Conformation and photochemical properties of 3-benzoyl-4-benzylamino-7- dimethylaminocoumarin

Article abstract of DOI:10.1016/j.tetlet.2013.03.016

3-Benzoyl-4-benzylamino-7-dimethylaminocoumarin was synthesized and its conformation in solid state and solution was determined. While the X-ray crystal analysis showed an aromatic π-π stacking interaction in the solid state, the proton NMR studies sugges

Full text of DOI:10.1016/j.tetlet.2013.03.016

Tetrahedron Letters 54 (2013) 2431–2434
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Conformation and photochemical properties of
3-benzoyl-4-benzylamino-7-dimethylaminocoumarin
⇑
Chi-Hui Lin, Rong-Ren Chuang, Pei-Yu Kuo, Ding-Yah Yang
Department of Chemistry, Tunghai University, No. 181, Section 3, Taichung Port Road, Taichung City 40704, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Benzoyl-4-benzylamino-7-dimethylaminocoumarin was synthesized and its conformation in solid
Received 7 December 2012
Revised 15 February 2013
Accepted 5 March 2013
Available online 14 March 2013
state and solution was determined. While the X-ray crystal analysis showed an aromatic
interaction in the solid state, the proton NMR studies suggested the presence of an intramolecular hydro-
gen bonding in solution. Adjacent functional group modifications through N-methylation, reduction of
p–p stacking
carbonyl group, or replacing the coumarin moiety to dimedone, all resulted in disrupting the p–p stack-
ing conformation. Upon UV irradiation, the 7-methylamino group can be oxidized by molecular oxygen to
the corresponding formamide in the absence of any external photosensitizers.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Coumarin
p–p Aromatic stacking
Intramolecular hydrogen bonding
Photooxidation
Introduction
with diazomethane in methylene chloride to give the 4-meth-
oxycoumarins 3a,b. Subsequent reaction of 3a,b with benzylamine
Coumarin-based diketone lactones and their derivatives have
been known for their extensive application as biologically active
substances.1 They exist in different tautomeric forms under differ-
ent conditions. For example, previous studies have demonstrated
that 2-acyl-4-hydroxycoumarin mainly exists in the endocyclic
enol form in the solid state,2 whereas in protic solvent the major
tautomer is in the exocyclic enol form (Fig. 1).3 Knowledge of the
geometric and electronic structures of their various tautomeric
forms in solution and solid state may not only provide valuable
information regarding their biological/pharmacological properties,
but also serve as a platform for the design of potential organic
functional materials. For instance, we recently reported the solvent
effect on the conformation of several coumarin-based diketone
lactones and their applications as acidichromic colorants,4 photo-
chromic colorants,5 and polarity-sensitive fluorescent probes.6 In
our continuing effort to explore the novel properties of couma-
rin-based amino lactones, we report here the synthesis of 3-ben-
zoyl-4-benzylamino-7-dimethylaminocoumarin and investigation
of its conformation in both solid state and solution. Further, the
photochemical product of this compound upon UV irradiation
under atmospheric conditions is also explored.
in MeOH at room temperature afforded 1a,b in good yields. Reduc-
tion of 1a with sodium borohydride in methanol at room temper-
ature furnished the corresponding alcohol 4. N-methylation of 1a
with methyl iodide in the presence of sodium hydride in dry THF
yielded the tertiary amine 5.
The structure of 1b was verified by X-ray crystallography as
depicted in Figure 2.8 The crystal data show that the two phenyl
groups lie parallel to each other and are almost orthogonal to the
coumarin moiety. The two rings are arranged face-to-face and
the distance between two benzene rings is measured to be approx-
0
imately 3.40 ÅA. No intramolecular hydrogen bonding is observed.
Interestingly, the 1H NMR spectra of 1b in CDCl3 show a broad
absorption peak around 11.55 ppm, indicating that there is a
strong intramolecular hydrogen bonding between amine hydrogen
and carbonyl oxygen atom. Furthermore, the doublet absorption
peak of the benzylic hydrogens at 4.95 ppm rather than an AB
quartet signal suggests that the benzyl group can freely rotate
when dissolved in solution. Similar observations are also made of
O
O
OH
O
OH
O
Results and discussion
O
O
exocyclic enol
endocyclic enol
Scheme 1 shows the preparation of the target compounds 1a,b
and their derivatives 4 and 5. It started with methylation of 2a,b7
dominant tautomer
in protic solvent
dominant tautomer
in solid state
⇑
Corresponding author. Tel.: +886 4 2359 7613; fax: +886 4 2359 0426.
E-mail address: yang@thu.edu.tw (D.-Y. Yang).
Figure 1. Conformation of 2-acetyl-4-hydroxycoumarin exists in solid state and
protic solvent.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.016

