Synthesis and characterization of coumarin and dimedone-derived diazabicycles

Article abstract of DOI:10.1016/j.tetlet.2007.09.006

A series of diazabicyclic derivatives were prepared in three to four steps from p-anisidine and p-nitrobenzaldehyde. The key step of the synthesis involved the acid-catalyzed coupling of 4-aminocoumarin or dimedone derivatives with amino alcohols 3 or 7 t

Full text of DOI:10.1016/j.tetlet.2007.09.006

Tetrahedron Letters 48 (2007) 7796–7800
Synthesis and characterization of coumarin and dimedone-derived
diazabicycles
Jiun-Ting Lai, Pei-Yu Kuo, Yung-Her Gau and Ding-Yah Yang*
Department of Chemistry and Center for Nanoscience and Technology, Tunghai University 181,
Taichung-Kang Road. Sec.3, Taichung 407, Taiwan
Received 12 July 2007; revised 1 September 2007; accepted 4 September 2007
Available online 6 September 2007
Abstract—A series of diazabicyclic derivatives were prepared in three to four steps from p-anisidine and p-nitrobenzaldehyde. The
key step of the synthesis involved the acid-catalyzed coupling of 4-aminocoumarin or dimedone derivatives with amino alcohols 3 or
7 to give the ring-opened forms 4, 10, 12 and the ring-closed diazabicycles 5, 6, 9, 11. When 4-alkylaminocoumarins were used as the
coupling reagents, the major cyclized product was N-dealkylated diazabicycle 5, rather than the corresponding N-alkylated
products. Alternatively, compound 4 was cyclized by DDQ oxidation to produce quinone imine 13. The molecular structures of
the synthesized compounds were characterized by X-ray crystallography.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
rin or dimedone-fused moiety on the ring system to
extend the dimension of the cleft. The coumarin-fused
moiety may serve as a fluorophore in future molecular
recognition studies. Moreover, the incorporation of
the gem-dimethyl groups at the C-9 position of the bicy-
clic structure prevents possible undesired aromatization
reactions upon UV irradiation. The preliminary photo-
chemical property of the newly prepared diazabicycles
and their potential to function as reversible redox
switches were also explored.
Molecules with heterobicyclic diamine functional groups
have attracted intense study because of their wide range
of potential applications in molecular recognition. For
example, Troger’s base1 derivatives have been used as
hosts in molecular recognition,2 ligands in DNA interca-
lation,3 and enzyme inhibition.4 Recently, we have
reported the syntheses of coumarin-based dioxabicyclic5
and oxazobicyclic6 molecules with rigid clefts that are
wider than that of Troger’s base. This work extends
our study to the synthesis and characterization of the
corresponding diazabicycles (Fig. 1) as potential hetero-
cyclic perimidine-like photochromic colorants.7 Unlike
Troger’s base, these heterobicyclic compounds have
two nitrogen atoms that are attached directly to the
bridgehead carbon. Additionally, they contain a couma-
2. Results and discussion
Schemes 1 and 2 describe the preparations of the target
molecules, which began with the MgSO4-mediated
condensation of p-anisidine and p-nitrobenzaldehyde
9
9
8
1
N
8
1
2NH
HN
2NH
HN
3
H
7
H
3
7
5
4
6
5
4
6
N
O
O
O
1
coumarin-fused diazabicycle dimedone-fused diazabicycle
Figure 1. Structures of Troger’s base 1 and two diazabicycles.
Keywords: Diazabicycle; Quinone imine; Redox switch.
*
Corresponding author. Tel.: +886 4 2359 7613; fax: +886 4 2359 0426; e-mail: yang@thu.edu.tw
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.006

