Knoevenagel condensation of cyclic ketones with benzoylacetonitrile and N,N′-dimethylbarbituric acid. Application of sterically hindered condensation products in the synthesis of spiro and dispiropyrans by hetero-Diels-Alder reactions

Article abstract of DOI:10.1016/j.tet.2010.12.053

Inverse-electron demand Diels-Alder cycloadditions of sterically hindered cycloalkylidene derivatives of benzoylacetonitrile and N,N′- dimethylbarbituric acid with enol ethers, cyclic enol ethers and also sterically hindered cycloalkylidenecycloalkanes we

Full text of DOI:10.1016/j.tet.2010.12.053

Tetrahedron 67 (2011) 1422e1431
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Knoevenagel condensation of cyclic ketones with benzoylacetonitrile and N,N0-
dimethylbarbituric acid. Application of sterically hindered condensation products
in the synthesis of spiro and dispiropyrans by hetero-DielseAlder reactions
,
b
Aleksandra Pa1asz a , Tadeusz Pa1asz
*
a
ꢀ
Department of Organic Chemistry, Jagiellonian University, Ingardena 3 St, 30-060 Krakow, Poland
Marian Smoluchowski Institute of Physics, Jagiellonian University, Reymonta 4 St, 30-059 Krakow, Poland
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Inverse-electron demand DielseAlder cycloadditions of sterically hindered cycloalkylidene derivatives of
benzoylacetonitrile and N,N0-dimethylbarbituric acid with enol ethers, cyclic enol ethers and also ste-
rically hindered cycloalkylidenecycloalkanes were investigated. New spiro, dispirodihydropyrans, spi-
rouracils, and dispirouracils were obtained. To confirm the experimental results, frontier orbital HOMO
and LUMO energies of heterodienes and dienophiles were calculated by semi-empirical AM1, PM3
methods and ab initio HartreeeFock calculations.
Received 20 September 2010
Received in revised form 28 November 2010
Accepted 20 December 2010
Available online 25 December 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Spiro compounds
Hetero-DielseAlder reactions
1-Oxa-1,3-butadienes
Uracils
1. Introduction
a,b-unsaturated carbonyl compounds representing an 1-oxa-1,3-
butadiene system with enol ethers.3 Itwasstatedthatintroducingan
electron-withdrawing group in the 1-oxa-1,3-diene system can en-
hance their reactivity.4 In recent work, we have shown that in-
termolecular and intramolecular HDA reactions are a powerful tool in
2H-pyran and policyclic 2H-pyran derivatives synthesis.5 In this pa-
per, the first examples of an inverse-electron demand hetero-Dielse
Alder reactions of 2-cycloalkylidene-3-oxo-3-phenylpropionitriles
and 5-cycloalkylidene-1,3-dimethyl-pyrimidine-2,4,6-triones as the
heterodienes are described.
Cycloaddition reactions provide rapid and elegant methods for
the construction of mono- and polycyclic systems. The development
of new cycloreactants is a continuous challenge in the field of
pericyclic reactions. The use of hetero-substituted diene and dien-
ophiles is of specific interest for the application of DielseAlder cy-
cloadditions toward natural and biologically active product
synthesis.1 Reports in this area mainly concern the use of hetero-
dienes with different substituents, but none have reported the use
of sterically hindered cycloalkylidene derivatives of heterodienes.
Pyran derivatives are common structural subunits in a variety of
important natural products, including carbohydrates, alkaloids,
polyether antibiotics, pheromones, and iridoids.1 Also fused uracils,
such as pyrano[2,3-d]pyrimidines, pyrido[2,3-d]pyrimidines, pyrazo
[3,4-d]pyrimidines or pyrimido[4,5-d]pyrimidines are reported to
have a wide range of biological activities, such as antiallergic, anti-
hypertensive, cardiotonic, bronchodilator, antibronchitic or antitu-
mor activity.2 The preparation of the mentioned compounds
containing a pyran and an uracil ring poses significant synthetic
challenges. 3,4-Dihydro-2H-pyrans can be efficiently synthesized by
an inverse-electron-demand hetero-DielseAlder (HDA) reactions of
The Knoevenagel condensation is a common synthetic method
for alkene formation.6 The Knoevenagel reaction of various aro-
matic and heteroaromatic aldehydes with active methylene com-
pounds, such as barbituric acids, Meldrum’s acid, dimedone,
malononitrile, ethyl cyanoacetate have been widely used in syn-
thesis of arylidene derivatives. The reactions with aromatic alde-
hydes are usually catalyzed by bases or acids. Amines, such as
piperidine or triethylamine, sodium ethoxide, acetic acid, or mix-
tures of acetic acid and sulfuric acid,7 acetic acid and piperidine,8
ammonium acetate and acetic acid9 have also been successfully
used as catalyst. Lewis acids, surfactants have also been employed
to catalyze the condensations reactions.10 However, reports de-
scribing analogous procedures for ketones are rare, because ke-
tones have low reactivity in the condensations with CH acids. Soto
et al. described Knoevenagel condensations of the cycloalkanones
* Corresponding author. E-mail addresses: palasz@chemia.uj.edu.pl (A. Pa1asz),
tadeusz.palasz@uj.edu.pl (T. Pa1asz).
with an aryl b-ketonitrile at reflux in benzene or toluene in the
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.053

A. Pałasz, T. Pałasz / Tetrahedron 67 (2011) 1422e1431
1423
presence of a mixture of piperidine and caproic acid as the cata-
lyst.11 The same reactions were carried out with using of mixture of
b
Compounds 7aeg and 8aee were characterized by 1H, 13C NMR,
IR, mass spectra, and elemental analysis. The 1H and 13C signal
assignments were confirmed by two-dimensional NMR COSY and
HETCOR spectra. The configuration of the C-20 substituents of spi-
ropyrans 7aeg or C-70 of 8aee was assigned on the basis of 1H NMR
spectra. They were deduced from the chemical shift values and
coupling constants of the protons attached to C-20or C-70 of the
-alanine and acetic acid as catalyst.12
2. Results and discussion
The aim of the work was to investigate if 1-oxa-1,3-butadienes
that are sterically hindered at the C-4 carbon, for example,
cycloalkylidene derivatives of benzoylacetonitrile 1 or N,N0-dime-
thylbarbituric acid 4 can act as active heterodienes in hetero-Dielse
Alder reactions in synthesis of spiro and dispirodihydropyrans.
First, potential heterodienes with cycloalkylidene moiety were
synthesized and in the second step their reactions with enol ethers
and cyclic enol ether were conducted. Heterodienes 3aee and
5aee were synthesized by Knoevenagel condensation of benzoy-
lacetonitrile 1 or N,N0-dimethylbarbituric acid 4 with appropriate
cycloalkanone 2aee (enantiomerically pure (R)-(þ)-3-methyl-
cyclohexanone 2e has been used) by refluxing in toluene or xylene
dihydropyran ring that exists in
a
half-chair conformation13
(Table 3).
1
In the H NMR spectra of spiropyrans 7aeg the signals of 20-H
appear as a doublet of doublets at
d
¼5.13e5.28 ppm with coupling
constants (3J¼7.2e8.4 and 2.4e3.0 Hz) due to coupling with two
protons at C-30 (Table 3). Thus, 20-H is in the axial position and the
alkoxy group occupies the equatorial position. (Fig. 1). The 1H NMR
spectra of 8aee reveal the signals of proton 70-H as a doublet of
doublets at
d
¼4.99e5.20 ppm with coupling constants (3J¼8.1e8.7
and 2.1e2.4 Hz) (Table 3). Thus, 70-H is in the axial position and the
alkoxy group is equatorial (Fig. 1).
For cycloadditions of compounds 3e or 5e with ether 6a high
diastereoselectivity was observed because products 7g and 8e were
obtained each as one diastereoisomer from four diastereoisomers
presented on the Fig. 2. Analysis of two-dimensional NMR COSY,
for 4e6 h in the presence of b-alanine and acetic acid as catalyst
according to a procedure described in ref. 12b. The progress of the
reactions was monitored by TLC. Compounds 3aee and 5aee were
obtained in good 77e87% yields (Scheme 1, Table 1).
R1
n
n
H2NCH2CH2COOH
CH3COOH
NC
NC
Ph
R1
+
Ph
O
O
O
1
2a-e
3a-e
O
O
N
R1
n
n
H2NCH2CH2COOH
CH3COOH
N
R1
+
N
O
N
O
O
O
O
2a-e
4
5a-e
Scheme 1. Knoevenagel condensations of benzoylacetonitrile 1 or N,N0-dimethylbarbituric acid 4 with cyclic ketones 2aee.
NOESY, and HETCOR spectra compounds 7g and 8e does not allow
Table 1
the configuration to be assigned unambiguously. It was impossible
to determinate the crystallographic structure of compounds 7g and
8e because they are oils.
Synthesis of cycloalkylidene derivatives 3aee and 5aee by Knoevenagel
condensation
Methylene
compound
Cyclic
ketone
n
R1
Knoevenagel
condensation
product
Reaction
time/ha
Yield %
Although only one diastereoisomer of the compounds 7g or 8e
was obtained in DielseAlder reactions, the formation of the minor
isomers has not been formally excluded. Therefore, acetals 7g and
8e were submitted to the action of Lewis acid to equilibrate one
isomer to another isomer. The diastereoisomers of the compounds
7g and 8e obtained in the cycloaddition reactions were mixed with
boron trifluoride diethyl etherate BF.3Et2O. In both examined cases
the mixtures of the diastereoisomer submitted to the action of
Lewis acid (diastereoisomer A) and a new diastereoisomer (dia-
stereoisomer B) was obtained (A/B¼1:2.3 for 7g, A/B¼1:1.9 for 8e)
after 24 h at room temperature. The ratios of isomers A/B were
determined on the basis of 1H NMR spectra of crude mixtures after
isomerization reactions.
1
1
1
1
1
4
4
4
4
4
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
1
0
2
3
1
1
0
2
3
1
H
H
H
H
CH3
H
H
H
H
3a
3b
3c
3d
3e
5a
5b
5c
5d
5e
5 (t)
4 (t)
5 (t)
6 (t)
6 (t)
5 (x)
4 (x)
5 (x)
5 (x)
6 (x)
87
86
84
82
81
82
87
86
86
77
CH3
a
Reaction mixture was heated to reflux in toluene (t) or xylene (x).
