Fused tetraeyclic heterocycles by thermally initiated intramolecular criss-cross cycloaddition of 3-substituted homoallenylaldazines

Article abstract of DOI:10.1002/ejoc.200400814

The thermally initiated intramolecular criss-cross cycloaddition of 3-substituted homoallenylaldazines 5 has been explored. Their cyclization led to interesting new fused heterocyclic systems 6 consisting of four five-membered rings with two nitrogen hete

Full text of DOI:10.1002/ejoc.200400814

FULL PAPER
Fused Tetracyclic Heterocycles by Thermally Initiated Intramolecular Criss-
Cross Cycloaddition of 3-Substituted Homoallenylaldazines
[a]
[a]
[b]
[a]
ˇ
ˇ
Hana Zachová, Stanislav Man, Marek Necas, and Milan Potácek*
Dedicated to Professor Dr. Peter Stanetty on the occasion of his 60th birthday
Keywords: Allenes / Cycloaddition / Nitrogen heterocycles / Sigmatropic rearrangement / Polycycles
The thermally initiated intramolecular criss-cross cycload-
dition of 3-substituted homoallenylaldazines 5 has been ex-
plored. Their cyclization led to interesting new fused hetero-
cyclic systems 6 consisting of four five-membered rings with
two nitrogen heteroatoms. The azines were prepared by the
reaction of homoallenyl aldehydes 4 with hydrazine. The
homoallenyl aldehydes 4 were synthesized by the Claisen
rearrangement of new N,N-disubstituted 4-[(2-methylprop-
1-en-1-yl)oxy]but-2-yn-1-amines 3a–f prepared by Mannich
reaction of 2-methylprop-1-en-1-yl prop-2-yn-1-yl ether (2).
The success of the reaction was based on the improved sol-
vent-free synthesis of 1-chloro-2-methylpropyl prop-2-yn-1-
yl ether (1) and its conversion to isolable 2-methylprop-1-en-
1-yl prop-2-yn-1-yl ether (2) in high yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Criss-cross cycloaddition reactions provide a route to the
“one-pot” synthesis of fused heterocyclic compounds. Most
of these reactions are reported in the literature to occur by
intermolecular processes to give two fused five-membered
rings,[1,2] with only a few intramolecular reactions having
been described. Thus, Marthur and Suschitzky[3] performed
intramolecular reactions with benzaldehyde and naphth-
aldehyde azines bearing allyloxy and propargyloxy
groups, respectively, ortho to the azine group. When the
other ortho position to the alkenyloxy group was blocked
by substitution in order to prevent Claisen rearrangement,
the reaction led to the formation of cycloadducts in which
the rings were connected laterally. We have found that bi-
s(homoallenyl) azines undergo another type of intramolecu-
lar reaction.[4] During this reaction a completely new type
of compound was formed having four centrally fused five-
membered heterocyclic rings. Apparently, the distance be-
tween the azine group and the multiple bonds determines
whether a “lateral”- or “central”-type cyclization is pre-
ferred (Scheme 1).
Scheme 1.
In this paper we would like to extend our knowledge of
this central type of intramolecular criss-cross cycloaddition
reactions and to investigate the effects of substitution upon
the reaction.
To carry out this research we needed to synthesize substi-
tuted homoallenyl aldehydes. These compounds can be pre-
pared by thermally initiated Claisen rearrangement of sub-
stituted propargyl vinyl ethers. Most of these transforma-
tions have been carried out at about 250 °C in a stream of
nitrogen by using a vertically oriented pyrolytic electrically
heated apparatus filled with glass wool[5,6] with the re-
arrangement product being collected in a cooled trap.
Sometimes the reactions were carried out at reflux in unre-
active high-boiling solvents.[5] Although homoallenyl alde-
hydes can be prepared in a single step starting from isobu-
tyraldehyde and substituted propargyl alcohols in the pres-
ence of an acid catalyst,[7,8] we found the method using 2-
methylprop-1-en-1-yl prop-2-yn-1-yl ether (2) as a starting
compound was more convenient because it enabled us to
use the appropriate substituents (including an amino func-
[a] Department of Organic Chemistry, Faculty of Science, Masaryk
University of Brno,
Kotlárˇská 2, 61137 Brno, Czech Republic
Fax: +420-549492688
E-mail: potacek@chemi.muni.cz
[b] Department of Inorganic Chemistry, Faculty of Science, Masa-
ryk University of Brno,
Kotlárˇská 2, 61137 Brno, Czech Republic
2548
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400814
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Fused Tetracyclic Heterocycles from Homoallenylaldazines
FULL PAPER
Scheme 2.
tion) and because the ether 2 can be stored in a refrigerator ning of the reaction, the mixture became rather viscous an-
for almost an unlimited time. dif it was not stirred sufficiently local overheating was ob-
The preparation of propargyl vinyl ethers has been re- served resulting in the formation of unwanted side-prod-
ported in the literature. Two methods for the synthesis of ucts. The end of the reaction was indicated by a reduction
chlorinated ether 1 and, consequently, ether 2 (Scheme 2) of the viscosity, no further absorption of gaseous HCl and
are also known. Both literature methods start from propar-
gyl alcohol and isobutyraldehyde. The older procedure,[9]
in some cases catalyzed by calcium chloride, afforded the
corresponding acetal, which, when treated with boron tri-
chloride, led to the chlorinated ether 1 in 47% yield. Ether
1 in diethyl ether, when treated overnight with trimeth-
ylamine at 0 °C, formed a hygroscopic solid. On heating
under vacuum at a temperature of 160–170 °C, this solid
afforded ether 2 in 75% yield. A more recent paper[10] de-
scribes the reaction in the presence of HCl at 0 °C, followed
by the application of a huge excess of N,N-dimethylaniline
at 75 °C. For our purposes we needed to be able to substi-
tute the alkynic hydrogen atom of 2 to form substituted
propargyl vinyl ethers 3 and therefore we had to find a pro-
cedure that would enable us to obtain ether 2 as a pure
and easily isolable compound. We intended to subject the
substituted propargyl vinyl ethers 3 to the Claisen re-
arrangement to give homoallenyl aldehydes 4. However the
isolation of pure ether 2 was difficult and we had to im-
prove the literature procedure in order to obtain starting
compounds for the preparation of substituted ethers 3.
finally by the formation of two layers. We changed the isola-
tion procedure so that no water was used. The upper layer
was separated and dried with magnesium sulfate. The more
volatile components were removed on a rotary evaporator
and the remainder by vacuum distillation. In this way a
high yield (87%) of chlorinated ether 1 was obtained. Ap-
plication of the purified ether 1 in the following procedure
allowed us to test the efficacy of various nitrogen-contain-
ing bases in the elimination reaction and to avoid side-reac-
tions with impurities and to remove unreacted amines at
the end of the reaction. Besides N,N-dimethylaniline we
tested N,N-diethylaniline, triethylamine, morpholine and
pyridine; we found an equimolar amount of pyridine to be
the best reagent. The reaction temperature had to be kept
below 80 °C and under these conditions the reaction time
was reduced from the recommended 24 h for the reaction
with N,N-dimethylaniline to the time needed for the slow
addition of chlorinated ether 1 to pyridine and the elimi-
nation of HCl (2–3 h). Although ether 2 may be isolated by
ether extraction and, after drying, by distillation, we have
found a more efficient procedure: direct distillation of the
reaction mixture, purification of the distillate by charcoal
absorption and finally by vacuum distillation. The first dis-
tillation process was shown to complete the elimination re-
action and increase the yield. By following this procedure
the product was isolated in a yield of 75% and was found
to be very pure with a very low water content (less than
10–4 g of water per 1 g of product). Note here that the yield
obtained by using this procedure depends on the precise
reproduction of the experimental conditions.
Results and Discussion
We started by preparing ethers 1 and 2. When we applied
the procedure described in the literature[10] to the prepara-
tion of ether 2 we were faced with two problems. At first
we found that heating 1 for a long time at 75 °C caused
Claisen rearrangement of the ether 2 to 2,2-dimethylpenta-
3,4-dienal and that we could not isolate the expected ether
2 as a pure entity. Secondly, removal of the excess N,N-
dimethylaniline after the reaction was difficult. Thus we
modified the process and divided the procedure into two
separate steps − the preparation of chlorinated ether 1 fol-
lowed by the elimination of HCl to give ether 2 (Scheme 2).