J.-T. Lai et al. / Tetrahedron Letters 48 (2007) 7796–7800
7797
NO2
NO2
NH
HN
+
NH
H
2N
H
H
O
O
O
O
O
O
5: 5%
NH2
4: 68%
ii
O
O
NO2
NO2
NH
HN
NO2
O
N
H
NH
i
ii
N
HO
O
O
H3CO
6: 56%
2
OCH3
3
R
HN
R= Et, Pr, t-Bu
ii
O
O
NO2
NH
HN
H
O
O
O
5: 50~70%
Scheme 1. Preparation of heterocycles 4–6. Reagents and conditions: (i) isobutyraldehyde, Yb(OTf)3 (cat.), THF/H2O, rt, 12 h, 75%; (ii) p-TsOH
(cat.), ClCH2CH2Cl, reflux, 3 h.
to afford imine 2, followed by a Yb(OTf)3-catalyzed
coupling with isobutyraldehyde to give the cyclized
aminoalcohol 3.8 The nitro group that was introduced
on benzaldehyde substantially increased the yield of
Coupling of 3 with 5,5-dimethyl-3-methylamino-2-
cyclohexenone under the same conditions resulted in
the N-methylated cyclized form 6 as the major prod-
uct. Interestingly, when 4-alkylaminocoumarins (i.e.,
N-ethyl, N-propyl, and N-t-butyl) were used as the cou-
pling reagents, the major cyclized product was N-dealkyl-
ated diazabicycle 5, rather than the corresponding
N-alkylated products.
1,2,3,4-tetrahydroquinoline
3
from the literature
reported 30–75%. Direct coupling of 3 with 4-amino-
coumarin in the presence of a catalytic amount of
p-toluenesulfonic acid in 1,2-dichloroethane under
reflux conditions yielded the ring-opened form 4 and
the cyclized product 5 in a ratio of 14 to 1. The yield
of diazabicycle 5 is much lower than the corresponding
oxazobicyclic derivatives as described previously.6 While
compound 4 contained two stereogenic centers, only the
diastereoisomer with 4-aminocoumarin and p-nitro-
phenyl groups in trans configuration was obtained. No
cis diastereoisomer was observed, perhaps because of
the steric hindrance between the two bulky groups. Also,
no attempt was made to separate the two enantiomers.
Scheme 2 describes the preparation of heterocycles 8–12.
Selective methylation of amino alcohol 3 at the nitro-
gen atom with methyl iodide using potassium carbon-
ate as a base in acetonitrile followed by a coupling
with 4-aminocoumarin under the aforementioned condi-
tions gave the corresponding ring-opened form 8 and
the cyclized form 9. When 5,5-dimethyl-3-methyl-
amino-2-cyclohexenone and 5,5-dimethyl-3-propylamino-
2-cyclohexenone were coupled with amino alcohol 7,

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J.-T. Lai et al. / Tetrahedron Letters 48 (2007) 7796–7800
NO2
NO2
N
N
N
H2
HN
+
H
H
O
O
O
O
O
O
8: 60%
9: 10%
NH2
ii
O
O
NO2
NO2
NO2
HN
N
N
NH
HN
O
H
H
+
3
N
i
ii
O
O
HO
O
O
10: 32%
11: 40%
OCH3
7
HN
ii
O
NO2
NO2
N
N
+
HN
NH
H
H
O
O
O
O
12: 29%
11: 45%
Scheme 2. Preparation of heterocycles 8–12. Reagents and conditions: (i) CH3I, K2CO3, CH3CN, rt, 12 h, 90%; (ii) p-TsOH (cat.), ClCH2CH2Cl,
reflux, 3 h.
the corresponding N-methylated ring-opened form 10 and
the N-propylated ring-opened form 12 were obtained,
respectively, along with the N-dealkylated cyclized
product 11.
rather flexibly rotates, but it is more rigid in 6, 9, and
11, which have two methyl groups at the C-9 position
and a methyl group on either of the nitrogen atoms,
presumably because of steric hindrance around the
congested bicyclic skeleton.
The molecular structures of 8 and 9 were elucidated by
X-ray crystallography as shown in Figure 2.9 The cleft
angles of the planes of the benzopyran moiety and the
p-methoxy aromatic rings of 5 and 9 are close to 108°,
which exceed that of Troger’s base and its derivatives
(80–104°).10 Like those of corresponding oxazobicyclic
derivatives,6 the proton NMR spectra of heterobicycles
5, 6, 9, and 11 reveal that the splitting patterns of the
four aromatic hydrogens on the p-nitrophenyl ring of
6, 9, and 11 were much more finely resolved (four
doublet doublets) than that of 5 (two doublets). This
observation demonstrated that the p-nitrophenyl ring
at the bridgehead on the ring system of compound 5
The proposed mechanism of the coupling of amino alco-
hols 3 or 7 with various 4-alkylaminocoumarins (except
4-methylaminocoumarin) and the subsequent cycliz-
ation reaction involved the initial formation of an
acid-catalyzed carbocation, which was then attacked
by 4-alkylaminocoumarin to yield the coupling adduct.
The second step was likely to be the dissociation of a
hydride from the p-nitrobenzylic position to form an
iminium ion. The hydride then served as a base to
abstract a b hydrogen on nearby N-alkylamino group.
This b-elimination reaction generated the free amine,
along with the evolution of alkene gas (ethene, propene

