Facile solid phase synthesis of 1,2-disubstituted-6-nitro-1,4- dihydroquinazolines using a tetrafunctional scaffold

Article abstract of DOI:10.1016/j.tetlet.2004.11.095

Solid phase synthesis of 1, 2-disubstituted-6-nitro-1,4-dihydroquinazolines is described. The new tetrafunctional scaffold N-Alloc-3-amino-3-(2-fluoro-5- nitrophenyl)propionic acid was prepared by nitration of 3-amino-3-(2- fluorophenyl)propionic acid. The scaffold was anchored to Rink resin via its carboxylic group and treated with primary amines to displace the arylfluorine followed by cyclization with aryl isothiocyanates in the presence of DIC upon Alloc deprotection to afford 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines in high yield.

Full text of DOI:10.1016/j.tetlet.2004.11.095

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 427–430
Facile solid phase synthesis of 1,2-disubstituted-6-nitro-1,4-
dihydroquinazolines using a tetrafunctional scaffold
Xiaobing Wang,a Aimin Song,a Seth Dixon,b Mark J. Kurthb and Kit S. Lama,*
aDivision of Hematology and Oncology, Department of Internal Medicine, UC-Davis Cancer Center, 4501 X Street,
Sacramento, CA 95817, USA
bDepartment of Chemistry, One Shields Avenue, UC-Davis, CA 95616, USA
Received 28 October 2004; accepted 17 November 2004
Abstract—Solid phase synthesis of 1, 2-disubstituted-6-nitro-1,4-dihydroquinazolines is described. The new tetrafunctional scaffold
N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid was prepared by nitration of 3-amino-3-(2-fluorophenyl)propionic acid.
The scaffold was anchored to Rink resin via its carboxylic group and treated with primary amines to displace the arylfluorine fol-
lowed by cyclization with aryl isothiocyanates in the presence of DIC upon Alloc deprotection to afford 1,2-disubstituted-6-nitro-
1,4-dihydroquinazolines in high yield.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Quinazoline rings represent a novel heterocyclic class of
pharmacophores for biological interaction. Some quin-
azolines have been identified as antibacterial drug1 as
well as potent and selective inhibitors of a variety of
kinases such as Src kinase,2 erbB1 (via ATP binding
site),3 CDK4/D1 and CDK2/E.4 Because of its valuable
pharmaceutical properties, synthesis of quinazolines has
gained considerable interest in the field of medicinal
chemistry. Many synthetic approaches have been
reported using conventional solution phase synthesis.5
Since solution phase synthesis usually requires tedious
workup after each reaction step, several research groups
have developed new methods for the synthesis of
quinazolines on solid support.6 Trifunctional scaffolds
of o- or p-nitro arylfluorines, for example, 4-fluoro-3-
nitrobenzoic acid7 and 2-fluoro-5-nitrobenzaldehyde,8
have been used as precursors to generate quinazolines
because of efficient displacement of arylfluorine by
nucleophiles. However, in solid phase synthesis, one of
the three functional groups on the scaffolds has to be
used as a handle to tether it to the solid support. Conse-
quently only the two remaining functional groups are
used for diversity generation. There is a need for devel-
oping methods to synthesize quinazoline libraries with
great diversity. Here, we report on the synthesis of a
novel tetrafunctional scaffold that can be used to pre-
pare 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines
via solid phase synthesis.
Ideally, such a tetrafunctional scaffold should be conve-
niently prepared by introducing a nitro group to an aryl-
fluoro-containing amino acid so that similar chemistry
used for the trifunctional scaffolds would be applicable
for this scaffold. We reasoned that 3-amino-3-(2-fluoro-
phenyl)propionic acid could be the appropriate amino
acid for this purpose because it is easy to prepare.
Scheme 1 illustrates the synthetic route of the tetra-func-
tional scaffold. 3-Amino-3-(2-fluorophenyl)propionic
acid 1 was first prepared by one-pot condensation of
2-fluorobenzaldehyde and malonic acid in the presence
of ammonium acetate under reflux overnight.9 The
resulting b-amino acid was then treated by the conven-
tional nitration agent, HNO3/H2SO4 (1:1) at 0 ꢁC for
6 h to yield pure 3-amino-3-(2-fluoro-5-nitrophenyl)
propionic acid 2 (>97%) in high yield (87.5%). FT-IR
(1519, 1354 cmꢀ1) and MS (M+H = 229.4) analysis
demonstrated the presence of a nitro group on product
2. 13C NMR data, in which nitro-substituted carbon at
d 144.50 ppm showed only one single peak, indicated
no fluorine–carbon coupling interaction on this carbon,
revealing that the nitration occurred at para-position
with respect to the arylfluorine. The free amino acid 2
Keywords: Tetrafunctional scaffold; Quinazoline; Solid phase
synthesis.
*
Corresponding author. Tel.: +1 916 734 8012; fax: +1 916 734
7946; e-mail: kit.lam@ucdmc.ucdavis.edu
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.095

