Multicomponent reaction of aldehydes, anhydrides, and dienophiles: Synthesis of butterfly -like diazatetradecenes

Article abstract of DOI:10.1002/ejoc.200400563

An operationally simple one-pot synthesis of functionalized bicyclo[2.2.2]oct-2-ene derivatives has been developed using a novel multicomponent coupling of α,β-unsaturated aldehydes, carboxylic acid anhydrides, and dienophiles. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400563

FULL PAPER
Multicomponent Reaction of Aldehydes, Anhydrides, and Dienophiles:
Synthesis of ‘‘Butterfly’’-Like Diazatetradecenes
Dirk Strübing,[a] Axel Jacobi von Wangelin,[a] Helfried Neumann,[a] Dirk Gördes,[a]
Sandra Hübner,[a] Stefan Klaus,[a] Anke Spannenberg,[a] and Matthias Beller*[a]
Keywords: Domino reactions / Multicomponent reactions / Diazatetradecenes / DielsϪAlder reaction
An operationally simple one-pot synthesis of functionalized
bicyclo[2.2.2]oct-2-ene derivatives has been developed using
a novel multicomponent coupling of α,β-unsaturated alde-
hydes, carboxylic acid anhydrides, and dienophiles.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
DielsϪAlder reaction affords the three-component MCR
product (Scheme 1).
To date, this AAD reaction (amide, aldehyde, dienophile)
has been developed as a powerful tool for the synthesis of
highly substituted cyclohexene derivatives.[12] Further suc-
cessful applications include the preparation of substituted
alkyl phthalates,[13] anilines,[14] and luminols.[15]
Herein, we report an extension of our AAD reaction,
which led to a novel method for the synthesis of ‘‘butter-
fly’’-like bicyclo[2.2.2]oct-2-enes directly from ubiquitously
available α,β-unsaturated aldehydes and dienophiles.
The development and use of domino[1] and multicom-
ponent[2] reactions for the preparation of natural products,
biologically active compounds and building blocks for or-
ganic synthesis is becoming more and more attractive for
synthetic organic chemists.[3] This is caused by the several
advantages of such methods over the usual stepwise forma-
tion of individual bonds. The obviation of time- and cost-
consuming separation steps and the high-atom economy are
important attributes, and make these methods ideally suited
for a sustainable chemistry. Numerous classical multicom-
ponent reaction (MCR) classics use the in situ condensation
of aldehydes, amines or amides to give reactive imine or
enamine derivatives, which subsequently react with other
different components. Typical examples include the Man-
nich[4] and Strecker[5] reaction, the Hantzsch pyrrole syn-
thesis,[6] the Biginelli synthesis of dihydropyrimidines,[7] and
the four-component BuchererϪBergs reaction,[8] as well as
the prominent Ugi-4CR.[9] Interestingly, the use of tran-
sition-metal catalysts, e.g. Pd complexes, enables the devel-
opment of new variants of MCRs. Here, a prominent ex-
ample is the amidocarbonylation of aldehydes to give N-
acyl α-amino acids.[10]
Results and Discussion
While studying the three-component reaction of acet-
amide, 2-methyl-2-pentenal and N-methyl maleimide in de-
tail we observed the formation of small amounts (Ͻ 25%
yield) of the diazatetradecene 1 as by-product at higher re-
action temperatures (Ͼ 120 °C). As shown in Scheme 2, we
assumed that 1 is formed by a remarkable sequence of en-
amide 1a formation, an endo-selective DielsϪAlder reaction
to 1b, and 1,4-elimination of acetamide from the resulting
cis-4-(N-acetylamino)-5,7-dimethyl-1,3-dioxo-2,3,3a,4,7,7a-
hexahydro-1H-isoindole to give the corresponding 1,3-
cyclohexadiene 1c, which then undergoes another selective
DielsϪAlder cycloaddition with maleimide to the final di-
azatetradecene 1.
A literature search revealed that these tetracyclic com-
pounds constitute interesting building blocks with promis-
ing biological activity. For example, several derivatives of
the structurally related mitindomide, a 1:2 photoadduct of
benzene and maleimide, were proven to exhibit high anti-
tumor activity.[16] Furthermore, these structures provide the
opportunity for chemical manipulation towards other at-
tractive bicyclo[2.2.2]octane derivatives and cage molecules.
Despite the interesting properties of the products, there are
More recently, we have developed mulicomponent reac-
tions by taking advantage of the intermediacy of 1-(N-acyl-
amino)-1,3-butadienes,[11] which are formed by the conden-
sation of an amide with simple or α,β-unsaturated alde-
hydes. In the presence of electron-deficient dienophiles, a
[a]
Leibniz-Institut für Organische Katalyse an der Universität
Rostock e.V.,
Buchbinderstr. 5Ϫ6, 18055 Rostock, Germany
Fax: (internat) ϩ 49-381-46693-24
E-mail: matthias.beller@ifok.uni-rostock.de
Eur. J. Org. Chem. 2005, 107Ϫ113
DOI: 10.1002/ejoc.200400563
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107

M. Beller et al.
FULL PAPER
Scheme 1. Formation and DielsϪAlder reaction of N-acylaminodienes
Scheme 2. Mechanism for the formation of the diazatetradecene 1 from 2-methyl-2-pentenal
only very few literature examples that report on the syn- spect to the formation of the intermediate 1-acyloxy-1,3-
thesis of related structures by DielsϪAlder reactions with butadienes. Hence, all of the following reactions were run
α,β-unsaturated aldehydes or pyrones or indoles.[17]
in this solvent.