2432
C.-H. Lin et al. / Tetrahedron Letters 54 (2013) 2431–2434
Ph
OH
O
OMe O
HN
O
O
H2N
Ph
Ph
Ph
CH2N2
Ph
R
O
O
MeOH, rt,
0.5 h
CH2Cl2,
R
O
O
R
O
0 oC, 6 h
3a, R = H, 80%
2a, R = H,
1a, R = H, 86%
, R = NMe2, 88%
3b
, R = NMe2, 75%
2b
, R = NMe2,
1b
CH3I,
NaH, THF,
0 oC to rt,
2 h
NaBH4
MeOH, rt,
0.5 h, 82%
H
H
Ph
N
O
O
Ph
N
O
O
Ph
Ph
O
O
R
4
5a
5b
, R = H, 76%
, R = NMe2, 80%
Scheme 1. Synthesis of coumarins 1a,b, 4, and 5a–b.
vored conformation. Similarly, N-methylation of 1b also results
in losing the aromatic stacking interaction, presumably to
p–p
avoid the severe steric hindrance that may exist between the
N-methyl group and the hydrogen atom at the C-5 position of 5b
when adopting the p–p aromatic stacking conformation.
To explore the role played by the coumarin moiety of 1a on its
conformation, dimedone 6 was prepared by a similar synthetic
pathway to that of 1a (Scheme 3). It can be readily accessed by first
O-methylation of 2-benzoyldimedone (7)9 with diazomethane in
methylene chloride to give the methylated compound 8, followed
by coupling with benzylamine in MeOH at room temperature to
afford 6 in a overall yield of 69%. Figure 4 shows the X-ray crystal
structure of 6,8 which clearly reveals an intramolecular hydrogen
bonding between amine hydrogen and carbonyl oxygen atom. Dis-
cernibly, replacing the coumarin moiety with the nonplanar dime-
Figure 2. X-ray crystal structure of 1b.
done also resulted in disintegrating the
suggesting that the planar coumarin structure is required for the
stacking crystal packing in the solid state. Our studies demon-
strates that this aromatic stacking interaction of 1a,b in the solid
state is highly sensitive to the variation of the surrounding func-
tional groups. Any subtle structural modifications may have a
p–p stacking interaction,
other deuterium solvents such as acetone and acetonitrile (see the
Supplementary data). These results imply that compound 1b
mainly exists in a stable p–p stacking form in the solid state, pre-
sumably due to the favored crystal packing during crystallization,
whereas the intramolecular hydrogen bonding becomes a major
force to dominate the conformation in solution (Scheme 2).
Namely, the two forces compete each other to control the confor-
mation of compound 1b, depending on the environment where it is
present.
p–p
major impact on its p–p aromatic stacking conformation.
A careful inspection shows that the 3-benzoyl carbonyl oxygen
atom of 1b is in close proximity to one of the benzylic hydrogens.
0
The distance between the two atoms reads only 2.30 ÅA (Fig. 2). This
observation suggests that 1b may exhibit light-sensitive properties
in the solid state via light-induced intramolecular hydrogen trans-
fer,10 if the other benzylic hydrogen is replaced with an appropri-
ate electron-withdrawing group to facilitate the hydrogen
abstraction process upon UV irradiation. Thus, this readily avail-
To investigate how sensitive this p–p stacking conformation to-
ward the structural variation of the surrounding functional groups,
compounds 1a,b were reduced and methylated to the correspond-
ing alcohol 4 and tertiary amines 5a,b, respectively (Scheme 1).
Figure 3 depicts the X-ray crystal structures of 4 and 5b.8 Appar-
ently, reduction of the benzoyl carbonyl group to the correspond-
able
p–p aromatic stacking molecular scaffold may function as a
ing alcohol 4 disrupts the
p–p aromatic stacking conformation in
potential template for future design of organic functional materials
such as photochromic colorants.
the solid state. The intramolecular hydrogen bonding between
amino hydrogen and hydroxyl oxygen atom now becomes the fa-
Interestingly, compound 1b was found to be sensitive to light.
Upon UV irradiation (306 nm) in chloroform under atmospheric
conditions, one of the methylamino groups on coumarin 1b was
swiftly oxidized to the corresponding formamide 9 in good yield
(Scheme 4). While the mechanism of photochemical oxidation of
methylamino group to the corresponding amide has been docu-
mented in the literature,11 this oxidation normally requires a pho-
tosensitizer such as benzophenone to convert the triplet oxygen
into the singlet oxygen as the active oxidant. In our case, however,
no external sensitizer was added. We speculate that the presence
of 3-benzoyl group in the coumarin moiety of 1b presumably
H
H
N
O
N
O
O
O
O
N
O
N
1b
in solid state
in solution
Scheme 2. Conformations of 1b in solid state and solution.

