Solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones via palladium-catalyzed amination

Article abstract of DOI:10.1016/S0040-4039(03)01876-8

A new procedure for the solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones is described. The method involves coupling of 2,4,6- and 2,4,7-trichloroquinazoline to a solid support via benzyl alcohol type linkers, subsequent displacement of chlorine at C-2 then at the C-6 or C-7 positions by amines (Fig. 1) and the cleavage of the products from the resin. The palladium-catalyzed amination of C-6 and C-7 positions with a representative set of amines in the presence of 2-(di-t-butylphosphino)biphenyl (DTBPBP), P(t-Bu)₃ and 2,2′-bis(diphenylphosphino)-1,1′ -binaphthyl (BINAP) ligands has been investigated. This method should prove to be a useful tool for constructing combinatorial libraries containing the 4(3H)-quinazolinone moiety.

Full text of DOI:10.1016/S0040-4039(03)01876-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7533–7536
Solid-phase synthesis of 2,6- and
2
,7-diamino-4(3H)-quinazolinones via palladium-catalyzed
ꢀ
amination
´
Csaba W e´ ber,* Ad a´ m Demeter, Gy o¨ rgyi I. Szendrei and Istv a´ n Greiner
Chemical and Biotechnological Research and Development, Gedeon Richter Ltd, PO Box 27, H-1475 Budapest, Hungary
Received 4 June 2003; revised 24 July 2003; accepted 1 August 2003
Abstract—A new procedure for the solid-phase synthesis of 2,6- and 2,7-diamino-4(3H)-quinazolinones is described. The method
involves coupling of 2,4,6- and 2,4,7-trichloroquinazoline to a solid support via benzyl alcohol type linkers, subsequent
displacement of chlorine at C-2 then at the C-6 or C-7 positions by amines (Fig. 1) and the cleavage of the products from the
resin. The palladium-catalyzed amination of C-6 and C-7 positions with a representative set of amines in the presence of
2
-(di-t-butylphosphino)biphenyl (DTBPBP), P(t-Bu) and 2,2%-bis(diphenylphosphino)-1,1%-binaphthyl (BINAP) ligands has been
3
investigated. This method should prove to be a useful tool for constructing combinatorial libraries containing the 4(3H)-quinazoli-
none moiety.
©
2003 Elsevier Ltd. All rights reserved.
2
-Amino-4(3H)-quinazolinones have a wide range of
none libraries which fulfil the following criteria: (1)
They cannot be prepared from easily accessible
anthranilic acid derivatives. (2) The diversity elements
coupled to the core structure are easily accessible in a
large number. (3) The advantages of the solid-phase
technique are exploitable in the synthesis. The synthesis
of 2-amino-6-alkoxy-4(3H)-quinazolinones demon-
1–5
6
biological activity.
Recently antitumor and anti-
7
HIV activities of quinazolinones have been disclosed
as well. These effects make 4(3H)-quinazolinones valu-
able target molecules in drug research. Combinatorial
chemistry has proven a highly powerful tool in drug
discovery and has become popular among medicinal
8
15
chemists. This new technique has encouraged chemists
strated in our previous publication, and the prepara-
to evolve new synthetic approaches suitable for the
preparation of combinatorial libraries. Such attempts
have led to the development of new, solid-phase strate-
gies in the synthesis of 4(3H)-quinazolinone
tion of 2,6- and 2,7-diamino-4(3H)-quinazolinones
which is our current subject fulfil these three criteria.
The goal of the present paper is to demonstrate the
feasibility of our approach for the synthesis of 2,6- and
9
–14
derivatives.
2
,7-diamino-4(3H)-quinazolinone libraries and to show
In our recent paper a novel general method for the
how the scope of this strategy can be widened by using
the appropriate linker. Application of the same 2-amino
substituents as used before permits us to compare our
solid-phase synthesis of 4(3H)-quinazolinones was
1
5
described. This approach is based on the coupling of
,4-dichloroquinazoline derivatives to solid-support at
2
C-4 via a benzyl alcohol type linker. The 2-chloro
substituent and a suitable functional group on the
benzene ring (X, Fig. 1) provide possibilities for the
introduction of diversity elements. This approach is
especially useful for the synthesis of 4(3H)-quinazoli-
Keywords: 4(3H)-quinazolinones; solid-phase synthesis; palladium;
amination.
ꢀ
Supplementary data associated with this article can be found at
doi:10.1016/S0040-4039(03)01876-8
Corresponding author. Tel./fax: +36
cs.weber@richter.hu
*
1
4326002; e-mail:
Figure 1. The resin bound form of the core structure for the
solid–phase synthesis of 4(3H)-quinazolinone derivatives.
