Investigation into selective debenzylation and ring cleavage of quinazoline based heterocycles

Article abstract of DOI:10.1016/j.tetlet.2014.03.109

The selective cleavage of different benzyl bonds within tetrahydroquinazoline and dihydroquinazolinone derived structures can be achieved by the usage of different reduction and debenzylation conditions thereby providing selective removal of O-benzyl protection groups as well as the cleavage of the ring structure within the quinazoline and quinazolinone systems.

Full text of DOI:10.1016/j.tetlet.2014.03.109

Tetrahedron Letters 55 (2014) 2973–2976
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Investigation into selective debenzylation and ring cleavage
of quinazoline based heterocycles
⇑
Edgar Sawatzky, Jerzy Bukowczan, Michael Decker
Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The selective cleavage of different benzyl bonds within tetrahydroquinazoline and dihydroquinazolinone
derived structures can be achieved by the usage of different reduction and debenzylation conditions
thereby providing selective removal of O-benzyl protection groups as well as the cleavage of the ring
structure within the quinazoline and quinazolinone systems.
Received 8 February 2014
Revised 20 March 2014
Accepted 24 March 2014
Available online 1 April 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Quinazolinone
Quinazoline
Debenzylation
Reduction
Over the last decades compounds bearing a quinazoline based
structure have been in the focus of different research areas first
due to their occurrence as a common core structure in several nat-
ural products1,2 like the alkaloids rutaecarpine 1, evodiamine 2,
O
N
A
B
O
N
O
N
N
N
N
HN
HN
HN
Cl
dehydroevodiamine 3, mackinazolinone
4 and vasicinone 5
1
3
2
(Fig. 1A). And as a result of its promising pharmacological effects
in different medicinal applications, the quinazoline core has be-
come to a privileged structure in medicinal chemistry.3–12
rutaecarpine
evodiamine
dehydroevodiamine
O
O
N
N
Therefore, many groups used this nitrogen bridgehead core
structure as a key element in the development of numerous exper-
imental therapeutics and prospective drug candidates, also includ-
ing chemical modifications of the above described natural
compounds. Such synthetic compounds are developed for diverse
therapeutic applications, such as anticonvulsant agents,13 in the
treatment of cancer,14,15 as cholinesterase inhibitors for Alzhei-
mer’s disease treatment,16–19 vasodilators,20 anti-inflammatory
agents,21 as a retrograde transport inhibitor for Shiga toxin treat-
ment22 or with regard to their effects on different receptors like
the serotonin receptor 7 (5-HT7 receptor),23 the thyroid stimulat-
N
N
OH
4
5
mackinazolinone
vasicinone
N
N
H
O
N
O
R
R
N
N
N
O
N
N
N
H
R
H
6
7
8
ChE-inhibitor
(Alzheimer's disease treatment)
anticonvulsant agent retrograde transport inibitor
(Shiga toxin treatment)
ing hormone (TSH) receptor24 or the histamine H3 receptor.25,26
A
Figure 1. (A) Molecules bearing a quinazoline derived core: (A) The alkaloids
rutaecarpine 1, evodiamine 2, dehydroevodiamine 3, mackinazolinone and
vasicinone 5. (B) Examples of some synthetic experimental therapeutics with
few examples of recently published compounds bearing quinazo-
line derived moieties are presented in Figure 1B.
Herein different ways for selective heteroatom (N and O)-carbon-
bond cleavage of the different benzyl positions within the tetrahy-
droquinazoline structure 9 and its precursor dihydroquinazolinone
10 will be described. Both compounds bear a quinazoline derived
4
related chemical structures.13,16,22
core structure like the above mentioned natural products and exper-
imental therapeutics. These compounds were used as intermediates
for the synthesis of selective butyrylcholinesterase inhibitors16 and
dual-acting AChE inhibitors/hH3 antagonists.26 In these structures
⇑
Corresponding author. Tel.: +49 931 31 89676; fax: +49 931 31 85494.
E-mail address: michael.decker@uni-wuerzburg.de (M. Decker).
http://dx.doi.org/10.1016/j.tetlet.2014.03.109
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2974
E. Sawatzky et al. / Tetrahedron Letters 55 (2014) 2973–2976
O
O
HO
B
N
HO
