Regioselective lithiation of chiral 3-acylamino-2-alkylquinazolin-4(3H)- ones: Application in synthesis

Article abstract of DOI:10.1055/s-2004-829169

Reaction of 3-amino-2-alkylquinazolin-4(3H)-ones with several chiral acid chlorides was found to be dependent on the molar proportions. When a 1:1 molar mixture was heated under reflux, the corresponding 3-(diacylamino)- derivatives were obtained in poor yields. However, when a 2:1 molar mixture was reacted in refluxing toluene, the 3-acylamino- derivatives were obtained in good yields based on the acid chloride. Lithiation of the 3-acylamino-2-alkyl-quinazolin- 4(3H)-ones was achieved by the use of lithium diisopropylamide (LDA) in anhydrous THF at -78°C and the reaction was regioselective at the carbon α to position 2 of the quinazolin-4(3H)-one moiety. The dilithio reagents thus obtained reacted with electrophiles to give the corresponding 2-substituted derivatives in very good yields. The NMR spectra of the products show the expected diastereotopism for all the CH₂ groups and provide evidence for long-range asymmetric induction.

Full text of DOI:10.1055/s-2004-829169

PAPER
2121
Regioselective Lithiation of Chiral 3-Acylamino-2-alkylquinazolin-4(3H)-
ones: Application in Synthesis
R
egioselective Lit
e
C
i
hiral
3
t
-Acyla
m
h
ino-2-alkylquinaz
S
olin-4(3
H
)-on
m
es ith,*a Gamal A. El-Hiti,a,1 Mohamed F. Abdel-Megeedb
a
Centre for Clean Chemistry, Department of Chemistry, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, UK
Fax +44(1792)295261; E-mail: k.smith@swansea.ac.uk
b
Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt
Received 14 May 2004
tempted. However, 1 was recovered unchanged, suggest-
ing that no reaction had occurred under these conditions.
A series of experiments was conducted in which the reac-
tion conditions were varied in an attempt to produce the
Abstract: Reaction of 3-amino-2-alkylquinazolin-4(3H)-ones with
several chiral acid chlorides was found to be dependent on the molar
proportions. When a 1:1 molar mixture was heated under reflux, the
corresponding 3-(diacylamino)- derivatives were obtained in poor
yields. However, when a 2:1 molar mixture was reacted in refluxing corresponding acylamino derivatives. When a 1:1 molar
toluene, the 3-acylamino- derivatives were obtained in good yields
mixture of 1 and an acid chloride in the presence of Et3N
based on the acid chloride. Lithiation of the 3-acylamino-2-alkyl-
was heated under reflux in anhydrous toluene for one
quinazolin-4(3H)-ones was achieved by the use of lithium diisopro-
hour, the corresponding diacylamino derivative 2 or 3 was
pylamide (LDA) in anhydrous THF at –78 °C and the reaction was
obtained in 41% or 25% isolated yield, respectively
regioselective at the carbon a to position 2 of the quinazolin-4(3H)-
(Scheme 1). The monoacylamino derivative (5 or 8) was
formed in only low yield and a substantial quantity of un-
reacted 1 remained.
one moiety. The dilithio reagents thus obtained reacted with electro-
philes to give the corresponding 2-substituted derivatives in very
good yields. The NMR spectra of the products show the expected
diastereotopism for all the CH2 groups and provide evidence for
long-range asymmetric induction.
O
O
N(COCHR1R2)2
Et
Key words: lithiation, quinazolin-4(3H)-ones, dilithio reagent,
asymmetric induction, diastereotopism
NH2
Et
N
N
R1R2CHCOCl
reflux
N
N
2 R1 = OPh, R2 = Me (41%)
3 R1 = Ph, R2 = Et (25%)
1
Directed metallation2,3 has found wide use in regioselec-
tive introduction of functional substituents into aromatic
and heterocyclic compounds. However, there are relative-
ly few examples concerning directed metallation of
quinazolin-4(3H)-ones to afford more complex substitut-
ed derivatives.4–13 Compounds possessing this ring sys-
tem are of interest because they show a variety of
biological activities.14 In continuation of our own interest
in the use of lithiation reactions for organic synthesis,15
we have demonstrated the lithiation of various quinazolin-
4(3H)-ones,6–8 including simple 3-acylamino deriva-
tives.9,10 We now report a study of the scope of the lithia-
tion reaction for more complex 3-acylamino-2-
alkylquinazolin-4(3H)-ones containing chiral acyl units.
We have been able to achieve regioselective lithiation of
a range of such quinazolin-4(3H)-ones by the use of lithi-
um diisopropylamide (LDA), and the synthesis of more
complex 2-substituted derivatives in good yields. The
products also show evidence of long-range asymmetric
induction.
Scheme 1
Product 2 appeared from its NMR spectra as a mixture of
two racemic diastereoisomers in unequal proportions,
while product 3 appeared from its 1H NMR spectrum as a
pair of racemic diastereoisomers in approximately equal
proportions. The H NMR spectrum of 3 showed diaste-
reotopism for the hydrogens of the CH2 groups at position
1
2 and in the acyl units.
In a modified procedure for the attempted synthesis of a
chiral 3-acylamino-2-alkylquinazolin-4(3H)-one a 2:1
molar mixture of 3-amino-2-ethylquinazolin-4(3H)-one
(1) and 2-phenoxypropanoyl chloride was heated under
reflux in anhydrous toluene for 1 hour in the presence of
Et3N. Work-up gave the desired product 5 in 78% yield.
Therefore, these conditions were applied in the synthesis
of a range of products (5–10, Scheme 2) derived from
both 1 and 3-amino-2-propylquinazolin-4(3H)-one (4)17
with a variety of acid chlorides. This procedure afforded
products 5–10 in very good yields based on the acid chlo-
ride (Table 1).
The first stage of this study required the synthesis of rep-
resentative chiral 3-acylamino-2-alkylquinazolin-4(3H)-
ones. Initially, reactions of 3-amino-2-ethylquinazolin-
4(3H)-one (1)16 with chiral but racemic acid chlorides in
the presence of Et3N at 0 °C or room temperature were at-
Products 5–10 appear from their NMR spectra as mixtures
of two diastereoisomers in unequal proportions, due to re-
stricted rotation around the N–N axis.18 The spectra also
showed diastereotopism for the CH2 protons of the ethyl
and propyl groups (see experimental section for details).
SYNTHESIS 2004, No. 13, pp 2121–2130
x
x.
x
x
.
2
0
0
4
Advanced online publication: 27.07.2004
DOI: 10.1055/s-2004-829169; Art ID: P04704SS
© Georg Thieme Verlag Stuttgart · New York
1
The H NMR spectra were temperature dependent and

2122
K. Smith et al.
PAPER
Table 2 Syntheses of Products 13–27 According to Scheme 3
O
N
O
NH2
NHCOCHR1R2
CH2R
Com-
pound
R
R1
R2
E
Yield
(%)a
N
N
0.5 R1R2CHCOCl
reflux
CH2R
N
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Et
OPh
OPh
OPh
Ph2C(OH)
80
82
78
79
76
80
79
77
75
88
76
80
90
80
78
1 R = Me
4 R = Et
5–10
PhCH(OH)
PhC(OH)Me
Scheme 2
1-naphthyl Ph2C(OH)
Table 1 Synthesis of Products 5–10 According to Scheme 2
OPh
OPh
OPh
Ph
Ph2C(OH)
Compound
R
R1
Me
Me
Et
R2
Yield (%)a
78
Et
PhCH(OH)
PhC(OH)Me
Ph2C(OH)
5
6
Me
Me
Me
Me
Et
OPh
Et
1-naphthyl 74
Et
7
OPh
Ph
80
79
90
93
Et
Ph
EtC(OH)Me
Ph2C(OH)
8
Et
Me
Me
Me
Et
OPh
OPh
OPh
OPh
OPh
OPh
9
Me
Et
OPh
H
Et
PhCH(OH)
PhC(OH)Me
Ph2C(OH)
10
Et
Et
a Yields of isolated, purified products based on acid chloride added.
Et
Et
Et
PhCH(OH)
PhC(OH)Me
showed some evidence of equilibration at 55–60 °C in
CDCl3. In DMSO-d6, the spectra showed a single set of
signals at 150 °C in all cases.
Et
Et
a Yields of isolated, purified (column chromatography) products.
In order to introduce more complex substituents at posi-
tion 2, lithiations of 5–10 were carried out. Lithiation was
achieved by the use of LDA in anhydrous THF at –78 °C
under N2 and the reaction was regioselective at the carbon
a to position 2 of the quinazolin-4(3H)-one moiety. Addi-
tion of one equivalent of LDA presumably produced the
monolithio reagents 11, which were converted into the
dilithio reagents 12 on addition of a second equivalent of
LDA. Reactions of the dilithio reagents 12 with several
electrophiles (benzophenone, benzaldehyde, acetophe-
none, 2-butanone) afforded the corresponding 2-substitut-
ed quinozolin-4(3H)-ones 13–27 (Scheme 3) in very good
yields (Table 2) following column chromatography.
The NMR spectra of all products containing a CH2 group
either in the side chain at position 2 or in the acylamino
group (compounds 17–27) showed the expected diaste-
reotopism for the CH2 protons. In addition, the spectra (of
the total product obtained following chromatography to
remove coloured impurities) revealed the presence of dia-
stereoisomers.
