Solid-phase synthesis of benzazoles, quinazolines, and quinazolinones using an alkoxyamine linker

Article abstract of DOI:10.1016/j.tetlet.2014.08.095

An alkoxyamine linker was applied for the solid-phase synthesis of benzazoles, quinazolines, and quinazolinones. Aromatic aldehydes were anchored by aldoxime linkage. After some reactions on a solid support, the products were cleaved with paraformaldehyde under the acidic conditions to afford the corresponding aldehydes, which were subsequently subjected to oxidative coupling with 2-substituted anilines under air atmosphere to give the desired compounds.

Full text of DOI:10.1016/j.tetlet.2014.08.095

Tetrahedron Letters 55 (2014) 5793–5797
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solid-phase synthesis of benzazoles, quinazolines, and
quinazolinones using an alkoxyamine linker
Kota Yamaguchi a, Takeshi Noda b, Yusuke Higuchi a, Naoyuki Aoki a, Rika Yamaguchi a, Miwa Kubo c,
Kenichi Harada c, Yoshiyasu Fukuyama c, Hideaki Hioki a,
⇑
a Faculty of Education, Gunma University, Maebashi, Gunma 371-8510, Japan
b Department of Applied Bioscience, Kanagawa Institute of Technology, Atsugi, Kanagawa 243-0292, Japan
c Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2014
Revised 5 August 2014
Accepted 25 August 2014
Available online 29 August 2014
An alkoxyamine linker was applied for the solid-phase synthesis of benzazoles, quinazolines, and quinaz-
olinones. Aromatic aldehydes were anchored by aldoxime linkage. After some reactions on a solid sup-
port, the products were cleaved with paraformaldehyde under the acidic conditions to afford the
corresponding aldehydes, which were subsequently subjected to oxidative coupling with 2-substituted
anilines under air atmosphere to give the desired compounds.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Solid-phase synthesis
Alkoxyamine Linker
Benzimidazole
Quinazoline
Quinazolinone
Nitrogen-containing heterocyclic compounds, such as benzaz-
oles, quinazolines, and quinazolinones are an important class of
compounds. They can be utilized as not only a wide variety of bio-
logically active and medicinally significant compounds1 but also as
advanced materials including non-linear optics (NLO),2 organic
light-emitting diodes (OLED),3 and liquid crystals.4 Hence, facile
preparation of these derivatives for rapid discovering of new drugs
and materials is highly desirable. Solid-phase combinatorial syn-
thesis is effective in providing a large number of compounds.
Therefore, solid-phase combinatorial syntheses of these com-
pounds have been reported by some groups.5 The selection of an
adequate linker in the solid-phase synthesis is one of the key fac-
tors for efficiently building the desired libraries.6 A connection
between a linker and substrates must be stable under the various
reaction conditions to construct the desired products. Meanwhile,
the linkage must be cleavable without damage to the product at
the final stage.
robust than the azomethine linkage prepared from our previously
reported alkoxyaniline linker 29 under the various reaction condi-
tions such as Mitsunobu reaction, nucleophilic substitution reac-
tion, and Pd-catalyzed reactions (Fig. 1).
The reaction sequence to synthesize benzothiazoles 5 is shown
in Scheme 1. The desired benzothiazoles 5 were released in good
yields by exchange reaction between solid-supported aldoxime 4
and 2-amino-thiophenol coupled with air-oxidation under the
weakly acidic conditions. However, treatment of 4 with other 2-
substituted anilines such as 1,2-phenylenediamine, 2-aminoben-
zylamine, and 2-aminobenzamide did not give the corresponding
benzimidazole, quinazoline, and quinazolinone due to the resis-
tance to aldoxime–azomethine exchange.8
Hence, we investigated the cleavage conditions how the linker 1
can be effectively employed for the preparation of these heterocy-
clic compounds. The key in the synthesis is the cleavage conditions
at the final stage. The products must be released without damage
We previously reported a new traceless alkoxyamine linker 1,
which can anchor ketones and aldehydes as ketoximes or aldoxi-
mes on a solid-support. It was applied to the solid-phase synthesis
of benzodiazepins7 and benzothiazoles.8 The oxime linkage formed
by anchoring carbonyl compounds on 1 has been shown to be more
NH2
O
O
N
H
ONH2
N
H
O
4
4
1
2
⇑
Corresponding author. Tel./fax: +81 27 220 7285.
E-mail address: hioki@gunma-u.ac.jp (H. Hioki).
Figure 1. Two traceless linkers which can anchor ketones and aldehydes as oximes
or azomethines.
http://dx.doi.org/10.1016/j.tetlet.2014.08.095
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