428
X. Wang et al. / Tetrahedron Letters 46 (2005) 427–430
F
NH2
ii
i
iii
F
COOH
COOH
F
F
+
NH-Alloc
COOH
NH2
CHO
O2N
O2N
COOH
COOH
3
2
1
Scheme 1. Synthetic route of N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid. Reagents and conditions: (i) ammonium acetate (2.2 equiv),
EtOH, reflux, overnight; (ii) HNO3/H2SO4 (1:1), 0 ꢁC, 6 h; (iii) Alloc-OSu, NaHCO3, overnight.
was readily protected with Alloc-OSu in aqueous NaH-
CO3 solution to afford N-Alloc-3-amino-3-(2-fluoro-5-
nitrophenyl)propionic acid 3.
out to give resin-bound 1,2-disubstituted-6-nitro-1,4-
dihydroquinazolines 6. The desired quinazolines 7 were
obtained by 95% TFA (in H2O) cleavage for 2 h in high
yield and purity. The results are summarized in Table 1,
which shows that either aliphatic or aryl R1 group on 5
give the corresponding product in good yield. However,
no desired product was obtained when the aliphatic
isothiocyanates (7j–k) were used in the cyclization step
as previously reported.12a
To demonstrate the utility of this new scaffold for drug-
like heterocyclic compound synthesis, we designed a
simple solid phase synthetic route to prepare 1,2-disub-
stituted-6-nitro-1,4-dihydroquinazolines (Scheme 2). To
ensure that all products are soluble in aqueous solution
for biological screening and characterization, we pur-
posely incorporated a hydrophilic linker, (2,20-ethylen-
edioxy)-bis(ethylamine) monosuccinamide10 on Rink
resin prior to the quinazoline synthesis. Scaffold 3 was
anchored to the resin via carboxyl group in the presence
of DIC. The arylfluorine of the resin-bound scaffold 4
was then displaced with a primary amine to afford a
resin-bound aniline 5. In order to optimize the reaction,
three basic conditions, DIEA alone, DIEA with a cata-
lytic amount of DMAP and DBU alone were investi-
gated. The resulting compounds were released from
the resin by 95% trifluoroacetic acid in H2O and ana-
lyzed by HPLC and MS, respectively. Although the
MS results demonstrated that fluorine displacement
could occur under all conditions, the HPLC results sug-
gested that the second condition was more desirable.
Therefore, for synthesis of the desired quinazolines,
DIEA with catalytic amount of DMAP was used as
the base in the SNAr displacement step. After the aryl-
fluorine displacement, the Alloc-protected amino group
on the scaffold was liberated by palladium reagent.11
The DIC-mediated cyclization12 between the resin-
bound diamine and an aryl isothiocyanate was carried
In summary, we have developed an easy method to pre-
pare a novel tetrafunctional scaffold, N-Alloc-3-amino-
3-(2-fluoro-5-nitrophenyl)propionic acid, that can be
subsequently transformed to 1,2-disubstituted-6-nitro-
1,4-dihydroquinazolines on solid support, with high
yield and satisfactory purity. Since the scaffold has four
functional groups, it enables one to extend this synthetic
route to generate large diverse combinatorial libraries at
positions of 1,2,4,6 of the quinazoline skeleton. For
example, for a four point diversity library, an amino
acid can be placed between the quinazolines and the
solid support prior to the coupling of the scaffold to
resin and the nitro group of quinazolines 6 can be
reduced by SnCl2 to generate a free amine for coupling
of another building block.
Synthesis of 3-amino-3-(2-fluoro-5-nitrophenyl)prop-
ionic acid 2: 2-fluorobenzaldehyde (30.0 g, 0.24 mol),
malonic acid (27.5 g, 0.26 mol) and ammonium acetate
(41.0 g, 0.53 mol) were mixed in 50 mL of ethanol and
heated under reflux overnight. The reaction mixture
was cooled to room temperature. The white solid was
F
iii
O
i, ii, i
H
N
NH-R
H2N
O
Linker
Fmoc-NH
O2N
O
N
H
Linker
O
(Rink resin)
4
O
(R=Alloc)
R1
NH
R1
N
R1
N
H
N
H
iv
vii
vi
N
R2
R2
NH-R
O
N
O2N
N
O2N
O2N
H
N
NH2
O
Linker
Linker
N
H
O
O
5
O
O
O
R=Alloc
R=H
v
7
6
Scheme 2. Solid phase synthesis of 1,2-disubstituted-6-nitro-1,4-dihydroquinazolines. Reagents and conditions: (i) 25% piperidine, 15 min; (ii) N-
Fmoc-2,20-ethylenedioxy-bis(ethylamine) monosuccinamide (3 equiv), DIC (3 equiv); (iii) N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)propionic acid
(3 equiv), HOBt (3 equiv), DIC (3 equiv); (iv) R1NH2 (3 equiv), DIEA (3 equiv), DMAP (0.05 equiv), overnight; (v) Pd(PPh3)4 (0.24 equiv), PhSiH3
(20 equiv), DCM, 1 h; (vi) R2NCS (3 equiv), DIC (3 equiv), overnight; (vii) TFA/H2O (95:5), 2 h.