The first step of the reaction can be realized without any
solvent when the reagents are used in a ratio of 1:1.5 (pro-
pargyl alcohol/isobutyraldehyde) but the reaction mixture
Having developed an efficient synthesis of ether 2 we
could concentrate on the preparation of its derivatives. We
tried to prepare a set of derivatives by the Mannich reac-
tion,[11] however when we followed the literature pro-
cedure[12] we could not obtain sufficient yields. We modified
the reported reaction and because both our starting ether 2
and the products 3 were liquids we decided to carry out the
reaction without any solvent. The components were mixed
must be stirred well by a mechanical stirrer. At the begin- so that the corresponding secondary amine was added last.
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H. Zachová, S. Man, M. Necˇas, M. Potácˇek
FULL PAPER
Table 1. Structures of compounds 3, 4, 5 and 6 and their yields.
To avoid a vigorous exothermic reaction and side-product The chlorinated ether 1 is characterized by an intense vi-
formation, the mixture had to be cooled during amine ad- bration band at 2123 cm–1 belonging to the nonsymmetri-
dition. After the reaction had ceased the reaction mixture cally substituted triple bond and also by the vibration of
was heated to 70 °C to complete the reaction. The water the adjacent hydrogen atom at 3299 cm–1. The ether 2
formed during the reaction was removed from the reaction formed after elimination of the chlorine atom contained an-
mixture on a rotary evaporator and the product finally dis- other characteristic band at 1693 cm–1 belonging to the
tilled under high vacuum on a kugelrohr apparatus. The double bond. Substitution of the alkynic hydrogen atom
structures of the products were proved by NMR spec- and formation of 3 is reflected by the disappearance of the
troscopy (Table 1). In the next step we carried out Claisen corresponding vibration and because of its intensity it is a
rearrangement of ethers 3, which gave homoallenyl alde- sufficient indicator of substitution. At the same time the
hydes 4. Although in most reports in the literature a pyro- vibration of the triple bond is shifted to 2256 cm–1 and its
lytic oven was used at a temperature of over 250 °C, we intensity is substantially reduced. The signal of the double-
have found that ether 2 rearranges easily, which led us to bond vibration 1693 cm–1 remains unchanged. The trans-
find some better conditions; after much experimentation we formation from 3 to 4 is accompanied by the disappearance
found 200 °C to be the best temperature. At this tempera- of the triple- and double-bond vibrations, but their disap-
ture the rearrangement was accomplished within 5–10 min pearances are not significant owing to their low intensity
depending on the substituent, after which it was necessary and therefore they cannot be used to prove the transforma-
to cool the mixture rapidly. Pure compounds were obtained tion. In addition the double-bond vibration is overlapped
by kugelrohr distillation under high vacuum. The structures by the appearance of
a
carbonyl-bond vibration
of compounds 4 were proved by IR and NMR spec- (1720 cm–1). However, a very significant and characteristic
troscopy.
band appeared at 1952 cm–1 belonging to the allenyl sys-
The course of the reaction was followed by IR spec- tem.
troscopy, which was found to be a good and very useful
Another derivative 4g with phenyl in the 3-position was
method for identification of the reaction course. All the prepared by the pathway shown in Scheme 3. Phenylacety-
products differ significantly in their characteristic bands. lene was used as the starting compound, which was mixed
Scheme 3. Preparation of allenyl aldehyde 4g.
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Fused Tetracyclic Heterocycles from Homoallenylaldazines
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Scheme 4. Intramolecular criss-cross cycloaddition of azines.
with paraformaldehyde and butyllithium as base. In this nomethyl group in the 3-position the cyclization reaction
way phenylpropargyl alcohol 7 was prepared, which was failed; it seems that some decomposition occurred.
treated with isobutyraldehyde and hydrogen chloride to
It is generally accepted that the reaction proceeds via a
produce chlorinated ether 8 with a chlorine atom in the 1- 1,3-dipole formed by the attack of one of the nitrogen
position. The elimination of hydrogen chloride was carried atoms on the sp carbon atom of the allenyl skeleton. A
out in refluxing pyridine. After following the isolation pro- successive attack of the dipole on the second allenyl moiety
cedure the product 4g of a [3,3] sigmatropic Claisen re- leads to the formation of a criss-cross adduct consisting of
arrangement of propargyl vinyl ether was obtained showing four five-membered rings. During the reaction two new ste-
that the product of the elimination reaction transformed reogenic centres are formed (Scheme 5).
1
immediately to aldehyde 4g.
To assign the signals observed in the H NMR spectra,
Symmetrical azines 5 were prepared from allenyl alde- 2D NMR NOESY experiments were performed and the re-
hydes 4 by reaction with hydrazine hydrate in a molar ratio sulting data are shown in Table 2 for compound 6e.
of 2:1. In this way we prepared the azines 5a–g with dif-
ferent substituents in the 3-position (Table 1 and Scheme 4).
The course of this reaction was also monitored by infra-
red spectroscopy, by analysing the differences in the inten-
Table 2. Chemical shifts, multiplicity and coupling constants of hy-
drogen atoms in compound 6e.
sities of the characteristic signals. In the spectra of 5a–g a
new signal at 1640 cm–1 belonging to the C=N group ap-
pears and at the same time the signal at 1725 cm–1 due to
1
the carbonyl group of 4 disappears. H NMR spectroscopy
was also used to monitor the reaction. The proton chemical
shift of the aldehyde at about 9.5 ppm was replaced by a
signal at 7.5 ppm belonging to the CH=N group. Of par-
ticular interest are the NMR spectra of allenyl aldehydes 4,
which reveal the pronounced interaction of hydrogen atoms
over five bonds (hydrogen atoms on both sides of the allene
cumulated double bonds) with coupling constants ranging
between 2.4–2.9 Hz.
Having obtained symmetrical azines 5 we then used them
in a thermally initiated intramolecular reaction. When re-
fluxed in an inert solvent (xylene) they afforded in five cases
centrally fused heterocyclic compounds 6c–g consisting of
four fused five-membered nitrogen-containing rings. The
course of the reaction was again monitored by IR spec-
troscopy. During the reaction the peaks arising from the
C=N group at 1640 cm–1 and the cumulated double bonds
at 1955 cm–1 decreased in intensity and at the same time the
signal at 1690 cm–1 belonging to C=C increased. When an
aliphatic chain was bonded to the nitrogen atom of the ami-
Scheme 5.
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H. Zachová, S. Man, M. Necˇas, M. Potácˇek
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Figure 1. A perspective view of 3,3,8,8-tetramethyl-2,7-bis(morpholin-4-ylmethyl)-11,12-diazatetracyclo[4.4.2.04,11.09,12]dodeca-1,6-diene
(6e).
Figure 2. A perspective view of 3,3,8,8-tetramethyl-2,7-bis[(4-methylpiperazin-1-yl)methyl]-11,12-diazatetracyclo[4.4.2.04,11.09,12]dodeca-
1,6-diene (6f).
Suitable crystals of the products 6e, 6f and 6g were grown four five-membered cycles has a significant impact on the
and analyzed by X-ray diffraction (Figures 1, 2, 3). The cen- internal bond angles, which are often less than their ideal
trally fused four heterocyclic rings in each of the crystallo- values. The angles at the sp3 carbon atoms are sometimes
graphically characterized molecules have very similar bond as low as 100.3°, similarly for the nitrogen atoms (angles of
lengths and angles. This is tantamount to saying that they ca. 103° and less). The most important bond lengths and
form a very rigid structure that is not very sensitive to the angles are listed in Table 3. The six-membered heterocyclic
nature of the attached substituents. The overall shape of moieties in 6e and 6f adopt, as might be expected, typical
the centrally fused structure might be most appropriately chair conformations; configurations at the chiral carbons
described as a “shallow dish” (Figure 3). The fusion of the are (R,R) and (S,S), respectively.
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Fused Tetracyclic Heterocycles from Homoallenylaldazines
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Figure 3. A perspective view of 3,3,8,8-tetramethyl-2,7-diphenyl-11,12-diazatetracyclo [4.4.2.04,11.09,12]dodeca-1,6-diene (6g) showing the
dish-like shape of the central heterocyclic moiety. The atoms marked with the A suffix are generated by rotation through the two-fold
symmetry axis that bisects the N11–N11A linkage and lies in the plane of paper.