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01876-8

7
534
C. W e´ ber et al. / Tetrahedron Letters 44 (2003) 7533–7536
2
1–24
new and previous results and hereby to study the effect
of the substituents at the benzene ring on the aromatic
nucleophilic substitution and on the ‘cleavage point’ of
the linker.
solid-phase chemistry
and has not been used before
for the synthesis of aminoquinazolines. To study this
reaction and to find general reaction conditions, 6- and
7-halo-2-(piperidin-1-yl) derivatives 4a–c, (NR R =
piperidin-1-yl) were chosen as model compounds. Three
types of aryl halide–Pd/ligand systems have been inves-
1
2
The solid-phase synthesis of 2,6- and 2,7-diamino-
25
4
7
(3H)-quinazolinones is outlined in Scheme 1. 6- And
tigated: aryl bromide–Pd/BINAP, aryl chloride–Pd/
26 27
16,17
-halo-2,4-dichloroquinazolines
2a–c were tethered
P(tBu)3
and aryl chloride–Pd/DTBPBP.
The
18
to Wang alcohol resin (4-benzyloxybenzyl alcohol,
reactions were carried out at 100°C in xylene using
NaOtBu. Our experimental results with the aryl bro-
mide–Pd/BINAP system (Table 1, entries 12–14) were
in accordance with the observations made by Wolfe et
al. It was shown that the system is effective with
primary amines while with certain acyclic secondary
amines the yields decrease because of the significant
reduction of the bromide. The aryl chloride–Pd/P(tBu)3
system, in accordance with Hartwig’s solution-phase
experiments gave the expected 6- and 7-amino com-
pounds in good yield with secondary amines (Table 1,
entries 17–20). The amount of reduced side product was
in the range of 1–7%. However, with primary amines,
even with a fivefold excess of amine, diarylation
occurred yielding about 30% of N,N-diaryl-N-alkyl-
amine side product (Table 1, entries 15–16). This side
reaction had also been observed in solution-phase
experiments. DTBPBP is one of the most recently
reported air-stable phosphine ligands. In our case the
aryl chloride–Pd/DTBPBP system worked well with
primary amines providing only 1–6% of reduced side
product (Table 1 entries 21–26). With secondary
amines, however, a higher amount of such impurities
was produced (Table 1, entries 27, 28) unlike in the case
polymer bound) 1a and 4-(4-hydroxymethyl-3-
1
9
methoxyphenoxy)benzyl polystyrene 1b, respectively.
The resins were deprotonated with n-BuLi at −20°C
then 2a–c were added. Complete conversion of 3a–c to
the resin bound 2-aminoquinazoline derivatives 4a–c
was achieved after treatment with aliphatic primary and
secondary amines at 80°C. Amines branched at the a
position required higher temperatures (100°C) or longer
reaction times (Table 1, entries 9, 10). These com-
pounds were cleaved from the resin with TFA/DCM
mixture to give 2-amino-6- and 2-amino-7-halo-4(3H)-
25
26
quinazolinones 5a –5c5 in high yield and excellent
1
purity (Table 1, entries 1–10). The yields and purities
were practically the same for the two different linkers
(
Table 1, entries 6–7). Comparing our new results to
15
our previous experiments with 6-hydroxy derivatives,
it was observed that with aryl amines neither the 6-
hydroxy nor the 7-halo derivatives afforded pure prod-
ucts (entry 11). On the other hand while 6-hydroxy
derivatives did not give pure products with primary
aliphatic amines the 6- and 7-halo compounds afforded
the expected 2-amino-4(3H)-quinazolinones in high
purity (Table 1, entries 1, 5, 9).
27
of Pd/P(tBu) (Table 1, entries 18, 19).
3
The next step was the introduction of the second amino
group into the C-6 and C-7 position via palladium-cat-
alyzed amination. According to our literature survey
In summary, P(tBu) proved to be the most suitable
3
2
0
ligand for the introduction of secondary aliphatic and
aromatic amines in palladium-catalyzed aminations,
this reaction has been rarely utilized in the field of
1
2
Scheme 1. Reagents and conditions: (i) 2.2 equiv. n-BuLi, −20°C, 5 equiv. 2a–c, rt, 16 h; (ii) 5 equiv. HNR R , DMF, 3 h, 80 or
3
4
1
00°C; (iii) 5% (R=MeO) or 20% (R=H) TFA/DCM, 2 h; (iv) 5 equiv. HNR R , 0.2 equiv. Pd-complex, 5 equiv. NaOtBu,
o-xylene, 100°C, 24 h; (v) 5% (R=MeO) or 20% (R=H) TFA/DCM, 2 h.