Encouraged by previous presented results, we next embarked
on the inverse-electron-demand hetero-DielseAlder reactions
between cycloalkylidene derivatives 3 or 5 and cyclic enol ether
2-methylenetetrahydropyrane 9. The compound 9 was prepared
according to the literature with a yield of 69% from 2-(chloro-
methyl)tetrahydropyrane14 that was prepared from tetrahy-
dropyran-2-methanol.15 The cycloaddition reactions of 3a, 3e, 5a,
The cycloaddition reactions of 2-cycloalkylidene-3-oxo-3-
phenylpropionitriles 3aee or 5-cycloalkylidene-1,3-dimethylpyr-
imidine-2,4,6-triones 5aee with enol ethers 6aec were performed
in toluene solution at 110 ꢀC for 24 h and the spiropyrans 7aeg and
8aee were obtained in good 78e93% yields (Scheme 2, Table 2).
The progress of the reactions was monitored by TLC.

1424
A. Pałasz, T. Pałasz / Tetrahedron 67 (2011) 1422e1431
R1
n
n
NC
Ph
NC
Ph
R1
R3
OR2
+
R3
OR2
O
O
3a-e
6a-c
7a-g
R1
n
O
N
O
N
n
R1
N
N
+
OC2H5
O
O
O
O
OC2H5
5a-e
6a
8a-e
Scheme 2. Hetero-DielseAlder reactions of cycloalkylidene derivatives 3aee and 5aee with enol ethers 6aec.
and 5e with 9 were performed in toluene solution at 110 ꢀC for 24 h
Table 2
and the spiropyrans 10a, 10b, 11a, and 11b were obtained in good
87e93% yields (Scheme 3, Table 4). The progress of the reactions
was monitored by TLC using mixture ethyl acetate/pet. ether as an
eluent.
Synthesis of spiropyrans 7aeg and 8aee by DielseAlder reactions
Diene
n
R1
Enol ether
R2
R3
Spiropyran
Yield %a
3a
3a
3a
3b
3c
3d
3e
5a
5b
5c
5d
5e
1
1
1
0
2
3
1
1
0
2
3
1
H
H
H
H
H
H
CH3
H
H
6a
6b
6c
6a
6a
6a
6a
6a
6a
6a
6a
6a
C2H5
i-Bu
CH3
H
H
CH3
H
H
H
H
H
H
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
89
91
84
87
86
83
87
79
93
91
88
78
Compounds 10a, 10b, 11a, and 11b were characterized by 1H, 13
C
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
NMR, IR, mass spectra, and elemental analysis. 1H and 13C signal
assignments were confirmed by two-dimensional NMR COSY and
HETCOR spectra.
Only one diastereoisomer was obtained as product in the
hetero-DielseAlder reaction of compounds 3e or 5e with cyclic
enol ether 9. Fig. 3 presents possible configurations of dis-
piropyrans diastereoisomers 10b and 11b. Again, the analysis of
two-dimensional NMR COSY and HETCOR spectra of compounds
10b and 11b does not allow the configuration to be unambiguously
assigned. There were also problems with preparing of crystals
suitable for crystallographic study.
H
H
CH3
H
H
H
a
Isolated yields after column chromatography.
Trispiropyrans provide an unusual synthetic challenge, so in the
next step, methodology for synthesis of dispiropyrans was applied
to prepare trispiropyrans. The DielseAlder reactions of cyclo-
alkylidene derivatives 3a and 5b with cycloalkylidenecycloalkane
12 and 14 were investigated. Cyclohexylidenecyclohexane 12 and
cyclopentylidenecyclopentane 14 were obtained by the new
method16 for reductive coupling of carbonyl compounds to olefins
with using of AlCl3 and Zn as efficient reagents comparable to
McMurry’s reagent. The reaction mixtures of 3a with 12 or 5b
with 14 were first heated to reflux in toluene solution for 24 h,
but the trispiropyrans 13 and 15 were not formed (Scheme 4).
The progress of the reactions was monitored by TLC using
mixture ethyl acetate/pet. ether as an eluent. The reaction con-
ditions were changed and the reaction mixtures were heated to
reflux in xylene solution for 24 h. There was no trace of desired
products 13 and 15 so reaction mixtures were heated in xylene
solution in the presence of catalytic amounts of the Lewis
acids,17 such as ZnCl2 or CoCl2 and no reaction occurred, even
after 24 h at reflux.
Table 3
Signals of protons 20-H and 70-H in 1H NMR spectra of spirodihydropyrans 7aeg and
8aee
7
dd 20-H
(ppm)
8
dd 70-H
(ppm)
d
d
0
0
0
0
0
0
0
0
J3 ax,2 /J3 eq,2 (Hz)
J6 ax,7 /J6 eq,7 (Hz)
7a
7b
7d
7e
7f
5.13
8.1/2.4
5.13
7.2/2.7
5.14
7.8/2.4
5.17
8a
8b
8c
8d
8e
5.13
8.4/2.1
5.08
8.1/2.1
5.18
8.7/2.1
5.20
8.1/2.4
5.22
8.7/2.4
4.99
8.4/2.7
5.28
8.7/2.4
7g
8.4/3.0
The cycloaddition reactions appear to be under frontier molec-
ular orbital (FMO) control. In order to confirm the experimental
results, frontier orbital (HOMO and LUMO) energies of hetero-
dienes 3a, 3b, 3e, 5a, 5b, 5e, and dienophiles 6a, 9, 12, 14 were
calculated by semi-empirical AM1 and PM3 methods and ab initio
HartreeeFock calculations using the Gaussian 03 suite of programs.
The geometries were fully optimized by PM3 semi-empirical
methods and used as the basis for optimization at the HartreeeFock
level using the 3-21G basis set (HF/3-21G). The calculated frontier
orbital energies are summarized in Table 5.
H3C
O
( )n
OR2
'
( )n
OR2
4
NC
N
'
5
O
Ph
O
N
'
2
R3
O
'
7
H3C
R3
7a-g
8a-e
Fig. 1. Preferred configurations and conformations of spirocycloadducts 7aeg and
8aee based on 1H NMR analysis.

A. Pałasz, T. Pałasz / Tetrahedron 67 (2011) 1422e1431
1425
CH3
CH3
CH3
CH3
3
3
3
3
1
1
1
1
NC
Ph
NC
Ph
NC
Ph
NC
Ph
4'
4'
4'
4'
H
OC2H5
2'
H
OC2H5
OC2H5
H
OC2H5
H
2'
2'
2'
O
O
O
O
(1S, 3R, 2'S)-7g
(1R, 3R, 2'S)-7g
(1S, 3R, 2'R)-7g
(1R, 3R, 2'R)-7g
CH3
CH3
CH3
CH3
3
3
3
3
O
O
O
O
1
1
1
1
4'
5'
4'
5'
4'
5'
4'
5'
N
3'
2'
N
3'
2'
N
N
3'
2'
3'
2'
H
OC2H5
H
OC2H5
OC2H5
H
OC2H5
H
7'
7'
7'
7'
1'
1'
1'
1'
O
N
O
O
N
O
O
N
O
O
N
O
(1S, 3R, 7'R)-8e
(1R, 3R, 7'R)-8e
(1S, 3R, 7'S)-8e
(1R, 3R, 7'S)-8e
Fig. 2. Diastereoisomers of spiropyrans 7g and 8e.
R1
n
n
NC
NC
Ph
R1
O
+
O
Ph
O
O
3a, 3e
9
10a-b
R1
n
O
n
O
N
R1
N
+
N
O
O
O
N
O
O
O
9
5a, 5e
11a-b
Scheme 3. Hetero-DielseAlder reactions of cycloalkylidene derivatives 3a, 3e, 5a, and 5e with cyclic enol ether 9.
Table 4
Investigated cycloadditions are an inverse-electron demand
DielseAlder reactions. In hetero-DielseAlder reactions with in-
verse-electron demand, the HOMO orbital of the dienophile (D)
overlaps with the LUMO orbital of the heterodiene (H), so energy
gaps ELUMO(H)ꢁEHOMO(D) were discussed (Table 6). In all the
studied cases, the energy gaps for the interaction of the HOMO
orbital of heterodiene and the LUMO orbital of the dienophile are
higher (from 11.181 to 15.699 eV) than energy differences for the
Synthesis of dispiropyrans 10a, 10b, 11a, and 11b by DielseAlder reactions
Diene
n
R1
Enol ether
Spiropyran
Yield %a
3a
3e
5a
5e
1
1
1
1
H
CH3
H
9
9
9
9
10a
10b
11a
11b
93
91
87
89
CH3
a
Isolated yields after column chromatography.
CH3
CH3
CH3
CH3
3
3
3
3
1
1
1
1
NC
Ph
NC
Ph
NC
Ph
NC
Ph
4'
4'
4'
4'
O
O
O
O
2'
2'
2'
2'
2''
2''
2''
2''
O
O
O
O
(1S, 3R, 2'S)-10b
(1R, 3R, 2'R)-10b
(1R, 3R, 2'S)-10b
(1S, 3R, 2'R)-10b
CH3
O
CH3
O
CH3
O
CH3
O
3
3
3
3
O
O
O
O
1
1
1
1
4'
5'
4'
5'
4'
5'
4'
5'
N
3'
2'
N
3'
2'
N
3'
2'
N
3'
2'
7'
7'
7'
7'
1'
1'
1'
1'
2"
2"
2"
2"
O
N
O
O
N
O
O
N
O
O
N
O
(1S, 3R, 7'R)-11b
(1R, 3R, 7'R)-11b
(1R, 3R, 7'S)-11b
(1S, 3R, 7'S)-11b
Fig. 3. Diastereoisomers of dispiropyrans 10b and 11b.

1426
A. Pałasz, T. Pałasz / Tetrahedron 67 (2011) 1422e1431
Table 6
Energy gaps (eV): FMO interactions of heterodienes (H) 3a, 3b, 3e, 5a, 5b, 5e with
dienophiles (D) 6a, 9, 12, 14 obtained by semi-empirical AM1, PM3, and ab initio HF/
3-21G calculations
NC
Ph
NC
Ph
+
DielseAlder
reaction
Method AM1
ELUMO(H)
Method PM3
ELUMO(H)
Method HF/3-21G
ELUMO(H)
O
O
ꢁEHOMO(D)
ꢁEHOMO(D)
ꢁEHOMO(D)
3a(H) and 6a(D)
3b(H) and 6a(D)
3e(H) and 6a(D)
5a(H) and 6a(D)
5b(H) and 6a(D)
5e(H) and 6a(D)
3a(H) and 9(D)
3e(H) and 9(D)
5a(H) and 9(D)
5e(H) and 9(D)
3a(H) and 12(D)
5b(H) and 14(D)
9.046
8.916
8.946
8.602
8.564
8.617
9.079
8.978
8.634
8.649
8.747
8.200
8.966
8.842
8.860
8.550
8.537
8.562
9.005
8.899
8.589
8.601
8.729
8.147
11.392
11.158
11.195
10.938
10.886
10.945
11.325
11.128
10.871
10.878
10.848
10.122
3a
12
13
O
O
N
N
N
+
O
N
O
O
O
15
5b
14
Scheme 4. DielseAlder reactions of cycloalkylidene derivatives 3a, 5b with cyclo-
alkylidenecycloalkane 12 and 14.
gaps for reaction of 3a or 5b with dienophiles 6a or 9 (Table 6).