The number of diastereoisomers of the product expected
when benzophenone is used as the electrophile is four. In-
deed, it was found that the NMR spectra of products 13,
22 and 25 showed a mixture of the expected four diaste-
reoisomers in unequal proportions. However, the NMR
spectra of products 17 and 20 showed the predominant
presence of two substantial diastereoisomers in unequal
proportions, while in the case of product 16, there were
two major diastereoisomers in approximately equal pro-
portions.
O
O
CHR1R2
NHCOCHR1R2
N
N
N
LDA, THF
–78 °C
OLi
CH2R
N
N
CH2R
5–10
11
Product 13 was separated into two fractions by crystalli-
sation. The first fraction (13a, 60%) showed the presence
of a single diastereoisomer. The x-ray crystallography of
this compound (Figure 1) indicated the presence of one
THF molecule for each molecule of 13a. The THF ap-
peared to be hydrogen-bonded to the NH proton of the
acylamino group. The crystal structure also showed that
this isomer was 2-[(1S*)-2,2-diphenyl-2-hydroxy-1-
methyl]-3-[(2R*)-2-phenoxypropionylamino]quinazolin-
4(3H)-one with (Ra*) configuration about the N–N axis.
The second fraction (40%) showed the presence of all four
diastereoisomers, with 13a being a minor component.
LDA, THF
–78 °C
O
O
NHCOCHR1R2
N
N
CHR1R2
N
i, Electrophile
ii, aq. NH4Cl
OLi
N
CHR
E
N
CHR
Li
13–27
12
Scheme 3
Synthesis 2004, No. 13, 2121–2130 © Thieme Stuttgart · New York

PAPER
Regioselective Lithiation of Chiral 3-Acylamino-2-alkylquinazolin-4(3H)-ones
2123
broadening, but it was still not clear whether the two ma-
jor isomers had different configurations at the new asym-
metric carbon atoms or whether they differed about the
N–N axis.
When an unsymmetrical carbonyl compound (benzalde-
hyde, acetophenone or 2-butanone) is used as electro-
phile, the number of diastereoisomers expected to be
formed is eight. The ambient temperature NMR spectra of
21 (2-butanone used as the electrophile) showed the pres-
ence of at least seven racemic diastereoisomers in unequal
proportions. However, the ambient temperature NMR
spectra of products 14, 15, 18, 19 and 24 showed mixtures
of no more than four substantial diastereoisomers in un-
equal proportions. Furthermore, for this group of prod-
ucts, the 1H NMR spectra recorded at 100 °C showed the
presence of only two major diastereoisomers in unequal
proportions, which indicates equilibration via rotation
about the N–N axis. In the case of products 23, 26 and 27
the ambient temperature NMR spectra showed mixtures
of only two significant diastereoisomers in unequal pro-
portions, which indicates a considerable long-range asym-
metric induction. Unfortunately, an attempt to bring about
Figure 1 X-ray crystal structure of 13a with numbered crystallogra-
phic atoms
1
Variable temperature H NMR of 13a up to 60 °C in
CDCl3 showed only minimal line broadening. However, a
sample of 13a left at room temperature for many months,
1
equilibration in these cases by recording the H NMR at
150 °C resulted in some decomposition to give benzalde-
hyde or acetophenone.
1
showed a H NMR spectrum corresponding to a mixture
of 13a and one other diastereoisomer, presumably the one
involving the alternative stereochemistry (Sa*) about the
N–N axis. This enabled identification of the two diaste-
reoisomers having the same configuration at the new
In conclusion, lithiation of chiral 3-acylamino-2-alkyl-
quinazolin-4(3H)-ones followed by reactions with carbo-
nyl compounds is useful for the elaboration of more
complex 2-substituted 3-acylaminoquinazolin-4(3H)-
ones, and in some cases gives considerable long-range
asymmetric induction at the newly created asymmetric
centre(s). This opens up possibilities for novel synthetic
approaches to certain types of chiral compounds, which
we intend to investigate.
1
asymmetric carbon atom. The H NMR spectrum of the
second fraction (mixture) showed that these two compo-
nents accounted for about 18% of the fraction, i.e. about
7% of the total product, bringing the total amount of the
isomers having that stereochemistry at the new asymmet-
ric carbon atom to around 67%. The other two diastereo-
isomers, having the alternative configuration at the new
asymmetric carbon atom, accounted for the remaining
33% or so. Therefore, the new asymmetric centre is
formed with a 2:1 stereoselectivity. Although this selec-
tivity is relatively small, it is nevertheless noteworthy,
since it represents a long-range asymmetric inductive ef-
fect (the two asymmetric carbon atoms have a 1,6-rela-
tionship).
Melting point determinations were performed by the open capillary
method using a Gallenkamp melting point apparatus and are report-
ed uncorrected. The laboratories of the University of Wales Cardiff
carried out microanalyses. 1H and 13C NMR spectra were recorded
on a Bruker AC400 spectrometer operating at 400 MHz for 1H and
100 MHz for 13C measurements. Chemical shifts are reported rela-
tive to TMS. Assignments of signals are based on coupling patterns
and expected chemical shift values and have not been rigorously
confirmed. Signals with similar characteristics might be inter-
changed. Low-resolution mass spectra were recorded on a VG 12-
253 spectrometer, electron impact (EI) at 70 eV and chemical ion-
ization (CI) by the use of NH3 as ionization gas. FAB mass spectra
were recorded on a VG-Autospec instrument. Accurate mass data
were obtained on a VG ZAB-E instrument. Column chromatogra-
phy was carried out using Merck Kieselgel 60 (230–400 mesh).
Lithium diisopropylamide (LDA) and other chemicals were ob-
tained from Aldrich Chemical Company and used without further
purification. THF was distilled from sodium benzophenone ketyl.
Other solvents were purified by standard procedures.19,20
For product 17, the two major diastereoisomers had the
same configuration at the new asymmetric carbon atom.
This was deduced by the fact that the newly created CH
signals for those two isomers in the 1H NMR spectrum be-
gan to coalesce at 60 °C. Furthermore, the chemical shift
positions were virtually identical to those for 13a and its
N–N isomer. The two major diastereoisomers accounted
for about 80% of the total, leading to the conclusion that
the long-range asymmetric induction produced a ratio of
configurations at the new centre of ca. 4:1.
For products 16 and 20, the NMR signals were more dif-
ficult to resolve and it was therefore much more difficult
to identify the individual diastereoisomers with any confi-
dence, although it was clear, particularly from the 13C
NMR spectra, that two diastereoisomers were predomi-
3-(Diacylamino)-2-ethylquinazolin-4(3H)-ones2 and 3;General
Procedure
To a stirred mixture of 1 (1.9 g, 10 mmol) and Et3N (5 mL) in anhyd
toluene (20 mL), was added a solution of the appropriate acid chlo-
ride (11 mmol) in anhyd toluene (5 mL). The mixture was heated
under reflux for 30 min, allowed to cool, washed with sat. aq
1
nant. At 60 °C the H NMR spectra showed some line
Synthesis 2004, No. 13, 2121–2130 © Thieme Stuttgart · New York

2124
K. Smith et al.
PAPER
NaHCO3 (2 × 10 mL) and H2O (2 × 15 mL), dried (MgSO4), and
evaporated under reduced pressure. The residue obtained was puri-
fied by column chromatography on silica gel (Et2O–hexane, 1:4) to
give 2 or 3 as a white powder.
ride (5 mmol) in anhyd toluene (5 mL). The mixture was heated un-
der reflux for 30 min, allowed to cool, washed with sat. aq NaHCO3
(2 × 10 mL) and H2O (2 × 15 mL), dried (MgSO4), and evaporated
under reduced pressure. The residue obtained was purified by col-
umn chromatography on silica gel (Et2O–hexane, 1:4) to give the
corresponding 3-acylamino derivatives 5–10. The yields obtained
are recorded in Table 1.
2-Ethyl-3-[di(2-phenoxypropionyl)amino]quinazolin-4(3H)-
one (2)
Mp 104–107 °C; pair of racemic diastereoisomers, 2a/2b = 3:5 (1H
NMR).
2-Ethyl-3-(2-phenoxypropionylamino)quinazolin-4(3H)-one (5)
Mp 90–92 °C; 5a/5b = 1:2 (1H NMR).
EI–MS: m/z (%) = 337 (22) [M+], 244 (13), 216 (100), 173 (32), 130
FAB–MS: m/z (%) = 508 (20) [M+ + Na], 486 (67) [MH+], 392 (10),
338 (31), 216 (33), 121 (100).
(34), 121 (81), 77 (99).
HRMS: m/z [M+] calcd for C19H19N3O3: 337.1426; found:
HRMS: m/z [MH+] calcd for C28H28N3O5: 486.2029; found:
486.2017.
337.1426.
Compound 2a
Anal. Calcd for C19H19N3O3: C, 67.65; H, 5.64; N, 12.46. Found: C,
67.6; H, 5.6; N, 12.6.
1H NMR (CDCl3): d = 8.17 (dd, J = 8, 1 Hz, 1 H, H5), 7.69 (approx.
dt, J = 8, 1 Hz, 1 H, H7), 7.48 (d, J = 8 Hz, 1 H, H8), 7.41 (approx.
dt, J =8, 1 Hz, 1 H, H6), 7.26–6.74 (m, 10 H, 2 × OPh), 5.43 (q, J =
6.5 Hz, 2 H, 2 × CH), 2.27 (q, J = 7 Hz, 2 H, CH2), 1.52 (d, J = 6.5
Hz, 6 H, 2 × CH3CH), 1.09 (t, J = 7 Hz, 3 H, CH3CH2).