Table 3. Crystal data and refinement parameters for compounds 6e, 6f and 6g.
6e
6f
6g
Empirical formula
Formula mass
Crystal system
Space group
a [Å]
b [Å]
c [Å]
C24H38N4O2
414.58
monoclinic
P21/c
10.400(2)
11.245(2)
19.525(4)
90
C26H44N6
440.67
monoclinic
P21/c
20.987(4)
15.098(3)
16.359(3)
90
C26H28N2
368.50
monoclinic
C2/c
19.947(3)
14.035(3)
7.2491(9)
90
α [°]
β [°]
95.58(3)
90
2272.6(8)
4
1.212
0.078
101.04(3)
90
5087.5(18)
8
1.151
0.070
91.75(2)
90
2028.5(5)
4
1.207
0.070
γ [°]
Volume [Å3]
Z
Calculated density [Mgm3]
Absorption coefficient [mm–1]
F(000)
904
1936
792
Crystal size [mm]
Crystal colour
θ range [°]
Index range h
Index range k
Index range l
Reflections collected/unique
Data/restraints/parameters
GOF
0.30×0.30×0.15
colourless
3.52–25.00
–12 Ǟ 7
–13 Ǟ 13
–23 Ǟ 23
13383/3981
3981/0/271
1.132
0.30×0.20×0.20
colourless
2.88–25.00
–17 Ǟ 24
–17 Ǟ 17
–19 Ǟ 19
30587/8899
8899/0/578
1.017
0.40×0.40×0.30
colourless
3.39–25.00
–23 Ǟ 23
–16 Ǟ 9
–8 Ǟ 8
6647/1772
1772/0/128
1.114
Final R/wR2 (I Ͼ 2σ/I)
Final R/wR2 (all data)
0.0575/0.1223
0.0815/0.1329
0.0518/0.1318
0.0756/0.1458
0.0397/0.0971
0.0520/0.1022
and these underwent Claisen rearrangement to homoallenyl
aldehydes 4a–f, both in good yields of around 80%. The
Conclusions
We have succeeded in developing an efficient and reliable ether 3g was prepared in a different way and was not iso-
method for the preparation of chlorinated ether 1 and a lated but transformed immediately to aldehyde 4g. All
procedure for the elimination of HCl from 1 to give 2-meth- ethers 3 and homoallenyl aldehydes 4, having an amino
ylprop-1-en-1-yl prop-2-yn-1-yl ether (2). By applying the group, are unstable at ambient temperature even under ar-
Mannich reaction we prepared a series of new ethers 3a–g gon and must be used immediately in subsequent transfor-
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H. Zachová, S. Man, M. Necˇas, M. Potácˇek
FULL PAPER
mations. Therefore compounds 4 were used in the prepara- Table 4. Selected bond lengths [Å] and angles [°] for compounds
6e, 6f and 6g. For the two crystallographically independent mole-
tion of stable symmetrical azines, which served as the start-
ing materials in thermally initiated reactions that lead to
substituted fused heterocycles. These fused heterocycles
cules in 6f, both values are given. Owing to the presence of sym-
metry equivalents in 6g, the atoms N12 and C5 in 6e and 6f corre-
spond to N11A and C10A in 6g, in accord with the labeling scheme
were formed by intramolecular criss-cross cycloaddition re-
actions that involve two successive 1,3-dipolar cycload-
dition reactions within the same molecule. Two new ste-
reogenic centres were formed through this reaction. The
compounds thus formed exist as racemic mixtures of
enantiomers with (R,R) and (S,S) configurations. Our ex-
periments with the 3-substituted homoallenyl aldehyde az-
ines have allowed us to formulate some conclusions about
the role of substitution. Generally, electron-donating sub-
stituents in the 3-position increase the reactivity of azines 5
shown in Figure 3.
6e
6f
6g
N11–N12
N11–C1
N12–C6
N11–C4
N12–C9
C1–C10
C5–C6
1.485(2)
1.434(3)
1.434(3)
1.496(3)
1.496(3)
1.488(3)
1.491(3)
1.560(3)
1.561(3)
1.324(3)
1.327(3)
1.530(3)
1.526(3)
1.550(3)
1.550(3)
1.492(3)
1.490(3)
102.8(1)
103.3(1)
106.2(2)
106.4(2)
103.2(2)
103.1(2)
1.479(2); 1.484(2)
1.435(2); 1.427(2)
1.433(2); 1.434(2)
1.492(2); 1.494(2)
1.493(2); 1.494(2)
1.492(2); 1.494(2)
1.496(2); 1.492(2)
1.558(2); 1.564(2)
1.562(2); 1.568(2)
1.327(2); 1.331(2)
1.326(2); 1.330(2)
1.533(2); 1.533(2)
1.530(2); 1.531(2)
1.561(2); 1.560(2)
1.553(2); 1.552(2)
1.491(2); 1.493(2)
1.498(2); 1.488(2)
103.2(1); 103.5(1)
103.0(1); 103.0(1)
106.9(1); 106.9(1)
106.5(1); 106.4(1)
103.5(1); 103.5(1)
103.4(1); 103.7(1)
1.497(2)
1.430(2)
1.502(2)
1.490(2)
1.560(2)
1.329(2)
1.535(2)
1.563(2)
1.483(2)
102.5(1)
106.7(1)
103.8(1)
C9–C10
C4–C5
towards criss-cross cycloaddition, whereas bulky substitu- C1–C2
C6–C7
ents cause steric hindrance reducing the reactivity of the
C2–C3
azines. Finally the thermally initiated criss-cross reaction
C7–C8
provides a route to interesting fused heterocyclic com-
C3–C4
pounds consisting of four fused five-membered heterocy-
cles.
C8–C9
C2–C21
C7–C71
C1–N11–N12
C6–N12–N11
C4–N11–N12
C9–N12–N11
C1–N11–C4
C6–N12–C9
Experimental Section
General Remarks: Melting points were measured on a Boetius Ra-
pido PHMK 73/2106 (Wägetechnik) instrument with a TM-1300K
thermometer. TLC was carried out on silica gel 60 F254 (Merck),
and detection was carried out with
a Fluotest Universal
1-Chloro-2-methylpropyl Prop-2-yn-1-yl Ether (1): After cooling
isobutyraldehyde (129 g, 1.8 mol) to –5 °C, a stream of HCl(g) was
introduced for 5 s and then propargyl alcohol (67 g, 1.2 mol) was
slowly added. The reaction temperature was kept between –5 and
0 °C, and the reaction mixture was vigorously agitated during the
further introduction of HCl(g). At the beginning of the reaction,
the reaction mixture became very viscous. After the viscosity of the
reaction mixture had lowered and two phases had appeared,
HCl(g) was slowly introduced into the mixture for another 30 min.
Then the organic layer was separated, dried with MgSO4 and after
filtration the low boiling portions were removed under vacuum.
The crude product was distilled under vacuum (Ϸ20 Torr, 53–
(Quarzlampen, Hanau) apparatus or in I2 vapours. NMR spectra
were recorded in chloroform with a Bruker Avance DRX 300 spec-
trometer. CHCl3 and CDCl3 were used as internal standards in the
1H (δ = 7.27 ppm) and 13C (triplet, δ = 77.23 ppm) NMR spectra.
The 13C and 1H NMR spectra were correlated with those obtained
by simulation (Advanced Chemistry Development, Inc., Toronto,
Canada). FTIR spectra were measured at GENESIS ATI (Unicam)
in a film between NaCl windows (wave numbers in cm–1). Mass
spectra (EI, 70 eV) were recorded with a FISONS TRIO 1000 in-
strument. Elemental analyses were performed with a FlashEA
1112, Thermo Finnigan instrument. Products 1, 2 and 3 were kept
under argon and refrigerated below –10 °C.
1
55 °C) to give ether 1 as a colourless liquid (87% yield). H NMR
X-ray Crystallographic Study: Diffraction data were collected on a
Kuma KM-4 four-circle single-crystal diffractometer (λ
(CDCl3): δ = 1.02 (d, J = 6.7 Hz, 6 H, CH3), 2.1 (sept d, J = 6.7,
J = 4.2 Hz, 1 H, CH3–CH–CH3), 2.47 (t, J = 2.4 Hz, 1 H, H–Cϵ),
4.33 (dd, J = 15.9, J = 2.4 Hz, 1 H, CH2–O), 4.39 (dd, J = 15.9, J
= 2.4 Hz, 1 H, CH2–O), 5.62 (d, J = 4.2 Hz, 1 H, O–CH–Cl) ppm.