Probably, steric effects dictate that heterodienes 3a and 5b cannot
react with sterically hindered dienophiles 12 or 14 and trispir-
opyrans 13 or 15 did not arise under these conditions.
Table 5
Energies of FMOs of heterodienes 3a, 3b, 3e, 5a, 5b, 5e, and dienophiles 6a, 9, 12, 14
obtained by semi-empirical AM1, PM3, and ab initio HF/3-21G calculations
Compound
FMO
E/eV (AM1)
E/eV (PM3)
E/eV (HF)
3a
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
HOMO
LUMO
ꢁ10.014
ꢁ0.304
ꢁ10.064
ꢁ0.434
ꢁ10.039
ꢁ0.405
ꢁ10.439
ꢁ0.749
ꢁ10.399
ꢁ0.786
ꢁ10.429
ꢁ0.734
ꢁ9.350
1.504
ꢁ10.119
ꢁ0.493
ꢁ10.157
ꢁ0.616
ꢁ10.150
ꢁ0.599
ꢁ10.146
ꢁ0.909
ꢁ10.082
ꢁ0.921
ꢁ10.138
ꢁ0.897
ꢁ9.459
1.329
ꢁ9.558
2.386
3. Conclusion
3b
3e
5a
5b
5e
6a
9
ꢁ9.574
2.152
In summary, DielseAlder cycloadditions of sterically hindered
cycloalkylidene derivatives of benzoylacetonitrile and N,N0-dime-
thylbarbituric acid were studied. Potential heterodienes were
synthesized in 77e87% yields by Knoevenagel condensation of
benzoylacetonitrile or N,N0-dimethylbarbituric acid with an ap-
propriate cycloalkanone by heating at reflux in toluene or xylene in
ꢁ9.541
2.189
ꢁ10.386
1.932
ꢁ10.346
1.879
ꢁ10.345
the presence of b-alanine and acetic acid as catalyst. The cycload-
1.939
dition reactions of 2-cycloalkylidene-3-oxo-3-phenylpropionitriles
or 5-cycloalkylidene-1,3-dimethylpyrimidine-2,4,6-triones with
enol ethers, including cyclic enol ether 2-methylenetetrahy-
dropyrane, were performed in toluene solution at reflux and the
spiropyrans and dispiropyrans were obtained in good 78e93%
yields. To confirm the experimental results semi-empirical AM1,
PM3 methods and ab initio HartreeeFock calculations of frontier
molecular orbital energies of heterodienes and dienophiles have
been performed. Energy gaps ELUMO(H)ꢁEHOMO(D) for reaction of
ethyl-vinyl ether are slightly lower for the cycloalkylidene de-
rivatives of N,N0-dimethylbarbituric acid than for the cyclo-
alkylidene derivatives of benzoylacetonitrile. For the studied
cycloadditions, the reactivity of cyclic enol ether is comparable with
the reactivity of ethyl-vinyl ether.
ꢁ9.006
5.313
ꢁ9.382
ꢁ9.498
ꢁ8.939
1.301
1.157
5.140
12
14
ꢁ9.051
1.235
ꢁ9.222
1.062
ꢁ8.462
5.019
ꢁ8.986
ꢁ9.068
ꢁ8.242
1.225
1.101
4.749
interaction of the LUMO orbital of heterodiene and the HOMO or-
bital of the dienophile (from 8.537 to 11.392 eV). For an inverse-
electron demand DielseAlder cycloaddition the presence of an
electron-withdrawing group in the heterodiene and an electron-
releasing substituent in the dienophile contracts the LUMO(H)ꢁ
HOMO(D) energy separation through raising the energy of the
HOMO(D) and lowering the energy of the LUMO(H) and hence in-
creases the reactivity.
This trend is observed in the present study too. Energy gaps
ELUMO(H)ꢁEHOMO(D) for reaction of ethyl-vinyl ether 6a are slightly
lower for the cycloalkylidene derivatives of N,N0-dimethylbarbituric
acid 5a, 5b, 5e, than for the cycloalkylidene derivatives of ben-
zoylacetonitrile 3a, 3b, 3e (Table 6). For the studied cycloadditions,
the reactivity of cyclic enol ether 9 is comparable with the reactivity
of ethyl-vinyl ether 6a. The calculated energy gaps for the in-
teraction LUMO orbital of heterodienes 3a, 3e, 5a, 5e, and HOMO
orbital of dienophile 9 are similar to the appropriate energy gaps for
heterodienes 3a, 3e, 5a, 5e, and dienophile 6a. However, the fron-
tier molecular orbital model does not seem capable of explaining
the observed reactivity for cycloadditions of heterodienes 3a or 5b
with cycloalkylidenecycloalkanes 12 or 14. The energy differences
for the interaction of the LUMO orbital of 3a or 5b and the HOMO
orbital of 12 or 14 are comparable or slightly lower than energy
4. Experimental
4.1. General
Melting points were determined on a Boetius hot stage appa-
ratus. IR spectra: Bruker IFS 48 as films or in KBr pellets. NMR
spectra: Bruker Avance II 300 (1H: 300.18 MHz, 13C: 75.48 MHz) in
CDCl3 with TMS as an internal standard. Mass spectra: Finningan
Mat 95 (70 eV). Microanalyses were performed with Euro EA 3000
Elemental Analyzer.
4.2. Materials
Benzoylacetonitrile 1, cycloalkanones 2aee, N,N0-dimethylbarbi-
turic acid 4, enol ethers 6aec were commercially available. 2-Cyclo-
alkylidene-3-oxo-3-phenylpropionitriles 3aee and 5-cycloalkylidene-

A. Pałasz, T. Pałasz / Tetrahedron 67 (2011) 1422e1431
1427
1,3-dimethylpyrimidine-2,4,6-triones 5aee were obtained according
13.5 Hz, cyclohexylidene), 1.29e1.16, 2.11e1.80 (6H, m, cyclo-
hexylidene), 0.91, 1.08 (3H, d, J 6.6 Hz, 30-Me); dC (75.5 MHz, CDCl3)
189.3, 189.2, 172.3, 172.1, 135.9, 134.2, 129.5, 128.9, 116.0, 108.3,
108.2, 43.4, 40.3, 35.2, 34.9, 33.9, 33.8, 32.1, 27.8, 27.1, 21.9; m/z (ESI)
240 (MHþ).
to the procedure described in the literature.12
4.3. General procedure for Knoevenagel condensation
A mixture consisting of 10 mmol methylene compound 1 or 4,
10 mmol cycloalkanone 2aee,
b
-alanine (180 mg, 2 mmol), acetic
4.3.4. 5-Cyclohexylidene-1,3-dimethylpyrimidine-2,4,6-trione
acid (2 mL), toluene or xylene (50 mL) was stirred and heated under
reflux in a flask fitted with a DeaneStark trap and condenser for
4e6 h. The progress of the reactions was monitored by TLC. The
solvent was evaporated and the mixture was purified by flash
chromatography on silica gel using ethyl acetate/pet. ether 1:2
(3aee) or ethyl acetate/pet. ether 1:1 (5aee) as an eluent. Re-
crystallization from n-hexane (3a, b) or n-hexane/tert-butyl methyl
ether 3:1 or 5:1 (5aee) gave 3aee and 5aee with yields 77e87%
listed in Table 1.
(5a). A mixture consisting of N,N0-dimethylbarbituric acid 4 (1.56 g,
10 mmol), cyclohexanone 2a (0.98 g, 1.04 mL, 10 mmol), b-alanine
(180 mg, 2 mmol), glacial acetic acid (2 mL) in xylene (50 mL) was
stirred and heated under reflux in a flask fitted with a DeaneStark
trap and condenser for 5 h. The solvent was evaporated and the
mixture was purified by flash chromatography (1:1 EtOAc/pet.
ether). Recrystallization (3:1 n-hexane/tert-butyl methyl ether)
gave the title compound 5a (1.94 g, 82%) as a white solid, mp 112 ꢀC;
[found: C, 61.13; H, 6.87; N, 12.01. C12H16N2O3 requires C, 61.00; H,
6.83; N, 11.86%]; nmax(KBr) 2936, 2833, 1741, 1702, 1658 cmꢁ1
; dH
4.3.1. 2-Cycloheptylidene-3-oxo-3-phenylpropionitrile (3c). A mix-
ture consisting of benzoylacetonitrile 1 (1.45 g, 10 mmol), cyclo-
(300 MHz, CDCl3) 3.33 (3H, s, NeMe), 3.32 (3H, s, NeMe), 3.08 (2H,
t, J 6.6 Hz, cyclohexylidene), 2.10e1.56 (8H, m, cyclohexylidene); dC
(75.5 MHz, CDCl3) 184.2, 167.4, 162.5, 131.5, 129.5, 28.7, 28.5, 26.6,
25.6, 25.4, 22.4, 21.4; m/z (ESI) 237 (MHþ), 169, 157, 112, 83.
heptanone 2c (1.12 g, 1.17 mL, 10 mmol),
b-alanine (180 mg,
2 mmol), glacial acetic acid (2 mL) in toluene (50 mL) was stirred
and heated under reflux in a flask fitted with a DeaneStark trap and
condenser for 5 h. The solvent was evaporated and the mixture was
purified by flash chromatography (1:2 EtOAc/pet. ether) to give the
title compound 3c (2.01 g, 84%) as a colorless oil; [found: C, 80.35; H,
7.29; N, 5.82. C16H17NO requires C, 80.30; H, 7.16; N, 5.85%];
4.3.5. 5-Cyclopentylidene-1,3-dimethylpyrimidine-2,4,6-trione
(5b). A mixture consisting of N,N0-dimethylbarbituric acid 4 (1.56 g,
10 mmol), cyclopentanone 2b (0.84 g, 0.89 mL, 10 mmol), b-alanine
(180 mg, 2 mmol), glacial acetic acid (2 mL) in xylene (50 mL) was
stirred and heated under reflux in a flask fitted with a DeaneStark
trap and condenser for 4 h. The solvent was evaporated and the
mixture was purified by flash chromatography (1:1 EtOAc/pet.
ether). Recrystallization (3:1 n-hexane/tert-butyl methyl ether) gave
the title compound 5b (1.93 g, 87%) as a white solid, mp 113 ꢀC;
[found: C, 59.46; H, 6.15; N, 12.67. C11H14N2O3 requires C, 59.45; H,
nmax(film) 3063, 2932, 2856, 2210, 1670, 1597 cmꢁ1
; dH (300 MHz,
CDCl3) 7.95e7.91 (2H, m, Ph), 7.65e7.59 (1H, m, Ph), 7.53e7.47 (2H,
m, Ph), 2.89e2.85 (2H, m, cycloheptylidene), 2.61e2.57 (2H, m,
cycloheptylidene), 1.88e1.81 (2H, m, cycloheptylidene), 1.74e1.52
(6H, m, cycloheptylidene); dC (75.5 MHz, CDCl3) 189.3, 176.5, 136.0,
134.1, 129.5, 128.8, 116.3, 110.6, 36.9, 33.9, 29.1, 28.8, 26.7, 26.6; m/z
(ESI) 240 (MHþ), 212, 158, 105.