Thus, we decided to investigate this novel reaction se-
quence more closely. Based on our experience with the
AAD reaction, we anticipated that elimination of acetamide
towards the intermediate 1,3-cyclohexadiene is slow and
therefore rate-determining. Obviously, oxygen nucleophiles
such as carboxylate anions would constitute superior leav-
ing groups under the (acidic) reaction conditions. Consist-
ently, we studied the model reaction of 2-methyl-2-pentenal
and N-methylmaleimide in the presence of various car-
boxylic acid anhydrides. Selected experiments of this opti-
mization study are shown in Table 1. A primary solvent
screening proved toluene to be a superior solvent with re-
In the presence of acetic anhydride, low to moderate
yields (up to 52%) were obtained (Table 1, Entries 1Ϫ5). In
order to observe significant formation of 1 elevated tem-
perature (Ͼ 120 °C) and long reaction times are required
(24Ϫ40 h). The use of other alkane- and arenecarboxylic
anhydrides was found to be inferior (Table 1, Entries 6Ϫ9).
However, to our delight, the use of trifluoroacetic anhydride
resulted in improved yields of 1 (up to 85%, Table 1, Entry
12). The selective 1-acyloxy-1,3-diene formation and the
twofold DielsϪAlder reaction with this high yield is es-
pecially remarkable when considering the numerous side re-
actions that are likely to proceed under these conditions
(aldol condensations, oligomerizations, aromatization).
We then aimed at the diversification of the general ‘‘but-
terfly’’-scaffold by employing various substituted α,β-un-
saturated aldehydes to the optimized set of conditions
(Table 2). The best results were obtained by employing 2-
ethyl-2-butenal, which was smoothly converted into the de-
sired product in 92% yield (Table 2, Entry 4). It is interest-
ing to note that a clever choice of reactants can result in
the generation of products with up to six annulated ring
systems in one step (Table 2, Entry 9)! Apart from N-meth-
ylmaleimide, maleimide and maleic anhydride are also
shown to be suitable dienophiles in this reaction sequence
Table 1. Screening of reaction conditions for the synthesis of 1
(Table 2, Entries 11 and 12).
Although several equilibrating cyclohexadiene isomers
can be produced upon elimination of trifluoroacetic acid,
the reactions selectively gave only one product. Thus, both
108
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Eur. J. Org. Chem. 2005, 107Ϫ113

Synthesis of “Butterfly”-Like Diazatetradecenes
FULL PAPER
cycloaddition reactions to the intermediate 1-acyloxy-1,3-
diene and cyclohexadiene species proceed with high endo
preference in all cases.
Table 2. Synthesis of substituted bicyclo[2.2.2]oct-2-ene derivatives;
reaction conditions: trifluoroacetic anhydride (4.5 mmol), aldehyde
(3.0 mmol), dienophile (9.0 mmol), p-TSA (4 mol %), toluene
(20 mL), 140 °C, 40 h
NMR spectra of 1Ϫ12 exhibit only one set of signals for
the two dihydromaleimide/dihydromaleic anhydride moiet-
1
ies, and the H resonances have double intensities. Consist-
ently, the isolated tetracyclic adducts are symmetric with
respect to an internal mirror plane. This structural assign-
ment is proven by the X-ray analysis of 11 (Figure 1).[18]
Here, suitable crystals were obtained by crystallization from
ethyl acetate.
˚
Figure 1. Crystal structure of 11; selected bond lengths [A]: C1ϪC2
1.511 (3); C2ϪN1 1.382 (2); C1ϪC3 1.546 (3); C1ϪC5 1.537(3);
C5ϪC11 1.334(3); C10Ϫ11 1.334(3); C9ϪC10 1.518(2); C3ϪC9
1.560(3); selected bond angles [°]: C5ϪC1ϪC3 110.4(2);
C11ϪC5ϪC1 107.74 (14); C10ϪC11ϪC5 112.9(2); C2ϪC1ϪC5
111.6(2); C2ϪC1ϪC3 104.92(15)
Enhanced structural diversification was realized by adop-
tion of a two-step procedure with different dienophiles
(Table 3). Exemplified by the reactions with crotonalde-
hyde, sequential condensations were performed that in-
volved isolation of the N-methylmaleimide adduct in 61%
yield.[19] Consumption thereof, by performing an additional
reaction step in the presence of secondary dienophiles like
maleic anhydride, fumarodinitrile, and diethyl fumarate, af-
forded the desired unsymmetrical bicyclo[2.2.2]oct-2-enes in
good yield (60Ϫ74%, Table 3, Entries 1Ϫ3).
Conclusions
In summary, we developed a novel multicomponent reac-
tion for the synthesis of highly functionalized bicyclo[2.2.2]-
oct-2-enes, which provides an easy entry into this class of
compounds and allows numerous further structural ma-
nipulations. The underlying domino condensation/
[a]
64 h.
Eur. J. Org. Chem. 2005, 107Ϫ113
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M. Beller et al.
FULL PAPER
4,10-Dimethyl-4,10-diazatetracyclo[5.5.2.02,6.08,12]tetradec-13-ene-
3,5,9,11-tetraone (2): Procedure A. 40 h. Rf (SiO2, n-heptane/E-
tOAc, 1:1): 0.25. Yield: 85%. Colorless solid. M.p. 197 °C. 1H
NMR (400 MHz, [D6]DMSO): δ ϭ 6.01 (dd, J ϭ 1.18 Hz and J ϭ
2.97 Hz, 2 H, HCϭCH), 3.35 (m, 2 H, 2 HCϭCHCH), 3.16 (s, 4
H, 4 CHCHCO), 2.71 (s, 6 H, 2 CONCH3) ppm. 13C{1H} NMR
(100.6 MHz, [D6]DMSO): δ ϭ 177.5 (4 CONCH3), 130.8 (CHϭ
CH), 42.3 (4 CHCHCO), 33.3 (2 CHϭCHCHCH), 24.3 (2
CONCH3) ppm. MS (EI, 70 eV): m/z (%) ϭ 274 (79) [M]ϩ, 163
(100), 104 (28), 78 (74), 40 (19), no other peaks Ͼ 10%. IR (KBr):
ν˜ ϭ 3458 (m), 3087 (w), 2987 (m), 2976 (m), 2931 (m), 1697 (s),
1433 (s), 967 (s), 612 (s) cmϪ1. HR MS (EI): calcd. for C14H14N2O4:
274.09536; found 274.09480 [M]ϩ.