13C NMR (CDCl3): δ = 17.5, 17.6, 36.4, 56.9, 75.8, 78.0,
=
0.71073 Å) equipped with a CCD camera using ω scan mode and
are corrected for Lorentz and polarization effects. Data collection
was carried out at 120(2) K. The intensity data were corrected for
Lorentz and polarization effects. All structures were solved by di-
rect methods and refined by full-matrix least-squares methods
using anisotropic thermal parameters for the non-hydrogen atoms.
The positions of the hydrogen atoms were calculated from the ge-
ometry of the structures and refined by using a riding model. The
software packages used were: Xcalibur CCD system for the data
collection/reduction,[13] and SHELXTL for the structure solution,
refinement and drawing preparation.[14] In Figures 1, 2, 3 the ther-
mal ellipsoids are drawn at the 50% probability level and hydrogen
atoms have been omitted for clarity. Details of the data collection
and structure refinement are listed in Table 4.
101.7 ppm. IR: ν = 1099, 1187, 1255, 1390, 1463, 2123 (CϵC),
˜
2879, 2933, 2971, 3299 (H–CϵC) cm–1. MS (EI, 70 eV): m/z (%) =
133 (100), 105 (28), 91 (13), 79 (37), 55 (40), 43 (93).
2-Methylprop-1-en-1-yl Prop-2-yn-1-yl Ether (2): Pyridine (79 g,
1.0 mol) was warmed to 75 °C and then ether 1 (146 g, 1.0 mol)
was added dropwise. The temperature was kept between 75 and
80 °C during all the reaction steps. The reaction mixture was agi-
tated for 20 minutes, and then the product was carefully distilled
under vacuum. The crude product 2 was mixed with charcoal and
left overnight at laboratory temperature, then filtered and distilled
under vacuum (Ϸ50 Torr; 55–58 °C). Colourless liquid (75% yield).
CCDC-246503–246505 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
IR: ν = 1024, 1147, 1274, 1367, 1446, 1693 (C=C), 2119 (CϵC),
˜
2861, 2919, 2962, 3295 (H–CϵC) cm–1. 1H NMR (CDCl3): δ =
1.54 (m, 3 H, -CH3), 1.60 (m, 3 H, -CH3), 2.43 (t, J = 2.3 Hz, 1 H,
H–Cϵ), 4.30 (d, J = 2.3 Hz, 2 H, CH2), 5.90 (m, 1 H, =CH) ppm.
2554
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2548–2557

Fused Tetracyclic Heterocycles from Homoallenylaldazines
FULL PAPER
13C NMR (CDCl3): δ = 15.1, 19.5, 58.6, 74.7, 79.6, 113.0,
138.7 ppm. MS (EI, 70 eV): m/z (%) = 111 (19) [M]+, 110 (38), 98
(17), 83 (31), 55 (52), 43 (100), 42 (57).
1-Methyl-4-{4-[(2-methylprop-1-en-1-yl)oxy]but-2-yn-1-yl}piper-
azine (3f): H NMR (CDCl3): δ = 1.40 (s, 3 H, CH3–C=), 1.45 (s,
3 H, CH3–C =), 2.14 (s, 3 H, CH3–N), 2.2–2.5 (m, 8 H, CH2–CH2),
3.19 (t, J = 1.9 Hz, 2 H, N–CH2–Cϵ), 4.16 (t, J = 1.9 Hz, 2 H, O–
CH2), 5.73 (m, 1 H, CH =) ppm. 13C NMR (CDCl3): δ = 15.0,
19.4, 45.9, 47.0, 51.9, 54.9, 58.8, 80.8, 81.5, 112.3, 138.6 ppm. IR:
1
Preparation of Substituted Ethers 3a–f. General Procedure: Under
argon, an appropriate amine (0.1 mol) was added to a mixture of
CuI (100 mg), paraformaldehyde (3.0 g, equivalent of 0.1 mol
CH2O) and ether 2 (11.0 g, 0.1 mol). The reaction mixture was co-
oled under cold water bath for 10 minutes and then heated at 70 °C
for 30 minutes. The water formed during the reaction was removed
under vacuum and the product was separated by kugelrohr distil-
lation under high vacuum (Ϸ1 Torr). Ethers 3 were produced as
colourless liquids.
ν = 1012, 1145, 1283, 1346, 1455, 1692, 2258 (CϵC), 2765, 2795,
˜
2840, 2934 cm–1. MS (EI, 70 eV): m/z (%) = 224.0 (52) [M + 1]+,
223.0 (100), 221.6 (19), 152.4 (17), 150.9 (91), 112.8 (98), 107.7 (36),
98.9 (41).
Preparation of Homoallenyl Aldehydes 4a–f by Claisen Rearrange-
ment. General Procedure: Ether 3 was heated under argon in an oil
bath preheated to 200 °C for 5–10 minutes. The product, after rapid
cooling in running tap water, was distilled under high vacuum
(Ϸ1 Torr) using a kugelrohr apparatus. Ethers 4 were produced as
colourless liquids.
3-[(Diethylamino)methyl]-2,2-dimethylpenta-3,4-dienal (4a): 1H
NMR (CDCl3): δ = 0.90 (t, J = 7.1 Hz, 6 H, CH3–CH2), 1.13 (s, 6
H, CH3–C–CH3), 2.44 (m, 4 H, CH3–CH2), 2.93 (t, J = 2.0 Hz, 2
H, N–CH2–C=), 4.78 (t, J = 2.0 Hz, 2 H, CH2=), 9.22 (s, 1 H,
CH=O) ppm. 13C NMR (CDCl3): δ = 10.7, 21.4, 45.6, 46.8, 53.9,
N,N-Diethyl-4-[(2-methylprop-1-en-1-yl)oxy]but-2-yn-1-amine (3a):
1H NMR (CDCl3): δ = 0.96 (m, 6 H, CH3–CH2–N), 1.47 (s, 3 H,
CH3–C=), 1.52 (s, 3 H, CH3–C=), 2.44 (m, 4 H, CH3–CH2–N),
3.35 (t, J = 2.0 Hz, 2 H, N–CH2–Cϵ), 4.22 (t, J = 2.0 Hz, 2 H, O–
CH2), 5.80 (m, 1 H, CH=) ppm. 13C NMR (CDCl3): δ = 12.6, 15.0,
19.5, 40.9, 47.2, 58.9, 80.3, 81.5, 112.4, 138.7 ppm. IR: ν = 1016,
˜
1101, 1146, 1321, 1384, 1454, 1693, 2256 (CϵC), 2821, 2927,
2972 cm–1. MS (EI, 70 eV): m/z (%) = 196.9 (38) [M + 2]+, 195.6
(100), 180.4 (30), 125.2 (57), 124.4 (30), 123.8 (73), 122.8 (29), 109.1
(49), 107.9 (31), 86.4 (10), 85.8 (21).
76.7, 105.6, 200.7, 207.7 ppm. IR: ν = 845, 1090, 1387, 1456, 1718
˜
(C=O), 1953 (C=C=C), 2708, 2808, 2933, 2970 cm–1. GC–MS:
m/z (%) = 196.2 (49) [M + 1]+, 167.3 (13), 166.2 (16), 152.1 (11),
86.0 (100).
N,N-Diisopropyl-4-[(2-methylprop-1-en-1-yl)oxy]but-2-yn-1-amine
1
(3b): H NMR (CDCl3): δ = 1.09 (d, J = 6.6 Hz, 12 H, CH3–CH–
CH3), 1.56 (s, 3 H, CH3–C=), 1.61 (s, 3 H, CH3–C=), 3.19 (sept, J
= 6.6 Hz, 2 H, CH3–CH–CH3), 3.46 (t, J = 1.9 Hz, 2 H, N–CH2–
Cϵ), 4.30 (t, J = 1.9 Hz, 2 H, O–CH2), 5.89 (m, 1 H, CH=) ppm.