6.35; N, 12.60%]; nmax(KBr) 2972, 2883, 1727, 1665, 1572 cmꢁ1
; dH
(300 MHz, CDCl3) 3.34 (6H, s, NeMe), 3.24 (4H, ddd, J 3.0, 7.5,
15.0 Hz, 20-H), 1.81 (4H, m, 30-H); dC (75.5 MHz, CDCl3) 194.6, 161.8,
151.3,135.3,114.1, 39.6, 28.3, 25.8; m/z (ESI) 223 (MHþ), 213,185,169.
4.3.2. 2-Cyclooctylidene-3-oxo-3-phenylpropionitrile (3d). A mix-
ture consisting of benzoylacetonitrile 1 (1.45 g, 10 mmol), cyclo-
octanone 2d (1.26 g, 1.32 mL, 10 mmol),
b-alanine (180 mg,
2 mmol), glacial acetic acid (2 mL) in toluene (50 mL) was stirred
and heated under reflux in a flask fitted with a DeaneStark trap and
condenser for 6 h. The solvent was evaporated and the mixture was
purified by flash chromatography (1:2 EtOAc/pet. ether) to give the
title compound 3d (1.96 g, 82%) as a colorless oil; [found: C, 80.51; H,
7.63; N, 5.69. C17H19NO requires C, 80.60; H, 7.56; N, 5.53%];
4.3.6. 5-Cycloheptylidene-1,3-dimethylpyrimidine-2,4,6-trione
(5c). A mixture consisting of N,N0-dimethylbarbituric acid 4 (1.56 g,
10 mmol), cycloheptanone 2c (1.12 g, 1.17 mL, 10 mmol), b-alanine
(180 mg, 2 mmol), glacial acetic acid (2 mL) in xylene (50 mL) was
stirred and heated under reflux in a flask fitted with a DeaneStark
trap and condenser for 5 h. The solvent was evaporated and the
mixture was purified by flash chromatography (1:1 EtOAc/pet.
ether). Recrystallization (5:1 n-hexane/tert-butyl methyl ether)
gave the title compound 5c (2.15 g, 86%) as a white solid, mp 68 ꢀC;
[found: C, 62.22; H, 7.20; N, 11.18. C13H18N2O3 requires C, 62.38; H,
nmax(film) 3059, 2948, 2853, 2210, 1675, 1592 cmꢁ1
; dH (300 MHz,
CDCl3) 7.94e7.90 (2H, m, Ph), 7.64e7.58 (1H, m, Ph), 7.52e7.47 (2H,
m, 2H, Ph), 2.78 (2H, ddd, J 3.6, 6.0, 8.7 Hz, cyclooctylidene), 2.58
(2H, ddd, J 3.9, 6.3, 9.0 Hz, cyclooctylidene), 2.03e1.95 (2H, m,
cyclooctylidene), 1.80e1.77 (2H, m, cyclooctylidene), 1.62e1.47 (6H,
m, cyclooctylidene); dC (75.5 MHz, CDCl3) 189.2, 179.4, 136.1, 134.0,
129.4, 128.8, 116.6, 110.2, 35.7, 33.2, 27.4, 27.2, 26.5, 25.8, 25.6; m/z
(ESI) 254 (MHþ), 105.
7.25; N, 11.19%]; nmax(KBr) 2930, 2854, 1729, 1670, 1566 cmꢁ1
; dH
(300 MHz, CDCl3) 3.32 (6H, s, NeMe), 3.11 (4H, t, J 6.3 Hz, 20-H),
1.90e1.82 (4H, m, cycloheptylidene), 1.57 (4H, m, cyclo-
heptylidene); dC (75.5 MHz, CDCl3) 187.7, 162.1, 151.3, 135.2, 117.9,
59.5, 38.3, 31.9, 28.7, 28.4, 27.8, 26.3, 26.1; m/z (ESI) 251(MHþ), 169,
112, 83.
4.3.3. (30R)-2-(30-Methylcyclohexylidene)-3-oxo-3-phenyl-
propionitrile (3e). A mixture consisting of benzoylacetonitrile 1
(1.45 g, 10 mmol), (R)-(þ)-3-methyl-cyclohexanone 2e (1.12 g,
4.3.7. 5-Cyclooctylidene-1,3-dimethylpyrimidine-2,4,6-trione
(5d). A mixture consisting of N,N0-dimethylbarbituric acid 4 (1.56 g,
1.22 mL, 10 mmol),
b-alanine (180 mg, 2 mmol), glacial acetic acid
(2 mL) in toluene (50 mL) was stirred and heated under reflux in
a flask fitted with a DeaneStark trap and condenser for 6 h. The
solvent was evaporated and the mixture was purified by flash
chromatography (1:2 EtOAc/pet. ether) to give the title compound
3e as a mixture of isomers E/Z (1:1) (1.94 g, 81%) as a colorless oil;
[found: C, 80.37; H, 7.31; N, 5.89. C16H17NO requires C, 80.30; H,
10 mmol), cyclooctanone 2d (1.26 g, 1.32 mL, 10 mmol), b-alanine
(180 mg, 2 mmol), glacial acetic acid (2 mL) in xylene (50 mL) was
stirred and heated under reflux in a flask fitted with a DeaneStark
trap and condenser for 5 h. The solvent was evaporated and the
mixture was purified by flash chromatography (1:1 EtOAc/pet.
ether). Recrystallization (5:1 n-hexane/tert-butyl methyl ether)
gave the title compound 5d (2.15 g, 86%) as a white solid, mp 54 ꢀC;
[found: C, 63.58; H, 7.57; N, 10.74. C14H20N2O3 requires C, 63.62; H,
7.16; N, 5.85%]; nmax(film) 3063, 2932, 2856, 2210, 1670, 1597 cmꢁ1
;
dH (300 MHz, CDCl3) 7.96e7.92 (2H, m, Ph), 7.66e7.60 (1H, m, Ph),
7.53e7.48 (2H, m, Ph), 3.05e3.00 (1H, m, cyclohexylidene),
2.72e2.64 (1H, m, cyclohexylidene), 2.31 (1H, ddd, J 5.1, 12.6,
7.63; N, 10.60%]; nmax(KBr) 2933, 2854, 1724, 1667, 1526 cmꢁ1
(300 MHz, CDCl3) 3.15 (3H, s, NeMe), 3.14 (3H, s, NeMe), 2.11e2.07
; dH

1428
A. Pałasz, T. Pałasz / Tetrahedron 67 (2011) 1422e1431
(4H, m, cyclooctylidene), 1.92e1.84 (1H, m, cyclooctylidene),
1.44e1.39 (9H, m, cyclooctylidene); dC (75.5 MHz, CDCl3) 187.2,
161.7, 151.6, 133.7, 131.9, 57.6, 36.0, 28.9, 28.1, 28.0, 27.5, 25.8, 25.2;
m/z (ESI) 265 (MHþ).
ether were evaporated and the mixture was purified by column
chromatography (1:3 EtOAc/pet. ether). Recrystallization (n-hex-
ane) gave the title compound 7b (1.48 g, 91%) as a white solid, mp
47 ꢀC; [found: C, 77.62; H, 8.63; N, 4.40. C21H27NO2 requires C,
77.50; H, 8.36; N, 4.30%]; Rf (1:3 EtOAc/pet. ether) 0.49; nmax(KBr)
4.3.8. (30R)-(ꢁ)-5-(30-Methylcyclohexylidene)-1,3-dimethylpyr-
imidine-2,4,6-trione (5e). A mixture consisting of N,N0-dimethyl-
2973, 2933, 2855, 2204, 1607, 1574, 1147, 1051 cmꢁ1
; dH (300 MHz,
CDCl3) 7.73e7.70 (2H, m, Ph), 7.43e7.40 (3H, m, Ph), 5.13 (1H, dd, J
2.7, 7.2 Hz, 20-H), 3.76 (1H, dd, J 6.6, 9.0 Hz, OCH2CH(CH3)2), 3.38
(1H, dd, J 6.6, 9.0 Hz, OCH2CH(CH3)2), 2.17 (1H, dd, J 2.7, 13.8 Hz, 30-
H), 1.92e0.88 (12H, m, OCH2CH(CH3)2, 3-H, cyclohexane), 0.95 (6H,
d, J 6.9 Hz, OCH2CH(CH3)2); dC (75.5 MHz, CDCl3) 161.9, 133.6, 130.5,
128.3, 128.2, 119.3, 99.8, 95.8, 76.4, 36.6, 36.4, 35.0, 34.4, 28.6, 25.2,
21.6, 21.3, 19.4, 19.3; m/z (ESI) 326(MHþ), 226, 181, 105.