Table 3. Synthesis of mixed adducts by sequential AAD reaction,
elimination and DielsϪAlder reaction; reaction conditions:
cis-4-acetoxy-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindole (2.25
mmol), dienophile (6.75 mmol), p-TSA (2 mol %), toluene (10 mL),
140 °C, 72 h
4,10,14-Trimethyl-4,10-diazatetracyclo[5.5.2.02,6.08,12]tetradec-13-
ene-3,5,9,11-tetraone (3): Procedure A. 40 h. Rf (SiO2, n-heptane/
EtOAc, 1:1): 0.12. Yield: 85%. Colorless solid. M.p. 213 °C. 1H
NMR (400 MHz, [D6]DMSO): δ ϭ 5.57 [d, J ϭ 5.9 Hz, 1 H, HCϭ
C(CH3)], 3.61 (m, 1 H, CϭCHCHCH), 3.16 (m, 2 H, 2 CHCHCO),
3.09 [m, 1 H, HCϭC(CH3)CHCH], 2.70 (s, 6 H, 2 CONCH3), 1.48
(d,
J ϭ 1.38 Hz, 3
H, HCϭCCH3) ppm. 13C{1H} NMR
(100.6 MHz, [D6]DMSO): δ ϭ 177.6 (2 CONCH3), 177.4 (2
CONCH3), 140.2 [CHC(CH3)ϭCH], 121.4 [C(CH3)ϭCHCH), 43.0
and 42.2 (2 CHCONCH3), 38.4 (CϭCHCHCH), 34.1 [HCϭ
C(CH3)CHCH], 24.3 (2 CONCH3), 21.0 (HCϭCCH3) ppm. MS
(EI, 70 eV): m/z (%) ϭ 288 (85) [M]ϩ, 177 (18), 112 (21), 92 (100),
no other peaks Ͼ 10%. IR (KBr): ν˜ ϭ 3442 (m), 2954 (m), 2919
(m), 1709 (s), 1434 (s), 784 (s) cmϪ1. HR MS (EI): calcd. for
C15H16N2O4: 288.11101; found 288.10972 [M]ϩ.
DielsϪAlder elimination/DielsϪAlder reaction sequence
with carboxylic anhydrides, aldehydes, and dienophiles ex-
hibits a marked increase in structural complexity, as six
stereogenic centers are formed in an operationally simple
one-pot procedure.
14-Ethyl-4,10-dimethyl-4,10-diazatetracyclo[5.5.2.02,6.08,12]tetradec-
13-ene-3,5,9,11-tetraone (4): Procedure A. 40 h. Rf (SiO2, n-hep-
tane/EtOAc, 1:1): 0.13. Yield: 92%. Colorless solid. M.p. 172Ϫ175
Experimental Section
1
Procedure A: Trifluoroacetic anhydride (4.5 mmol), α,β-unsatu-
rated aldehyde (3 mmol), dienophile (9 mmol) and p-toluenesul-
fonic acid monohydrate (4 mol %) were combined in a pressure
tube, and toluene (20 mL) was added. The reaction mixture was
stirred at 140 °C for 40Ϫ64 h. After cooling, all volatile compounds
were removed under reduced pressure. Silica gel flash chromatogra-
phy (n-heptane/EtOAc) afforded the corresponding products.
°C. H NMR (400 MHz, [D6]DMSO): δ ϭ 5.55 [dd, J ϭ 1.38 Hz
and J ϭ 4.75 Hz, 1 H, C(Et)ϭCHCH], 3.29 [m, 1 H, HCϭ
C(Et)CHCHCO], 3.20 (m, 1 H, CϭCCHCH), 3.14 (m, 2 H, 2
CHCHCO), 2.71 (s, 6 H, 2 CONCH3), 1.77 (m, 2 H, CH3CH2Cϭ
CH), 0.71 (t, J ϭ 7.33 Hz, 3 H, CH3CH2CϭCH) ppm. 13C{1H}
NMR (100.6 MHz, [D6]DMSO): δ ϭ 177.6 (2 CONCH3), 177.4 (2
CONCH3), 145.5 [CHϭC(Et)CH], 120.1 [C(Et)ϭCHCH], 43.0 [2
C(Et)CHCHCO], 42.4 (2 CϭCHCHCH), 37.6 [C(Et)CHCHCO],
33.9 (CϭCHCHCH), 27.5 (2 CONCH3), 24.2 (CH3CH2CϭCH),
11.3 (CH3CH2CϭCH) ppm. MS (EI, 70 eV): m/z (%) ϭ 302 (100)
[M]ϩ, 287 (46), 191 (24), 112 (42), 106 (86), 91 (64), no other peaks
Ͼ 10%. IR (KBr): ν˜ ϭ 3450 (m), 3062 (w), 2961 (m), 1700 (s), 1436
(s), 973 (s), 782 (s) cmϪ1. HR MS (EI): calcd. for C16H18N2O4:
302.12666; found 302.12655 [M]ϩ.