13C NMR (CDCl3): δ = 15.1, 19.6, 20.7, 34.4, 48.6, 59.3, 79.1, 86.2,
1
3-[(Diisopropylamino)methyl]-2,2-dimethylpenta-3,4-dienal (4b): H
NMR (CDCl3): δ = 0.95 (d, J = 6.7 Hz, 12 H, CH3–CH–CH3),
1.18 (s, 6 H, CH3–C–CH3), 3.05 (sept, J = 6.7 Hz, 2 H, CH3–CH–
CH3), 3.08 (t, J = 2.1 Hz, 2 H, N–CH2–C=), 4.79 (t, J = 2.1 Hz, 2
H, CH2=), 9.32 (s, 1 H, CH=O) ppm. 13C NMR (CDCl3): δ = 20.2,
112.4, 138.9 ppm. IR: ν = 1014, 1144, 1269, 1340, 1383, 1464, 1693,
˜
2256 (CϵC), 2828, 2927, 2966 cm–1. MS (EI, 70 eV): m/z (%) =
225.0 (33) [M + 2] +, 223.7 (76), 152.3 (19), 151.2 (15), 137.2 (17),
136.1 (17), 121.9 (15), 114.0 (8), 109.9 (8).
21.4, 45.2, 47.0, 47.1, 76.6, 106.0, 201.8, 208.5 ppm. IR: ν = 843,
˜
1174, 1363, 1390, 1462, 1720 (C=O), 1952 (C=C=C), 2707, 2834,
2872, 2933, 2966 cm–1.GC–MS: m/z (%) = 224.6 (5) [M + 1]+, 194.6
(8), 180.2 (16), 136.1 (13), 114.1 (100).
2,2-Dimethyl-3-(pyrrolidin-1-ylmethyl)penta-3,4-dienal (4c): 1H
NMR (CDCl3): δ = 1.07 (s, 6 H, CH3–C–CH3), 1.59 (m, 4 H, CH2–
CH2–N), 2.38 (m, 4 H, CH2–CH2–N), 2.95 (t, J = 2.4 Hz, 2 H, N–
CH2–C=), 4.75 (t, J = 2.4 Hz, 2 H, CH2=), 9.13 (1 H, s,
CH=O) ppm. 13C NMR (CDCl3): δ = 21.2, 23.8, 46.8, 53.5, 55.2,
1-{4-[(2-Methylprop-1-en-1-yl)oxy]but-2-yn-1-yl}pyrrolidine (3c): 1H
NMR (CDCl3): δ = 1.47 (s, 3 H, CH3–C=), 1.52 (s, 3 H, CH3–C=),
1.71 (m, 4 H, CH2–CH2–N), 2.52 (m, 4 H, CH2–CH2–N), 3.35 (t,
J = 1.8 Hz, 2 H, N–CH2–Cϵ), 4.23 (t, J = 1.8 Hz, 2 H, O–CH2),
5.81 (m, 1 H, CH=) ppm. 13C NMR (CDCl3): δ = 15.0, 19.5, 23.8,
43.2, 52.5, 58.9, 79.9, 82.5, 112.3, 138.7 ppm. IR: ν = 1014, 1146,
˜
1272, 1322, 1346, 1448, 1693, 2256 (CϵC), 2789, 2910, 2962 cm–1.
MS (EI, 70 eV): m/z (%) = 194.3 (100) [M + 1]+, 192.1 (13), 123.2
(37), 122.2 (40), 121.3 (33), 119.6 (20), 93.6 (16), 84.0 (14).
77.2, 105.8, 200.0, 206.6 ppm. IR: ν = 847, 1142, 1346, 1460, 1716
˜
(C=O), 1954 (C=C=C), 2706, 2796, 2875, 2929, 2968 cm–1. GC–
MS: m/z (%) = 194.2 (17) [M + 1]+, 164.7 (15), 150.1 (8), 84.0 (100).
1-{4-[(2-Methylprop-1-en-1-yl)oxy]but-2-yn-1-yl}piperidine (3d): 1H
NMR (CDCl3): δ = 1.42 (m, 2 H, CH2–CH2–CH2–N), 1.5–1.7 (m,
4 H, CH2–CH2–N), 1.55 (s, 3 H, CH3–C=), 1.60 (s, 3 H, CH3–C=),
2.47 (t, J = 5.1 Hz, 4 H, CH2–CH2–N), 3.28 (t, J = 2.0 Hz, 2 H,
N–CH2–Cϵ), 4.32 (t, J = 2.0 Hz, 2 H, O–CH2), 5.90 (m, 1 H,
CH=) ppm. 13C NMR (CDCl3): δ = 15.1, 19.5, 24.0, 26.0, 48.0,
2,2-Dimethyl-3-(piperidin-1-ylmethyl)penta-3,4-dienal (4d): 1H
NMR (CDCl3): δ = 1.15 (s, 6 H, CH3–C–CH3), 1.3–1.5 (m, 6 H,
CH2–CH2–CH2–N), 2.33 (m, 4 H, CH2–CH2–CH2–N), 2.83 (t, J
= 2.1 Hz, 2 H, N–CH2–C=), 4.80 (t, J = 2.1 Hz, 2 H, CH2=), 9.28
(1 H, s, CH=O) ppm. 13C NMR (CDCl3): δ = 21.4, 24.5, 25.7, 47.0,
54.3, 58.9, 76.8, 105.0, 201.0, 207.4 ppm. IR: ν = 844, 993, 1116,
˜
53.3, 59.0, 80.5, 82.2, 112.4, 138.8 ppm. IR: ν = 1016, 1146, 1340,
˜
1338, 1454, 1716 (C=O), 1954 (C=C=C), 2715, 2796, 2935 cm–1.
1444, 1691, 2256 (CϵC), 2754, 2798, 2854, 2933 cm–1.MS (EI,
70 eV): m/z (%) = 209.6 (13) [M + 2]+, 208.3 (100), 206.2 (15), 137.3
(15), 136.0 (70), 134.0 (14), 108.0 (13), 98.0 (16).
GC–MS: m/z (%) = 208.3 (20) [M + 1]+, 178.2 (11), 98.0 (100).
2,2-Dimethyl-3-(morpholin-4-ylmethyl)penta-3,4-dienal (4e): 1H
NMR (CDCl3): δ = 1.10 (s, 6 H, CH3–C–CH3), 2.36 (t, J = 4.5 Hz,
4 H, N–CH2–CH2–O), 2.84 (t, J = 2.0 Hz, 2 H, N–CH2–C=), 3.52
(t, J = 4.5 Hz, 4 H, N–CH2–CH2–O), 4.77 (t, J = 2.0 Hz, 2 H,
CH2=), 9.27 (1 H, s, CH=O) ppm. 13C NMR (CDCl3): δ = 21.6,
4-{4-[(2-Methylprop-1-en-1-yl)oxy]but-2-yn-1-yl}morpholine
(3e):
1H NMR (CDCl3): δ = 1.53 (s, 3 H, CH3–C=), 1.59 (s, 3 H, CH3–
C=), 2.52 (t, J = 4.7 Hz, 4 H, O–CH2–CH2–N), 3.29 (t, J = 1.8 Hz,
2 H, N–CH2–Cϵ), 3.70 (t, J = 4.7 Hz, 4 H, O–CH2–CH2–N), 4.30
(t, J = 1.8 Hz, 2 H, O–CH2), 5.90 (m, 1 H, CH=) ppm. 13C NMR
(CDCl3): δ = 15.2, 19.6, 47.6, 52.4, 59.0, 67.0, 81.3, 81.4, 112.8,
46.9, 53.1, 58.5, 66.7, 77.0, 103.6, 201.1, 207.7 ppm. IR: ν = 863,
˜
1007, 1116, 1308, 1456, 1716 (C=O), 1954 (C=C=C), 2704, 2810,
2856, 2964 cm–1. GC–MS: m/z (%) = 210.2 (20) [M + 1]+, 181.4
(13), 179.9 (10), 166.1 (14), 122.7 (12), 99.9 (100).
138.8 ppm. IR: ν = 1004, 1117, 1147, 1288, 1346, 1452, 1693, 2256
˜
(CϵC), 2762, 2814, 2856, 2914, 2960 cm–1. MS (EI, 70 eV): m/z
(%) = 211.6 (7) [M + 2]+, 210.3 (95), 139.4 (13), 137.9 (100), 107.9
(20), 100.0 (22).