barbituric acid
cyclohexanone 2e (1.12 g, 1.22 mL, 10 mmol),
4
(1.56 g, 10 mmol), (R)-(þ)-3-methyl-
b
-alanine (180 mg,
2 mmol), glacial acetic acid (2 mL) in xylene (50 mL) was stirred and
heated under reflux in a flask fitted with a DeaneStark trap and
condenser for 6 h. The solvent was evaporated and the mixture was
purified by flash chromatography (1:1 EtOAc/pet. ether). Re-
crystallization (5:1 n-hexane/tert-butyl methyl ether) gave the title
compound 5e (1.93 g, 77%) as a white solid, mp 73 ꢀC; [found: C,
4.4.3. (20RS)-30,40-Dihydro-20methoxy-20-methyl-60-phenylspiro[cy-
clohexane-1,40-[2H]pyran]-50-carbonitrile (7c). A solution of 2-
cyclohexylidene-3-oxo-3-phenylpropionitrile 3a (1.13 g, 5 mmol) in
anhydrous toluene (10 mL) and isopropenyl-methyl ether 6c
(3.62 g, 4.72 mL, 50 mmol) and some crystals of hydroquinone was
heated at 110 ꢀC in a pressure flask for the 24 h. The solvent and
excess of ether were evaporated and the mixture was purified by
column chromatography (1:3 EtOAc/pet. ether). Recrystallization
(n-hexane/tert-butyl methyl ether 5:1) gave the title compound 7c
(1.25 g, 84%) as a white solid, mp 122 ꢀC; [found: C, 76.50; H, 7.63; N,
4.80. C19H23NO2 requires C, 76.74; H, 7.80; N, 4.71%]; Rf (1:3 EtOAc/
pet. ether) 0.51; nmax(KBr) 2975, 2927, 2856, 2199, 1612, 1575, 1100,
62.51; H, 7.32; N, 11.26. C13H18N2O3 requires C, 62.38; H, 7.25; N,
22
11.19%]; [
a
]
D
ꢁ13.1 (c 0.08, CHCl3); nmax(KBr) 2952, 2929, 2870,
1737,1672,1599 cmꢁ1
; dH (300 MHz, CDCl3) 3.33 (3H, s, NeMe), 3.32
(3H, s, NeMe), 2.25e1.23 (9H, m, cyclohexylidene), 1.06 (3H, d, J
6.3 Hz, 30-Me); dC (75.5 MHz, CDCl3) 183.2, 167.3, 162.5, 130.9, 129.2,
57.7, 42.6, 37.0, 34.4, 34.2, 28.6, 28.5, 22.3; m/z (ESI) 251 (MHþ).
4.4. General procedure for the synthesis of spiropyrans 7aeg,
8aee, and dispiropyrans 10a, b and 11a, b
A
solution of 2-cycloalkylidene-3-oxo-3-phenylpropionitrile
3aee or 5-cycloalkylidene-1,3-dimethylpyrimidine-2,4,6-trione
5aee (5 mmol) in anhydrous toluene (10 mL), and 50 mmol the
appropriate vinyl ethers 6aec, 9 (10 equiv) and some crystals of
hydroquinone was heated at 110 ꢀC in a pressure flask (a round-
bottomed flask 100 mL with a screw cap and a Teflon seal) for the
24 h. The progress of the reactions was monitored by TLC. The sol-
vent and excess of ethers were evaporated and the mixture was
purified by column chromatography on silica gel using ethyl acetate/
pet. ether 1:3 (7aef), ethyl acetate/pet. ether 1:6 (7g), ethyl acetate/
pet. ether 1:1 (8aed), ethyl acetate/pet. ether 1:2 (8e, 10a, b, 11a, b)
as an eluent. Recrystallization from n-hexane (7a, 7b, 7e, 7f, 8a, 8c,
8e) or n-hexane/tert-butyl methyl ether 5:1 (7c, 7d, 10a, 10b, 11a)
gave 7aeg, 8aee, 10aeb, and 11aeb with yields listed in Table 2.
1063 cmꢁ1
; dH (300 MHz, CDCl3) 7.75e7.72 (2H, m, Ph), 7.42e7.40
(3H, m, Ph), 3.35 (3H, s, OMe), 2.56 (1H, d, J 14.4 Hz, 30-H), 2.22e2.19
(1H, m, 30-H), 1.57 (3H, s, 20-Me), 1.91e1.22 (10H, m, cyclohexane);
dC (75.5 MHz, CDCl3) 160.8, 134.0, 130.3, 128.3, 119.6, 101.3, 96.9,
49.5, 39.8, 38.9, 34.4, 32.6, 25.4, 23.4, 22.1, 21.0; m/z (ESI) 320
(MNaþ), 298(MHþ), 280, 266, 238, 226, 105.
4.4.4. (20RS)-20-Ethoxy-30,40-dihydro-60-phenylspiro[cyclopentane-
1,40-[2H]pyran]-50-carbonitrile (7d). A solution of 2-cyclo-
pentylidene-3-oxo-3-phenylpropionitrile 3b (1.06 g, 5 mmol) in
anhydrous toluene (10 mL) and ethyl-vinyl ether 6a (3.62 g,
4.80 mL, 50 mmol) and some crystals of hydroquinone were heated
at 110 ꢀC in a pressure flask for the 24 h. The solvent and excess of
ether were evaporated and the mixture was purified by column
chromatography (1:3 EtOAc/pet. ether). Recrystallization (n-hex-
ane/tert-butyl methyl ether 5:1) gave the title compound 7d (1.23 g,
87%) as a white solid, mp 72 ꢀC; [found: C, 76.41; H, 7.53; N, 4.82.
C18H21NO2 requires C, 76.30; H, 7.47; N, 4.94%]; Rf (1:3 EtOAc/pet.
ether) 0.57; nmax(KBr) 2969, 2947, 2871, 2200, 1613, 1599, 1114,
4.4.1. (20RS)-20-Ethoxy-30,40-dihydro-60-phenylspiro[cyclohexane-
1,40-[2H]pyran]-50-carbonitrile (7a). A solution of 2-cyclo-
hexylidene-3-oxo-3-phenylpropionitrile 3a (1.13 g, 5 mmol) in
anhydrous toluene (10 mL) and ethyl-vinyl ether 6a (3.62 g,
4.80 mL, 50 mmol) and some crystals of hydroquinone was heated
at 110 ꢀC in a pressure flask for the 24 h. The solvent and excess of
ether were evaporated and the mixture was purified by column
chromatography (1:3 EtOAc/pet. ether). Recrystallization (n-hex-
ane) gave the title compound 7a (1.32 g, 89%) as a white solid, mp
115 ꢀC; [found: C, 76.78; H, 7.84; N, 4.81. C19H23NO2 requires C,
76.74; H, 7.80; N, 4.71%]; Rf (1:3 EtOAc/pet. ether) 0.47; nmax(KBr)
1061 cmꢁ1
; dH (300 MHz, CDCl3) 7.74e7.71 (2H, m, Ph), 7.44e7.40
(3H, m, Ph), 5.14 (1H, dd, J 2.4, 7.8 Hz, 20-H), 4.06 (1H, dq, J 7.2,
9.3 Hz, OCH2CH3), 3.70 (1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 1.98 (1H, dd,
J 2.4, 13.8 Hz, 30-H), 1.85e1.57 (9H, m, 3-H, cyclopentane), 1.29 (3H,
t, J 7.2 Hz, OCH2CH3); dC (75.5 MHz, CDCl3) 161.8, 133.5, 130.5, 128.3,
128.2, 119.4, 100.1, 93.7, 65.2, 42.5, 40.2, 38.9, 24.5, 24.0, 15.2; m/z
(ESI) 306 (MNaþ), 284 (MHþ), 212, 139, 105.
2975, 2935, 2857, 2197, 1613, 1598, 1114, 1064 cmꢁ1
; dH (300 MHz,
CDCl3) 7.73e7.71 (2H, m, Ph), 7.42e7.40 (3H, m, Ph), 5.13 (1H, dd, J
2.4, 8.1 Hz, 20-H), 4.06 (1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 3.70 (1H, dq, J
7.2, 9.3 Hz, OCH2CH3), 2.26 (1H, dd, J 2.4, 13.8 Hz, 30-H), 1.87e1.40
(11H, m, 30-H, cyclohexane), 1.29 (3H, t, J 7.2 Hz, OCH2CH3); dC
(75.5 MHz, CDCl3) 161.9, 133.5, 130.5, 128.3, 128.2, 119.3, 99.6, 95.8,
65.3, 36.9, 35.9, 35.4, 34.8, 25.1, 21.7, 21.2, 15.2; m/z (ESI) 298 (MHþ),
226, 153, 105.
4.4.5. (20RS)-20-Ethoxy-30,40-dihydro-60-phenylspiro[cycloheptane-
1,40-[2H]pyran]-50-carbonitrile (7e). A solution of 2-cyclo-
heptylidene-3-oxo-3-phenylpropionitrile 3c (1.20 g, 5 mmol) in
anhydrous toluene (10 mL) and ethyl-vinyl ether 6a (3.62 g,
4.80 mL, 50 mmol) and some crystals of hydroquinone were heated
at 110 ꢀC in a pressure flask for the 24 h. The solvent and excess of
ether were evaporated and the mixture was purified by column
chromatography (1:3 EtOAc/pet. ether). Recrystallization (n-hex-
ane) gave the title compound 7e (1.34 g, 86%) as a white solid, mp
105 ꢀC; [found: C, 77.00; H, 8.02; N, 4.62. C20H25NO2 requires C,
77.14; H, 8.09; N, 4.50%]; Rf (1:3 EtOAc/pet. ether) 0.54; nmax(KBr)
4.4.2. (20RS)-30,40-Dihydro-20-isobutoxy-60-phenylspiro[cyclohexane-
1,40-[2H]pyran]-50-carbonitrile (7b). A solution of 2-cyclo-
hexylidene-3-oxo-3-phenylpropionitrile 3a (1.13 g, 5 mmol) in
anhydrous toluene (10 mL) and isobutyl-vinyl ether 6b (5.02 g,
6.54 mL, 50 mmol) and some crystals of hydroquinone was heated
at 110 ꢀC in a pressure flask for the 24 h. The solvent and excess of
2979, 2943, 2925, 2854, 2200, 1610, 1597, 1159, 1071 cmꢁ1
(300 MHz, CDCl3) 7.72e7.68 (2H, m, Ph), 7.44e7.37 (3H, m, Ph), 5.17
; dH

A. Pałasz, T. Pałasz / Tetrahedron 67 (2011) 1422e1431
1429
(1H, dd, J 2.4, 8.1 Hz, 20-H), 4.06 (1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 3.70
(1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 2.10 (1H, dd, J 2.4, 13.8 Hz, 30-H),
2.03e1.54 (13H, m, 30-H, cycloheptane), 1.29 (3H, t, J 7.2 Hz,
OCH2CH3); dC (75.5 MHz, CDCl3) 161.1, 133.5, 130.4, 128.3, 128.2,
119.9, 99.5, 96.0, 65.2, 40.8, 40.2, 38.4, 37.9, 29.5, 29.3, 23.0, 22.9,
15.2; m/z (ESI) 334 (MNaþ), 312(MHþ), 240, 167, 158, 105.