h
A
A
N
N
O
O
N
C
N
17
N
C
N
N
14
D
10
D
i
9
f or g
a
Figure 2. Illustration of benzyl bonds of tetrahydroquinazoline 9 and dihydroqui-
nazolinone 10 that might be cleaved under debenzylation conditions.
O
N
BnO
BnO
HO
N
N
N
a, b, c
h
N
NH
15
four different benzyl-bonds can be distinguished; A: the O-benzyl-
protection group, B: the benzylamine N–C bond (only in 9), C: the
central N–C bond and D: the anilinic N–C bond (Fig. 2).
10
9
j
d, e,
m
j or k
a
O
This letter shall provide a systematic overview on conditions
suitable to selectively cleave and reduce the respective bonds
where possible, for example, to induce more flexibility into similar
biologically active compounds, and to prevent undesired cleavage
reactions during debenzylation and reduction chemistry.
The starting point for this investigation was the synthesis of tet-
rahydroquinazoline 9 in four steps as described in Scheme 1. Hy-
droxyl anthranilic acid 11 was treated with triphosgene to yield
hydroxy isatoic anhydride 12 quantitatively in high purity, fol-
lowed by the selective N-methylation to yield compound 13.16
Compound 13 was then first O-benzyl protected and subsequently
fused to the tetracyclic dihydroquinazolinone 14 in a two-step
one-pot-synthesis with a yield of 53%. Benzylation and ring-fusion
can also be performed in two separate steps, but this led to much
lower yields. Ring fusion is also possible without protection of the
phenol group, but only with a yield of 23%.16 Tetrahydroquinazo-
line 9 was synthesized by the reduction of 10 with LiAlH4 in 80%
yield.
The described synthetic procedure can of course also be used for
other substitution patterns in the aromatic systems of the anthra-
nilic acid derivative as well as for the dihydroisoquinoline com-
pound providing the synthetic basis for performing structure–
activity relationship (SAR) investigations in medicinal chemistry
approaches.16,17
The standard strategy for O-debenzylation (cleavage of bond A)
of dihydroquinazolinone 10 and tetrahydroquinazoline 9 applies
the usage of Pd/C and hydrogen in methanol. For compound 10 this
procedure led to the desired cleavage of bond A to yield the phenolic
compound 14 quantitatively (Scheme 2 and Table 1, path a). Inter-
estingly, in the case of tetrahydroquinazoline 9, under these condi-
tions bond A was cleaved but additionally also aniline bond D was
reduced yielding compound 15 in moderate yield (44%). As these
conditions were not applicable for the selective O-debenzylation
of compound 9, hydrogenation with Pd/C as the catalyst was
performed applying different solvent systems. Using EtOH and
BnO
BnO
H
N
NH
NH
18
16
Scheme 2. Reaction pathways during debenzylation and reduction reactions of
tetrahydroquinazoline 9 and dihydroquinazolinone 10 towards different products.
Table 1
Reaction conditions for debenzylation strategies via Scheme 2
Path Starting-material Product Conditions
Yield (%)
a
a
a
b
c
d
e
f
g
h
h
i
j
j
k
k
l
10
16
9
9
9
9
9
9
9
14
10
17
9
10
10
9
14
15
15
15
15
16
16
17
17
17
9
15
16
16
—
16
—
H2, Pd/C, methanol, 50 °C
H2, Pd/C, methanol, 50 °C
H2, Pd/C, methanol, 50 °C
H2, Pd/C, ethanol, 50 °C
H2, Pd/C, acetic acid, 50 °C
H2, Pd/C, THF, rt
H2, PtO2, methanol, 50 °C
AlCl3, PhNMe2 CH2Cl2, rt
concd HCl, reflux
100
49
44
37
14
93
80
65
80
98
93
28
42
47
—
LiAlH4, THF, reflux
LiAlH4, THF, reflux
H2, Pd/C, methanol, rt
BH3ÁTHF, THF, reflux
BH3ÁTHF, THF, reflux
NaBH4, ethanol, reflux
NaBH4, ethanol, reflux
NaCNBH3, acetic acid, 50 °C
LiAlH4, THF, rt
60
—
19
10
10
m
18
AcOH resulted into the same reaction product as with MeOH (path
b and c). Only the usage of dry THF as the solvent surprisingly led
to the selective hydrogenation of the anilinic N–C-bond D to aniline
16 (path d) in excellent yield without affecting the O-benzyl bond A.
A different catalyst for hydrogenation with H2 can also result in
different products, but even the usage of PtO2 in MeOH just led to
O
O
Cl3CO
THF
OCCl3
O
HO
MeI, DMAc, DIPEA
40°C, 24 h
HO
COOH
NH2
HO
O
O
70°C, 3.5 h
N
O
N
H
O
11
12
13
100%
77%
1) BnBr, K2CO3
O
DMF
BnO
BnO
40 °C, 3.5 h
LiAlH4, THF
reflux, 2 h
N
N
N
N
N
2)
DMF
120°C, 5 h
9
10
53%
93%
Scheme 1. Synthesis of dihydroquinazolinone 9 and tetrahydroquinazoline 10.