J.-T. Lai et al. / Tetrahedron Letters 48 (2007) 7796–7800
7799
Figure 2. X-ray crystal structures of ring-opened form 8, diazabicycle 9, and quinone imine 13.
and 2-methylpropene). The final intramolecular nucleo-
philic addition of the coumarin nitrogen atom to the
iminium carbon furnished the heterobicyclic skeleton.
The mechanism of demethylation, however, is different
from the cleavage of longer alkyl groups. For example,
when a 4-methylamino derivative was used as the cou-
pling agent, the hydride generated in situ acted as a
nucleophile by attacking the N-methylamino carbon to
evolve methane gas. Final addition of the nitrogen atom
to the iminium carbon afforded the N-demethylated
diazabicycle product (compound 11 in Scheme 2).
imine 13. Reduction of quinone imine13 with NaBH4
in methanol yielded 4-aminophenol 14, quantitatively.
The resulting reduced 14 was readily converted back
to 13 by DDQ oxidation in methylene chloride. This
reversible interconversion between quinone imine 13
and 4-aminophenol 14 was repeated more than ten times
without the detection of noticeable byproducts. Since
coumarins are excellent fluorophores and quinones are
widely recognized as efficient fluorescence quenchers,11
this system offers the possibility of the external control
of fluorescent property by reversible redox switching.
Future modulation of the chemical reactivity of the
molecular structure of 13 may have the potential to pro-
duce a reversible redox switch that can be turned on or
off by electron transfer with a high signal output, as in
fluorescence enhancement.
Given the availability of these Troger’s base derivatives,
their photochemical property was then evaluated.
Regrettably, none of the prepared diazabicycles 5, 6, 9,
and 11 exhibited the perimidine-like photochromic
behavior even under prolonged UV irradiation, which
indicated that the diazabicyclic skeletons are more stable
than the corresponding spiroperimidine compounds.
Interestingly, compound 4 could also be cyclized by
treating it with 2 equiv of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) in methylene chloride at 40 °C
to yield the cyclized quinone imine 13 (Scheme 3). The
X-ray crystal structure of 13 is shown in Figure 2.9
The amino group on anisidine moiety of 4 was proposed
to be initially oxidized by the first equivalent of DDQ to
yield the corresponding imine, and then underwent
intramolecular cyclization to produce diazabicycle 5.
Further oxidation of the anisidine moiety of 5 by the
second equivalent of DDQ afforded the final quinone
3. Conclusions
Several novel diazabicyclic derivatives were synthesized
and characterized in three to four steps. The conforma-
tion of the p-nitrophenyl group at the bridgehead on the
ring system of these heterobicycles is found to be
restricted by the presence of the gem-dimethyl groups
at the C-9 position and a methyl group on either of
the ring nitrogen atoms. Although these rigid hetero-
bicyclic molecules do not exhibit any photochromic
property, the wide interplanar angles between the planes
of the aromatic rings on their clefts may provide an easy
NO2
NH
NO2
NO2
ii
i
HN
N
NH
HN
N
H2
H
H
H
iii
O
O
O
O
O
O
OH
O
O
4
14
13
Scheme 3. Reagents and conditions: (i) DDQ (2 equiv), CH2Cl2, 40 °C, 1 h, 95%; (ii) NaBH4, CH3OH, rt, 10 min, 100%; (iii) DDQ, CH2Cl2, rt,
10 min, 100%.

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3. Bailly, C.; Laine, W.; Demeunynck, M.; Lhomme, J.
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access to a range of new molecular clefts for future
molecular recognition studies. Additionally, an interest-
ing acid-catalyzed N-dealkylated cyclization reaction
was reported. The redox active building block of
quinone imine 13 is currently being modified further to
enable it to function as an effective redox switch.
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Acknowledgments
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The authors would like to thank the National Science
Council of the Republic of China, Taiwan, for finan-
cially supporting this research under Contract No.
NSC 95-2113-M-029-003. We also thank the reviewers’
helpful comments and suggestions.
8. Annunziata, R.; Cinquini, M.; Cozzi, F.; Molteni, V.;
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9. Crystallographic data (excluding structure factors) for 8,
9, and 13 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion numbers CCDC-617090, -279874, and -616844,
respectively. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
09.006.
References and notes
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2. Demeunynck, M.; Tatibouet, A. Recent developments in
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