(8a). A solution of 5-cyclohexylidene-1,3-dimethylpyrimidine-
2,4,6-trione 5a (1.18 g, 5 mmol) in anhydrous toluene (10 mL) and
ethyl-vinyl ether 6a (3.62 g, 4.80 mL, 50 mmol) and some crystals of
hydroquinone was heated at 110 ꢀC in a pressure flask for the 24 h.
The solvent and excess of ether were evaporated and the mixture
was purified by column chromatography (1:1 EtOAc/pet. ether).
Recrystallization (n-hexane) gave the title compound 8a (1.22 g,
79%) as a white solid, mp 75 ꢀC; [found: C, 62.44; H, 7.89; N, 9.32.
C16H24N2O4 requires C, 62.32; H, 7.84; N, 9.08%]; Rf (1:1 EtOAc/pet.
ether) 0.49; nmax(KBr) 2977, 2925, 2863, 1707, 1638, 1614,
4.4.6. (20RS)-20-Ethoxy-30,40-dihydro-60-phenylspiro[cyclooctane-
1,40-[2H]pyran]-50-carbonitrile (7f). A solution of 2-cyclooctylidene-
3-oxo-3-phenylpropionitrile 3d (1.27 g, 5 mmol) in anhydrous
toluene (10 mL) and ethyl-vinyl ether 6a (3.62 g, 4.80 mL, 50 mmol)
and some crystals of hydroquinone was heated at 110 ꢀC in a pres-
sure flask for the 24 h. The solvent and excess of ether were
evaporated and the mixture was purified by column chromatog-
raphy (1:3 EtOAc/pet. ether) to give the title compound 7f (1.35 g,
83%) as a colorless oil; [found: C, 77.72; H, 8.51; N, 4.53. C21H27NO2
requires C, 77.50; H, 8.36; N, 4.30%]; Rf (1:3 EtOAc/pet. ether) 0.55;
nmax(film) 2985, 2943, 2931, 2853, 2215, 1610, 1592, 1153,
1161 cmꢁ1 dH (300 MHz, CDCl3) 5.13 (1H, dd, J 2.1, 8.4 Hz, 70-H),
;
3.99 (1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 3.69 (1H, dq, J 7.2, 9.3 Hz,
OCH2CH3), 3.36 (3H, s, NeMe), 3.31 (3H, s, NeMe), 2.75 (1H, ddd, J
4.2, 8.7, 12.9 Hz, cyclohexane), 2.51 (1H, ddd, J 4.2, 9.3, 12.9 Hz,
cyclohexane), 2.36 (1H, dd, J 2.1, 14.1 Hz, 60-H), 1.71 (1H, ddd, J 1.2,
8.4, 14.1 Hz, 60-H), 1.63e1.26 (8H, m, cyclohexane), 1.31 (3H, t, J
7.2 Hz, OCH2CH3); dC (75.5 MHz, CDCl3) 161.9, 154.1, 150.9, 101.2,
95.2, 65.7, 36.4, 28.7, 27.7, 34.5, 33.9, 33.1, 25.1, 21.9, 21.6, 15.1; m/z
(ESI) 309(MHþ), 263, 237, 213, 185, 169, 112.
1068 cmꢁ1
; dH (300 MHz, CDCl3) 7.95e7.90 (2H, m, Ph), 7.69e7.59
(1H, m, Ph), 7.53e7.48 (2H, m, Ph), 5.22 (1H, dd, J 2.7, 8.4 Hz, 20-H),
4.04 (1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 3.68 (1H, dq, J 7.2, 9.6 Hz,
OCH2CH3), 2.08 (1H, dd, J 2.7, 13.5 Hz, 30-H), 2.03e1.47 (15H, m, 30-
H, cyclooctane), 1.26 (3H, t, J 7.2 Hz, OCH2CH3); dC (75.5 MHz, CDCl3)
161.5, 136.1, 134.0, 129.4, 128.6, 116.6, 110.2, 99.4, 65.2, 39.1, 36.9,
35.7, 33.2, 27.4, 27.2, 26.5, 25.8, 25.6, 15.2; m/z (ESI) 348 (MNaþ),
326(MHþ), 158, 105.
4.4.9. (70RS)-70-Ethoxy-10,50,60,70-tetrahydro-10,30-dimethylspiro[cy-
clopentane-1,50-[2H]pyrano[2,3-d]pyrimidine]-20,40(30H)-dione
(8b). A solution of 5-cyclopentylidene-1,3-dimethylpyrimidine-
2,4,6-trione 5d (1.11 g, 5 mmol) in anhydrous toluene (10 mL) and
ethyl-vinyl ether 6a (3.62 g, 4.80 mL, 50 mmol) and some crystals of
hydroquinone was heated at 110 ꢀC in a pressure flask for the 24 h.
The solvent and excess of ether were evaporated and the mixture
was purified by column chromatography (1:1 EtOAc/pet. ether) to
give the title compound 8b (1.37 g, 93%) as a colorless oil; [found: C,
61.29; H, 7.62; N, 9.47. C15H22N2O4 requires C, 61.21; H, 7.53; N,
9.52%]; Rf (1:1 EtOAc/pet. ether) 0.45; nmax(film) 2955, 2873, 1704,
4.4.7. Diastereoisomer
A
(ꢁ)-20-Ethoxy-30,40-dihydro-3-methyl-60-
phenylspiro[cyclohexane-1,40-[2H]pyran]-50-carbonitrile
(7g). A
solution of (30R)-2-(30-methylcyclohexylidene)-3-oxo-3-phenyl-
propionitrile 3e (1.20 g, 5 mmol) in anhydrous toluene (10 mL) and
ethyl-vinyl ether 6a (3.62 g, 4.80 mL, 50 mmol) and some crystals of
hydroquinone was heated at 110 ꢀC in a pressure flask for the 24 h.
The solvent and excess of ether were evaporated and the mixture
was purified by column chromatography (1:6 EtOAc/pet. ether) to
give the title compound 7g (0.94 g, 61%) as a colorless oil; [found: C,
77.31; H, 8.20; N, 4.48. C20H25NO2 requires C, 77.14; H, 8.09; N,
1645, 1613, 1178 cmꢁ1
; dH (300 MHz, CDCl3) 5.08 (1H, dd, J 2.1,
8.1 Hz, 70-H), 3.93 (1H, dq, J 7.2, 9.6 Hz, OCH2CH3), 3.65 (1H, dq, J 7.2,
9.6 Hz, OCH2CH3), 3.30 (3H, s, NeMe), 3.25 (3H, s, NeMe), 2.37 (1H,
ddd, J 3.0, 6.9, 12.6 Hz, cyclopentane), 2.16 (1H, ddd, J 3.9, 8.7,
12.6 Hz, cyclopentane), 1.93 (1H, dd, J 2.1, 13.8 Hz, 60-H), 1.72 (1H,
dd, J 8.1,13.8 Hz, 60-H),1.87e1.38 (6H, m, cyclopentane),1.24 (3H, t, J
7.2 Hz, OCH2CH3); dC (75.5 MHz, CDCl3) 161.7, 153.7, 150.8, 101.8,
93.7, 65.6, 41.7, 40.3, 38.8, 36.9, 28.6, 27.6, 25.5, 25.1, 14.9; m/z (ESI)
295(MHþ), 221.
4.50%]; Rf (1:6 EtOAc/pet. ether) 0.48; nmax(film) 2952, 2928, 2870,
22
2200, 1593, 1572, 1156, 1072 cmꢁ1; [
a
]
ꢁ34.2 (c 0.12, CHCl3); dH
D
(300 MHz, CDCl3) 7.69e7.66 (2H, m, Ph), 7.43e7.40 (3H, m, Ph), 5.28
(1H, dd, J 3.0, 8.4 Hz, 20-H), 4.03 (1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 3.68
(1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 1.11e1.03, 1.45e1.35, 2.32e1.60
(11H, m, 30-H, cyclohexane),1.27 (3H, t, J 7.2 Hz, OCH2CH3), 0.91 (3H,
d, J 6.6 Hz, 3-Me); dC (75.5 MHz, CDCl3) 162.8, 133.9, 128.5, 127.5,
127.2, 120.5, 99.3, 91.6, 64.1, 45.6, 42.4, 37.9, 34.0, 32.6, 26.3, 21.6,
20.0, 14.1; m/z (ESI) 312(MHþ).
4.4.10. (70RS)-70-Ethoxy-10,50,60,70-tetrahydro-10,30-dimethylspiro[cy-
cloheptane-1,50-[2H]pyrano[2,3-d]pyrimidine]-20,40(30H)-dione
(8c). A solution of 5-cycloheptylidene-1,3-dimethylpyrimidine-
2,4,6-trione 5c (1.25 g, 5 mmol) in anhydrous toluene (10 mL) and
ethyl-vinyl ether 6a (3.62 g, 4.80 mL, 50 mmol) and some crystals of
hydroquinone was heated at 110 ꢀC in a pressure flask for the 24 h.
The solvent and excess of ether were evaporated and the mixture
was purified by column chromatography (1:1 EtOAc/pet. ether).
Recrystallization (n-hexane) gave the title compound 8c (1.47 g,
91%) as a white solid, mp 100 ꢀC; [found: C, 63.62; H, 8.33; N, 8.52.
C17H26N2O4 requires C, 63.33; H, 8.13; N, 8.69%]; Rf (1:1 EtOAc/pet.
ether) 0.47; nmax(KBr) 2972, 2928, 2878, 2858, 1705, 1639, 1621,
Diastereoisomer A of the compound 7g (0.6 g, 2 mmol) was
submitted to the action of boron trifluoride diethyl etherate
BF.3Et2O (5 mL) and a mixture of diastereoisomer A and a new di-
astereoisomer B (A/B¼1:2.3) was obtained after 24 h at room
temperature. The diastereoisomers A and B were separated by
column chromatography (1:6 EtOAc/pet. ether). The di-
astereoisomer B of compound 7g (0.37 g) was obtained as a color-
less oil; [found: C, 77.29; H, 8.15; N, 4.57. C20H25NO2 requires C,
77.14; H, 8.09; N, 4.50%]; Rf (1:6 EtOAc/pet. ether) 0.54; nmax(film)
1156 cmꢁ1 dH (300 MHz, CDCl3) 5.18 (1H, dd, J 2.1, 8.7 Hz, 70-H),
;
4.00 (1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 3.71 (1H, dq, J 7.2, 9.3 Hz,
OCH2CH3), 3.35 (3H, s, NeMe), 3.31 (3H, s, NeMe), 2.74 (1H, ddd, J
2.4, 8.7, 11.1 Hz, cycloheptane), 2.42 (1H, ddd, J 1.8, 9.3, 11.1 Hz,
cycloheptane), 2.23 (1H, dd, J 2.4, 13.8 Hz, 60-H), 1.75 (1H, dd, J 8.7,
13.8 Hz, 60-H), 1.68e1.36 (10H, m, cycloheptane), 1.31 (3H, t, J 7.2 Hz,
OCH2CH3); dC (75.5 MHz, CDCl3) 162.1, 153.2, 150.9, 101.2, 97.4, 65.8,
39.4, 39.3, 37.8, 37.4, 28.8, 28.5, 28.2, 27.8, 23.8, 23.1, 15.1; m/z (ESI)
323(MHþ), 277, 251, 213, 185, 169, 112.