C. W e´ ber et al. / Tetrahedron Letters 44 (2003) 7533–7536
7535
a
Table 1. The purities and yields of the 2-amino-4(3H)-quinazolinones
Ligandb
NR R
1
2
NR R
3
4
Purity (%)c
Yield (%)d
Entry
Comp.
Precursor
Linker
e
1
2
3
4
5
6
7
8
9
5a1
5a2
3a
3a
3b
3b
3c
3c
3c
3c
3c
3c
3c
3b
3b
3b
3a
3c
3a
3c
3c
3c
3a
3c
3c
3c
3c
3c
3c
3c
1a
1a
1a
1a
1a
1a
1b
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
1b
1a
1b
1b
–
–
–
–
–
–
–
–
2-Phenylethylamino
Piperidin-1-yl
Bis(n-butyl)amino
Piperidin-1-yl
n-Hexylamino
Piperidin-1-yl
Piperidin-1-yl
Bis(n-butyl)amino
sec-Butylamino
2-Methylpiperidin-1-yl
N-Methylphenylamino
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
Piperidin-1-yl
–
–
–
–
–
–
–
–
–
–
–
97
98
97
95
96
98
98
95
84
89
91
86
81
82
85
78
81
87
–
57
–
–
–
–
66
61
65
68
58
62
63
58
71
61
-
e
5b1
5b2
5c1
5c2
5c2
5c3
5c4
5c5
5c6
7a1
7a2
7a3
7a3
7b1
7a2
7b2
7b3
7b4
7a3
7b5
7b1
7b1
7b6
7b6
7b2
7b3
f
–
–
–
96
98
f
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
26
81
65
76
63
43
83
85
BINAP
BINAP
BINAP
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
P(t-Bu)3
DTBPBP
DTBPBP
DTBPBP
DTBPBP
DTBPBP
DTBPBP
DTBPBP
DTBPBP
2-Phenylethylamino
Bis(n-butyl)amino
n-Hexylamino
n-Hexylamino
Benzylamino
Bis(n-butyl)amino
Bis(n-butyl)amino
N-Methylphenylamino 94
N,N-Diphenylamino
n-Hexylamino
n-Hexylamino
Benzylamino
Benzylamino
2-Phenylethylamino
2-Phenylethylamino
Bis(n-butyl)amino
96
82
94
92
86
96
82
48
N-Methylphenylamino 37
-
a
1
All compounds were characterized by MS spectroscopy. The structures of compounds having at least 80% purity were confirmed by H NMR
spectroscopy. Spectroscopic characterization data are given in the Supplementary Material.
b
c
d
e
f
Ratio of BINAP/Pd=2/1, P(tBu) /Pd=1/1, DTBPBP/Pd=2/1.
3
The purities and MWs of the crude products were determined by HPLC-MS at 254 nm. All purities reported are the average of at least two runs.
The overall yield was determined by weight based on the loading of 3a–c. The yields refer to compounds purified by flash chromatography.
28
Known compounds.
Reaction conducted at 100°C.
while DTBPBP proved to be superior in the case of
primary aliphatic amines.
tion 4 is more reactive than at position 2, while the 6
and 7 positions are considerably less active. Although
the same order of selectivity is expected, such investiga-
tions with the salts of alcohols in solid-phase synthesis
has not been established. One would expect that linking
of the starting quinazolines 2a–c to the resin will occur
at position 4, thus the 2-amino isomer will be the main
product. However, formation of the 4-amino isomer
could not be excluded on an a priori basis. This struc-
tural question was settled by NMR and HPLC-MS
studies. According to HPLC-MS, peaks with a molecu-
lar mass equal to the molecular mass of the main
product could not be detected among the impurities in
either case, indicating considerably high regioselectivity.