2,2-Dimethyl-3-[(4-methylpiperazin-1-yl)methyl]penta-3,4-dienal-
1
(4f): H NMR (CDCl3): δ = 1.13 (s, 6 H, CH3–C–CH3), 2.21 (s, 3
Eur. J. Org. Chem. 2005, 2548–2557
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2555

H. Zachová, S. Man, M. Necˇas, M. Potácˇek
FULL PAPER
H, N–CH3), 2.2–2.5 (m, 8 H, N–CH2–CH2–N), 2.86 (t, J = 2.0 Hz, drate (0.28 g, 5.5 mmol). Yield: 2.19 g (96%). Light yellow solid,
2 H, N–CH2–C=), 4.80 (t, J = 2.0 Hz, 2 H, CH2=), 9.28 (s, 1 H,
m.p. 51–55 °C. 1H NMR (CDCl3): δ = 1.29 (s, 12 H, CH3), 1.51
CH=O) ppm. 13C NMR (CDCl3): δ = 21.4, 46.1, 47.0, 52.8, 54.9, (m, 12 H, CH2), 2.34 (m, 8 H, CH2N), 2.88 (t, J = 2.4 Hz, 4 H,
58.1, 77.0, 104.3, 201.4, 207.6 ppm. IR: ν = 822, 1011, 1163, 1282,
C–CH2–N), 4.80 (t, J = 2.4 Hz, 4 H, =CH2), 7.68 (s, 2 H,
˜
1456, 1716 (C=O), 1954 (C=C=C), 2694, 2796, 2935, 2966 cm–1.
CH=N) ppm. 13C NMR (CDCl3): δ = 24.77, 25.08, 26.16, 39.80,
GC–MS: m/z (%) = 221.2 (1) [M]+, 193.2 (45), 113.0 (53). MS (EI,
54.69, 58.87, 77.15, 106.33, 168.24, 207.27 ppm. IR (KBr): ν = 842,
˜
70 eV): m/z (%) = 223.4 (100) [M + 1]+, 221.7 (18), 220.6 (9), 194.7 991, 1114, 1265, 1305, 1342, 1450, 1641 (C=N), 1951 (C=C=C),
(22), 193.2 (58), 113.0 (74).
2751, 2856, 2933 cm–1. MS (EI, 70 eV): m/z (%) = 410 (52) [M]+,
395 (14), 326 (100), 312 (46), 242 (89), 227 (35), 213 (18).
2,2-Dimethyl-3-phenylpenta-3,4-dienal (4g):[15] Pyridine (6.82 g,
0.086 mol) was heated to reflux and then ether 8 (15.6 g, 0.070 mol)
was added dropwise. The reaction mixture was refluxed for an hour
whilst stirring. Then the mixture was mixed with water and ex-
tracted with diethyl ether. The ether layer was dried with MgSO4.
The solvent and the excess of the pyridine were removed under
vacuum. The remainder was distilled under vacuum (Ϸ1 Torr, 133–
2,2-Dimethyl-3-(morpholin-4-ylmethyl)penta-3,4-dienal Azine (5e):
Reaction mixture: aldehyde 4e (4.06 g, 19.1 mmol), hydrazine hy-
drate (0.49 g, 9.6 mmol). Yield: 3.44 g (86%). Yellow solid, m.p.
1
56–58 °C. H NMR (CDCl3): δ = 1.29 (s, 12 H, CH3), 2.41 (t, J =
4.5 Hz, 8 H, CH2–N), 2.93 (t, J = 2.2 Hz, 4 H, C–CH2–N), 3.65
(t, J = 4.5 Hz, 8 H, CH2–O), 4.81 (t, J = 2.2 Hz, 4 H, =CH2), 7.69
(s, 2 H, CH=N) ppm. 13C NMR (CDCl3): δ = 24.98, 39.74, 53.57,
1
138 °C). Colourless liquid (9.2 g, 70% yield). H NMR (CDCl3): δ
58.46, 67.09, 77.25, 105.38, 168.47, 207.46 ppm. IR (KBr): ν = 862,
˜
= 1.27 (s, 6 H, CH3), 5.09 (s, 2 H, C=CH2), 7.2–7.3 (m, 5 H, Har.),
9.60 (s, 1 H, CHO) ppm. 13C NMR (CDCl3): δ = 22.08, 48.71,
1004, 1118, 1346, 1450, 1643 (C=N), 1951 (C=C=C), 2688, 2800,
2854, 2971 cm–1. MS (EI, 70 eV): m/z (%) = 414 (16) [M]+, 328
(20), 207 (80), 122 (28), 100 (100), 56 (20).
78.56, 108.48, 128.59, 135.36, 203.38, 209.24 ppm. IR (NaCl): ν =
˜
1030, 1144, 1442, 1728 (C=O), 1940 (C=C=C), 2701, 2802, 2931,
3056 cm–1. MS (EI, 70 eV): m/z (%) = 186 (33) [M]+, 171 (96), 143
(40), 128 (55), 115 (100), 91 (30), 77 (32), 43 (58).
2,2-Dimethyl-3-[(4-methylpiperazin-1-yl)methyl]penta-3,4-dienal Az-
ine (5f): Reaction mixture: aldehyde 4f (3.00 g, 13.5 mmol), hydra-
zine hydrate (0.34 g, 6.8 mmol). Yield: 2.88 g (96%). Yellow solid,
m.p. 61–66 °C. 1H NMR (CDCl3): δ = 1.27 (s, 12 H, CH3), 2.3–2.5
(m, 22 H, CH2, CH3), 2.92 (t, J = 2.3 Hz, 4 H, C–CH2–N), 4.79
(t, J = 2.3 Hz, 4 H, =CH2), 7.66 (s, 2 H, CH=N) ppm. 13C NMR
(CDCl3): δ = 25.10, 39.80, 46.23, 53.11, 55.32, 58.03, 77.19, 105.88,
Synthesis of Azines 5a–g. General Procedure: Using a Dean–Stark
apparatus, hydrazine hydrate was added dropwise to allenyl alde-
hyde 4 (in a hydrazine hydrate/allenylaldehyde molar ratio of 1:2)
in dichloromethane (10 mL) in a flask fitted with a magnetic stir-
ring. The reaction mixture was refluxed and water was removed by
azeotropic distillation for 6 hours. Then the solvent was removed
under vacuum and the residue was washed with petroleum ether,
dried and identified.
168.26, 207.38 ppm. IR (KBr): ν = 847, 1012, 1162, 1346, 1456,
˜
1643 (C=N), 1952 (C=C=C), 2761, 2798, 2931 cm–1. MS (EI,
70 eV): m/z (%) = 440 (43) [M]+, 425 (12), 341 (31), 242 (100), 227
(20).
3-[(Diethylamino)methyl]-2,2-dimethylpenta-3,4-dienal Azine (5a):
2,2-Dimethyl-3-phenylpenta-3,4-dienal Azine (5g): Reaction mix-
ture: aldehyde 4g (8.53 g, 45.8 mmol), hydrazine hydrate (1.15 g,
22.9 mmol). Yield: 5.08 g (60%). White solid, m.p. 73–83 °C. 1H
NMR (CDCl3): δ = 1.37 (s, 12 H, CH3), 5.01 (s, 4 H, =CH2), 7.2–
7.3 (m, 10 H, Har.), 7.78 (s, 2 H, CH=N) ppm. 13C NMR (CDCl3):
δ = 25.73, 40.68, 77.89, 111.20, 127.09, 128.25, 128.92, 130.52,
Reaction mixture: aldehyde 4a (2.47 g, 12.7 mmol), hydrazine hy-
1
drate (0.32 g, 6.3 mmol). Yield: 2.39 g (97 %). Yellow liquid. H
NMR (CDCl3): δ = 0.97 (m, 12 H, CH3), 1.28 (s, 12 H, CH3), 2.49
(m, 8 H, CH2), 3.01 (t, J = 2.5 Hz, 4 H, C–CH2–N), 4.80 (t, J =
2.5 Hz, 4 H, =CH2), 7.67 (s, 2 H, CH=N) ppm. 13C NMR (CDCl3):
δ = 11.58, 25.04, 39.73, 46.46, 53.36, 77.16, 106.94, 168.16,
168.54, 208.39 ppm. IR (KBr): ν = 865, 948, 1124, 1155, 1446,
˜
207.40 ppm. IR (NaCl): ν = 843, 1089, 1145, 1295, 1382, 1459,
˜
1490, 1633 (C=N), 1940 (C=C=C), 2865, 2929, 3077 cm–1. MS (EI,
70 eV): m/z (%) = 368 (16) [M]+, 353 (32), 184 (45), 141 (58), 128
(82), 115 (100), 77 (25).
