Photoinduced elimination in 2,3-dihydro-2-tert -butyl-3-benzyl-4(1 h)-quinazolinone: Theoretical calculations and radical trapping using TEMPO derivatives

Article abstract of DOI:10.1055/s-0031-1290492

Photochemical irradiation of 2,3-dihydro-2-tert-butyl-3-benzyl-4(1H)- quinazolinone produced 3-benzyl-4(3H)-quinazolinone through photoinduced elimination via a radical mechanism. The use of photochemical conditions such as chloroform and UV irradiation (δ= 254 nm) got the 3-benzyl-4(3H)- quinazolinone in a high yield. Some theoretical calculations were achieved to explain the mechanism and the presence of radical intermediates was confirmed by trapping with different 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) derivatives. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290492

LETTER
▌1057
letter
Photoinduced Elimination in 2,3-Dihydro-2-tert-butyl-3-benzyl-4(1H)-
quinazolinone: Theoretical Calculations and Radical Trapping Using TEMPO
Derivatives
Fanny Araceli Cabrera-Rivera,a Claudia Ortíz-Nava,a Jaime Escalante,*a Julio M. Hernández-Pérez,b Minhhuy Hôa
a
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, Av. Universidad 1001, C. P. 62209 Cuernavaca,
Morelos, México
Fax +52(777)3297000; E-Mail: jaime@ciq.uaem.mx
b
Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, 14 Sur y Av. San Claudio, Col. San Manuel, 72530 Puebla,
México
Received: 30.12.2011; Accepted after revision: 10.02.2012
2-ones6 as well as the photoaddition of 4(3H)-quinazo-
Abstract: Photochemical irradiation of 2,3-dihydro-2-tert-butyl-3-
linone derivatives to olefins.7
benzyl-4(1H)-quinazolinone produced 3-benzyl-4(3H)-quinazo-
linone through photoinduced elimination via a radical mechanism.
The use of photochemical conditions such as chloroform and UV ir-
radiation (λ = 254 nm) got the 3-benzyl-4(3H)-quinazolinone in a
high yield. Some theoretical calculations were achieved to explain
the mechanism and the presence of radical intermediates was con-
firmed by trapping with different 2,2,6,6-tetramethylpiperidine-1-
oxyl (TEMPO) derivatives.
In this study we analyzed the behavior of 2,3-dihydro-2-
tert-butyl-3-benzyl-4(1H)-quinazolinone under UV irra-
diation, and theoretical calculations were developed to
propose a mechanism, and trapping of the radical interme-
diate was achieved using TEMPO derivatives. Knowl-
edge of these reactions could help to develop
photochemically controlled reactions of other 2,3-di-
hydro-4(1H)-quinazolinone derivatives.
Key words: 2,3-dihydro-4(1H)-quinazolinones, mechanism, photo-
chemical reaction, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO),
AIM, MO analysis, density analysis
Our research was focused on the preparation of starting
materials following the methodology previously reported
by our group8 in which a reaction between isatoic anhy-
dride and benzylamine in ethyl acetate at 40 °C results in
the corresponding aminobenzamide 1 in 90% yield. Next,
the cyclocondensation of 1 with pivalaldehyde in dichlo-
romethane and p-toluenesulfonic acid monohydrate gives
2 in 86% yield (Scheme 1).
4-Quinazolinone derivatives are important building
blocks of active molecules isolated from different natural
sources.1 Their principal derivatives are 2,3-dihydro-
4(1H)-quinazolinones and 4(3H)-quinazolinones. These
compounds possess a wide range of useful biological ac-
tivities and interesting pharmacological properties,2 and
their syntheses have been well described in the literature.3
Preliminary studies rapidly led to the conclusion that it
was necessary to protect the reaction from light source
since this would suffer photoinduced elimination and
hence reduces the yield of compound 2.
The use of photochemical irradiation in these compounds,
however, has been less common, and only a few have
been reported such as preparation of fused quinazolin-4-
one derivatives, for example, luotonin A and related fused
compounds through radical intermediates,4 photodecom-
position of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-im-
idazo[1,5-a][1,4]benzodiazepine (Midazolam) to get a
4(3H)-quinazolinone derivative,5 and irradiation of 4-
phenylquinazolin-2-ones in the presence of a hydrogen
donor in order to get the reduced 3,4-dihydroquinazolin-
The absorption spectrum of 2 (Figure 1) presents two ab-
sorption bands at λ = 242 and 341 nm, attributed to π–π*
and n–π* transitions, respectively. The fluorescence spec-
trum is shown in the Figure 2 and presents a maximum
emission at λ = 404 nm. The quantum yield of fluores-
cence was measured at 25 °C using quinine sulfate
(H2SO4 0.5 M, Φ = 0.55) as standard and employing exist-
ing equations for calculating quantum fluorescence yield;
O
O
O
N
Ph
N
Ph
H2N
AcOEt
Ph
Me3CCHO
O
H
CH2Cl2
PTSA
N
NH2
N
O
40 °C
H
H
1
2
90% yield
86% yield
Scheme 1 Preparation of 2,3-dihydro-2-tert-butyl-3-benzyl-4(1H)-quinazolinone (2)
SYNLETT 204012, 237, 1057–1063
Advanced online publication: 29.03.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290492; Art ID: ST-2011-S0822-L
© Georg Thieme Verlag Stuttgart · New York