Compound 5a
1H NMR (CDCl3): d = 8.73 (s, exch., 1 H, NH), 8.16 (dd, J = 8, 1
Hz, 1 H, H5), 7.72 (m, 1 H, H7), 7.64 (d, J = 8 Hz, 1 H, H8), 7.41
(approx. dt, J = 8, 1 Hz, 1 H, H6), 7.35 (t, J = 7.5 Hz, 2 H, H3 of
OPh), 7.07 (t, J = 7.5 Hz, 2 H, H2 of OPh), 6.99 (d, J = 7.5 Hz, 1 H,
H4 of OPh), 4.97 (q, J = 7 Hz, 1 H, CH), 2.44 (2 × dq, J = 15, 7.5
Hz, 2 H, CH2), 1.81 (d, J = 7 Hz, 3 H, CH3CH), 1.06 (t, J = 7.5 Hz,
3 H, CH3CH2).
13C NMR (CDCl3): d = 172.6 (s, C=O), 160.2 (s, C4), 157.1 (s, C2),
156.8 (s, C1 of 2 × OPh), 146.6 (s, C8a), 135.2 (d, C7), 129.7 (d, C3
of OPh), 127.6 (d, C5), 127.0 (d, C6), 126.8 (d, C8), 122.4 (d, C4 of
OPh), 120.3 (s, C4a), 115.3 (d, C2 of OPh), 72.9 (d, CH), 25.5 (t,
CH2), 17.8 (q, CH3CH), 9.7 (q, CH3CH2).
13C NMR (CDCl3): d = 172.8 (s, C=O), 159.9 (s, C4), 158.5 (s, C2),
156.8 (s, C1 of OPh), 147.0 (s, C8a), 134.8 (d, C7), 129.9 (d, C3 of
OPh), 127.5 (d, C5), 126.9 (d, C6), 126.7 (d, C8), 122.5 (d, C4 of
OPh), 120.6 (s, C4a), 115.2 (d, C2 of OPh), 74.7 (d, CH), 27.0 (t,
CH2), 18.8 (q, CH3CH), 10.5 (q, CH3CH2).
Compound 2b
1H NMR (CDCl3): d = 8.17 (dd, J = 8, 1 Hz, 1 H, H5), 6.69 (approx.
dt, J = 8, 1 Hz, 1 H, H7), 7.53 (d, J = 8 Hz, 1 H, H8), 7.41 (approx.
dt, J = 8, 1 Hz, 1 H, H6), 7.26–6.60 (m, 10 H, 2 × OPh), 5.83 (q,
J = 6.5 Hz, 2 H, 2 × CH), 2.31 (q, J = 7 Hz, 2 H, CH2), 1.64 (d, J =
6.5 Hz, 6 H, 2 × CH3CH), 1.18 (t, J = 7 Hz, 3 H, CH3CH2).
Compound 5b
13C NMR (CDCl3): d = 171.8 (s, C=O), 160.2 (s, C4), 157.2 (s, C2),
155.7 (s, C1 of OPh), 146.6 (s, C8a), 135.3 (d, C7), 129.6 (d, C3 of
OPh), 127.7 (d, C5), 127.1 (d, C6), 126.8 (d, C8), 122.0 (d, C4 of
OPh), 120.3 (s, C4a), 115.0 (d, C2 of OPh), 73.4 (d, CH), 25.6 (t,
CH2), 17.8 (q, CH3CH), 9.8 (q, CH3CH2).
1H NMR (CDCl3): d = 8.93 (s, exch., 1 H, NH), 8.12 (d, J = 8 Hz, 1
H, H5), 7.72 (m, 1 H, H7), 7.64 (d, J = 8 Hz, 1 H, H8), 7.41 (approx.
dt, J = 8, 1 Hz, 1 H, H6), 7.35 (t, J = 7.5 Hz, 2 H, H3 of OPh), 7.07
(t, J = 7.5 Hz, 2 H, H2 of OPh), 6.99 (d, J = 7.5 Hz, 1 H, H4 of OPh),
4.95 (q, J = 7 Hz, 1 H, CH), 2.81 (2 × dq, J = 15, 7.5 Hz, 2 H, CH2),
1.68 (d, J = 7 Hz, 3 H, CH3CH), 1.34 (t, J = 7.5 Hz, 3 H, CH3CH2).
2-Ethyl-3-[di(2-phenylbutyryl)amino]quinazolin-4(3H)-one (3)
Mp 155–156 °C; pair of racemic diastereoisomers (NMR).
13C NMR (CDCl3): d = 172.6 (s, C=O), 159.9 (s, C4), 158.4 (s, C2),
156.8 (s, C1 of OPh), 147.0 (s, C8a), 134.8 (d, C7), 129.9 (d, C3 of
OPh), 127.5 (d, C5), 126.9 (d, C6), 126.7 (d, C8), 122.9 (d, C4 of
OPh), 120.7 (s, C4a), 116.5 (d, C2 of OPh), 75.8 (d, CH), 26.8 (t,
CH2), 18.7 (q, CH3CH), 10.6 (q, CH3CH2).
1H NMR (CDCl3): d = 8.30 (dd, J = 8, 1 Hz, 1 H, H5), 7.80 (approx.
dt, J = 8, 1 Hz, 1 H, H7), 7.68 (d, J = 8 Hz, 1 H, H8), 7.50 (approx.
dt, J = 8, 1 Hz, 1 H, H6), 7.33 (m, 4 H, H3 of 2 × Ph), 7.12 (m, 4 H,
H2 of 2 × Ph), 6.70 (d, J = 7.5 Hz, 2 H, H4 of 2 × Ph), 4.98, 3.23 (2
× t, J = 7 Hz, 2 H, 2 × CH), 2.24, 2.14 (2 × dq, J = 14, 7 Hz, 2 H,
CH2CH3), 1.85–1.68 (m, 2 H, CH2CH), 1.30–0.93 (m, 2 H,
CH2CH), 0.93, 0.80 (2 × t, J = 7 Hz, 6 H, 2 × CH3CH2CH), 0.57 (t,
J = 7 Hz, 3 H, CH3CH2).
13C NMR (CDCl3): d = 174.2, 173.9 (2 × s, C=O), 160.4 (s, C4),
158.2 (s, C2), 147.0 (s, C8a), 137.8, 136.6 (2 × s, C1 of Ph), 135.3
(d, C7), 129.0, 128.9 (2 × d, C3 of Ph), 128.5, 128.4 (2 × d, C4 of
Ph), 127.8, 127.7 (2 × d, C2 of Ph), 127.5 (d, C5), 127.4 (d, C6),
126.8 (d, C8), 120.5 (s, C4a), 54.0, 53.5 (2 × d, CH), 27.7, 27.0 (2
× t, CH2CH), 24.3 (t, CH3CH2), 11.9, 11.7 (2 × q, CH3CH2CH), 9.5
(q, CH3CH2).
2-Ethyl-3-[2-(1-naphthalene)propionylamino]quinazolin-
4(3H)-one (6)
Mp 180–182 °C; 6a/6b = 5:6 (13C NMR).
1H NMR (CDCl3): d = 8.20–7.37 (m, 12 H, ArH, NH), 4.71–4.62
(m, 1 H, CH), 2.54–2.28 (m, 2 H, CH2), 1.89, 1.74 (2 × d, J = 7 Hz,
3 H, CH3CH), 0.99 (t, J = 7.5 Hz, 3 H, CH3CH2).
EI–MS: m/z (%) = 371 (5) [M+], 216 (40), 182 (38), 155 (100), 153
(34), 130 (15), 115 (9), 90 (8), 76 (10).
CI–MS: m/z (%) = 372 (7) [MH+], 217 (9), 175 (100), 159 (7), 91
(6).
HRMS: m/z [MH+] calcd for C23H21N3O2: 371.1634; found:
371.1634.
FAB–MS: m/z (%) = 504 (23) [M+ + Na], 482 (69) [MH+], 336 (86),
216 (36), 190 (36), 119 (100).
HRMS: m/z [MH+] calcd for C30H32N3O3: 482.2444; found:
482.2459.
Compound 6a
13C NMR (CDCl3): d = 175.0 (s, C=O), 160.2 (s, C4), 158.8 (s, C2),
146.9 (s, C8a), 136.0 (s, C1¢), 134.8 (d, C7), 133.8 (s, C4¢a), 131.1
(s, C8¢a), 129.1 (d, C5¢), 128.7 (d, C5), 127.8 (d, C6), 126.8 (d, C8),
126.7 (d, C3¢), 126.5 (d, C2¢), 126.1 (d, C4¢), 125.8 (d, C7¢), 124.9
(d, C6¢), 123.2 (d, C8¢), 120.6 (s, C4a), 42.0 (d, CH), 26.8 (t, CH2),
17.7 (q, CH3CH), 10.5 (q, CH3CH2).