C.-H. Lin et al. / Tetrahedron Letters 54 (2013) 2431–2434
2433
Figure 3. X-ray crystal structures of 4 and 5b.
H
Ph
OH
O
O
OMe O
N
O
O
H2N
Ph
CH2N2
Ph
Ph
Ph
MeOH, rt,
CH2Cl2, 0 °C,
1.5 h, 78%
O
0.5 h, 88%
8
7
6
Scheme 3. Synthesis of dimedone 6.
ergy to 3O2 to form 1O2. The subsequent exciplex formation be-
tween 1O2 and 1b can undergo either intersystem crossing (isc)
to regenerate 1b and 3O2 (physical quenching) or be converted into
the carbon radical 1d and hydroperoxide radical. For the latter
chemical quenching process, the recombination of the two radicals
forms the hydroperoxide 1e. Final dehydration of 1e by losing a
molecule of water affords the formamide 9. To gain more mecha-
nistic details, the photoreaction of 1b was also performed in the
presence of 1,4-diazabicyclo[2.2.2]octane (DABCO, an 1O2 quench-
er).12 A progressive decrease in the product yields was observed by
increasing the concentration of DABCO, which supports the singlet
oxygen oxidation mechanism (see the Supplementary data). Note
that only the N-methyl group of 1b was oxidized upon irradiation,
no oxidation for the benzyl amino group was observed. This regi-
oselectivity might be accounted for the fact that the benzyl amino
nitrogen atom is less susceptible to form an exciplex with singlet
oxygen than that of the N-methyl nitrogen atom, since the former
is connected to two strong electron-withdrawing carbonyl groups.
Conclusions
Figure 4. X-ray crystal structure of 6.
In summary, a coumarin derivative 1b was synthesized in two
steps to investigate its conformation in both solid state and solu-
tion. The X-ray crystal analysis shows a
p–p aromatic stacking
function as a built-in sensitizer to photochemically generate the
singlet oxygen upon irradiation. To test this hypothesis, compound
10, which lacks a benzoyl group at the 3-position of the coumarin
ring, was prepared and subjected to UV irradiation. As expected, no
formamide product was observed even under prolonged irradia-
tion (Scheme 4).
Scheme 5 depicts the proposed mechanism for the photooxida-
tion of 1b–9. It presumably begins with the excitation of 1b with
UV irradiation to its excited state 1c, which then transfers its en-
interaction dominates the conformation in solid state, whereas
the 1H NMR studies suggested the presence of an intramolecular
hydrogen bonding in solution. Functional group modifications such
as N-methylation, reduction of carbonyl group, and replacing the
coumarin moiety to dimedone, all resulted in disrupting the
p–p
stacking conformation in the solid state. Further utilizing this
molecular skeleton in design and synthesis of potential organic
photochromic colorants is currently underway and will be re-
ported in due course.

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C.-H. Lin et al. / Tetrahedron Letters 54 (2013) 2431–2434
H
H
N
O
N
O
O
O
hv
O
CHCl3
O
N
O
H
N
2 h, 80%
1b
9
H
N
hv
No reaction
CHCl3
N
O
O
10
Scheme 4. Photochemical reactions of 1b and 10.
hv
O*
O
R
Ph
R
Ph
1b
1c
H
Ph
N
O
O
isc
Ph
3O2
1b
δ+
+
1O2
Ph
3O2
+
1b
H3C
δ−
N
O
1O2
CH3
H
N
exciplex
R=
H3C
N
CH3
O
O
H
H
Ph
Ph
N
H
N
O
O
O
Ph
Ph
O
C
H
H2C
H
+
N
CH3
O
O
O
N
CH3
O
O
HO
1d
1e
-H2O
9
Scheme 5. Proposed photooxidation mechanism.
2. Traven, V. F.; Manaev, A. V.; Safronova, O. B.; Chibisova, T. A.; Lysenko, K. A.;
Antipin, M. Y. Russ. J. Gen. Chem. 2000, 70, 798–808.
Acknowledgments
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We thank the National Science Council of the Republic of China,
Taiwan, for financially supporting this research under Contract No.
NSC 100-2113-M-029-005-MY2. We also thank the reviewers for
their suggestions and comments.
4. (a) Lin, C. T.; Shih, J. H.; Chen, C. L.; Yang, D. Y. Tetrahedron Lett. 2005, 46, 5033–
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8. Crystallographic data (excluding structure factors) for 1b, 4, 5a, 5b, and 6 have
been deposited with the Cambridge Crystallographic Data Centre as
Supplementary data
supplementary publication number CCDC-669310, -880563, -880564,
921695, and -880565, respectively. These data can be obtained free of charge
via http://www.ccdc.cam.ac.uk/data_request/cif, by emailing data_
-
Supplementary data (synthesis of compounds 1a,b, 3a,b, and
4–10 experimental details, additional spectra, and X-ray crystal
structure for 5a) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.016.
request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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