2975, 2935, 2857, 2197, 1613, 1598, 1114, 1064 cmꢁ1; [
a
]
22 ꢁ27.2 (c
D
0.12, CHCl3); dH (300 MHz, CDCl3) 7.71e7.66 (2H, m, Ph), 7.42e7.39
(3H, m, Ph), 5.34 (1H, dd, J 5.4, 6.0 Hz, 20-H), 4.03 (1H, dq, J 7.2,
9.3 Hz, OCH2CH3), 3.68 (1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 2.30e1.57,
1.45e1.35,1.14e1.03 (11H, m, 30-H, cyclohexane),1.29 (3H, t, J 7.2 Hz,
OCH2CH3), 0.89 (3H, d, J 6.6 Hz, 3-Me); dC (75.5 MHz, CDCl3) 163.0,
132.7, 129.3, 127.6, 127.1, 120.6, 98.2, 91.2, 64.1, 47.0,42.8, 35.9, 33.7,
32.9, 26.6, 21.9, 20.3, 14.1; m/z (ESI) 312(MHþ).
4.4.11. (70RS)-70-Ethoxy-10,50,60,70-tetrahydro-10,30-dimethylspiro[cy-
clooctane-1,50-[2H] pyrano[2,3-d]pyrimidine]-20,40(30H)-dione (8d). A
4.4.8. (70RS)-70-Ethoxy-10,50,60,70-tetrahydro-10,30-dimethylspiro[cy-
clohexane-1,50-[2H]pyrano[2,3-d]pyrimidine]-20,40(30H)-dione
solution
of
5-cyclooctylidene-1,3-dimethylpyrimidine-2,4,6-

1430
A. Pałasz, T. Pałasz / Tetrahedron 67 (2011) 1422e1431
trione 5d (1.32 g, 5 mmol) in anhydrous toluene (10 mL) and
ethyl-vinyl ether 6a (3.62 g, 4.80 mL, 50 mmol) and some crystals
of hydroquinone was heated at 110 ꢀC in a pressure flask for the
24 h. The solvent and excess of ether were evaporated and the
mixture was purified by column chromatography (1:1 EtOAc/pet.
ether). Recrystallization (n-hexane) gave the title compound 8d
(1.48 g, 88%) as a white solid, mp 138 ꢀC; [found: C, 64.28; H, 8.47;
N, 8.45. C18H28N2O4 requires C, 64.26; H, 8.39; N, 8.33%]; Rf (1:1
EtOAc/pet. ether) 0.63; nmax(KBr) 2972, 2928, 2878, 2858, 1705,
was evaporated and the mixture was purified by column chro-
matography (1:2 EtOAc/pet. ether). Recrystallization (n-hexane/
tert-butyl methyl ether 5:1) gave the title compound 10a (1.50 g,
93%) as a white solid, mp 134 ꢀC; [found: C, 78.08; H, 7.84; N, 4.51.
C21H25NO2 requires C, 77.99; H, 7.79; N, 4.33%]; Rf (1:2 EtOAc/pet.
ether) 0.61; nmax(KBr) 2956, 2930, 2857, 2197, 1620, 1161 cmꢁ1
; dH
(300 MHz, CDCl3) 7.80e7.77 (2H, m, Ph), 7.43e7.41 (3H, m, Ph),
3.84 (1H, ddd, J 3.9, 5.1,11.4 Hz, 60-H), 3.71 (1H, ddd, J 1.8, 4.0,
10.8 Hz, 60-H), 2.44 (1H, d, J 14.4 Hz, 30-H), 2.21e2.16 (1H, br, 30-H),
2.01e1.22 (16H, m, cyclohexane, and tetrahydropyrane); dC
(75.5 MHz, CDCl3) 160.6, 134.2, 130.2, 128.3, 128.2, 119.7, 99.0, 96.6,
62.2, 39.7, 39.0, 34.9, 34.2, 32.8, 25.3, 24.6, 22.0, 21.0, 18.4; m/z (ESI)
324(MHþ).
1639, 1621, 1156 cmꢁ1
; dH (300 MHz, CDCl3) 5.20 (1H, dd, J 2.4,
8.7 Hz, 70-H), 4.00 (1H, dq, J 7.2, 9.6 Hz, OCH2CH3), 3.70 (1H, dq, J
7.2, 9.6 Hz, OCH2CH3), 3.36 (3H, s, NeMe), 3.32 (3H, s, NeMe),
2.92 (1H, ddd, J 2.4, 8.1, 14.7 Hz, 60-H), 2.45 (1H, dd, J8.1, 14.7 Hz,
60-H), 2.27 (1H, dd, J 2.4, 14.1 Hz, cyclooctane), 1.99e1.87 (1H, m,
cyclooctane), 1.74e1.35 (12H, m, cyclooctane), 1.31 (3H, t, J 7.2 Hz,
OCH2CH3); dC (75.5 MHz, CDCl3) 162.3, 153.6, 150.9, 101.1, 97.3,
65.8, 36.9, 39.1, 35.4, 34.5, 28.8, 28.5, 28.4, 27.9, 23.1, 22.0, 21.9,
15.1; m/z (ESI) 337(MHþ).
4.4.14. (ꢁ)-30,40,300,400,500,600-Hexahydro-3-methyl-60-phenyldispiro
[cyclohexane-1,40-[2H]pyran-20,200-[2H]pyran]-50-carbonitrile
(10b). A solution of (30R)-2-(30-methylcyclohexylidene)-3-oxo-3-
phenylpropionitrile 3e (1.20 g, 5 mmol) in anhydrous toluene
(10 mL) and 2-methylenetetrahydropyrane 9 (0.49 g, 5 mmol) and
some crystals of hydroquinone was heated at 110 ꢀC in a pressure
flask for the 24 h. The solvent was evaporated and the mixture was
purified by column chromatography (1:2 EtOAc/pet. ether). Re-
crystallization (n-hexane/tert-butyl methyl ether 5:1) gave the title
compound 10b (1.54 g, 91%) as a white solid, mp 185 ꢀC; [found: C,
4.4.12. Diastereoisomer A (ꢁ)-70-Ethoxy-10,50,60,70-tetrahydro-10,30,3-
trimethylspiro[cyclohexane-1,50-[2H]pyrano[2,3-d]pyrimidine]-20,40
(30H)-dione (8e). A solution of (30R)-(ꢁ)-5-(30-methylcyclohex-
ylidene)-1,3-dimethylpyrimidine-2,4,6-trione 5e (1.25 g, 5 mmol)
in anhydrous toluene (10 mL) and ethyl-vinyl ether 6a (3.62 g,
4.80 mL, 50 mmol) and some crystals of hydroquinone was heated
at 110 ꢀC in a pressure flask for the 24 h. The solvent and excess of
ether were evaporated and the mixture was purified by column
chromatography (1:2 EtOAc/pet. ether) to give the title compound
8e (1.26 g, 78%) as a colorless oil; [found: C, 63.41; H, 8.27; N, 8.82.
C17H26N2O4 requires C, 63.33; H, 8.13; N, 8.69%]; Rf (1:2 EtOAc/pet.
78.44; H, 8.25; N, 4.40. C22H27NO2 requires C, 78.30; H, 8.06; N,
22
4.15%]; Rf (1:2 EtOAc/pet. ether) 0.51; [
a
]
ꢁ74.5 (c 0.13, CHCl3);
D
nmax(KBr) 2949, 2915, 2869, 2195, 1588, 1152 cmꢁ1
; dH (300 MHz,
CDCl3) 7.72e7.69 (2H, m, Ph), 7.43e7.41 (3H, m, Ph), 0.89 (3H, d, J
6.3 Hz, 3-CH3), 3.89 (1H, ddd, J 3.6, 4.8, 11.4 Hz, 60-H), 3.77 (1H, ddd,
J 1.8, 4.3, 11.0 Hz, 60-H), 2.45 (1H, ddd, J 1.8, 1.8, 13.8 Hz, 30-H),
2.34e2.27 (1H, m, cyclohexane, and tetrahydropyrane), 2.21e2.12
(1H, m, 30-H), 1.99e1.57 (12H, m, cyclohexane, and tetrahydropyr-
ane), 1.99e1.07 (1H, m, cyclohexane, and tetrahydropyrane),
1.45e1.34 (1H, m, cyclohexane, and tetrahydropyrane); dC
(75.5 MHz, CDCl3) 162.7, 134.5, 130.1, 128.7, 128.2, 122.4, 99.4, 93.1,
62.2, 49.1, 47.5, 38.5, 35.0, 34.0, 33.9, 27.6, 24.5, 23.0, 21.6, 18.3; m/z
(ESI) 338(MHþ).
ether) 0.36; [
a
]
22 ꢁ42.3 (c 0.21, CHCl3); nmax(film) 2967, 2909, 2868,
D
2850,1706,1648,1157 cmꢁ1
;
dH (300 MHz, CDCl3) 4.99 (1H, dd, J 2.4,
8.7 Hz, 70-H), 3.92 (1H, dq, J 7.2, 9.3 Hz, OCH2CH3), 3.63 (1H, dq, J 7.2,
9.3 Hz, OCH2CH3), 3.28 (3H, s, NeMe), 3.23 (3H, s, NeMe), 2.75 (1H,
dd, J 6.0, 13.5 Hz, 2-H), 2.39 (1H, m, 3-H), 2.29 (1H, dd, J2.4, 13.8 Hz,
60-H), 2.09 (1H, m, 2-H), 1.69 (1H, ddd, J 1.2, 9.0, 14.1 Hz, 60-H),
1.64e1.51 (3H, m, cyclohexane), 1.23e1.16 (3H, m, cyclohexane),
1.25 (3H, t, J 7.2 Hz, OCH2CH3), 0.97 (3H, d, J 7.2 Hz, 3-Me); dC
(75.5 MHz, CDCl3) 161.9, 154.3, 150.8, 101.0, 95.6, 65.8, 40.6, 40.0,
34.7, 33.1, 30.3, 28.7, 27.8, 27.7, 21.3, 17.0, 15.1; m/z (ESI) 323(MHþ).
