Preparation of a useful synthetic precursor, 2-substituted 4(3h)-quinazolinone: Directed lithiation and N3-deprotection of 3-t-butoxycarbonyl-4(3h)-quinazolinone

Article abstract of DOI:10.3987/COM-01-9386

Directed lithiation of 3-t-butoxycarbonyl-4(3H)-quinazolinone using LDA was accomplished to afford 2-substituted 3-t-butoxycarbonyl-4(3H)-quinazolinones. The t-butoxycarbonyl group of these products was easily deprotected to give key intermediates for the

Full text of DOI:10.3987/COM-01-9386

HETEROCYCLES, Vol. 57, No. 2, 2002, pp. 323-326, Received, 7th November, 2001
PREPARATION
OF
A
USEFUL
SYNTHETIC
PRECURSOR,
2-SUBSTITUTED 4(3H)-QUINAZOLINONE: DIRECTED LITHIATION AND
3
N -DEPROTECTION OF 3-t-BUTOXYCARBONYL-4(3H)-
QUINAZOLINONE
Osamu Sugimoto,* Yasuhiro Yamauchi, and Ken-ichi Tanji*
Laboratory of Organic Chemistry, School of Food and Nutritional Sciences
University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan
Abstract – Directed lithiation of 3-t-butoxycarbonyl-4(3H)-quinazolinone using
LDA was accomplished to afford 2-substituted 3-t-butoxycarbonyl-4(3H)-
quinazolinones. The t-butoxycarbonyl group of these products was easily
deprotected to give key intermediates for the synthesis of quinazoline derivatives,
2-substituted 4(3H)-quinazolinones, in good yield.
INTRODUCTION
Fused pyrimidinones (fused hydroxypyrimidines) are well known as substrates for the synthesis of fused
1
2
halogenopyrimidines. Fused pyrimidinones react with phosphorus oxyhalide, phosphorus pentahalide,
3
or triphenylphosphine / N-halogenosuccinimide to give the corresponding fused halogenopyrimidines.
3
Recently, directed lithiation (hydrogen-lithium exchange reaction) of N -protected 4(3H)-quinazolinone
4
was reported by Smith, et al. This is a useful method for the introduction of an electrophilic substituent
into 4(3H)-quinazolinones, but it is difficult to convert the product, 2-substituted 4(3H)-quinazolinones,
3
into 2-substituted quinazolines because deprotection of the N -acylamino group is difficult. In this paper,
a synthetic route to 2-substituted 4(3H)-quinazolinones aimed at their conversion into 2-substituted
quinazolines is demonstrated.
RESULTS AND DISCUSSION
At first, directed lithiation of 4(3H)-quinazolinone was attempted, but only the starting material was
recovered when lithium diisopropylamide (LDA) or lithium 2,2,6,6-tetramethylpiperidide (LTMP) was
used as a lithiating reagent. These results would indicate that lithium amides such as LDA or LTMP
have insufficient reactivity to effect dilithiation of an aromatic ring to give the dilithio intermediate.
When n-butyllithium was used, 2-n-butyl-2,3-dihydro-4(1H)-quinazolinone was obtained in 40% yield

by the undesirable reaction of a nucleophilic attack by n-butyllithium at the 2-position of the substrate.
3
From these results, directed lithiation of N -protected 4(3H)-quinazolinones was planned. The
3
t-butoxycarbonyl group was expected to be favorable for the N -protection of 4(3H)-quinazolinone
because the N-t-butoxycarbonyl group can be readily deprotected by acids. As shown in Table 1,
directed lithiation of 3-t-butoxycarbonyl-4(3H)-quinazolinone (1) was carried out. The use of
n-butyllithium or LTMP followed by addition of pivalaldehyde gave the desired product (2) in 5%, 19%
yield, respectively (Entries 1,2). When 1.0-2.0 equivalent(s) of LDA was used, the product (2) was
obtained in 35% yield (Entries 3,4). Next, directed lithiation of 1 using a stoichiometric amount of LDA
followed by addition of a variety of carbonyl compounds (benzaldehyde, acetone, and cyclohexanone)
was undertaken to afford the corresponding products (3-5) in moderate yields. The structure of 2-5 was
identified by the disappearance of the C2-proton signal at 1H-NMR and elemental analysis.
Table 1. Directed lithiation of 3-t-butoxycarbonyl-4(3H)-quinazolinone
O
O
O
N
CO2Bu-t
CO2Bu-t
CO2Bu-t
N
N
N
i)
ii),iii)
Li
E
N
N
2-5
1
o
+
Reagents and conditions: i) Lithiating reagent / THF / -78 C, 10 min; ii) Electrophile; iii) H O .
3
Lithiating
reagent
Lithiating
reagent
Entry
1
Entry
Electrophile
-E (Product) Yield (%)
Electrophile
PhCH=O
-E (Product) Yield (%)
n-BuLi (1.1 eq)
t-BuCH=O -CH(OH)Bu-t (2)
5
LDA (1.0 eq)
LDA (1.0 eq)
LDA (1.0 eq)
5
6
7
-CH(OH)Ph (3)
42
42
48
LTMP (2.0 eq) t-BuCH=O -CH(OH)Bu-t (2)
2
3
4
19
Me C=O
-C(OH)Me (4)
2
2
t-BuCH=O -CH(OH)Bu-t (2)
t-BuCH=O -CH(OH)Bu-t (2)
LDA (1.0 eq)
LDA (2.0 eq)
C H C=O -C(OH)C H (5)
35
35
5
10
5 10
The compounds (2-5) were deprotected to give the corresponding products (6-9) using trifluoroacetic
acid in good yields as shown in Table 2. As the deprotected products (6-9) are expected to be converted
1-3
by the method using some halogenating reagents
5
into 2-substituted 4-halogenoquinazolines, which
would react with nucleophiles to introduce nucleophilic substituents at the 4-position of quinazoline
ring, this lithiation-deprotection method seems to be useful for the synthesis of quinazoline derivatives.
Table 2. Deprotection of N3-t-butoxycarbonyl group of 4(3H)-quinazolinone derivatives
O
O
Entry
-E (Product) Yield (%)
CO2Bu-t
1
2
3
-CH(OH)Bu-t (6)
-CH(OH)Ph (7)
-C(OH)Me2 (8)
-C(OH)C5H10 (9)
92
68
76
91
N
NH
TFA
dichloromethane
E
E
N
N
4
2-5
6-9