3-Acylamino-2-alkylquinazolin-4(3H)-ones 5–10; General Pro-
cedure
To a stirred mixture of 1 or 4 (10 mmol) and Et3N (3 mL) in anhyd
toluene (20 mL), was added a solution of the appropriate acid chlo-
Synthesis 2004, No. 13, 2121–2130 © Thieme Stuttgart · New York

PAPER
Regioselective Lithiation of Chiral 3-Acylamino-2-alkylquinazolin-4(3H)-ones
2125
Compound 6b
(d, C8), 120.1 (d, C4 of Ph), 118.5 (s, C4a), 52.3 (d, CH), 26.6 (t,
13C NMR (CDCl3): d = 174.9 (s, C=O), 160.0 (s, C4), 158.7 (s, C2),
146.9 (s, C8a), 136.0 (s, C1¢), 134.7 (d, C7), 134.2 (s, C4¢a), 131.1
(s, C8¢a), 129.2 (d, C5¢), 128.5 (d, C5), 127.3 (d, C6), 126.8 (d, C8),
126.7 (d, C3¢), 126.5 (d, C2¢), 126.2 (d, C4¢), 125.9 (d, C7¢), 125.6
(d, C6¢), 122.8 (d, C8¢), 120.5 (s, C4a), 42.0 (d, CH), 26.9 (t, CH2),
17.6 (q, CH3CH), 10.5 (q, CH3CH2).
CH2CH), 25.4 (t, CH2), 12.1 (q, CH3CH2CH), 11.3 (q, CH3CH2).
Compound 8b
1H NMR (DMSO-d6): d = 11.38 (s, exch., 1 H, NH), 8.10 (d, J = 8
Hz, 1 H, H5), 7.99 (t, J = 8 Hz, 1 H H7), 7.75 (t, J = 8 Hz, 1 H, H6),
7.52–7.30 (m, 6 H, H8, Ph), 3.90 (t, J = 7 Hz, 1 H, CH), 3.34, 3.10
(2 × dq, J = 14, 7 Hz, 2 H, CH2CH), 2.22, 1.91 (2 × dq, J = 15, 7.5
Hz, 2 H, CH2), 1.44 (t, J = 7 Hz, 3 H, CH3CH2CH), 1.03 (t, J = 7.5
Hz, 3 H, CH3CH2).
2-Ethyl-3-(2-phenoxybutyrylamino)quinazolin-4(3H)-one (7)
Mp 93–94 °C; 7a/7b = 1:2 (1H NMR).
EI–MS: m/z (%) = 351 (10) [M+], 258 (7), 230 (13), 216 (60), 173
(40), 135 (100), 107 (65), 94 (31), 77 (75), 41 (43).
CI–MS: m/z (%) = 352 (10) [MH+], 197 (25), 176 (18), 175 (100),
136 (5), 105 (7), 58 (5).
13C NMR (DMSO-d6): d = 173.8 (s, C=O), 167.6 (s, C4), 155.7 (s,
C2), 138.7 (s, C8a), 138.0 (s, C1 of Ph), 136.4 (d, C7), 129.6 (d,
C5), 128.6 (d, C3 of Ph), 128.3 (d, C6), 128.2 (d, C2 of Ph), 127.6
(d, C8), 120.2 (d, C4 of Ph), 118.5 (s, C4a), 52.7 (d, CH), 26.60 (t,
CH2CH), 25.1 (t, CH2), 12.2 (q, CH3CH2CH), 11.9 (q, CH3CH2).
HRMS: m/z [M+] calcd for C20H21N3O3: 351.1583; found:
351.1583.
2-Propyl-3-(2-phenoxypropionylamino)quinazolin-4(3H)-one
(9)
Anal. Calcd for C20H21N3O3: C, 68.36; H, 6.02; N, 11.96. Found: C,
68.4; H, 6.2; N, 11.8.
Mp 87–89 °C; 9a/9b = 1:2 (1H NMR).
EI–MS: m/z (%) = 352 (12) [M+ + 1], 337 (20) [M+], 323 (100), 285
(35).
CI–MS: m/z (%) = 352 (16) [MH+], 189 (100), 183 (32), 91 (17).
HRMS: m/z [MH+] calcd for C20H22N3O3: 352.1661; found:
Compound 7a
1H NMR (CDCl3): d = 8.69 (s, exch., 1 H, NH), 8.16 (d, J = 8 Hz, 1
H, H5), 7.73 (approx. dt, J = 8, 1 Hz, 1 H, H7), 7.60 (d, J = 8 Hz, 1
H, H8), 7.40 (t, J = 8 Hz, 1 H, H6), 7.36 (t, J = 7.5 Hz, 2 H, H3 of
OPh), 7.18–6.99 (m, 3 H, H2, H4 of OPh), 4.78 (t, J = 7 Hz, 1 H,
CH), 2.41 (dq, J = 14, 7 Hz, 2 H, CH2CH), 2.18 (dq, J = 15, 7.5 Hz,
2 H, CH2), 1.20 (t, J = 7 Hz, 3 H, CH3CH2CH), 1.02 (t, J = 7.5 Hz,
3 H, CH3CH2).
352.1664.
Compound 9a
1H NMR (CDCl3): d = 8.98 (s, exch., 1 H, NH), 8.17 (dd, J = 8, 1
Hz, 1 H, H5), 7.76–7.60 (m, 2 H, H7, H8), 7.42 (approx. dt, J = 8,
1 Hz, 1 H, H6), 7.37–7.33 (m, 2 H, H3 of OPh), 7.10–7.06 (m, 1 H,
H4 of OPh), 7.00 (d, J = 7.5 Hz, 2 H, H2 of OPh), 4.96 (q, J = 7 Hz,
1 H, CH), 2.79–2.73 (m, 2 H, CH2), 1.79 (d, J = 7 Hz, 3 H, CHCH3),
1.63–1.49 (m, 2 H, CH2), 1.05 (t, J = 7.5 Hz, 3 H, CH3CH2).
13C NMR (CDCl3): d = 172.1 (s, C=O), 159.9 (s, C4), 158.5 (s, C2),
157.2 (s, C1 of OPh), 146. 9 (s, C8a), 134.8 (d, C7), 129.9 (d, C3 of
OPh), 127.0 (d, C5), 126.6 (d, C6), 126.5 (d, C8), 122.4 (d, C4 of
OPh), 120.5 (s, C4a), 115.1 (d, C2 of OPh), 79.5 (d, CH), 26.9 (t,
CH2CH), 26.5 (t, CH2), 10.5 (q, CH3CH2CH), 9.5 (q, CH3CH2).
13C NMR (CDCl3): d = 172.4 (s, C=O), 159.9 (s, C4), 157.5 (s, C1
of OPh), 156.8 (s, C2), 146.9 (s, C8a), 134.9 (d, C7), 129.9 (d, C3
of OPh), 126.9 (d, C5), 126.8 (d, C6), 126.6 (d, C8), 122.8 (d, C4 of
OPh), 120.7 (s, C4a), 116.5 (d, C2 of OPh), 75.7 (d, CH), 35.6 (t,
CH2), 20.0 (t, CH2), 18.7 (q, CH3CH), 13.9 (q, CH3CH2).
Compound 7b
1H NMR (CDCl3): d = 8.88 (s, exch., 1 H, NH), 8.16 (d, J = 8 Hz, 1
H, H5), 7.43 (approx. dt, J = 8, 1 Hz, 1 H, H7), 7.60 (d, J = 8 Hz, 1
H, H8), 7.40 (t, J = 8 Hz, 1 H, H6), 7.36 (t, J = 7.5 Hz, 2 H, H3 of
OPh), 7.18–6.99 (m, 3 H, H2, H4 of OPh), 4.78 (t, J = 7.4 Hz, 1 H,
CH), 2.87 (dq, J = 14, 7 Hz, 2 H, CH2CH), 2.08 (dq, J = 15, 7.5 Hz,
2 H, CH2), 1.33 (t, J = 7 Hz, 3 H, CH3CH2CH), 1.11 (t, J = 7.5 Hz,
3 H, CH3CH2).
Compound 9b
1H NMR (CDCl3): d = 8.75 (s, exch., 1 H, NH), 8.17 (dd, J = 8, 1
Hz, 1 H, H5), 7.76–7.60 (m, 2 H, H7, H8), 7.42 (approx. dt, J = 8,
1 Hz, 1 H, H6), 7.37–7.33 (m, 2 H, H3 of OPh), 7.10–7.06 (m, 1 H,
H4 of OPh), 7.00 (d, J = 7.5 Hz, 2 H, H2 of OPh), 4.94 (q, J = 7 Hz,
1 H, CH), 2.44–2.38 (m, 2 H, CH2), 1.83 (d, J = 7 Hz, 3 H, CH3CH),
1.63–1.49 (m, 2 H, CH2), 0.80 (t, J = 7.4 Hz, 3 H, CH3CH2).
13C NMR (CDCl3): d = 172.1 (s, C=O), 159.8 (s, C4), 158.3 (s, C2),
157.5 (s, C1 of OPh), 146. 9 (s, C8a), 134.8 (d, C7), 127.4 (d, C3 of
OPh), 127.0 (d, C5), 126.8 (d, C6), 126.7 (d, C8), 122.9 (d, C4 of
OPh), 120.6 (s, C4a), 116.7 (d, C2 of OPh), 80.9 (d, CH), 26.9 (t,
CH2CH), 26.1 (t, CH2), 10.3 (q, CH3CH2CH), 9.2 (q, CH3CH2).
13C NMR (CDCl3): d = 172.9 (s, C=O), 159.9 (s, C4), 157.7 (s, C1
of OPh), 156.9 (s, C2), 146.9 (s, C8a), 134.9 (d, C7), 130.0 (d, C3
of OPh), 127.4 (d, C5), 126.8 (d, C6), 126.6 (d, C8), 122.5 (d, C4 of
OPh), 120.5 (s, C4a), 116.5 (d, C2 of OPh), 74.6 (d, CH), 35.5 (t,
CH2), 19.9 (t, CH2), 18.9 (q, CH3CH), 13.6 (q, CH3CH2).