5794
K. Yamaguchi et al. / Tetrahedron Letters 55 (2014) 5793–5797
R1= OH:
R1
Mitsunobu Reaction,
O-alkylation with alkyl
halide
O
R1
O
O
H
R1 = Br
Suzuki-Miyaura Coupling,
Mizoroki-HeckReaction
N
N
H
ONH2
N
H
O
4
4
3
1
NH2
SH
R2
R2
O
N
N
N
O
4
R2 = variousfunctional
group
H
5% TFA, DCE,
air, rt
S
5
4
Scheme 1. Solid-phase synthesis of benzothiazoles 5 using an alkoxyamine linker 1.
from the highly robust aldoxime linkage on a solid-support.
Sakamoto and Kikugawa reported mild deoximation using parafor-
maldehyde in the presence of AmberlystÒ 15 (acidic ion exchange
resins).10 We have envisioned that this deoximation condition
would be applied to the cleavage step.
In advance of investigation on a solid-phase synthesis, the
cleavage conditions were optimized in solution. TFA was employed
instead of AmberlystÒ 15 as acidic catalyst because solid catalyst
could not be applied for solid-phase reaction. Aldoxime 6 was trea-
ted with paraformaldehyde in 1,2-dichloroethane (DCE) solution
in good yield although much longer reaction time was required
(entries 2 and 3). However, treatment of crude 7 with 2-aminophe-
nol 9 (Y = O), did not give benzoxazole 10 (Y = O) even in the pres-
ence of DarcoÒ KB, which was an effective catalyst for the oxidative
coupling between aromatic aldehydes and 2-aminophenol
9
(Y = O).11 Oxidative decomposition of 2-aminophenol 9 (Y = O)
occurred in preference to oxidative coupling. Desired benzoxazole
10 (Y = O) was obtained in 12% yield at elevated temperature. The
yield was improved to 53% in xylene (entries 4 - 6). In case of qui-
nazoline synthesis, yields were improved from 27% to 80% when
crude 7 was treated with 2-aminobenzylamine 9 (Y = CH2NH) for
18 h to form N,N-cyclic acetal before addition of DarcoÒ KB which
caused oxidative decomposition of unreacted 2-aminobenzyl-
amine 9 (Y = CH2NH) (entries 7 and 8). Quinazolinone 12 was also
obtained in good yield even without pretreatment with 2-amino-
benzamide 9 (Y = CONH) due to its resistance for oxidative decom-
position (entry 9).
containing 5% TFA. Desired 4-methoxybenzaldehyde
7 was
observed by TLC as expected. After 3 h at room temperature, TFA
and the solvent were removed under reduced pressure. The residue
was successively treated with various 2-substituted anilines 9
under air atmosphere at 100–120 °C to drive 7 to Schiff base for-
mation and sequential oxidative cyclization. The results are sum-
marized in Table 1.
Treatment of crude 2-methoxybenzaldehyde 7 with 4-equiva-
lent of 1,2-phenylenediamine 9 (Y = NH) at 100 °C for 18 h gave
the corresponding benzimidazole 10 (Y = NH) in 77% yield (entry
1). N-methyl-2-arylbenzimidazole 10 (Y = NMe) was also obtained
On the basis of the preliminary experimental results in solution,
we investigated the solid-phase synthesis of these heterocycles by
using the alkoxyamine linker 1. After loading 4-methoxy benzalde-
hyde 7, the resin 13 was treated under the same conditions as
Table 1
Deoximation of 6 using paraformaldehyde under the acidic conditions and successive oxidative coupling with various 2-substituted anilines 9
OMe
NH2
YH
N
Y
9
10Y =NH, NMe, O
Y = NH, NMe,
OMe
O, CH2NH,
OMe
OMe
(CH2O)
CONH
N
n
O
N
N
MeO
5% TFA
in DCE
rt, 3h
air, conditions
H
7
6
+
11
OMe
(E:Z = 10:1)
N
MeO
N
8
NH
12
O
Entry
Y
Additive
Solvent
Temp (°C)
Period (h)
Yield (%)
1
2
3
4
5
6
7
81
9
NH
NMe
DMF
DMF
DMF
DMF
DMF
Xylene
DMF
DMF
DMF
100
100
100
100
120
120
100
100
100
18
48
72
18
18
18
18
18
18
77
41
79
0
12
53
27
80
83
O
DarcoÒ KB
DarcoÒ KB
DarcoÒ KB
DarcoÒ KB
DarcoÒ KB
DarcoÒ KB
CH2NH
CONH
1
DarcoÒ KB was added after stirring 7 with 2-aminobenzylamine 9 (Y = CH2NH) at rt for 18 h.