E. Sawatzky et al. / Tetrahedron Letters 55 (2014) 2973–2976
2975
cleavage of D yielding aniline 16 (80%) (path e). Cleavage of A in the
O-benzyl protected tetrahydroquinazoline 9 towards the unpro-
tected tetrahydroquinazoline 17 was finally achieved by two differ-
ent reactions. The conditions of the first one have been reported by
Akiyama et al.27 and used a combined system of the Lewis acid AlCl3
and the Lewis base N,N-dimethylaniline in methylene chloride at
room temperature and yielded 65% of product 17 (path f). The
second reaction applied harsher reaction conditions, whereby usage
of concentrated HCl under reflux conditions for 16 h gave 17 in a
yield of 80% (path g). Although both reactions led to the desired
product, both have the disadvantage that column chromatography
was necessary for purification. Therefore, the synthesis of tetrahy-
droquinazoline 17 was more easily achieved via reduction of 14 by
LiAlH4 (path h) in an excellent yield of 98% and without the necessity
of column chromatography purification. Altering the sequence of
LiAlH4 reduction and debenzylation with hydrogen of 10 (changing
pathway a followed by h into pathway h followed by a) yields two
different products (15 and 17). It was further demonstrated that
the usage of Pd/C and H2 in MeOH selectively cleaved bond D in
the case of tetrahydroquinazoline 17 (path i) and cleaved bond A
in the case of aniline 16, both ultimately leading to compound 15
in low yields. The low yields can be explained by the low stability
of 15, as its p-amino phenol structure rapidly undergoes decomposi-
tion under oxygen exposure and during heating. GC–MS studies
show that bond D is also cleaved thereby leading to complete
decomposition of the ring system and yielding isoquinoline and
dehydroisoquinoline as well as p-aminomethyl phenols bearing a
methyl group adjacent to the N-methyl amino one.
temperature as described above (path h), the product formation at
lower temperature was subsequently investigated. Interestingly,
reduction towards tetrahydroquinazoline 9 starting from 10 was
completely suppressed when only 1 equiv of LiAlH4 was used at
room temperature. In this case, besides starting material 10
(63%), only aldehyde 18 (19%) was isolated (path m).
In conclusion, first the syntheses of the quinazolin derived
structures tetrahydroquinazoline 9 and dihydroquinazolinone 10
were achieved. Both compounds bear different N- and O-benzyl
bonds which were selectively cleaved under different debenzyla-
tion and reduction conditions. Thereby the best conditions for
the selective cleavage of the O-benzyl bond A in dihydroquinazoli-
none 10 was the usage of Pd/C with hydrogen in methanol (path a,
100% yield) and for tetrahydroquinazoline 9 the usage of concen-
trated HCl-solution (path g, 80% yield). The cleavage of the anilinic
bond D was in the case of 10 achieved via reduction with BH3ÁTHF
(path j, 47%) and in the case of 9 using Pd/C and hydrogen in dry
THF (path d, 93% yield). Furthermore, it is remarkable, that apply-
ing 1 equiv of LiAlH4 on dihydro-quinazolinone 10 led to the cleav-
age of the amide bond and the benzylamine N–C bond C in one step
(path m, 19% yield) therefore leading to aldehyde 18.
Acknowledgements
M.D. gratefully acknowledges the German Science Foundation
(DFG) for financial support (DFG DE1546/6-1). J.B. thanks the
ERASMUS student mobility program.
Earlier investigations had already shown how to selectively
open the central N–C bond C of quinazolinones 19 and the related
structure 21 using BH3ÁTHF to yield medium sized heterocyclic ring
systems 20 and 2228–30 (Scheme 3).
Supplementary data
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2014.03.109.
Therefore, borane reduction was applied for the reductive re-
moval of the amide oxygen and cleavage of the central N–C bond
C in dihydroquinazolinone 10 in one step. Interestingly, the usage
of BH3ÁTHF did not lead to the expected cleavage of the central C–N
bond C, but rather reduced the amide bond and cleaved the anilinic
bond D to give the ring opened compound 16 in 47% yield (path j).
As it was expected that milder reducing agents were necessary to
break the anilinic bond D, quinazolinone 10 was treated with
NaBH4 (path k) and NaCNBH3 (path l), respectively, but in both
cases no reaction took place. Besides, for tetrahyroquinazoline 9
cleavage of the anilinic bond D to compound 16 was achieved by
treatment with BH3ÁTHF in 42% yield (path j). Alternatively com-
pound 16 was obtained from 9 using NaBH4 in 60% yield (path
k). From these results it can be expected that cleavage of the cen-
tral C–N bond C with BH3ÁTHF is only possible in quinazolinones
(Scheme 3) as described in the literature and not in dihydroquinaz-
olinones like compound 10.
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O
.
BH3 THF
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N
H
n
n
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O
20
.
N
N
H
BH3 THF
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Scheme 3. Selective cleavage of bond C.28–30

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