2-Ethyl-3-(2-phenylbutyrylamino)quinazolin-4(3H)-one (8)
Mp 180–183 °C; 8a/8b = 1:3 (1H NMR).
EI–MS: m/z (%) = 335 (5) [M+], 216 (40), 189 (17), 173 (12), 119
(65), 91 (100).
2-Propyl-3-(2-phenoxybutyrylamino)quinazolin-4(3H)-one (10)
Mp 115–117 °C; 10a/10b = 1:2 (1H NMR).
EI–MS: m/z (%) = 365 (4) [M+], 337 (6), 244 (15), 230 (30), 187
(20), 173 (20), 160 (60), 135 (45), 117 (34), 107 (40), 94 (43), 77
(100), 65 (35).
CI–MS: m/z (%) = 366 (30) [MH+], 197 (32), 189 (100), 173 (13),
136 (5), 105 (33).
HRMS: m/z [M+] calcd for C20H21N3O2: 335.1634; found:
335.1634.
Compound 8a
1H NMR (DMSO-d6): d = 11.66 (s, exch., 1 H, NH), 8.10 (d, J = 8
Hz, 1 H, H5), 7.99 (t, J = 8 Hz, 1 H, H7), 7.75 (t, J = 8 Hz, 1 H, H6),
7.52–7.30 (m, 6 H, H8, Ph), 3.98 (t, J = 7 Hz, 1 H, CH), 3.00, 3.62
(2 × dq, J = 14, 7 Hz, 2 H, CH2CH), 2.22, 1.91 (2 × dq, J = 15, 7.5
Hz, 2 H, CH2), 1.05 (t, J = 7 Hz, 3 H, CH3CH2CH), 1.00 (t, J = 7.5
Hz, 3 H, CH3CH2).
HRMS: m/z [MH+] calcd for C21H24N3O3: 366.1819; found:
366.1819.
13C NMR (DMSO-d6): d = 173.7 (s, C=O), 167.8 (s, C4), 155.9 (s,
C2), 138.7 (s, C8a), 138.0 (s, C1 of Ph), 136.7 (d, C7), 129.5 (d,
C5), 128.8 (d, C3 of Ph), 128.3 (d, C6), 128.0 (d, C2 of Ph), 127.6
Compound 10a
1H NMR (CDCl3): d = 8.39 (s, exch., 1 H, NH), 8.16 (m, 1 H, H5),
7.71 (m, 1 H, H7), 7.60 (d, J = 8 Hz, 1 H, H8), 7.44–7.00 (m, 6 H,
Synthesis 2004, No. 13, 2121–2130 © Thieme Stuttgart · New York

2126
K. Smith et al.
PAPER
H6, OPh), 4.81–4.77 (m, 1 H, CH), 2.74–2.70 (m, 2 H, CH2), 2.13–
2.81 (m, 2 H, CH2), 1.84–1.79 (m, 2 H, CH2), 1.12 (t, J = 7 Hz, 3 H,
CH3), 1.04 (t, J = 7.5 Hz, 3 H, CH3).
2-(2,2-Diphenyl-2-hydroxy-1-methylethyl)-3-(2-phenoxypropi-
onylamino)quinazolin-4(3H)-one (13)
Mp 171–173 °C; four diastereoisomers (NMR).
13C NMR (CDCl3): d = 172.1 (s, C=O), 159.8 (s, C4), 157.5 (s, C1
of OPh), 157.5 (s, C2), 146.9 (s, C8a), 134.8 (d, C7), 129.8 (d, C3
of OPh), 127.4 (d, C5), 126.8 (d, C6), 126.6 (d, C8), 122.4 (d, C4 of
OPh), 120.7 (s, C4a), 116.7 (d, C2 of OPh), 80.9 (d, CH), 35.7 (t,
CH2), 26.1 (t CH2), 20.0 (t, CH2), 13.8 (q, CH3), 9.1 (q, CH3).
1H NMR (CDCl3): d = 8.58, 8.55 (2 × s, exch., 1 H, NH), 8.09, 7.85
(2 × dd, J = 8, 1 Hz, 1 H, H5), 7.80–6.85 (m, 19 H, ArH, OH), 5.12,
5.02 (2 × q, J = 7 Hz, 1 H, CH), 4.36, 4.01, 3.96, 3.73 (4 × q, J = 7
Hz, 1 H, CH), 1.94, 1.86, 1.76 (3 × d, J = 7 Hz, 3 H, CH3), 1.36,
1.30, 0.75 (3 × d, J = 7 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 173.6, 173.4 (2 × s, C=O), 161.5 (s, C4),
159.1 (s, C2), 156.8 (s, C1 of OPh), 147.9 (s, C8a), 145.4, 145.0 (2
× s, C1 of 2 × Ph), 135.1 (d, C7), 130.5, 130.2 (2 × d, C3 of OPh),
128.4, 128.3, 128.1, 128.0 (4 × d, C3 of 2 × Ph), 127.2, 127.1 (2 ×
d, C5), 126.9, 126.8 (2 × d, C6), 126.4, 126.3 (2 × d, C8), 126.0,
125.5 (2 × d, C2 of 2 × Ph), 125.4, 125.0 (2 × d, C4 of 2 × Ph), 123.1,
122.5 (2 × d, C4 of OPh), 120.2 (s, C4a), 116.6, 114.4 (2 × d, C2 of
OPh), 80.0, 79.3 (2 × s, C-OH), 75.9, 74.6 (2 × d, CH), 42.4, 41.9 (2
× d, CH) 19.2, 18.9 (2 × q, CH3), 15.8, 14.9, 13.8 (3 × q, CH3).
Compound 10b
1H NMR (CDCl3): d = 8.73 (s, exch., 1 H, NH), 8.16 (m, 1 H, H5),
7.71 (m, 1 H, H7), 7.60 (d, J = 8 Hz, 1 H, H8), 7.44–7.00 (m, 6 H,
H6, OPh), 4.81–4.77 (m, 1 H, CH), 2.35–2.31 (m, 2 H, CH2), 2.25–
2.20 (m, 2 H, CH2), 1.57–1.52 (m, 2 H, CH2), 1.21 (t, J = 7 Hz, 3 H,
CH3), 0.76 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 172.2 (s, C=O), 159.9 (s, C4), 157.7 (s, C1
of OPh), 157.3 (s, C2), 146.9 (s, C8a), 134.8 (d, C7), 129.9 (d, C3
of OPh), 127.0 (d, C5), 126.8 (d, C6), 126.6 (d, C8), 122.9 (d, C4 of
OPh), 120.5 (s, C4a), 115.0 (d, C2 of OPh), 79.8 (d, CH), 35.5 (t,
CH2), 26.6 (t CH2), 19.8 (t, CH2), 13.6 (q, CH3), 9.6 (q, CH3).
EI–MS: m/z (%) = 355 (6), 337 (12), 216 (42), 182 (30), 173 (20),
121 (55), 105 (90), 77 (100), 51 (41).
CI–MS: m/z (%) = 520 (45) [MH+], 357 (90), 338 (100).
HRMS: m/z [MH+] calcd for C32H30N3O4: 520.2236; found:
520.2198.
2-Substituted 3-Acylaminoquinazolin-4(3H)-ones (13–27);
General Procedure
A solution of LDA in pentane (1.6 M, 1.3 mL, 2.2 mmol) was added
under N2 in a dropwise manner to a stirred solution of the appropri-
ate 3-acylamino-2-alkylquinazolin-4(3H)-ones (5–10, 1 mmol) in
anhyd THF (10 mL) at –78 °C. Formation of the dilithio reagent was
observed as a very deep red solution. The mixture was stirred at –78
°C for 30 min, after which an electrophile (1.1 mmol) (as a solution
in anhyd THF for benzophenone, otherwise neat) was added. The
mixture was stirred for 2 h at –78 °C then removed from the cooling
bath and allowed to warm to r.t., diluted with Et2O (10 mL), and
quenched with sat. aq NH4Cl solution (10 mL). The organic layer
was washed with H2O (2 × 20 mL), dried (MgSO4), and evaporated
under reduced pressure. The products obtained were purified by
column chromatography on silica gel (Et2O–hexane, 1:4) to give the
corresponding 2-substituted derivatives 13–27 as white powders.
The yields obtained are recorded in Table 2.
Anal. Calcd for C32H29N3O4: C, 73.97; H, 5.63; N, 8.09. Found: C,
74.2; H, 5.6; N, 8.0.
2-(2-Hydroxy-1-methyl-2-phenylethyl)-3-(2-phenoxypropi-
onylamino)quinazolin4(3H)-one (14)
Mp 90–93 °C; four diastereoisomers (NMR).