Procedure B: cis-4-Acetoxy-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-
isoindole (2.25 mmol), dienophile (6.75 mmol) and p-toluenesul-
fonic acid monohydrate (2 mol %) were combined in a pressure
tube, and toluene (10 mL) was added. The reaction mixture was
stirred at 140 °C for 72 h. After cooling, all volatile compounds
were removed under reduced pressure. Silica gel flash chromatogra-
phy (n-heptane/EtOAc) afforded the corresponding products.
4,10-Dimethyl-14-phenyl-4,10-diazatetracyclo[5.5.2.02,6.08,12]-
tetradec-13-ene-3,5,9,11-tetraone (5): Procedure A. 40 h. Rf (SiO2,
n-heptane/EtOAc, 1:1): 0.21. Yield: 81%. Colorless solid. M.p.
1,4,10,14-Tetramethyl-4,10-diazatetracyclo[5.5.2.02,6.08,12]tetradec-
13-ene-3,5,9,11-tetraone (1): Procedure A. 40 h. Rf (SiO2, n-hep-
tane/EtOAc, 1:1): 0.11. Yield: 82%. Colorless solid. M.p. 212Ϫ214 247Ϫ249 °C. 1H NMR (400 MHz, [D6]DMSO): δ ϭ 7.45Ϫ7.28 (m,
°C. 1H NMR (400 MHz, [D6]DMSO):
C(CH3)CHϭC(CH3)], 3.19 [d, 2.97 Hz,
C(CH3)CHCH], 3.15 (m, 2 H, 2 CHCHCO), 2.79 (m, 2 H, 2 CHCHCON), 3.38 (dd, J ϭ 2.77 Hz and J ϭ 5.15 Hz, 2 H, 2
CH3CCHCO), 2.70 (s, 6 H, 2 CONCH3), 1.64 (s, 3 H, CH3Cϭ
PhCCHCHCON), 2.76 (s, 6 H, 2 CONCH3) ppm. 13C{1H} NMR
δ
ϭ
5.36 [s,
1
1
H,
5 H, H-Ar), 6.37 (m, 1 H, CHCHϭCPh), 4.00 (m, 1 H,
J
ϭ
H, HCϭ PhCCHCH), 3.63 (m, 1 H, PhCϭCHCHCH), 3.46 (m, 2 H, 2
CH), 1.49 (s, 3 H, CϭCHCCH3) ppm. 13C{1H} NMR (100.6 MHz, (100.6 MHz, [D6]DMSO): δ ϭ 177.5 (2 CONCH3), 177.2 (2
[D6]DMSO): δ ϭ 177.2 (2 CONCH3), 176.5 (2 CONCH3), 139.0 CONCH3), 142.1 (i-C-Ar), 128.6 and 128.0 (2 o-CH-Ar and 2 m-
[CHC(CH3)ϭCH], 126.7 [C(CH3)ϭCHCH], 48.0 and 43.5 CH-Ar), 125.2 (p-CH), 137.0 (PhCϭCH), 123.3 (CHCHϭCPh),
(CHCONCH3), 38.2 (ϭCHCHCH), 36.2 [CϭCHC(CH3)CH], 24.2 42.7 and 42.6 (2 CHCON), 36.5 (PhCCHCH), 34.4 (CHCHCH),
(2 CONCH3), 21.0 (HCϭCCH3), 19.2 (CϭCHCCH3) ppm. MS
(EI, 70 eV): m/z (%) ϭ 302 (52) [M]ϩ, 191 (48), 106 (100), 91 (29), 239 (22), 154 (100), no other peaks Ͼ 10%. IR (KBr): ν˜ ϭ 3449
no other peaks Ͼ 10%. IR (KBr): ν˜ ϭ 3445 (m), 3048 (w), 2936 (m), 3054 (w), 3001 (w), 2967 (m), 2952 (m), 1697 (s), 1436 (s), 971
24.3 (2 CONCH3) ppm. MS (EI, 70 eV): m/z (%) ϭ 350 (75) [M]ϩ,
(m), 1645 (s), 1418 (s) cmϪ1. HR MS (EI): calcd. for C16H18N2O4: (s), 617 (m) cmϪ1. HR MS (EI): calcd. for C20H18N2O4: 350.12666;
302.12666; found 302.12464 [M]ϩ.
found 350.12647 [M]ϩ.
110
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Synthesis of “Butterfly”-Like Diazatetradecenes
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1,4,10-Trimethyl-4,10-diazatetracyclo[5.5.2.02,6.08,12]tetradec-13-
ene-3,5,9,11-tetraone (6): Procedure A. 40 h. Rf (SiO2, n-heptane/
EtOAc, 1:1): 0.13. Yield: 78%. Colorless solid. M.p. 228Ϫ230 °C.