K. Yamaguchi et al. / Tetrahedron Letters 55 (2014) 5793–5797
5795
Table 2
Solid-phase synthesis of benzimidazoles 10 (Y = NH, NMe), benzoxazole 10 (Y = O), quinazoline 11, and quinazolinone 12 using the alkoxyamine linker 1
OMe
O
OMe
O
O
(CH2O)n
H
7
N
N
H
ONH2
N
H
O
4
4
5% TFA in DCE
rt, 3h
13
1
NH2
YH
OMe
N
9
Y
Y = NH, NMe,
O, CH2NH,
CONH
10Y =NH, NMe, O
OMe
O
OMe
OMe
air, conditions
H
7
N
N
O
N
NH
12
11
Entry
Y
Additive
Solvent
Temp (°C)
Period (h)
Yield (%)
1
2
NH
NMe
O
CH2NH
CONH
—
—
DMF
DMF
xylene
DMF
DMF
100
100
120
100
100
18
72
18
18
18
75
73
35
75
77
3
DarcoÒ KB
DarcoÒ KB
DarcoÒ KB
41
5
1
DarcoÒ KB was added after stirring 7 with 2-aminobenzylamine 9 (Y = CH2NH) at rt for 18 h.
solution-phase synthesis for cleavage of the benzaldehyde 7 and
oxidative coupling with 2-substituted anilines 9. The isolated
yields of corresponding heterocycles from 1 are shown in Table 2.
The yields were comparable to those in solution-phase synthesis
(Table 1).
To test the utility of the linker, some reactions on a solid-sup-
port were explored. After 4-formyl benzoic acid was loaded on 1,
oxime 14 was condensed with n-butanol or diisobutylamine.
Finally, desired esters or amide was released from 15 under the
optimized reaction conditions described above. Table 3 summa-
rizes the yields, which were compared with those for the reaction
using the alkoxyaniline linker 2. In the series of n-butyl esters, they
were comparable to those using the alkoxyaniline linker 2. On the
other hand, the yields of amide 16–18 (R = N(Me2CHCH2)2) were
improved by using the linker 1 because aldoxime 14 is more stable
for the undesirable aminolysis of C = N linkage in 14 by diisobutyl-
amine than corresponding azomethine formed by aromatic alde-
hydes and alkoxyaniline linker 2.
4-Hydroxy benzaldehyde was loaded onto 1 to explore Mitsun-
obu reaction of phenol with 2-butanol on a solid-support. The
Table 3
Condensation with n-butanol, diisobutylamine on a solid-support
O
OH
O
n-BuOHor
O
O
(Me2CHCH2)2NH
OH
O
H
N
N
H
ONH2
4
N
H
O
4
DIC, DMAP
DCM, rt, 3h
O
DMF, rt, 24 h
14
1
R
1) (CH2O)n
5%TFA in DCE
rt, 3h
N
O
Y
16
O
R
Y =NH, NMe, O
N
O
N
H
4
2)
O
NH2
O
15
, air
R
R
YH
N
N
O
9
R = On-Bu, N(Me2CHCH2)2
Y = NH, NMe,
O, CH2NH,
CONH
N
NH
18
17
Yields from 11 (%)
R
Y
NH
NMe
O
CH2NH
CONH
On-Bu
N(Me2CHCH2)2
76 (84)
73 (40)
84 (77)
53 (47)
57 (58)
16 (15)
82 (82)
61 (33)
95 (74)
48 (39)
1
Values in parenthesis refers to a yield when the alkoxyaniline linker 2 was applied for the synthesis.