1H NMR (CDCl3): d = 8.85, 8.75, 8.67, 8.61 (4 × s, exch., 1 H, NH),
8.11–6.82 (m, 14 H, ArH), 4.90 (m, 1 H, CH), 4.79, 4.57 (2 × d, J =
6 Hz, 1 H, CH), 4.03, 3.89 (2 × br s, exch., 1 H, OH), 3.46, 3.15,
2.84 (3 × pentet, J = 7 Hz, 1 H, CH), 1.71, 1.61 (2 × d, J = 7 Hz, 3
H, CH3), 1.22, 1.17, 0.61 (3 × d, J = 7 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 172.9, 172.6, 172.1, 171.1 (4 × s, C=O),
160.2, 160.1, 159.6 (3 × s, C4), 159.6, 159.1 (2 × s, C2), 156.8,
156.7 (2 × s, C1 of OPh), 146.3, 146.2 (2 × s, C8a), 142.7, 142.3,
141.7 (3 × s, C1 of Ph), 135.1, 135.0, 134.8 (3 × d, C7), 128.6, 128.4
(2 × d, C3 of OPh), 128.2, 128.1 (2 × d, C3 of Ph), 127.6, 127.2 (2
× d, C5), 127.2, 127.1 (2 × d, C6), 127.0, 126.8 (2 × d, C2 of Ph),
126.2, 125.8 (2 × d, C8), 122.7, 122.5, 122.4, 122.3 (4 × d, C4 of
Ph), 120.9, 120.7 (2 × s, C4a), 116.3 (d, C4 of OPh), 114.9, 114.6
(2 × d, C2 of OPh), 78.5, 77.8, 77.2 (3 × d, CH), 76.1, 75.2, 74.6,
74.3 (4 × d, CH), 43.5, 42.8, 42.6, 42.0 (4 × d, CH) 19.0, 18.9, 18.4
(3 × q, CH3), 16.9, 16.5, 16.3 (3 × q, CH3).
(Ra*)-2-[(1S*)-2,2-Diphenyl-2-hydroxy-1-methylethyl]-3-
[(2R*)-2-phenoxypropionylamino]quinazolin-4(3H)-one (13a)
Mp 172 °C; a single diastereoisomer (NMR).
1H NMR (CDCl3): d = 8.34 (s, exch., 1 H, NH), 8.09 (dd, J = 8, 1
Hz, 1 H, H5), 7.73 (approx. dt, J = 8, 1 Hz, 1 H, H7), 7.61 (d, J = 8
Hz, 1 H, H8), 7.51–6.92 (m, 17 H, ArH, OH), 5.02 (q, J = 6.7 Hz, 1
H, CH), 4.00 (q, J = 7 Hz, 1 H, CH), 3.75 (t, J = 6.5 Hz, 4 H, H2 of
THF), 1.86 (t, J = 6.5 Hz, 4 H, H3 of THF), 1.82 (d, J = 6.7 Hz, 3
H, CH3), 1.30 (d, J = 7 Hz, 3 H, CH3).
EI–MS: m/z (%) = 337 (3), 216 (11), 173 (8), 130 (15), 121 (33), 94
(29), 77 (100), 39 (41).
13C NMR (CDCl3): d = 173.7 (s, C=O), 161.6 (s, C4), 159.0 (s, C2),
157.2 (s, C1 of OPh), 147.6 (s, C8a), 145.3, 144.3 (2 × s, C1 of 2 ×
Ph), 135.2 (d, C7), 130.4 (d, C3 of OPh), 128.1 (d, C5), 127.2 127.0
(2 × d, C3 of 2 × Ph), 126.9 (d, C6), 126.6 (d, C8), 126.5, 125.5 (2
× d, C2 of 2 × Ph), 124.7 (d, C4 of 2 × Ph), 122.7 (d, C4 of OPh),
120.2 (s, C4a), 114.4 (d, C2 of OPh), 79.2 (s, C-OH), 74.5 (d, CH),
68.0 (t, C2 of THF), 42.1 (d, CH), 25.6 (t, C3 of THF), 19.2 (q,
CH3), 15.1 (q, CH3).
CI–MS: m/z (%) = 444 (10) [MH+], 338 (5), 281 (41), 183 (40), 175
(56), 122 (48), 91 (100), 74 (38).
HRMS: m/z [MH+] calcd for C26H26N3O4: 444.1923; found:
444.1926.
2-(2-Hydroxy-1-methyl-2-phenylpropyl)-3-(2-phenoxypropi-
onylamino)quinazolin-4(3H)-one (15)
Mp 148–150 °C; four diastereoisomers (1H NMR).
EI–MS: m/z (%) = 355 (5), 337 (10), 216 (42), 182 (49), 173 (37),
121 (50), 105 (100), 77 (95), 51 (42).
CI–MS: m/z (%) = 520 (33) [MH+], 357 (100), 338 (40), 262 (20),
228 (15).
HRMS: m/z [MH+] calcd for C32H30N3O4: 520.2236; found:
520.2206.
1H NMR (CDCl3): d = 9.16, 9.11, 8.92, 8.88 (4 × s, exch., 1 H, NH),
8.23–6.90 (m, 14 H, ArH), 6.51, 6.15 (2 × br s, exch., 1 H, OH),
5.06, 4.96 (2 × q, J = 7 Hz, 1 H, CH), 3.50, 3.30, 3.20, 3.00 (4 × q,
J = 7 Hz, 1 H, CH), 1.91, 1.89, 1.78 (3 × d, J = 7 Hz, 3 H, CH3) 1.64,
1.48, 1.21 (3 × s, 3 H, CH3), 1.11, 1.07, 1.02, 0.60 (4 × d, J = 7 Hz,
3 H, CH3).
13C NMR (CDCl3): d = 172.3, 172.2, 171.9 (3 × s, C=O), 162.1,
161.8 (2 × s, C4), 159.5, 159.4 (2 × s, C2), 157.0, 156.7, 156.6 (3 ×
Anal. Calcd for C32H29N3O4·THF: C, 73.08; H, 6.30; N, 7.10.
Found: C, 73.2; H, 6.2; N, 7.3.
Synthesis 2004, No. 13, 2121–2130 © Thieme Stuttgart · New York

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Regioselective Lithiation of Chiral 3-Acylamino-2-alkylquinazolin-4(3H)-ones
2127
s, C1 of OPh), 146.3, 146.1 (2 × s, C8a), 145.5, 145.4, 145.3 (3 × s,
C1 of Ph), 135.3 (d, C7), 130.2, 130.1 (2 × d, C3 of OPh), 129.9,
128.2, 128.1 (3 × d, C3 of Ph), 127.3, 127.2, 127.1 (3 × d, C2 of Ph),
127.0, 126.8 (2 × d, C5), 126.5, 126.4 (2 × d, C6), 124.9, 124.8,
124.7 (3 × d, C8), 122.9, 122.6, 122.5 (3 × d, C4 of Ph), 120.5 (s,
C4a), 116.5, 116.4 (2 × d, C4 of OPh), 114.7, 114.6 (2 × d, C2 of
OPh), 77.4, 75.8, 75.4 (3 × d, CH), 74.9, 74.6 (2 × s, C-OH), 44.6,
44.2 (2 × d, CH), 30.0, 29.9 (2 × q, CH3), 20.7, 19.2, 19.1, 18.9 (4 ×
q, CH3), 15.2, 14.9, 14.7, 14.5 (4 × q, CH3).
Compound 17b
1H NMR (DMSO-d6): d = 11.74 (s, exch., 1 H, NH), 8.07 (dd, J =
8, 1 Hz, 1 H, H5), 7.77–6.86 (m, 19 H, ArH, OH), 4.82 (t, J = 7 Hz,
1 H, CH), 3.95 (q, J = 7 Hz, 1 H, CH), 2.50 (m, 2 H, CH2), 1.22 (t,
J = 7 Hz, 3 H, CH3), 0.95 (d, J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 172.6 (s, C=O), 162.3 (s, C4), 158.2 (s,
C2), 157.5 (s, C1 of OPh), 148.2 (s, C8a), 145.1, 144.7 (2 × s, C1 of
2 × Ph), 135.0 (d, C7), 129.5 (d, C3 of OPh), 128.0, 127.8 (2 × d, C3
of 2 × Ph), 127.0 (d, C5), 126.5 (d, C6), 126.4 (d, C8), 125.9 (d, C4
of 2 × Ph), 125.1, 124.8 (2 × d, C2 of 2 × Ph), 121.7 (d, C4 of OPh),
120.1 (s, C4a), 114.9 (d, C2 of OPh), 78.9 (s, C-OH), 78.8 (d, CH),
41.1 (d, CH), 26.5 (t, CH2), 14.1 (q, CH3), 9.6 (q, CH3).
EI–MS: m/z (%) = 337 (6), 216 (37), 173 (20), 130 (15), 121 (38),
105 (53), 94 (29), 77 (100).
CI–MS: m/z (%) = 458 (88) [MH+], 338 (25), 295 (100).
HRMS: m/z [MH+] calcd for C27H28N3O4: 458.2080; found:
458.2073.
2-(2-Hydroxy-1-methyl-2-phenylethyl)-3-(2-phenoxybutyryl-
amino)quinazolin-4(3H)-one (18)
Mp 100–102 °C; four diastereoisomers (1H NMR).
2-(2,2-Diphenyl-2-hydroxy-1-methylethyl)-3-[2-(1-naphtha-
lene)propionylamino]quinazolin-4(3H)-one (16)
Mp 131–133 ºC; two diastereoisomers in equal proportions (1H
NMR).
1H NMR (CDCl3): d = 8.45–6.50 (m, 23 H, ArH, OH, NH), 4.75,
4.66 (2 × q, J = 7 Hz, 1 H, CH), 3.78, 3.66 (2 × q, J = 7 Hz, 1 H,
CH), 2.03, 1.77 (2 × d, J = 7 Hz, 3 H, CH3), 1.26, 1.24 (2 × d, J = 7
Hz, 3 H, CH3).