In conclusion, we have accomplished a novel synthesis of 2-substituted 4(3H)-quinazolinones as a
synthetic precursor of 2-substituted quinazolines using the directed lithiation and deprotection of the
3
N -t-butoxycarbonyl group.
EXPERIMENTAL
1
All melting points were not corrected. H-NMR spectra were measured with HITACHI R-90H
spectrometer using TMS as an internal standard.
Synthesis of 3-t-butoxycarbonyl-4(3H)-quinazolinone (1): To a suspension of 4(3H)-quinazolinone
(2923 mg, 20.0 mmol) in THF (250 mL), sodium hydride (60% in oil, 880 mg, 22.0 mmol) was added
little by little and stirred for 2.5 h. A solution of di-t-butyl dicarbonate (6548 mg, 30.0 mmol) in THF
(50 mL) was added to the mixture, stirred for further 45 min. The reaction mixture was quenched with
water and extracted with ethyl acetate (400 mL). The organic layer was purified with silica gel
chromatography (eluted with hexane-ethyl acetate (3:1)) to give 1 (3666 mg, 74%) as a pale yellow oil.
1H-NMR (CDCl3) ppm: 1.66 (9H, s, OBu-t), 7.37-7.90 (3H, m, C6, C7 and C8-H), 8.31 (1H, dd, J=7.1 Hz,
0.8 Hz, C5-H), 8.45 (1H, s, C2-H). Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found: C,
63.50; H, 5.73; N, 11.64.
Reaction of 1 with organolithiums (General procedure of Table 1): To a solution of 1 (498 mg, 2.00
mmol) in dry THF (30 mL), organolithium solution (2.00-4.00 mmol) was added dropwise so as to keep
o
the inside temperature –78 C and stirred for 10 min. Electrophile (10.0 mmol) was added and the
mixture was raised to rt. The reaction mixture was quenched and neutralized with 1 N hydrochloric acid,
extracted with ethyl acetate. The organic layer was purified with silica gel chromatography (Eluate:
shown below) to give the corresponding product.
2,2-Dimethyl-1-(3-t-butoxycarbonyl-4(3H)-quinazolinon-2-yl)-1-propanol (2): White needles (recryst.
o
1
from hexane-ethyl acetate). mp 191-192 C. Eluate=hexane-ethyl acetate (4:1-1:1). H-NMR (CDCl3)
ppm: 1.09 (9H, s, CBu-t), 1.47 (9H, s, OBu-t), 5.26 (1H, s, CH), 7.39-7.61 (1H, m, C6-H), 7.65-7.93 (2H,
m, C7 and C8-H), 8.31 (1H, d, J=7.7 Hz, C5-H), 9.35 (1H, br s, OH). Anal. Calcd for C18H24N2O4: C,
65.04; H, 7.28; N, 8.43. Found: C, 64.97; H, 7.29; N, 8.57.
(3-t-Butoxycarbonyl-4(3H)-quinazolinon-2-yl)phenylmethanol (3): White powder (recryst. from
o
1
hexane-ethyl acetate). mp 193 C. Eluate=hexane-ethyl acetate (2:1-1:1). H-NMR (CDCl3) ppm: 1.47
(9H, s, OBu-t), 4.69 (1H, s, OH), 6.48 (1H, s, CH), 7.15-7.84 (8H, m, C6, C7, C8 and phenyl-H), 8.27
(1H, d, J=7.7 Hz, C5-H). Anal. Calcd for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95. Found: C, 68.07; H,
5.74; N, 8.10.
2-(3-t-Butoxycarbonyl-4(3H)-quinazolinon-2-yl)-2-propanol (4): White plates (recryst. from
o
1
hexane-ethyl acetate). mp 144-146 C. Eluate=hexane-ethyl acetate (2:1-1:1). H-NMR (CDCl3) ppm:
1.41 (9H, s, t-Bu), 1.87 (6H, s, C(CH3)2), 7.35-7.89 (3H, m, C6, C7 and C8-H), 8.31 (1H, d, J=8.1 Hz,
C5-H), 9.85 (1H, br s, OH). Anal. Calcd for C16H20N2O4: C, 63.14; H, 6.62; N, 9.20. Found: C, 63.12; H,