5796
K. Yamaguchi et al. / Tetrahedron Letters 55 (2014) 5793–5797
OH
HO
O
OH
O
O
H
N
N
H
ONH2
4
N
H
O
4
DIAD, PPh3
DCM, rt, 4 h
DMF, rt, 24 h
19
1
O
N
58%(Y = NH)
52%(Y = NMe)
9% (Y = O)
Y
21
1) (CH2O)n
5% TFA in DCE
rt, 3h
O
O
O
N
N
O
N
H
4
2)
NH2
N
38%
O
20
, air
YH
9
22
N
Y = NH, NMe,
O, CH2NH,
CONH
NH
86%
23
O
Scheme 2. Mitsunobu reaction with 2-butanol on a solid-support.
Table 4
Suzuki–Miyaura coupling with phenylboronic acid and Mizoroki–Heck reaction with n-butyl acrylate on a solid-support
Br
phenylboronic acid,
Na2CO3, PdCl2 (dppf)
DME/H2O, reflux, 16 h
O
Br
O
O
H
N
N
H
ONH2
N
H
4
O
4
or
DMF, rt, 24 h
24
n-butyl acrylate,
PdCl2 (dppf), TEA
DMF, 100°C, 10h
1
R
N
Y
26
1) (CH2O)n
5% TFA in DCE
rt, 3h
R
O
R
N
N
H
O
4
2)
NH2
N
N
, air
25
YH
9
R = Ph, CHCHCO2n-Bu
27
R
Y = NH, NMe,
O, CH2NH,
CONH
N
NH
O
28
Yields from 1 (%)
R
Y
NH
NMe
O
CH2NH
CONH
Ph
72
56
76
64
48
27
79
23
76
47
CHCHCO2n-Bu
overall yield of heterocycles from 1 is shown in Scheme 2. Desired
products 21–23 except benzoxazole 21 (Y = O) were obtained in
moderate to good yields.
coupling (Table 2). However, yields were slightly reduced in Mizor-
oki–Heck reaction on a solid-support.
In conclusion, we found the alkoxyamine linker 1 to be an effi-
cient traceless linker used for the solid-phase synthesis of not only
benzothiazoles and benzodiazepins but also other benz-fuzed
azoles, quinazolines, and quinazolinones. The aldoximes on a solid
support are robust under some reaction conditions such as
condensation with alcohols and amines, Mitsunobu reaction, and
palladium catalyzed reactions. Meanwhile, the corresponding
aldehydes were easily cleaved under the mild conditions using
paraformaldehyde in weakly acidic solvent. The aldehydes can be
oxidatively coupled with 2-substituted anilines under air
Finally, 4-bromobenzaldehyde was linked with 1 to examine
two kinds of palladium catalyzed reactions.12 The aldoxime on a
solid-support 24 was subjected to Suzuki–Miyaura coupling with
phenylboronic acid. Mizoroki–Heck reaction with n-butyl acrylate
was also applied to 24. Desired products 26–28 were obtained
from 25 under the optimized conditions described above. Yields
are summarized in Table 4. Suzuki–Miyaura couplings were shown
to proceed smoothly on a solid support by comparing the cou-
pling yields with those of simple loading, cleavage, and oxidative

K. Yamaguchi et al. / Tetrahedron Letters 55 (2014) 5793–5797
5797
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Fukuyama, Y. Tetrahedron Lett. 2012, 53, 4337–4342.
9. (a) Hioki, H.; Matsushita, K.; Nakamura, S.; Horiuchi, H.; Kubo, M.; Harada, K.;
Fukuyama, Y. J. Comb. Chem. 2008, 10, 620–623; (b) Hioki, H.; Matsushita, K.;
Kubo, M.; Harada, K.; Kodama, M.; Fukuyama, Y. Tetrahedron 2007, 63, 11315–
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3713–3715.
atmosphere without purification. Application to the synthesis of
other heterocycles using the alkoxyamine linker 1 is currently
under investigation.
References and notes
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12. Representative procedure for the synthesis: Three pieces of the solid supported
alkoxyamine 1 (loading: 3 Â 75
l
mol)7 were reacted with 4-bromobenzalde-
hyde (167 mg, 0.90 mmol, 4 equiv) in DMF solution (8 mL) at rt for 24 h. The
solution was removed by decantation and the resulting resins were washed
with DMF (3 Â 2 min) and DCM (3 Â 2 min). The resulting solid supported
aldoxime 24 was mixed with phenylboronic acid (165 mg, 1.35 mmol, 6 equiv)
and PdCl2 (dppf) CH2Cl2 (18.3 mg, 22.5
l
mol, 0.1 equiv) in degassed dime-
thoxyethane (8 mL) and 2 mol LÀ1 aqueous Na2CO3 solution (900
lL,
1.80 mmol, 8 equiv) under argon atmosphere. The mixture was refluxed for
16 h. The solution was removed by decantation and the resulting resins were
washed with MeOH (3 Â 2 min), DMF (3 Â 2 min), and DCM (3 Â 2 min). The
resins 24 (R = Ph) were reacted with paraformaldehyde (33.9 mg, 1.13 mmol,
5 equiv) in 5% TFA-1,2-DCE solution (8 mL) at rt under argon atmosphere for
3 h. The resulting resins were washed with DCM (3 Â 2 min), DMF (3 Â 2 min),
and DCM (3 Â 2 min). The combined DCM and DMF solutions were evaporated
and the residue was treated with 1,2-phenylenediamine 9 (Y = NH) (97.3 mg,
0.90 mmol, 4 equiv) in DMF (3 mL) at 100 °C for 18 h. The reaction mixture was
concentrated and purified by silica gel chromatography (hexane/EtOAc = 1/1)
to give benzimidazole 26 (R = Ph, Y = NH) in 72% yield (44.0 mg, 163
flesh color solid (mp 276-277 °C).
lmol) as
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Y.; Hioki, H. J. Comb. Chem. 2010, 12, 311–314.