13C NMR (CDCl3): d = 177.3, 174.9 (2 × s, C=O), 161.5, 161.4 (2 ×
s, C4), 159.6, 159.1 (s, C2), 147.2, 147.1 (2 × s, C8a), 145.4, 145.3
(2 × s, C1 of 2 × Ph), 136.5 (s, C1¢), 135.2, 135.1 (2 × d, C7), 134.2,
134.03 (2 × s, C4¢a), 132.1, 130.9 (2 × s, C8¢a), 129.7, 129.5 (2 × d,
C5¢), 129.2, 128.8 (2 × d, C5), 128.1, 127.8 (2 × d, C3 of 2 × Ph),
127.7, 127.2 (2 × d, C2 of Ph), 127.1, 126.9 (2 × d, C6), 126.9, 126.8
(2 × d, C8), 126.5, 126.4 (2 × d, C3¢), 126.2, 126.0 (2 × d, C2¢),
126.0, 125.7 (2 × d, C4¢), 125.4, 125.3 (2 × d, C7¢), 124.4, 124.2 (2
× d, C6¢), 124.3 (d, C4 of 2 × Ph), 123.1, 122.6 (2 × d, C8¢), 120.2
(s, C4a), 79.0, 78.9 (2 × s, C-OH), 43.0, 42.1 (2 × d, CH), 41.6, 41.6
(2 × d, CH), 17.2, 17.1 (2 × q, CH3), 15.0 (q, CH3).
1H NMR (CDCl3): d = 9.19, 9.08, 8.98, 8.72 (4 × s, exch., 1 H, NH),
8.04–6.51 (m, 14 H, ArH), 5.65, 5.52, 5.30, 5.20 (4 × s, exch., 1 H,
OH), 4.79–4.19 (m, 2 H, 2 × CH), 3.37, 3.02, 2.71, 2.51 (4 × pentet,
J = 7 Hz, 1 H, CH), 2.24–1.98 (m, 2 H, CH2), 1.32–0.96 (m, 3 H,
CH3), 0.91, 0.87, 0.46, 0.35 (4 × d, J = 7 Hz, 3 H, CH3).
13C NMR (CDCl3): d = 171.2, 171.0 (2 × s, C=O), 161.0, 160.1 (2 ×
s, C4), 159.0, 158.7 (2 × s, C2), 157.5, 157.4 (2 × s, C1 of OPh),
145.2, 145.0 (2 × s, C8a), 143.9, 143.6, 143.6 (3 × s, C1 of Ph),
135.1 (d, C7), 129.6 (d, C3 of OPh), 127.9, 127.8 (2 × d, C3 of Ph),
127.7 (d, C5), 127.2 (d, C6), 127.0, 126.7 (2 × d, C2 of Ph), 126.6,
125.4 (2 × d, C4 of Ph), 126.3 (d, C8), 121.6, 121.5 (2 × d, C4 of
OPh), 121.4 (s, C4a), 115.6, 115.4, 115.1 (3 × d, C2 of OPh), 78.2,
78.0, 77.4 (3 × d, CH), 73.7, 72.9 (2 × d, CH), 42.9, 42.6 (2 × d, CH)
26.1, 26.0, 25.8 (3 × t, CH2), 13.5, 13.2, 13.1 (3 × q, CH3), 9.4, 9.3
(2 × q, CH3).
EI–MS: m/z (%) = 230 (6), 216 (28), 173 (32), 135 (44), 105 (49),
94 (33), 77 (100).
CI–MS: m/z (%) = 458 (33) [MH+], 281 (70), 197 (40), 175 (53),
136 (46), 114 (41), 105 (100), 94 (56).
HRMS: m/z [MH+] calcd for C27H28N3O4: 458.2080; found:
458.2074.
EI–MS: m/z (%) = 372 (38), 371 (100), 356 (15), 355 (61).
CI–MS: m/z (%) = 554 (100) [MH+], 372 (20), 200 (75), 183 (30).
HRMS: m/z [MH+] calcd for C36H32N3O3: 554.2444; found:
554.2444.
2-(2-Hydroxy-1-methyl-2-phenylpropyl)-3-(2-phenoxybutyryl-
amino)quinazolin-4(3H)-one (19)
Mp 157–158 °C; four diastereoisomers (NMR).
1H NMR (CDCl3): d = 8.91, 8.89, 8.76, 8.71 (4 × s, exch., 1 H, NH),
8.15–6.79 (m, 14 H, ArH), 5.60, 6.04 (2 × br s, exch., 1 H, OH),
4.79–4.63 (m, 1 H, CH), 3.48, 3.21, 3.11, 2.90 (4 × q, J = 7 Hz, 1 H,
CH), 2.14–1.98 (m, 2 H, CH2), 1.56, 1.54, 1.37, 1.35 (4 × s, 3 H,
CH3), 1.15, 1.13 (2 × t, J = 7 Hz, 3 H, CH3), 0.92, 0.51 (2 × d, J = 7
Hz, 3 H, CH3).
2-(2,2-Diphenyl-2-hydroxy-1-methylethyl)-3-(2-phenoxybu-
tyrylamino)quinazolin-4(3H)-one (17)
Mp 183–184 °C; 17a/17b = 1:4 (1H NMR).
EI–MS: m/z (%) = 351 (4), 216 (12), 182 (35), 135 (22), 105 (100),
77 (85), 51 (40).
CI–MS: m/z (%) = 534 (19) [MH+], 357 (100).
HRMS: m/z [MH+] calcd for C33H32N3O4: 534.2393; found:
13C NMR (CDCl3): d = 172.9, 172.8, 172.6 (3 × s, C=O), 162.1,
161.9, 161.8 (3 × s, C4), 159.5, 159.4 (2 × s, C2), 157.4, 157.1 (2 ×
s, C1 of OPh), 146.2, 146.1 (2 × s, C8a), 145.5, 145.3 (2 × s, C1 of
Ph), 135.3 (d, C7), 130.2, 130.1, 130.0 (3 × d, C3 of OPh), 128.2,
128.1 (2 × d, C3 of Ph), 127.3, 127.2 (2 × d, C2 of Ph), 127.0 (d,
C5), 126.5, 126.4 (2 × d, C6), 124.9, 124.8 (2 × d, C8), 123.1, 122.6,
122.4 (3 × d, C4 of Ph), 120.6 (s, C4a), 116.8, 116.7 (2 × d, C4 of
OPh), 114.7, 114.6 (2 × d, C2 of OPh), 81.0, 80.8, 79.9, 79.6 (4 × d,
CH), 75.5, 75.4 (2 × s, C-OH), 44.7, 44.6, 44.2 (3 × d, CH), 30.0,
29.8 (2 × q, CH3), 26.9, 26.8, 26.2 (3 × t, CH2), 15.0, 14.9, 14.4 (3
× q, CH3), 9.8, 9.7, 9.0 (3 × q, CH3).
534.2393.
Anal. Calcd for C33H31N3O4: C, 74.28; H, 5.86; N, 7.87. Found: C,
74.2; H, 5.7; N, 8.1.
Compound 17a
1H NMR (DMSO-d6): d = 11.45 (s, exch., 1 H, NH), 8.07 (dd, J =
8, 1 Hz, 1 H, H5), 7.77–6.86 (m, 19 H, ArH, OH), 4.94 (t, J = 7 Hz,
1 H, CH), 3.99 (q, J = 7 Hz, 1 H, CH), 2.20 (m, 2 H, CH2), 1.16 (t,
J = 7 Hz, 3 H, CH3), 0.90 (d, J = 7 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 171.6 (s, C=O), 161.8 (s, C4), 159.0 (s,
C2), 157.5 (s, C1 of OPh), 148.1 (s, C8a), 145.7, 144.6 (2 × s, C1 of
2 × Ph), 135.0 (d, C7), 129.1 (d, C3 of OPh), 127.9, 127.7 (2 × d, C3
of 2 × Ph), 127.0 (d, C5), 126.5 (d, C6), 126.4 (d, C8), 125.5 (d, C4
of 2 × Ph), 125.0, 124.8 (2 × d, C2 of 2 × Ph), 121.6 (d, C4 of OPh),
120.2 (s, C4a), 115.5 (d, C2 of OPh), 78.7 (s, C-OH), 77.7 (d, CH),
41.8 (d, CH), 26.1 (t, CH2), 14.0 (q, CH3), 9.5 (q, CH3).
EI–MS: m/z (%) = 351 (54), 258 (29), 220 (52), 216 (100), 202 (98),
189 (64).
EI–MS: m/z (%) = 472 (6) [MH+], 295 (12), 175 (23), 138 (100),
105 (32).
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K. Smith et al.
PAPER
HRMS: m/z [MH+] calcd for C28H30N3O4: 472.2236; found:
472.2239.
2-(1-Diphenylhydroxymethylpropyl)-3-(2-phenoxypropionyl-
amino)quinazolin-4(3H)-one (22)
Mp 112–114 °C; four diastereoisomers (NMR).