Diastereoisomer A of the compound 8e (0.7 g, 2 mmol) was
submitted to the action of boron trifluoride diethyl etherate
BF.3Et2O (5 mL) and a mixture of diastereoisomer A and a new di-
astereoisomer B (A/B¼1:1.9) was obtained after 24 h at room
temperature. The diastereoisomers A and B were separated by
column chromatography (1:6 EtOAc/pet. ether). The di-
astereoisomer B of compound 8e (0.39 g) was obtained as a color-
less oil; [found: C, 63.25; H, 8.22; N, 8.74. C17H26N2O4 requires C,
4.4.15. (70RS)-10,50,60,70,300,400,500,600-Oktahydro-10,30-dimethyldispiro
[cyclohexane-1,50-[2H]pyrano[2,3-d]pyrimidine-70,200-[2H]pyran]-
20,40(30H)-dione (11a). A solution of 5-cyclohexylidene-1,3-dime-
thylpyrimidine-2,4,6-trione 5a (1.18 g, 5 mmol) in anhydrous tol-
uene (10 mL) and 2-methylenetetrahydropyrane 9 (0.49 g, 5 mmol)
and some crystals of hydroquinone was heated at 110 ꢀC in a pres-
sure flask for the 24 h. The solvent was evaporated and the mixture
was purified by column chromatography (1:2 EtOAc/pet. ether).
Recrystallization (n-hexane/tert-butyl methyl ether 5:1) gave the
title compound 11a (1.45 g, 87%) as a white solid, mp 162 ꢀC; [found:
C, 64.81; H, 7.89; N, 8.54. C18H26N2O4 requires C, 64.65; H, 7.84; N,
8.38%]; Rf (1:2 EtOAc/pet. ether) 0.55; nmax(KBr) 2974, 2937, 2872,
63.33; H, 8.13; N, 8.69%]; Rf (1:2 EtOAc/pet. ether) 0.43; [
a
]
22 ꢁ31.5
D
(c 0.21, CHCl3); nmax(film) 2969, 2912, 2863, 2848, 1701, 1644,
1149 cmꢁ1
;
dH (300 MHz, CDCl3) 5.23 (1H, dd, J 2.4, 7.5 Hz, 70-H),
1703, 1644, 1623, 1168, 1048 cmꢁ1
; dH (300 MHz, CDCl3) 3.72 (1H,
3.97 (1H, dq, J 7.2, 9.6 Hz, OCH2CH3), 3.69 (1H, dq, J 7.2, 9.6 Hz,
OCH2CH3), 3.36 (3H, s, NeMe), 3.31 (3H, s, NeMe), 2.68 (1H, m,
3-H), 2.48 (1H, dd, J 6.0, 13.8 Hz, 2-H), 2.24 (1H, dd, J 2.4, 14.1 Hz,
60-H), 2.09 (1H, m, 2-H), 1.87 (1H, dd, J 7.5, 14.1 Hz, 60-H), 1.69e1.59
(3H, m, cyclohexane), 1.34e1.26 (3H, m, cyclohexane), 1.30 (3H, t, J
7.2 Hz, OCH2CH3), 1.03 (3H, d, J 7.2 Hz, 3-Me); dC (75.5 MHz, CDCl3)
161.9, 154.1, 150.9, 101.0, 95.8, 65.6, 41.6, 41.2, 34.2, 32.6, 30.1, 28.8,
27.8, 27.3, 22.1, 17.6, 15.1; m/z (ESI) 323(MHþ).
ddd, J 1.8, 3.9, 10.8 Hz, 60-H), 3.59 (1H, ddd, J 3.9, 4.5, 11.7 Hz, 60-H),
3.42 (3H, s, NeCH3), 3.32 (3H, s, NeCH3), 2.77 (1H, m, cyclohexane
or tetrahydropyrane), 2.54 (1H, d, J 14.4 Hz, 60-H), 2.32 (1H, d, J
13.9 Hz, 60-H), 1.91e1.04 (15H, m, cyclohexane, and tetrahy-
dropyrane); dC (75.5 MHz, CDCl3) 162.1,153.5,151.1,101.4, 95.4, 62.4,
40.5, 36.3, 34.6, 33.7, 30.2, 28.6, 27.7, 25.4, 24.3, 22.2, 21.6, 18.6; m/z
(ESI) 335(MHþ).
4.4.16. (ꢁ)-10,50,60,70,300,400,500,600-Oktahydro-10,30,3-trimethyldispiro
[cyclohexane-1,50-[2H]pyrano[2,3-d]pyrimidine-70,200-[2H]pyran]-
20,40(30H)-dione (11b). A solution of (30R)-(ꢁ)-5-(30-methyl-
cyclohexylidene)-1,3-dimethylpyrimidine-2,4,6-trione 5e (1.25 g,
5 mmol) in anhydrous toluene (10 mL) and 2-methylenetetrahy-
dropyrane 9 (0.49 g, 5 mmol) and some crystals of hydroquinone
was heated at 110 ꢀC in a pressure flask for the 24 h. The solvent was
4.4.13. (20RS)-30,40,300,400,500,600-hexahydro-60-phenyldispiro[cyclohex-
ane-1,40-[2H] pyran-20,200-[2H]pyran]-50-carbonitrile (10a). A solu-
tion of 2-cyclohexylidene-3-oxo-3-phenylpropionitrile 3a (1.13 g,
5 mmol) in anhydrous toluene (10 mL) and 2-methylenetetrahy-
dropyrane 9 (0.49 g, 5 mmol) and some crystals of hydroquinone
was heated at 110 ꢀC in a pressure flask for the 24 h. The solvent

A. Pałasz, T. Pałasz / Tetrahedron 67 (2011) 1422e1431
1431
3. (a) Tietze, L. F.; Hartfiel, U.; Hubsch, T.; Voss, E.; Bogdanowicz-Szwed, K.;
Wichmann, J. Liebigs Ann. Chem. 1991, 275; (b) Tietze, L. F.; Harfiel, U.; Hubsch,
T.; Voss, E.; Wichmann, J. Chem. Ber. 1991, 124, 881; (c) Ager, D. J.; East, M. B.
Tetrahedron 1993, 49, 5683; (d) Tietze, L. F. J. Heterocycl. Chem. 1990, 27, 45.
4. (a) John, R. A.; Schmidt, V.; Wyler, H. Helv. Chim. Acta 1987, 70, 600; (b) Zhuo, J. C.;
Wyler, H. Helv. Chim. Acta 1995, 78, 151; (c) Yamauchi, M.; Katajama, S.; Baba, O.;
Watanabe, T. J. Chem. Soc., Chem. Commun. 1983, 281; (d) Dvorak, D.; Arnold, Z.
Tetrahedron Lett.1982, 23, 4401; (e) Haag-Zeino, B.; Schmidt, R. R. Liebigs Ann. Chem.
1990, 1197; (f) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron 1996, 52, 4007.
5. (a) Bogdanowicz-Szwed, K.; Pa1asz, A. Monatsh. Chem. 1995, 126, 1341;
(b) Bogdanowicz-Szwed, K.; Pa1asz, A. Monatsh. Chem. 1997, 128, 1157;
(c) Bogdanowicz-Szwed, K.; Pa1asz, A. Monatsh. Chem. 1999, 130, 795;
(d) Bogdanowicz-Szwed, K.; Pa1asz, A. Z. Naturforsch. 2001, 56b, 416;
(e) Bogdanowicz-Szwed, K.; Pa1asz, A. Monatsh. Chem. 2001, 132, 393;
evaporated and the mixture was purified by column chromatog-
raphy (1:2 EtOAc/pet. ether) to give the title compound 11b (1.55 g,
89%) as a colorless oil; [found: C, 65.72; H, 8.19; N, 8.15. C19H28N2O4
requires C, 65.49; H, 8.10; N, 8.04%]; Rf (1:2 EtOAc/pet. ether) 0.41;
[
a]
22 ꢁ63.2 (c 0.15, CHCl3); nmax(film) 2946, 2915, 2870, 1701, 1638,
D
1623, 1167, 1047 cmꢁ1
;
dH (300 MHz, CDCl3) 3.64 (1H, ddd, J 2.0,
4.1,11.2 Hz, 60-H), 3.54 (1H, ddd, J 3.9, 4.2, 11.5 Hz, 60-H), 3.35 (3H, s,
NeMe), 3.24 (3H, s, NeMe), 2.78 (1H, m, cyclohexane, and tetra-
hydropyrane), 2.63 (1H, d, J 13.8 Hz, 60-H), 2.41 (1H, d, J14.0 Hz, 60-
H), 1.97e1.18 (15H, m, cyclohexane, and tetrahydropyrane), 0.96
(3H, d, J 7.2 Hz, 3-Me); dC (75.5 MHz, CDCl3) 162.0, 153.5, 151.0,
100.8, 95.2, 62.4, 41.6, 35.7, 34.5, 34.1, 30.8, 28.7, 27.7, 25.0, 24.2,
22.7, 21.3, 18.5, 17.6; m/z (ESI) 349(MHþ).
_ꢀ
(f) Pa1asz, A. Org. Biomol. Chem. 2005, 3, 3207; (g) Pa1asz, A.; Jelska, K.; Ozog,
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1.11, p. 341.
Frontier orbital (HOMO and LUMO) energies of heterodienes 3a,
3b, 3e, 5a, 5b, 5e and dienophiles 6a, 9, 12, 14 were calculated by
semi-empirical AM1 and PM3 methods and ab initio HartreeeFock
calculations using the Gaussian 03 suite of programs. The geome-
tries were fully optimized by PM3 semi-empirical methods and
used as the basis for optimization at the HartreeeFock level using
the 3-21G basis set (HF/3-21G).
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Acknowledgements
We thank the ACK Cyfronet for generous allocation of comput-
ing time on SGI Altix 3700 (Gaussian 03 suite of programs, grant No.
MNiSW/SGI3700/UJ/084/2009).
11. Soto, J. L.; Seoane, C.; Martin, N.; Quinteiro, M. Heterocycles 1984, 22, 1.
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