1058
F. A Cabrera-Rivera et al.
LETTER
the quantum yield of 2 was 0.43. This implies that there
might be other processes involved in addition to the fluo-
rescence decay. On the other hand, for compound 2 we did
not observe phosphorescence in solution at 25 °C.
Table 1 Photochemical Irradiations of Compound 2
O
O
"
"
hν (254 nm)
N
Ph
N
Ph
+
CDCl3
45 °C
N
H
N
2
3
Entry
Irradiation time (min)
Ratio 2/3
1
2
3
4
5
0
60
100:0
63:37
36:64
14:86
0:100
120
180
240
the product 3 as compared to the signals Hc and Hc′ (δ =
3.92 and 5.81 ppm, respectively) of the benzylic protons
of 2. One observes that Hc and Hc′ are diminished with ir-
radiation,8c,9 which finally disappeared after 240 minutes
of irradiation.
Figure 1 UV absorption spectrum, 2⋅10–4 M in CHCl3 at 25 °C
Figure 2 Fluorescence spectrum, 2⋅10–6 M in CHCl3 at 25 °C
(λex = 336 nm)
Figure 3 Partial 400MHz 1H NMR spectra resulting from the irra-
diation of 2 with UV light (λ = 254 nm) in CDCl3 at different reaction
times
Coupling with the fact that the reaction may involve ab-
stractions of either a hydrogen atom or a tert-butyl radical,
we have decided to employ photochemical irradiation to
facilitate radical cleavage. We first dissolved 2 in chloro-
form at room temperature, and then the compound under-
went irradiation by means of UV light at λ = 254 nm. The
result shows a mixture of starting material 2 and product
3, which were further characterized by the partial 400
MHz 1H NMR spectrum shown in Figure 3 (Table 1). Ta-
ble 1 shows that this protocol permits better yield of prod-
uct 3 under longer irradiation, close to 100% after 240
minutes.
As shown below, the tert-butyl radical plays an important
role in the mechanism, partially due to its well-known sta-
bility. We have decided to confirm the presence of this in-
termediate using TEMPO and derivatives.10
We employed 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) (4a), 4-hydroxy-TEMPO (TEMPOL, 4b), 4-
methoxy-TEMPO (4c), and 4-butoxy-TEMPO (4d). The
results from Table 2 clearly show the corresponding tert-
butyl derivatives 5a–d.
The spectra of 2 following various irradiation durations
are shown in Figure 3. Most notable here is the intensity
of the signal Hd (δ = 5.16 ppm) of the benzylic protons of
It is important to note that the reaction times for entries in
Table 2 were significantly longer than the time for the first
Synlett 2012, 23, 1057–1063
© Georg Thieme Verlag Stuttgart · New York