1641 (C=N), 1951 (C=C=C), 2802, 2933, 2967 cm–1.
3-[(Diisopropylamino)methyl]-2,2-dimethylpenta-3,4-dienal Azine
(5b): Reaction mixture: aldehyde 4b (2.00 g, 8.9 mmol), hydrazine
hydrate (0.22 g, 4.5 mmol). Yield: 1.69 g (85%). Yellow solid, m.p.
Criss-Cross Cycloaddition to 6c–g. General Procedure: Azine 5 was
refluxed in dry xylene under argon for 2 hours. Then the solvent
was then removed under vacuum and the solid residue was washed
with diethyl ether and then with acetonitrile. After filtration of the
solid the compound was identified as a pure product.
1
44–48 °C. H NMR (CDCl3): δ = 0.98 (m, 24 H, CH3), 1.27 (s, 12
H, CH3), 3.0–3.1 (m, J = 2.7 Hz, 8 H, C–CH2–N, CH), 4.76 (t, J
= 2.7 Hz, 4 H, =CH2), 7.71 (s, 2 H, CH=N) ppm. 13C NMR
(CDCl3): δ = 20.63, 25.24, 39.81, 44.89, 47.48, 77.12, 108.94,
3,3,8,8-Tetramethyl-2,7-bis(pyrrolidin-1-ylmethyl)-11,12-diazatetra-
cyclo[4.4.2.04,11.09,12]dodeca-1,6-diene (6c): Reaction mixture: azine
5c (256.3 mg, 0.67 mmol) in dry xylene (5 mL). Yield: 117 mg
168.70, 207.93 ppm. IR (KBr): ν = 840, 1041, 1139, 1380, 1461,
˜
1641 (C=N), 1951 (C=C=C), 2823, 2869, 2966 cm–1.
1
2,2-Dimethyl-3-(pyrrolidin-1-ylmethyl)penta-3,4-dienal Azine (5c):
Reaction mixture: aldehyde 4c (2,00 g, 10.4 mmol), hydrazine hy-
drate (0.26 g, 5.2 mmol). Yield: 1.49 g (75%). White solid, m.p. 23–
(46%). White solid, m.p. 115–119 °C. H NMR (CDCl3): δ = 1.10
(s, 6 H, CH3), 1.30 (s, 6 H, CH3), 1.70 (m, 8 H, CH2), 2.21 (dd, J1
= 9.8, J2 = 15.9 Hz, 2 H, CH2), 2.3–2.4 (m, 8 H, CH2–N), 2.54
(dd, J1 = 3.0, J2 = 15.9 Hz, 2 H, CH2), 2.73 (d, J = 12.9 Hz, 2 H,
1
26 °C. H NMR (CDCl3): δ = 1.24 (s, 12 H, CH3), 1.69 (m, 8 H,
CH2–CH2), 2.45 (m, 8 H, CH2–N), 3.01 (t, J = 3.0 Hz, 4 H, C–
CH2 –N), 4.82 (t, J = 3.0 Hz, 4 H, =CH2 ), 7.54 (s, 2 H,
CH=N) ppm. 13C NMR (CDCl3): δ = 23.70, 24.78, 39.76, 54.23,
CH2), 3.07 (d, J = 12.9 Hz, 2 H, CH2), 3.73 (dd, J1 = 3.0, J2
=
9.8 Hz, 2 H, CH) ppm. 13C NMR (CDCl3): δ = 22.89, 23.83, 25.06,
28.56, 51.49, 54.49, 77.54, 118.66, 149.21 ppm. IR (KBr): ν = 879,
˜
1045, 1110, 1261, 1348, 1461, 1699 (C=C), 2728, 2775, 2960 cm–1.
MS (EI, 70 eV): m/z (%) 382 [M+, 9], 312 (9), 242 (20), 147 (11),
120 (24), 84 (88), 79 (33), 70 (100), 42 (84). C24H38N4 (382.59):
calcd. C 75.34, H 10.01, N 14.64; found C 75.00, H 10.33, N 14.50.
55.14, 78.07, 107.37, 167.31, 206.55 ppm. IR (KBr): ν = 842, 933,
˜
1143, 1346, 1459, 1641 (C=N), 1953 (C=C=C), 2726, 2780,
2962 cm–1. MS (EI, 70 eV): m/z (%) = 382 (9) [M]+, 312 (15), 242
(14), 227 (12), 191 (53), 122 (30), 84 (100).
2,2-Dimethyl-3-(piperidin-1-ylmethyl)penta-3,4-dienal Azine (5d): 3,3,8,8-Tetramethyl-2,7-bis(piperidin-1-ylmethyl)-11,12-diazatetra-
Reaction mixture: aldehyde 4d (2.28 g, 11.0 mmol), hydrazine hy-
cyclo[4.4.2.04,11.09,12]dodeca-1,6-diene (6d): Reaction mixture: azine
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2548–2557

Fused Tetracyclic Heterocycles from Homoallenylaldazines
5d (490 mg, 1.20 mmol) in dry xylene (5 mL). Yield: 0.32 g (65%). extracted with diethyl ether (40 mL) and dried with MgSO4. The
FULL PAPER
1
Light yellow solid, m.p. 118–122 °C. H NMR (CDCl3): δ = 1.10
solvent was removed under vacuum and the residue distilled under
(s, 6 H, CH3), 1.30 (s, 6 H, CH3), 1.47 (m, 12 H, CH2), 2.1–2.3 (m, vacuum (Ϸ7 Torr, 126–132 °C). Yield: 7.58 g (65%) as a colourless
10 H, CH2), 2.51 (dd, J1 = 3.3, J2 = 15.9 Hz, 2 H, CH2), 2.64 (d, oil. 1H NMR (CDCl3): δ = 2.6–2.7 (m, 1 H, OH), 4.52 (d, 2 H,
J = 13.2 Hz, 2 H, CH2), 2.83 (d, J = 13.2 Hz, 2 H, CH2), 3.74 (dd,
CH2), 7.3–7.4 (m, 5 H, Har.) ppm. 13C NMR (CDCl3): δ = 51.57,
J1 = 3.3, J2 = 9.6 Hz, 2 H, CH) ppm. 13C NMR (CDCl3): δ = 85.73, 87.49, 122.73, 128.58, 131.82 ppm. IR (NaCl): ν = 1029,
˜
22.89, 24.91, 24.98, 26.40, 28.50, 51.50, 54.79, 77.56, 117.56, 1095, 1257, 1448, 1601, 2237, 2856, 2923, 3346 cm–1. MS (EI,
149.88 ppm. IR (KBr): ν = 788, 985, 1041, 1105, 1342, 1440, 1698 70 eV): m/z (%) = 132 (65) [M]+, 131 (100), 115 (33), 103 (60), 77
˜
(C=C), 2751, 2935 cm–1. MS (EI, 70 eV): m/z (%) = 410 (32) [M]+,
326 (48), 241 (63), 120 (26), 98 (100), 84 (43), 41 (29). C26H42N4
(410.64): calcd. C 76.05, H 10.31, N 13.64; found C 76.00, H 10.53,
N 13.60.
(70), 51 (40), 39 (15).
1-Chloro-2-methylpropyl 3-Phenylprop-2-yn-1-yl Ether (8): Isobu-
tyraldehyde (19.8 g, 0.272 mol) was cooled to –5 °C, then HCl(g)
was introduced into the flask and propargyl alcohol (12.0 g,
0.091 mol) was slowly added. The reaction temperature was kept
between –5 and 0 °C and the reaction mixture was vigorously
stirred. HCl(g) must be added as fast as possible. The end of the
reaction was indicated by the formation of two layers. Then the
3,3,8,8-Tetramethyl-2,7-bis(morpholin-1-ylmethyl)-11,12-diazatetra-
cyclo[4.4.2.04,11.09,12]dodeca-1,6-diene (6e): Reaction mixture: azine
5e (2.00 g, 4.83 mmol) in dry xylene (5 mL). Yield: 1.49 g (75%).