[D6]DMSO): δ ϭ 177.1 (2 CONCH3), 176.8 (2 CONCH3), 139.1
(C), 132.6 (C), 131.7 (C), 130.1 (C), 127.8 (CH-Ar), 127.4 (CH-
Ar), 127.0 (CH-Ar), 125.6 (CH-Ar), 48.7 (2 COCHC), 44.0
1H NMR (400 MHz, [D6]DMSO): δ ϭ 5.89 [dd, J ϭ 2.01 Hz and (COCHC), 43.6 (2 COCHCH), 40.6 (COCHCH), 27.2 (CH2), 26.2
J ϭ 6.14 Hz, 1 H, CHCHϭCHC(CH3)], 5.73 [d, J ϭ 8.32 Hz, 1 H,
C(CH3)CHϭCH], 3.23 (m, 1 H, CHϭCHCH), 3.10 (dd, J ϭ (%) ϭ 390 (100) [M]ϩ, 279 (43) [M Ϫ C5H5NO2]ϩ, 278 (51), 264
2.97 Hz and J ϭ 4.95 Hz, 2 H, 2 CHCHCO), 2.77 [m, 2 H, 2
(7), 219 (6), 194 (62) [M Ϫ C5H5NO2 Ϫ C3H3NO2]ϩ, 178 (56), 165
(CH2), 24.4 (2 CONCH3), 21.6 (CH3C) ppm. MS (EI, 70 eV): m/z
C(CH3)CHCO], 2.63 (s, 6 H, 2 CONCH3), 1.63 (s, 3 H, CCH3) (12), 113 (71), 58 (12), 43 (15), 29 (11), no other peaks Ͼ 10%. IR
ppm. 13C{1H} NMR (100.6 MHz, [D6]DMSO): δ ϭ 177.3 (2 (KBr): ν˜ ϭ 3442 (m), 3030 (w), 3015 (w), 2939 (s), 2879 (m), 1765
CONCH3), 176.4 (2 CONCH3), 135.8 and 129.6 (CHϭCH), 47.4 (s), 1697 (vs), 1481 (m), 1439 (vs), 1384 (s), 1315 (s), 1289 (vs),
(2 CHCHCONCH3), 43.7 (2 C(CH3)CHCO), 40.1 (Cϭ
CHCHCH), 33.1 [CϭCHC(CH3)CH], 24.3 (2 CONCH3), 19.3 (Cϭ
1230 (s), 1178 (m), 1160 (s), 1133 (s), 1078 (w), 1047 (w), 1018 (w),
997 (m), 977 (s), 928 (w), 914 (w), 840 (w), 822 (w), 804 (w), 772
CHCHCH3) ppm. MS (EI, 70 eV): m/z (%) ϭ 288 (13) [M]ϩ, 177 (vs), 744 (w), 699 (w), 685 (w), 644 (m), 615 (m), 595 (w), 540 (w),
(23), 112 (17), 92 (100), no other peaks Ͼ 10%. IR (KBr): ν˜ ϭ 3438 482 (w), 446 (w), 408 (m) cmϪ1. HR MS (EI): calcd. for
(m), 3051 (w), 2993 (m), 2949 (m), 1696 (s), 1437 (s), 779 (m) cmϪ1
.
C23H22N2O4: 390.15796; found 390.15506 [M]ϩ.
HR MS (EI): calcd. for C15H16N2O4: 288.11101; found 288.11106
1,4,10,14-Tetramethyl-13-phenyl-4,10-diazatetracyclo-
[5.5.2.02,6.08,12]tetradec-13-ene-3,5,9,11-tetraone (10): Procedure A.
64 h. Rf (SiO2, n-heptane/EtOAc, 1:1): 0.16. Yield: 26%. Colorless
solid. M.p. 255 °C. 1H NMR (400 MHz, [D6]DMSO): δ ϭ
[M]ϩ.
1,14-Diethyl-4,10-dimethyl-4,10-diazatetracyclo[5.5.2.02,6.08,12]-
tetradec-13-ene-3,5,9,11-tetraone (7): Procedure A. 40 h. Rf (SiO2,
n-heptane/EtOAc, 1:1): 0.14. Yield: 86%. Colorless solid. M.p. 7.32Ϫ7.19 and 6.54Ϫ6.46 (m, 5 H, H-Ar), 3.31 (d, J ϭ 2.97 Hz, 1
1
167Ϫ168 °C. H NMR (400 MHz, [D6]DMSO): δ ϭ 5.24 [s, 1 H, H, CHCHCH), 3.28 (dd, J ϭ 3.17, J ϭ 7.92 Hz, 2 H, CHCHCH),
C(Et)ϭCHCH] 3.18 (m, 2 H, 2 CHCHCON), 3.14 [d, J ϭ 2.97 Hz, 2.94 (d, J ϭ 7.92 Hz, 2 H, CHCCH), 2.83 (s, 6 H, 2 CONCH3),
1 H, HCϭC(Et)CHCH] 3.02 [m, 2 H, 2 CH(Et)CHCON] 2.69 (s, 1.42 (s, 3 H, CϭCCH3), 1.31 (s, 3 H, CH3CCH) ppm. 13C{1H}
6 H, 2 CONCH3), 2.17 (m, 2 H, CH3CH2CϭCH), 1.81 (m, 2 H,
NMR (100.6 MHz, [D6]DMSO): δ ϭ 177.3 (2 CONCH3), 176.8 (2
CCH2CH3), 1.13 (t, J ϭ 7.23 Hz, 3 H, CH3CH2Cϭ), 0.72 (t, J ϭ CONCH3), 138.0 and 136.4 (CϭC), 133.3 (i-C-Ar), 128.3 and 128.1
7.43 Hz, 3 H, CH3CH2CH) ppm. 13C{1H} NMR (100.6 MHz, (2 o-CH-Ar and 2 m-CH-Ar), 126.9 (p-CH-Ar), 48.7 (2 CHCCH),
[D6]DMSO): δ ϭ 177.4 (2 CONCH3), 176.2 (2 CONCH3), 144.3 43.3 (2 CHCHCH), 42.8 (CHCCH), 39.2 (CHCHCH), 24.4 (2
[CHϭC(Et)CH], 126.0 [C(Et)ϭCHCH], 43.7 (2 C(Et)CHCHCO), CONCH3), 19.1 (CϭCCH3), 18.9 (CHCCH3) ppm. MS (EI,
43.3 (2 CϭCHCHCH), 43.1 [C(Et)CHCHCO], 37.6 [Cϭ
70 eV): m/z (%) ϭ 378 (73) [M]ϩ, 267 (60), 182 (100), 167 (37), 112
CHC(Et)CH], 27.4 (2 CONCH3), 24.2 (CH3CH2Cϭ), 23.6 (15), no other peaks Ͼ 10%. IR (KBr): ν˜ ϭ 3442 (m), 3074 (w),
(CH3CH2CH), 11.3 (CH3CH2Cϭ), 8.1 (CH3CH2CH) ppm. MS 2994 (w), 2979 (w), 2953 (m), 2909 (w), 1767 (s), 1696 (s), 1433 (s),
(EI, 70 eV): m/z (%) ϭ 330 (75) [M]ϩ, 315 (17), 219 (100), 134 (86),
972 (m) cmϪ1. HR MS (EI): calcd. for C22H22N2O4: 378.15796;
119 (32), 112 (24), 105 (48), no other peaks Ͼ 10%. IR (KBr): ν˜ ϭ found 378.15317 [M]ϩ.