LETTER
Photoinduced Elimination in 2,3-Dihydro-2-tert-butyl-3-benzyl-4(1H)-quinazolinone
1059
Table 2 Reaction of 2 with TEMPO Derivatives
O
R
R
O
N
Ph
hν (254 nm)
N
Ph
+
+
CHCl3
45 °C
N
H
N
O
N
O
N
2
3
4a R = H
5a R = H
4b R = OH
4c R = OMe
4d R = OBu
5b R = OH
5c R = OMe
5d R = OBu
Entry
TEMPO derivatives
Irradiation time (h)
Yield of 2 (%)
Yield of 3 (%)
Yield of 5 (%)
1
2
3
4
4a
4b
4c
4d
25
25
25
25
31
17
33
0
63
81
64
95
5a 23
5b 50
5c 36
5d 60
reaction showed in Table 1. This behavior could be ex- Table 3 shows only product 3 in moderate yield and traces
plained by the variation in the rate constants of the trap- of other products, which were further characterized by
ping process, associated with the structure of the tertiary- mass spectrometry and no evidence of nitroxide 7a was
centered carbon radicals in the presence of TEMPO deriv- found; maybe because the persistence of the spin adducts
atives, ranging from 109 to as low as 106 M–1s–1 for steri- is very short or because the nitrones are inefficient to trap
cally hindered species.11 For this reason, the reactions particular types of radicals as have been reported.12
were carried out with different reaction times, but no sig-
We wish to further explore the reaction mechanism by
nificant change was detected. In our case, we have a sys-
means of a theoretical model. To this end, we have per-
tem in which a dissociative mechanism would give rise to
formed calculations using the Gaussian 98 suit of pro-
2 in the presence of TEMPO derivative: re-association
grams.13 To render the calculations tractable, we have
could then take place at either end. Inspection of the prod-
reduced the size of the molecule by removing the two phe-
ucts shows that the tert-butyl radical has been trapped in
nyl rings, shown here as structure 1′ while the rest of the
moderate yield in all cases (Table 2). These results con-
geometry parameters was taken from the X-ray structure
of 2 (Figure 4).
firm the presence of the radical intermediate and support
the idea that the mechanism occurs via free radicals.
We wish to determine various bond energies of 1′, in par-
We have also applied a stronger thermal condition using a
ticular, we follow three pathways. The first involves the
reflux system to 2,3-dihydro-2-tert-butyl-3-benzyl-
elimination of the tert-butyl group (2′) followed by the ab-
4(1H)-quinazolinone in toluene and have not detected any
straction of the hydrogen atom Ha (8′). In the second path-
way the hydrogen atom Ha has been removed (3′) which
then can either lose also hydrogen atom Hb to form 9′ or
elimination product after eight hours. It is suggested that
the reaction is not thermodynamically driven.
Nitrones are a class of compounds, which are used as lose the tert-butyl group as in 8′. The remaining possibil-
spin-trapping reagents, in particular DMPO [5,5-dimeth- ity is the abstraction of hydrogen atom Hb followed by Ha
yl-1-pyrroline-N-oxide (6a)] is one of the most commonly leaving the compound with the tert-butyl group 9′. The
used. DMPO can spin trap superoxide, hydroxyl, and three pathway mechanisms are shown in Scheme 2. Note
small carbon-centered free radicals, giving spin-trapped that these are only parts of the mechanism as the newly
adducts with defined EPR spectra. We carried out an ex- formed radicals (6′ and 7′ or 5′ and 7′) would then go on
periment using DMPO as radical scavenger. The result in and form the final products.
Table 3 Reaction of 2 with DMPO
O
O
hν (254 nm)
N
Ph
N
Ph
+
+
N
O
CHCl3
45 °C
N
N
N
H
O
6a
7a
3
2
Nitrone
6a DMPO
Irradiation time (h)
75
Yield of 3 (%)
Yield of 7a (%)
70.6
–
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1057–1063

