (C3a-H) and G 38.25 (C7a), 57.92 (C4), and between G 5.11 (C7-H) and G 43.22 (C3a),
36.89 (C5), between G 2.58 (C3a-H), 5.32 (C6-H) and G 36.89 (C5).; IR (neat) 2980, 1799, 1733, 1465,
1368, 1265, 1209, 1185, 1099, 1002 cm-1; MS (EI) m/z 296 (M+, 41), 251 (29), 223 (100%); HRMS (EI)
M+ 296.1261 (calcd for C15H20NO6 296.1260); Anal. Calcd for C15H20O6: C, 60.80; H, 6.80. Found: C, C,
61.05; H, 7.02.
ACKNOWLEDGEMENTS
This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology
(MEXT), Japan and JSPS KAKENHI Grant Number 26410048. This work was partly supported by
Nanotechnology Platform Program of MEXT. We thank Nara Institute of Science and Technology
(NAIST) and Prof. K. Kakiuchi (NAIST) for mass spectrometry. We also thank Ms E. Hirai and Mr. K.
Ueda (Nara University of Education) for experimental help.
Supporting Information available: Cartesian coordinates of the optimized geometries, Crystallographic
data, 1H and 13C NMR spectral data, and 2D NOESY spectra.
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