3439 (m), 3050 (w), 2979 (s), 2966 (s), 2939 (m), 2888 (w), 1701 (s),
1,14-Diethyl-4,10-diazatetracyclo[5.5.2.02,6.08,12]tetradec-13-ene-
779 (s) cmϪ1. HR MS (EI): calcd. for C18H22N2O4: 330.15796;
found 330.15737 [M]ϩ.
3,5,9,11-tetraone (11): Procedure A. 40 h. Rf (SiO2, n-heptane/
EtOAc, 1:1): 0.15. Yield: 83%. Colorless solid. M.p. Ͼ 311 °C (dec).
1H NMR (400 MHz, [D6]DMSO): δ ϭ 11.09 (s, 2 H, 2 CONHCO),
5.34 [s, 1 H, C(Et)ϭCHCH], 3.09 [q, J ϭ 1.45 Hz, 1 H, C(Et)CH-
4,10,14-Trimethylcyclohexa[m]-4,10-diazatetracyclo[5.5.2.02,6.08,12]-
tetradec-13-ene-3,5,9,11-tetraone (8): Rf (SiO2; n-heptane/EtOAc,
1:1): 0.13. Yield: 50%. Colorless solid. M.p. 199Ϫ201 °C. 1H NMR CON], 3.06 [dd,
J
ϭ
3.17 Hz and
J ϭ 4.75 Hz, 2 H, 2
(400 MHz, [D6]DMSO): δ ϭ 3.10 (m, 1 H, COCHCHCHCO), 3.07
C(Et)CHCHCO], 2.91 [d, J ϭ 7.9 Hz, 2 H, 2 C(Et)CHCO], 2.15
(dd, J ϭ 7.74 Hz and J ϭ 3.17 Hz, 2 H, COCHCHCHCO), 2.80 (q, J ϭ 7.3 Hz, 2 H, CH3CH2Cϭ), 1.88 (dq, J ϭ 1.6 Hz and J ϭ
(d, J ϭ 7.73 Hz, 2 H, COCHCCHCO), 2.70 (s, 6 H, 2 CONCH3), 7.3 Hz, 2 H, CHCH2CH3), 1.07 (t, J ϭ 7.3 Hz, 3 H, CH3CH2Cϭ),
2.57 (m, 2 H, CH2), 1.93 (t, J ϭ 5.94 Hz, 2 H, CH2), 1.51 (m, 2 H,
0.82 (t, J ϭ 7.3 Hz, 3 H, CH3CH2CH) ppm. 13C{1H} NMR
CH2), 1.43 (s, 3 H, CϭCCH3), 1.25 (m, 2 H, CH2) ppm. 13C{1H} (100.6 MHz, [D6]DMSO): δ ϭ 178.7 (2 CONCH3), 177.8 (2
NMR (100.6 MHz, [D6]DMSO): δ ϭ 177.3 (2 CONCH3), 177.2 (2 CONCH3), 144.1 [CHϭC(Et)CH], 125.8 [C(Et)ϭCHCH], 45.0 [2
CONCH3), 131.7 and 129.2 (CϭC), 49.3 (COCHCCHCO), 43.0 C(Et)CHCHCO], 44.4 (2 CϭCHCCHCO), 42.9 [C(Et)CHCHCO],
(COCHCHCHCO), 41.3 (COCHCHCHCO), 27.5 and 25.4 and 37.4 [CϭCHC(Et)CH], 27.5 (CH3CH2Cϭ), 23.5 (CH3CH2CH),
22.4 and 21.3 (4 CH2), 24.3 (2 CONCH3), 17.3 (CϭCCH3) ppm. 10.9 (CH3CH2CϭC), 8.0 (CH3CH2CH) ppm. MS (EI, 70 eV): m/z
MS (EI, 70 eV): m/z (%) ϭ 342 (29) [M]ϩ, 231 (100), 146 (58), 131 (%) ϭ 302 (28) [M]ϩ, 205 (100), 134 (72), 105 (43), no other peaks
(21), 118 (15), 112 (16), no other peaks Ͼ 10%. IR (KBr): ν˜ ϭ 3446
Ͼ 10%. IR (KBr): ν˜ ϭ 3180 (br. m), 3077 (m), 2969 (m), 2924 (w),
(m), 2931 (m), 2870 (m), 2827 (w), 1771 (m), 1701 (s), 1437 (m), 2877 (w), 2775 (w), 1768 (s), 1704 (vs), 1461 (w), 1441 (w), 1353
1286 (m), 1129 (m), 776 (m) cmϪ1. HR MS (EI): calcd. for
C19H22N2O4: 342.15796; found 342.15744 [M]ϩ.
(s), 1320 (s), 1205 (s), 1167 (s), 1136 (m), 1042 (m), 1005 (m), 828
(m), 709 (m), 633 (m) cmϪ1. HR MS (EI): calcd. for C16H18N2O4:
302.12666; found 302.12682 [M]ϩ.