1060
F. A Cabrera-Rivera et al.
LETTER
Figure 5 Reaction coordinates of the three (partial) mechanisms
Figure 4 Structures of 2 and 1′
The latter, most energetically favorable of the three,
shows a difference of almost 70 kcal for the first step,
which could come from the UV radiation and eventually
leads to product 8′, the analogue of which were in fact ob-
served experimentally. The difference in energy in the lat-
ter processes, 10 and 30 kcal/mol, respectively, is
reasonable within normal experimental conditions.
The energies were determined using the complete basis
set method (CBS-4M) to extrapolate the energy missing
from incomplete basis set.14,15
The resulting energies are shown in Figure 5. We ob-
served that the third pathway mechanism in which the two
hydrogen atoms are removed (via 4′ and 5′) requires the
most energy, with a difference of more than 100 kcal com-
paring to that of 1′.
The nature of the mechanisms can be further explained by
studying the electronic properties of the pertinent species.
We have performed a topological analysis of the electron-
ic density using the theory of atoms in molecule16 at the
B3LYP/6-311++G** levels. To this end, we have opti-
mized the geometry of 1′ and 2, which are then character-
ized by frequency analysis. Since the reaction occurs
under radiation, one would suggest that the molecule
should first convert into the triplet or singlet excited states
before bond breaking could take place. We have therefore
The analogue product of this mechanism was not ob-
served experimentally. The second pathway mechanism
(via 3′ and 7′) leads either to the same high-energy prod-
ucts 9′ and the two hydrogen atoms, or a lower energy
product 8′ and hydrogen atom Ha. The energy of this
mechanism is lower than the one mentioned above, but it
is still almost 10 kcal higher than the first mechanism (via
2′ and 6′).
O
Me
N
+
N
Hb
O
Ha
Me
N
2'
6'
Ha
+
+
N
Hb
O
O
O
Me
Hb
Me
Hb
Me
Hb
6'
8'
7'
hν
N
2
N
N
Ha
+
1 N
N
N
3'
O
3
O
N
Ha
1'
Ha
1'*
Me
7'
N
+
+
Ha
Hb
Me
N
Hb
+
9'
7'
5'
N
Ha
4'
5'
Scheme 2 The three pathway mechanisms
Synlett 2012, 23, 1057–1063
© Georg Thieme Verlag Stuttgart · New York

LETTER
Photoinduced Elimination in 2,3-Dihydro-2-tert-butyl-3-benzyl-4(1H)-quinazolinone
1061
calculated the transition probability to both states using Ha bond. Together with the fact that the value of the lapla-
the time-dependent DFT method at the same level of the- cian is most positive for the C2–C9 bond in all three cases,
ory B3LYP/6-311++G**. The result shows that the this bade well for mechanism 1 where the cleavage of the
ground state to the triplet transition state is forbidden, C2–C9 takes place before the two hydrogen atoms. This is
while the transition to the first singlet state is possible with not surprising considering the known stability of the tert-
the excitation energy of λ = 354.22 nm. These results are butyl radical.
in agreement with experiment evidences. In particular, we
In going from the ground state to the excited singlet state,
observe that the first singlet state involves the excitation
one also notes that there is a displacement of electron
of electrons from the S/HOMOs to the LUMO orbital.
away from atoms C2 to the other side of the pyrimidine
The electronic charge density and laplacian of the density ring, namely atoms C8A, C4, and C4A (see X-ray struc-
at the bond critical points of the N1–Ha, C2–Hb, and C2– ture in Figure 4) while the two hydrogen bonds are essen-
C9 bonds of 2, 1′ and 1′* were calculated using the PRO- tially unaffected.
AIM program17 and tabulated in Table 4. In short, the the-
ory of atoms in molecules states that a chemical bond is
characterized by properties at its critical points, in partic-
This observation is further supported by the HOMO and
LUMO diagrams of 1′ shown in Figure 6, where it is noted
that there is a (albeit small) bonding contribution to the
ular, the bond critical point where the gradient of the den-
C2–C9 bond in the HOMO while the LUMO shows a non-
sity vanishes along the trace of the gradient path that
bonding contribution at this bond. Furthermore, the
connect two atoms.
LUMO exhibits a building up of electron density in the
left half of the ring. Thus, going from the ground state to
the excited state brings a small weakening effect to the
C2–C9 bond while the Ha and Hb bonds remain un-
Table 4 Topological Properties of 2, our Model 1′, and the First
Singlet State 1′* from 1′ for the Relevant Bonds
Property
N1–Ha
C2–Hb
C2–C9
changed.
ρ (2)
0.16137
–0.03475
0.34248
0.13269
0.02148
0.28389
–0.97352
0.28610
–1.00997
0.10533
0.15110
0.22638
–0.46088
0.22812
–0.46496
∇2 ρ (2)
ρ (1′)
∇2 ρ (1′)
ρ (1′*)
∇2 ρ (1′*)
–1.59994
0.34600
–1.79885
Figure 6 HOMO and LUMO of 1′. Note the absence of the contri-
bution to the C–C9 bond in the LUMO and in both HOMO and
LUMO for N1–Ha and C2–Hb
A negative laplacian indicates a local concentration of
electron (normally associated with covalent bond) and a
positive laplacian indicates a local depletion of electron
which normally characterizes an ionic bonding environ-
ment.
Thus, theoretical evidences suggest the following mecha-
nism: the UV light irradiation of 2 leads to an excited sin-
glet state 2* which favors the homolytic rupture of the
bond between C2 and the tert-butyl group, shown here in
step 2 in Scheme 3. In the next step, the newly formed in-
termediate quinazolinonyl radical loses the hydrogen
atom at position N1 to form 3.
We observe in Table 4 that the trend in 1′, our model, fol-
low well that of compound 2 implying that the removal of
the phenyl rings affects the reaction side of the molecule
only qualitatively, and therefore, justifies our model. In all
three cases, the C2–C9 bond shows the significantly
smaller value of density at the bond critical point, showing
that it is a weaker bond than the other two.
The evolution of the tert-butyl radical is worth mentioning
since it does raise an interesting question although it does
not alter our conclusions. Pryor et al.18 showed that isobu-
tane, isobutylene, hexamethylethane, etc. are major prod-
ucts derived from the tert-butyl radical, while Fischer and
collaborators found isobutene produced from the photo-
dissociation of the tert-butyl radical.19 A separate study is
In the case of the excited singlet state 1′*, the density at
the bond critical point of the C2–C9 bond is smaller than
the C2–Hb bond and is only two thirds of that of the N1–
*
O
O
O
O
N
Ph
N
Ph
N
Ph
N
Ph
+
H
+
N
H
N
H
N
H
N
2
2*
3
Scheme 3 Proposed mechanism
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1057–1063