White solid, m.p. 160–165 °C. 1H NMR (CDCl3): δ = 1.10 (s, 6 H,
CH3), 1.30 (s, 6 H, CH3), 2.2–2.4 (m, 8 H, CH2–N; dd, J1 = 9.8, organic layer was separated, dried with MgSO4 and after filtration
J2 = 15.9 Hz, 2 H, CH2), 2.47 (dd, J1 = 3.0, J2 = 15.9 Hz, 2 H,
CH2), 2.65 (d, J = 12.9 Hz, 2 H, CH2), 2.87 (d, J = 12.9 Hz, 2 H,
the low-boiling portions were removed under vacuum. The crude
product was distilled under vacuum (Ϸ1 Torr, 112–116 °C). Yield:
CH2), 3.65 (m, 8 H, CH2–O), 3.75 (dd, J1 = 3.0, J2 = 9.8 Hz, 2 H, 15.9 g (79%) as a colourless liquid. 1H NMR (CDCl3): δ = 1.0–1.1
CH) ppm. 13C NMR (CDCl3): δ = 22.85, 24.99, 28.48, 51.52, 53.89, (m, 6 H, CH3), 2.1–2.2 (m, 1 H, CH), 4.52 (s, 2 H, CH2), 5.73 (d,
54.44, 67.33, 77.55, 116.34, 150.77 ppm. IR (KBr): ν = 864, 1002,
1 H, CH), 7.3–7.5 (m, 5 H, Har.) ppm. 13C NMR (CDCl3): δ =
˜
1116, 1272, 1346, 1450, 1698 (C=C), 2759, 2944 cm–1. MS (EI, 17.68, 36.51, 57.81, 85.04, 86.50, 102.16, 122.70, 128.54 ppm. IR
70 eV): m/z (%) = 414 (21) [M]+, 328 (31), 241 (53), 147 (59), 120 (NaCl): ν = 690, 1139, 1363, 1596, 1689, 2239, 2924, 2967,
˜
(28), 100 (100), 77 (44), 56 (75). C24H38N4O2 (414.58): calcd. C 3059 cm–1.
69.53, H 9.24, N 13.51; found C 69.49, H 9.32, N 13.49.
3,3,8,8-Tetramethyl-2,7-bis[(4-methylpiperazin-1-yl)methyl]-11,12-di-
Acknowledgments
azatetracyclo[4.4.2.04,11.09,12]dodeca-1,6-diene (6f): Reaction mix-
ture: azine 5f (500 mg, 1.13 mmol) in dry xylene (5 mL). Yield:
The authors acknowledge the Ministry of Education of the Czech
Republic (MSM, 143100011) and the Grant Agency of the Czech
Republic (203/02/0436) for their financial support, and Radovan
Kares for kind measurement of the mass spectra.
ˇ
218.7 mg (44%). Yellow solid, m.p. 135–140 °C. 1H NMR (CDCl3):
δ = 1.09 (s, 6 H, CH3), 1.29 (s, 6 H, CH3), 2.1–2.4 (m, 24 H, CH2,
CH3), 2.48 (dd, J1 = 3.3, J2 = 15.9 Hz, 2 H, CH2), 2.68 (d, J =
12.9 Hz, 2 H, CH2), 2.88 (d, J = 12.9 Hz, 2 H, CH2), 3.72 (dd, J1
= 3.3, J2 = 9.8 Hz, 2 H, CH) ppm. 13C NMR (CDCl3): δ = 22.88,
25.01, 28.52, 46.31, 51.53, 53.36, 53.97, 55.60, 77.58, 116.97,
[1] R. Grashey, Azomethine imines, in 1,3-Dipolar Cycloaddition
Chemistry (Ed.: A. Padwa), John Wiley & Sons, New York,
1984, pp. 757–763.
[2] For examples of criss-cross cycloaddition reactions, see: S.
Rádl, Aldrichimica Acta 1997, 30, 97–100.
150.39 ppm. IR (KBr): ν = 822, 1011, 1161, 1284, 1348, 1456, 1701
˜
(C=C), 2759, 2933 cm–1. MS (EI, 70 eV): m/z (%) = 440 (9) [M]+,
340 (42), 241 (100), 147 (20), 120 (35), 99 (51), 70 (75), 58 (69), 42
(78). C26H44N6 (440.67): calcd. C 70.86, H 10.06, N 19.07; found
C 70.58, H 9.89, N 18.75.
[3] S. Marthur, H. Suschitzky, J. Chem. Soc., Perkin Trans. 1 1975,
2479–2483.
3,3,8,8-Tetramethyl-2,7-diphenyl-11,12-diazatetracyclo[4.4.2.04,11
.
ˇ
[4] M. Potácˇek, R Marek, Z. Zák, J. Trottier, Z. Janousˇek, H. G.
09,12]dodeca-1,6-diene (6g): Reaction mixture: azine 5g (79.6 mg,
0.22 mmol) in dry xylene (5 mL). Yield: 61.4 mg (77%). White so-
lid, m.p. 159–163 °C. 1H NMR (CDCl3): δ = 1.20 (s, 6 H, CH3),
1.44 (s, 6 H, CH3), 2.52 (dd, J1 = 9.6, J2 = 16.2 Hz, 2 H, CH2),
2.69 (dd, J1 = 3.6, J2 = 16.2 Hz, 2 H, CH2), 3.94 (dd, J1 = 3.6, J2
= 9.6 Hz, 2 H, CH), 7.2–7.3 (m, 10 H, Har.) ppm. 13C NMR
(CDCl3): δ = 24.58, 26.52, 29.05, 52.99, 77.55, 122.63, 126.53,
Viehe, Tetrahedron Lett. 1993, 34, 8341–8344.
[5] D. K. Black, S. R. Landor, Proc. Chem. Soc., London 1963,
183–185.
[6] D. K. Black, S. R.Landor, J. Chem. Soc. 1965, 6784–6788.
[7] J. Grimaldi, M. Malacria, M. Bertrand, Bull. Soc. Chim. Fr.
1975, 1720 –1724.
[8] T. Tsuno, H. Hoshino, R. Okuda, K. Sugiyama, Tetrahedron
2001, 57, 4831–4840.
128.62, 135.70, 149.73 ppm. IR (KBr): ν = 806, 910, 1026, 1250,
˜
[9] D. K. Black, S. R. Landor, J. Chem. Soc. 1965, 5225–5230.
[10] D. K. Black, Z. T. Fomum, P. D. Landor, S. R. Landor, J.
Chem. Soc. Perkin Trans. 1 1973, 1349–1351.
[11] C. Mannich, W. Krösche, Arch. Pharm. 1912, 250, 647.
[12] A. S. Atavin, A. N. Mirskova, E. F. Zorina, Yu. L. Frolov, A. S.
Atavin, J. Org. Chem. USSR 1968, 4, 1281–1285; Zh. Org.
Khim. 1968, 4, 1328–1333.
[13] Xcalibur CCD System, CrysAlis Software System, Version
1.170, Oxford.
[14] SHELXTL, Version 5.10, Bruker AXS Inc., Madison, WI,
USA, 1997.
1465, 1599, 1670 (C=C), 2859, 2966, 3059 cm–1. MS (EI, 70 eV):
m/z (%) = 368 (78) [M]+, 353 (25), 312 (37), 184 (100), 170 (67),
141 (44), 128 (73), 115 (41), 91 (18), 77 (22), 41 (17). C26H28N2
(368.51): calcd. C 84.74, H 7.66, N 7.60; found C 84.79, H 7.82, N
7.56.
3-Phenylprop-2-yn-1-ol (7): Phenylacetylene (9.0 g, 0.088 mol) was
dissolved in dry tetrahydrofuran (60 mL) and cooled to –78 °C
whilst stirring. Then 1.6 m butyllithium (51 mL, 0.092 mol) was
added dropwise. After addition the reaction mixture was warmed
to 0 °C and paraformaldehyde (5.2 g, 0.173 mol) was added in one
portion. Then the reaction mixture was stirred overnight at room
temperature. Finally the mixture was treated with H2O (20 mL),
[15] J. Corbier, P. Cresson, C. R. Seances Acad. Sci., Ser. C 1970,
270, 2077–2079.
Received: November 15, 2004
Eur. J. Org. Chem. 2005, 2548–2557
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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