4,10,14-Trimethyl-1,2,3,4-tetrahydronaphthaleno[1,2-m]-4,10-di-
azatetracyclo[5.5.2.02,6.08,12]tetradec-13-ene-3,5,9,11-tetraone (9):
Procedure A. 40 h. Rf (SiO2, n-heptane/EtOAc, 1:1): 0.11. Yield:
1,4,10,14-Tetramethyl-4,10-dioxatetracyclo[5.5.2.02,6.08,12]tetradec-
13-ene-3,5,9,11-tetraone (12): Procedure A. 40 h. Rf (SiO2, n-hep-
73%. Colorless solid. M.p. 162Ϫ163 °C. 1H NMR (400 MHz, tane/EtOAc, 1:1): 0.19. Yield: 60%. Colorless solid. M.p. 284 °C.
[D6]DMSO): δ ϭ 7.09Ϫ7.06 (m, 4 H, CH-Ar.), 3.35 (t, J ϭ 3.2 Hz, 1H NMR (400 MHz, [D6]DMSO): δ ϭ 5.69 [s, 1 H, CH(CH3)CHϭ
1 H, CH3CCH), 3.27 (dd, J ϭ 8.1, J ϭ 3.2 Hz, 2 H, 2 COCHCH), C], 3.67 (dd, J ϭ 3.17, J ϭ 5.35 Hz, 2 H, 2 CHCHCOO), 3.28 (m,
3.00 (d, J ϭ 8.1 Hz, 2 H, 2 COCHC), 2.72 (t, J ϭ 6.2 Hz, 2 H,
CH2), 2.62 (s, 6 H, 2 CONCH3), 2.57 (t, J ϭ 6.2 Hz, 2 H, CH2), CCH3), 1.62 (s, 3 H, CϭCCH3) ppm. 13C{1H} NMR (100.6 MHz,
1.94 (s,
H, CH3C) ppm. 13C{1H} NMR (100.6 MHz, [D6]DMSO): δ ϭ 172.4 (2 CHCOO), 171.1 (2 CHCOO), 141.3
1 H, CHCHCH), 3.25 [m, 2 H, 2 C(CH3)CHCOO], 1.63 (m, 3 H,
3
Eur. J. Org. Chem. 2005, 107Ϫ113
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
111

M. Beller et al.
FULL PAPER
(CH3CϭCH), 128.3 [C(CH3)CHϭC), 48.4 [C(CH3)CHCOO], 44.4 analytical assistance. Generous financial support from the State of
(CHCHCOO), 38.3 (CHCHCH), 21.2 (CH3CϭCH), 18.1 Mecklenburg-Vorpommern (Landesforschungsschwerpunkt), the
[CHC(CH3)] ppm. MS (EI, 70 eV): m/z (%) ϭ 276 (6) [M]ϩ, 178 BMBF and the Fonds der Chemischen Industrie is gratefully
(18), 150 (18), 106 (100), 91 (45), no other peaks Ͼ 10%. IR (KBr):
ν˜ ϭ 3433 (m), 2968 (w), 2946 (w), 1854 (m), 1783 (s)1221 (s), 1094
(s), 935 (s), 755 (m) 414 (m) cmϪ1. HR MS (EI): calcd. for
C17H18N2O3: 276.06339; found 276.06393 [M]ϩ.
acknowledged.
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carbonitrile (13): Procedure B. 72 h. Rf (SiO2, n-heptane/EtOAc,
1:1): 0.4. Yield: 74%. Colorless solid. M.p. 138 °C. 1H NMR
(400 MHz, [D6]DMSO): δ ϭ 6.31 (m, 2 H, CHϭCH), 3.69 and
3.39 (both m, both 1 H, CHCHCON), 3.37 and 3.28 (both m, both
1 H, CHCHCN), 3.14 and 2.83 (both m, both 1 H, ϭCHCHCH),
2.73 (s, 3 H, CONCH3) ppm. 13C{1H} NMR (100.6 MHz,
[D6]DMSO): δ ϭ 176.9 and 176.6 (2 CONCH3), 133.0 and 130.8
(CHϭCH), 120.0 and 119.2 (CHCN), 41.6 and 38.9 (CHCHCON),
33.8 and 33.5 (CHCHCN), 30.8 and 29.8 (HCϭCHCHCH), 24.5
(CONCH3) ppm. MS (EI, 70 eV): m/z (%) ϭ 241 (17) [M]ϩ, 163
(100), 129 (25), 77 (22), 51 (18), no other peaks Ͼ 10%. IR (KBr):
ν˜ ϭ 3464 (m), 3065 (w), 3006 (w), 2949 (w), 2949 (m), 2922 (m),
2242 (m), 1783 (s), 1699 (s), 1440 (s), 739 (m) cmϪ1. HR MS (EI):
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dicarboxylate (14): Procedure B. 72 h. Rf (SiO2, n-heptane/EtOAc,
1:1): 0.35. Yield: 73%. Colorless oil. 1H NMR (400 MHz,
[D6]DMSO): δ ϭ 6.21 and 6.02 (both m, both 1 H, CHϭCH), 4.14
and 4.04 (both m, both 2 H, CH3CH2O), 3.36 and 3.28 (both m,
both 1 H, CHCON), 3.14 (dd, J ϭ 1.98 Hz and J ϭ 3.76 Hz, 1 H,
CHCHCOO), 3.10 (dd, J ϭ 2.97, J ϭ 4.95 Hz, 1 H, CHCHCOO),
2.86 (dd, J ϭ 3.17, J ϭ 4.95 Hz, 1 H, CHϭCHCHCH), 2.79 (q,
J ϭ 2.84 Hz, 1 H, CHϭCHCHCH), 2.69 (s, 3 H, CONCH3), 1.19
(t, J ϭ 7.03 Hz, 3 H, CH2CH3), 1.14 (t, J ϭ 7.13 Hz, 3 H, CH2CH3)
ppm. 13C{1H} NMR (100.6 MHz, [D6]DMSO): δ ϭ 177.9 and
177.5 (2 CONCH3), 172.2 and 172.0 (2 COO), 132.8 and 130.6 (2
CHϭCH), 61.0 and 60.8 (2 CH3CH2O), 44.2 and 43.7 (2
CHCHCON), 42.9 and 34.0 (2 CHCHCOO), 33.9 and 29.5 (2
CHCHCH), 24.3 (CONCH3), 14.0 and 13.9 (2 OCH2CH3) ppm.