1062
F. A Cabrera-Rivera et al.
LETTER
being conducted in this laboratory, which may shed light
on the low yields of the scavenging reactions with
TEMPO derivatives.
Finally, Washida and Bayes20 reported that the tert-butyl
radical can react with an oxygen atom to form the tert-
butoxy molecule, which then decomposes to form acetone
and methyl radicals. The same products are observed
when the tert-butyl radical reacts with molecular oxygen,
albeit with different ratios. To evaluate the role of oxygen,
we performed the same reaction with degassed solvent.
The results shown in Table 5 suggest that the presence of
oxygen accelerates the elimination reaction but does not
modify the mechanism in any significant way (Figure 7).
Figure 7 Reaction of 2 with UV radiation (λ = 254 nm) in degassed
and normal solvent
Table 5 Reaction of 2 with Degassed Solventa
O
O
"
"
N
Ph
hν (254 nm)
N
Ph
Acknowledgment
+
CDCl3
45 °C
N
H
N
We would like to thank Drs. David Crich (Institut de Chimie des
Substances Naturelles ICSN, Gif-sur-Yvette, France) and David
Rippon (UQUIFA-México) for their suggestions and contributions
to use of TEMPO derivatives. We are grateful to CONACYT for
financial support (Project No. 48356-Q) and for scholarships to
C.O.-N. and F.A.C.-R.; J.M.H.-P. and M.H. acknowledge support
from SEP-FORMES2000 for unlimited CPU time on the IBM-p690
32-procesor supercomputer at UAEM.
2
3
Time (min)
Degassed proportion 2/3
Normal proportion 2/3
0
30
100:0
84:16
75:25
63:37
54:46
48:52
42:58
39:61
33:67
30:70
24:76b
100:0
84:16
70:30
54:46
47:53
35:65
28:72
20:80
18:82c
–
60
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmornifIatngonimSorfniturItagponiSutpor
90
120
150
180
210
240
270
300
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In conclusion, we have studied the mechanism of a photo-
induced elimination in 2,3-dihydro-2-tert-butyl-3-benzyl-
4(1H)-quinazolinone.21 It was found that the reaction was
not thermodynamically driven but proceeded only under
photochemical conditions, and a free radical mechanism
involving abstraction of the tert-butyl radical was pro-
posed via theoretical calculations. The presence of the
tert-butyl radical as intermediate in the reaction was con-
firmed using different TEMPO derivatives as scavengers.
Applications of this methodology to other related 4-quin-
azolinone derivatives are currently being carried out in
our laboratory.
Synlett 2012, 23, 1057–1063
© Georg Thieme Verlag Stuttgart · New York

LETTER
Photoinduced Elimination in 2,3-Dihydro-2-tert-butyl-3-benzyl-4(1H)-quinazolinone
1063
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equipment RPR-100. The reaction mixture was monitored
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the starting material. The reaction mixture was concentrated
under reduced pressure, and the crude of the reaction was
purified by flash chromatography. When the reaction was
examined by 1H NMR at 400 MHz, peak ratios were
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Synlett 2012, 23, 1057–1063

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