6.60; N, 9.07.
1-(3-t-Butoxycarbonyl-4(3H)-quinazolinon-2-yl)cyclohexanol (5): White needles (recryst. from
o
1
hexane-ethyl acetate). mp 199-203 C. Eluate=hexane-ethyl acetate (2:1-1:1). H-NMR (CDCl3) ppm:
1.20-2.53 (10H, m, cyclohexyl-H), 1.41 (9H, s, OBu-t), 7.32-7.58 (1H, m, C6-H), 7.58-7.80 (2H, m, C7
and C8-H), 8.27 (1H, d, J=7.5 Hz, C5-H), 9.53 (1H, br s, OH). Anal. Calcd for C19H24N2O4: C, 66.26; H,
7.02; N, 8.13. Found: C, 66.25; H, 6.94; N, 8.10.
Deprotection of N-t-Butoxycarbonyl group (General procedure of Table 2): TFA was added to a solution
of the substrate (2-5) in dichloromethane (12 mL) at rt and stirred until the reaction was complete
(checked by TLC). The reaction mixture was neutralized by 1 N sodium hydrooxide, extracted with
dichloromethane. Organic layer was dried over sodium sulfate and purified with silica gel
chromatography to give the product.
2,2-Dimethyl-1-(4(3H)-quinazolinon-2-yl)-1-propanol (6): Colorless prisms (recryst. from hexane-ethyl
o
1
acetate). mp 169-172 C. H-NMR (CDCl3) ppm: 1.06 (9H, s, t-Bu), 3.74 (1H, d, J=5.5 Hz, OH), 4.37
(1H, d, J=5.5 Hz, CH), 7.30-7.88 (3H, m, C6, C7 and C8-H), 8.26 (1H, dd, J=7.6 Hz, 0.9 Hz, C5-H),
10.59 (1H, br s, NH). Anal. Calcd for C13H16N2O2: C, 67.21; H, 6.94; N, 12.06. Found: C, 67.21; H,
6.80; N, 12.01.
Phenyl(4(3H)-quinazolinon-2-yl)methanol (7): Pale yellow needles (recryst. from hexane-ethyl acetate).
mp 213-215 oC. 1H-NMR (DMSO-d6) ppm: 5.46 (1H, br s, CH), 6.26 (1H, br s, OH), 7.06-7.85 (8H, m,
C6, C7, C8 and phenyl-H), 7.97 (1H, d, J=8.1 Hz, C5-H), 12.30 (1H, brs, NH). Anal. Calcd for
C15H12N2O2: C, 71.40; H, 4.79; N, 11.10. Found: C, 71.60; H, 4.80; N, 10.92.
2-(4(3H)-Quinazolinon-2-yl)-2-propanol (8): Colorless prisms (recryst. from hexane-ethyl acetate). mp
o
1
159-161 C. H-NMR (CDCl3) ppm: 1.72 (6H, s, C(CH3)2), 3.93 (1H, s, OH), 7.32-7.60 (1H, m,
C6-H), 7.60-7.93 (2H, m, C7 and C8-H), 8.30 (1H, d, J=8.1 Hz, C5-H), 11.08 (1H, br s, NH). Anal. Calcd
for C11H12N2O2: C, 64.70; H, 5.92; N, 13.72. Found: C, 64.75; H, 5.91; N, 13.52.
1-(4(3H)-Quinazolinon-2-yl)cyclohexanol (9): Colorless prisms (recryst. from hexane-ethyl acetate). mp
202 oC. 1H-NMR (CDCl3) ppm: 1.10-2.40 (10H, m, cyclohexyl-H), 3.73 (1H, s, OH), 7.30-7.60 (1H, m,
C6-H), 7.60-7.90 (2H, m, C7 and C8-H), 8.26 (1H, d, J=8.1 Hz, C5-H), 10.86 (1H, br s, NH). Anal. Calcd
for C14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.84; H, 6.60; N, 11.62.
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