X. Wang et al. / Tetrahedron Letters 46 (2005) 427–430
Table 1. Synthesis of compounds 7a–k via Scheme 2
429
R1
N
H
N
R2
O
N
O2N
H
N
NH2
O
N
H
O
O
O
7a-k
Entry
R1
R2
Crude yielda (%)
90
Purityb (%)
100
MSc (found, M+H+)
Cl
7a
686.3
O
O
7b
75
65
714.4
7c
7d
82
71
83
70
642.4
687.3
O
F
O
N
Cl
7e
85
92
734.1
Cl
O
7f
77
85
97
685.2
736.2
O2N
7g
100
O
7h
7i
73
77
94
90
676.4
724.3
Br
d
d
7j
CH3(CH2)2
—
—
—
—
—
—
7k
CH3(CH2)3
N
a Yield of the crude product was based on Rink resin substitution.
b Purity was detected by RP-HPLC at k = 254 nm.
c Molecular weight was measured by MALDI-TOF MS.
d No desired product was obtained.
1
collected by filtration and washed with ethanol three
times (3 · 50 mL) and ether two times (2 · 50 mL).
The dry solid (26.0 g, purity >97%) was added into an
ice-chilled mixture of HNO3/H2SO4 (100 mL/100 mL)
and stirred for 6 h in ice bath. The yellowish solution
was poured into 600 mL of ice and neutralized with
NaOH to pH = 6. The mixture was allowed to warm
to room temperature. The precipitate was collected by
suction–filtration, washed with water (25 mL), ethanol
(3 · 50 mL), and ether (50 mL). Weight: 28.0 g, yield:
87.5%, purity: >97%, mp 222–228 ꢁC. FT-IR (selected,
cmꢀ1): 1519, 1354. MS (M+H+): 229.4. 1H NMR
(500 MHz, D2O): d 8.38 (t, 1H), 8.32 (m, 1H), 7.40 (t,
1H), 4.95 (t, 1H), 2.95 (m, 2H). 13C NMR (500 MHz,
D2O): d 176.5, 165.5 (d, JCF = 246 Hz), 144.5, 132.2 (d,
2JCF3 = 23.0 Hz), 127.6 (d, JCF = 10.6 Hz), 124.9
(d, JCF = 8.4 Hz), 117.9 (d, JCF = 24.8 Hz), 46.8, 39.1.
3
2
Synthesis of N-Alloc-3-amino-3-(2-fluoro-5-nitrophenyl)
propionic acid 3: To the solution of 3-amino-3-(2-
fluoro-5-nitrophenyl)propionic acid (10.0 g, 0.044 mol)
in aqueous NaHCO3 (9.2 g, 0.11 mol) solution was
dropwise added Alloc-OSu (8.7 g, 0.044 mol) solution
in DMF. The mixture was stirred at room temperature
overnight and washed with ethyl acetate twice
(2 · 40 mL). The aqueous solution was neutralized with
HCl to pH = 3. The solidified powder was collected by
filtration, washed with water (5 · 50 mL) and dried

430
X. Wang et al. / Tetrahedron Letters 46 (2005) 427–430
in vacuo. Weight: 9.0 g, yield: 66%, purity: 98%, mp
139–140 ꢁC. FT-IR (selected, cmꢀ1): 1531, 1346. MS
(M+H+): 313.5. 1H NMR (DMSO-d6, 500 MHz): d
12.5 (s, 1H), 8.37 (d, 1H), 8.22 (m, 1H), 8.14 (d, 1H),
7.49 (t, 1H), 5.89 (m, 1H), 5.29 (m, 2H), 5.17 (d, 1H),
4.48 (m, 2H), 2.75 (m, 2H). 13C NMR (DMSO-d6): d
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171.8, 164.5 (d, JCF = 250 Hz), 155.8, 144.9, 134.1,
2
3
132.5 (d, JCF = 16.4 Hz), 125.9 (d, JCF = 10.4 Hz),
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Typical procedure: synthesis of N-{2-[2-(2-{2-[2-(2-
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incubation with cycloheptylamine (3 equiv)/DIEA
(3 equiv)/DMAP (0.05 equiv) overnight. After Alloc-
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(20 equiv) in DCM for 1 h, the beads were incubated
with 2-chlorophenyl isothiocyanate (3 equiv)/DIC
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oughly washed with DMF (3 · 10 mL), MeOH
(3 · 10 mL), DCM (3 · 10 mL) and incubated with
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1
purity: 100%. MS (M+H+): 686.3. H NMR (DMSO-
d6 500 MHz): d 8.23 (d, 2H), 8.08 (t, 1H), 7.84 (t, 1H),
7.59 (d, 1H), 7.51 (t, 2H), 7.34 (t, 1H), 7.27 (d, 2H),
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3H), 3.10 (m, 2H), 2.78 (m, 2H), 2.27 (s, 5H), 2.0–0.8
(br m, 12H). 13C NMR (DMSO-d6): d 182.1, 174.2,
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Acknowledgements
This work was supported by NIH R33CA-86364, NIH
R33CA-99136, R01CA-098116 and NSF CHE-
0302122. The authors thank Ms. Amanda Enstrom for
editorial assistance.