The structure of the main products (5a–c) was proved
by detailed NMR studies. The following spectroscopic
pieces of evidence support the 2-amino-4(3H)-quina-
zolinone structure of compound 5a–c: Firstly, we could
not detect NOE interactions between the protons of the
amino groups and the aromatic protons of the quina-
zolinone ring. Secondly, the H-5 proton shows correla-
tion in the PFG-HMBC spectrum with the C-4
carbonyl carbon. Thirdly, due to the peri effect of the
carbonyl group the H-5 proton resonates considerably
The synthesis of diamino-4(3H)-quinazolinones was
achieved on both linkers. While 2-amino-6-halo-4(3H)-
quinazolinones and 2-amino-7-halo-4(3H)-quinazoli-
nones as well as 2-amino-6-hydroxy-4(3H)-quina-
zolinones
and
2-amino-6-alkoxy-4(3H)-quinazoli-
1
5
nones can be cleaved from 1a in pure form, the
cleavage of 2,6- and 2,7-diamino derivatives from 1a
has resulted in the formation of significant amounts
(
4
1–20%) of 4-(4-hydroxybenzyloxy)-2,6(7)-diamino-
(3H)-quinazoline impurities. This type of side product
was completely eliminated by employing 1b, a more
acid sensitive linker (Table 1, entries 23–24, 25–26).
The solid-phase method developed involves two steps
where the issue of regioselectivity should be considered:
Due to the presence of three halogens in the quinazo-
line ring the coupling to the resin as well as the amine
substitution steps might, in principle, lead to regioiso-
mers in the route toward the quinazolinone 5a–c. It is
well known from the literature that in solution phase
the 2,4,6- and 2,4,7-trichloroquinazolines can be selec-
2
9
tively substituted with amines. The halogen at posi-

7
536
C. W e´ ber et al. / Tetrahedron Letters 44 (2003) 7533–7536
downfield relative to the H-7, H-8 (5a,b) as well as the
H-6, H-8 (5c) protons—see Supporting material.
Tetrahedron Lett. 1997, 38, 8445–8452.
10. Villalgordo, J. M.; Obrecht, D.; Chucholowsky, A. Syn-
lett 1998, 1405–1407.
In DMSO-d solution at 30°C at 500 MHz we have
observed exchange broadening of the H-8 signal in
11. Gopalsamy, A.; Yang, H. J. Comb. Chem. 2000, 2,
378–381.
6
compounds 5a , 5b , 5b , 5c , 7b , 7b , 7b and 7b
12. Yang, R.-Y.; Kaplan, A. Tetrahedron Lett. 2000, 41,
7005–7008.
13. Keserwani, A. P.; Srivasta, G. K.; Rastogi, S. K.; Kundu,
B. Tetrahedron Lett. 2002, 43, 5579–5581.
14. O’Mahony, D. J. R.; Krchnak, V. Tetrahedron Lett.
2002, 43, 939–942.
2
1
2
3
1
2
4
5
indicating an ongoing N(1)HlN(3)H tautomerization
process that is moderately fast on the NMR chemical
shift timescale. Literature data suggest that the 4(3H)-
quinazolinone tautomer stabilized by amide resonance
30
is preferred over the 4(1H)-quinazolinone tautomer.
The measured weak NOE interaction between the
quinazolinone NH and the H-8 protons indicates that
the 4(1H)-quinazolinone tautomer is measurably popu-
lated under the applied conditions.
15. W e´ ber, C.; Bielik, A.; Szendrei, I. Gy.; Greiner, I. Tetra-
hedron Lett. 2002, 43, 2971–2974.
16. Lee, S. J.; Konishi, Y.; Yu, D. T.; Miskowski, T. A.;
Riviello, C. M. J. Med. Chem. 1995, 38, 3547–3557.
17. Volzhina, O. N.; Medvedev, B. A.; Kazakov, A. A.;
In summary, we have developed a new solid phase
method for the synthesis of combinatorial libraries of
Zhikhareva, G. P. Pharm. Chem. J. 1987, 21, 478–483.
18. Wang resin was purchased from Novabiochem. Catalog
Number: 01-64-0014. 4-Benyzloxybenyzl alcohol resin.
Grain size: 100–200 mesh. Substitution: 0.78 mmol/g. The
polymer matrix is copoly(styrene–1% DVB).
19. 4-Hydroxy-2-methoxybenzyl alcohol (polymer-bound)
was purchased from Aldrich. Catalog Number: 54,073-0.
Grain size: 50–90 mesh. Substitution: 0.4 mmol/g. The
polymer matrix is copoly(styrene–1% DVB).
2
,6- and 2,7-diamino-4(3H)-quinazolinones. The route
features the use of an o-methoxybenzylalcohol linker
and palladium complexes supported by new phosphine
ligands as well as the use of a huge number of commer-
cially available building blocks. The library obtained
was characterized by HPLC-MS and NMR
spectroscopy.
2
0. Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
25–146.
21. Willoughby, C. A.; Chapman, K. T. Tetrahedron Lett.
996, 37, 7181–7184.
1
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