MS (EI, 70 eV): m/z (%) ϭ 335 (58) [M]ϩ, 289 (36), 262 (34), 216
(25), 163 (26), 151 (38), 131 (21), 123 (21), 105 (31), 78 (100), 29
(80), no other peaks Ͼ 10%. IR (KBr): ν˜ ϭ 3449 (m), 3054 (w),
2965 (m), 2952 (w), 1770 (m), 1697 (s), 1436 (m), 971 (m) cmϪ1. HR
MS (EI): calcd. for C17H21NO6: 335.13689; found 335.13656 [M]ϩ.
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EtOAc, 1:1): 0.26. Yield: 60%. Colorless solid. M.p. 344Ϫ345 °C.
1H NMR (400 MHz, [D6]DMSO): δ ϭ 6.19 (m, 2 H, CHϭCH),
3.55 (m, 2 H, 2 CHCHCON), 3.41 (m, 2 H, 2 CHCHCOO), 3.21
(m, 2 H, 2 CHCHCH), 2.72 (s, 3 H, CONCH3) ppm. 13C{1H}
NMR (100.6 MHz, [D6]DMSO): δ ϭ 177.1 (CONCH3), 172.8
(COO), 131.7 (CHϭCH), 43.5 (2 CHCON), 41.7 (2 CHCOO), 33.3
(2 CHCHCH), 24.3 (CONCH3) ppm. MS (EI, 70 eV): m/z (%) ϭ
261 (4) [M]ϩ, 189 (22), 104 (13), 78 (100), 51 (11), no other peaks
Ͼ 10%. IR (KBr): ν˜ ϭ 1/λ ϭ 3461 (w), 2952 (w), 1842 (m), 1769
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www.eurjoc.org
Eur. J. Org. Chem. 2005, 107Ϫ113

Synthesis of “Butterfly”-Like Diazatetradecenes
FULL PAPER
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Crystal structure analysis of 11: X-ray data of 11 were collected
with a STOE-IPDS diffractometer using graphite-monochrom-
ated Mo-Kα radiation, λ ϭ 0.71069 A. The structure was solved
W. Oppolzer, L. Bieber, E. Francotte, Tetrahedron Lett. 1979,
16, 4537.
˚
[12] [12a]
H. Neumann, A. Jacobi von Wangelin, D. Gördes, A.
by direct methods (SHELXS-86: G. M. Sheldrick, Acta Crys-
tallogr., Sect. A 1990, 46, 467) and refined by full-matrix least-
squares techniques against F2 (G. M. Sheldrick, SHELXL-93,
University of Göttingen, Germany, 1993). XP (Bruker AXS)
was used for structure representation. All non-hydrogen atoms
were refined anisotropically. The hydrogen atoms (except the
hydrogen atom attached to a nitrogen atom) were included at
calculated positions and refined by using the riding model.
Crystal data: 0.4 ϫ 0.3 ϫ 0.2 mm, colorless prism, space group
Spannenberg, M. Beller, J. Am. Chem. Soc. 2001, 123, 8398.
[12b]
A. Jacobi von Wangelin, H. Neumann, D. Gördes, S.
Klaus, D. Strübing, M. Beller, Chem. Eur. J. 2003, 9, 4286. [12c]
A. Jacobi von Wangelin, H. Neumann, D. Gördes, A. Span-
nenberg, M. Beller, Org. Lett. 2001, 3, 2895. [12d] H. Neumann,
A. Jacobi von Wangelin, D. Gördes, A. Spannenberg, W. Bau-
[12e]
mann, M. Beller, Tetrahedron 2002, 58, 2381.
H. Neumann, S. Klaus, A. Jacobi von Wangelin, D. Gördes,
D. Strübing,
M. Beller, P. Braiuca, C. Ebert, L. Gardossi, U. Kragl, Tetra-
P21/c, monoclinic, a ϭ 11.578(2), b ϭ 14.992(3), c ϭ 14.027(3)
[12f]
3
˚
˚
hedron 2004, 60, 683.
S. Klaus, S. Hübner, H. Neumann,
A, β ϭ 113.56(3)°, V ϭ 2231.8(8) A , Z ϭ 4, ρcalcd. ϭ 1.365
g·cmϪ3, 6585 reflections measured, 3528 were independent of
symmetry, of which 2791 were observed [I Ͼ 2σ(I)], R1 ϭ
0.0344, wR2 (all data) ϭ 0.0963, 303 parameters.
Unpublished results.
D. Strübing, D. Gördes, M. Beller, Adv. Synth. Catal., in press.
H. Neumann, A. Jacobi von Wangelin, D. Gördes, S. Klaus,
H. Jiao, A. Spannenberg, M. Beller, T. Krüger, C. Wendler, K.
Thurow, N. Stoll, Chem. Eur. J. 2003, 9, 2273.
[13]
[19]
Received August 6, 2004
Eur. J. Org. Chem. 2005, 107Ϫ113
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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