2-(2,2-Diphenyl-2-hydroxy-1-methylethyl)-3-(2-phenylbutyryl-
amino)quinazolin-4(3H)-one (20)
1H NMR (DMSO-d6): d = 11.47, 11.24 (2 × br s, exch., 1 H, NH),
8.07 (m, 1 H, H5), 7.79–6.83 (m, 19 H, ArH, OH), 5.35, 5.24 (2 ×
q, J = 7 Hz, 1 H, CH), 4.28, 4.06, 3.96, 3.84 (4 × t, J = 7.5 Hz, 1 H,
CH), 1.98–1.44 (m, 2 H, CH2), 1.82, 1.78, 1.75, 1.68 (4 × d, J = 7
Hz, 3 H, CH3), 0.71, 0.41, 0.35, 0.30 (4 × t, J = 7.5 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 173.5, 173.3, 172.6, 172.4 (4 × s, C=O),
161.8, 161.7, 161.4 (3 × s, C4), 158.3, 158.2, 158.1, 158.0 (4 × s,
C2), 157.3, 157.2, 157.1 (3 × s, C1 of OPh), 148.6, 148.5, 148.4,
148.3 (4 × s, C8a), 145.7, 145.4, 144.7, 144. 5 (4 × s, C1 of 2 × Ph),
135.5, 135.4 (2 × d, C7), 129.9, 129.8, 129.7 (3 × d, C3 of OPh),
128.3, 128.0 (2 × d, C3 of 2 × Ph), 127.9, 127.8, 127.5 (3 × d, C2 of
2 × Ph), 126.8, 126.5 (2 × d, C5), 126.2, 126.1 (2 × d, C6), 125.5,
125.3 (2 × d, C8), 125.1, 125.0 (2 × d, C4 of 2 × Ph), 121.9, 121.6
(2 × d, C4 of OPh), 119.9, 119.8 (2 × s, C4a), 115.4, 115.3, 114.6 (3
× d, C2 of OPh), 79.7, 79.5, 79.2 (3 × s, C-OH), 73.6, 73.4, 71.8 (3
× d, CH), 47.9, 74.5, 47.3, 47.1 (4 × d, CH), 22.9, 22.7 (2 × t, CH2),
19.4, 19.1, 18.8, 18.5 (4 × q, CH3), 12.6, 12.3, 12.1, 12.0 (4 × q,
CH3).
Mp 182–183 °C; 20a/20b = 1:4 (1H NMR).
CI–MS: m/z (%) = 518 (90) [MH+], 357 (12), 336 (100), 200 (22),
183 (50), 175 (33), 105 (21).
HRMS: m/z [MH+] calcd for C33H32N3O3: 518.2444; found:
518.2444.
Anal. Calcd for C33H31N3O3: C, 76.59; H, 6.00; N, 8.12. Found: C,
76.6; H, 6.0; N, 8.1.
Compound 20a
1H NMR (DMSO-d6): d = 11.71 (br s, exch., 1 H, NH), 8.14 (dd,
J = 8, 1 Hz, 1 H, H5), 7.77–6.86 (m, 18 H, ArH), 6.73 (s, exch., 1
H, OH), 4.12 (q, J = 7 Hz, 1 H, CH), 3.66 (t, J = 7 Hz, 1 H, CH),
2.34–2.07 (m, 2 H, CH2), 1.33 (d, J = 7 Hz, 3 H, CH3), 1.07 (t, J =
7 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 172.8 (s, C=O), 162.4 (s, C4), 158.6 (s,
C2), 148.5 (s, C8a), 146.2, 145.1 (2 × s, C1 of Ph’s), 135.2 (d, C7),
129.5, 128.3, 128.1 (3 × d, C3 of Ph’s), 128.0 (d, C5), 127.4 (d, C6),
127.3 (d, C8), 126.6, 126.0 (2 × d, C4 of Ph’s), 125.8, 125.7, 125.4
(3 × d, C2 of Ph’s), 120.3 (s, C4a), 79.1 (s, C-OH), 52.3 (d, CH),
41.6 (d, CH), 25.8 (t, CH2), 14.3 (q, CH3), 12.7 (q, CH3).
EI–MS: m/z (%) = 369 (12), 351 (43), 173 (18), 323 (100), 258 (44).
CI–MS: m/z (%) = 534 (33) [MH+], 371 (19), 352 (100), 260 (16),
217 (18).
HRMS: m/z [MH+] calcd for C33H32N3O4: 534.2393; found:
534.2397.
Compound 20b
1H NMR (DMSO-d6): d = 11.71 (br s, exch., 1 H, NH), 8.12 (dd,
J = 8, 1 Hz, 1 H, H5), 7.77–6.86 (m, 18 H, ArH), 6.73 (s, exch., 1
H, OH), 3.86 (q, J = 7 Hz, 1 H, CH), 3.63 (t, J = 7 Hz, 1 H, CH),
2.28–1.87 (m, 2 H, CH2), 1.21 (d, J = 7 Hz, 3 H, CH3), 0.90 (t, J =
7 Hz, 3 H, CH3).
2-(1-Phenylhydroxymethylpropyl)-3-(2-phenoxypropionylami-
no)quinazolin-4(3H)-one (23)
Mp 158–159 °C; 23a/23b = 3:5 (1H NMR).
EI–MS: m/z (%) = 323 (10), 230 (24), 187 (12), 160 (23), 121 (44),
77 (100).
CI–MS: m/z (%) = 458 (9) [MH+], 295 (48), 189 (53), 183 (46), 166
(17), 122 (52), 106 (41), 91 (100).
HRMS: m/z [MH+] calcd for C27H28N3O4: 458.2080; found:
458.2075.
13C NMR (DMSO-d6): d = 173.3 (s, C=O), 162.7 (s, C4), 158.5 (s,
C2), 148.3 (s, C8a), 145.9, 145.0 (s, C1 of Ph’s), 135.4 (d, C7),
129.2, 128.8, 128.5 (3 × d, C3 of Ph’s), 127.8 (d, C5), 127.6 (d, C6),
126.8 (d, C8), 126.3, 126.1 (2 × d, C4 of Ph’s), 125.0, 124.8, 124.7
(3 × d, C2 of Ph’s), 120.1 (s, C4a), 79.0 (s, C-OH), 51.6 (d, CH),
41.6 (d, CH), 24.7 (t, CH2), 14.0 (q, CH3), 12.4 (q, CH3).
Compound 23a
1H NMR (DMSO-d6): d = 11.15 (br s, exch., 1 H, NH), 7.94–6.75
(m, 14 H, ArH), 4.91 (q, J = 7 Hz, 1 H, CH), 4.79 (d, J = 3.5 Hz,
exch., 1 H, OH), 4.74 (d, J = 5 Hz, 1 H, CHOH), 2.87 (m, 1 H, CH),
1.63 (m, 1 H, CHH), 1.48 (d, J = 7 Hz, 3 H, CH3), 1.32 (m, 1 H,
CHH), 0.40 (t, J = 7.5 Hz, 3 H, CH3).
2-(1,2-Dimethyl-2-hydroxybutyl)-3-(2-phenylbutyrylami-
no)quinazolin-4(3H)-one (21)
Mp 90–93 °C; at least seven diastereoisomers (1H NMR).
1H NMR (CDCl3): d = 8.94, 8.84, 8.83, 8.76, 8.64, 8.46, 8.39 (7 × s,
exch., 1 H, NH), 8.19 (m, 1 H, H5), 7.77–6.90 (m, 8 H, ArH), 6.13,
6.06, 5.81, 5.67, 5.23, 5.10, 4.56 (7 × s, exch., 1 H, OH), 3.65–3.58
(m, 1 H, CH), 3.11, 2.88, 2.74, 2.70, 2.59, 2.46, 2.37 (7 × q, J = 7
Hz, 1 H, CH), 2.30–2.18 (m, 2 H, CH2), 1.92, 1.88, 1.85, 1.80 (4 ×
s, 3 H, CH3), 1.69–0.52 (m, 11 H, CH2, 3 × CH3).
13C NMR (CDCl3): d = 174.3, 174.1, 173.2 (3 × s, C=O), 162.7,
162.5, 161.9, 161.7 (4 × s, C4), 160.3, 160.1, 160.0 (3 × s, C2),
146.5, 146.3 (2 × s, C8a), 138.9, 138.8, 138.7 (3 × s, C1 of Ph),
135.1, 135.0 (2 × d, C7), 129.0, 128.9 (2 × d, C3 of Ph), 128.1, 128.0
(2 × d, C2 of Ph), 127.9, 127.8 (2 × d, C5), 127.7, 127.6 (2 × d, C6),
127.3, 127.2 (2 × d, C8), 127.1, 127.0, 126.9 (3 × d, C4 of Ph),
120.5, 120.4 (2 × s, C4a), 74.6, 73.9, 73.8, 73.6 (4 × s, C-OH), 53.3,
52.9, 52.8 (3 × d, CH), 41.4, 41.1, 40.6, 40.4 (4 × d, CH), 34.4, 33.8,
31.9, 26.8, 25.7, 25.6 (6 × t, 2 × CH2), 23.0, 22.6, 20.0 (3 × q, CH3),
14.3, 14.1, 13.7, 13.5 (4 × q, CH3), 12.4, 12.1, 12.0, 10.6 (4 × q,
CH3), 8.4, 8.2, 8.1, 7.7 (4 × q, CH3).
13C NMR (DMSO-d6): d = 172.0 (s, C=O), 159.5 (s, C4), 158.8 (s,
C2), 157.1 (s, C1 of OPh), 145.9 (s, C8a), 143.9 (s, C1 of Ph), 135.1
(d, C7), 129.6 (d, C3 of OPh), 127.7 (d, C3 of Ph), 127.3 (d, C5),
127.0 (d, C2 of Ph), 126.7 (d, C6), 126.4 (d, C8), 126.1 (d, C4 of
Ph), 121.5 (d, C4 of OPh), 120.4 (s, C4a), 115.1 (d, C2 of OPh),
73.2 (d, CH), 72.1 (d, CH), 50.1 (d, CH), 20.5 (t, CH2), 19.1 (q,
CH3), 10.6 (q, CH3).
Compound 23b
1H NMR (DMSO-d6): d = 11.15 (br s, exch., 1 H, NH), 7.94–6.75
(m, 14 H, ArH), 5.15 (d, J = 3.5 Hz, exch., 1 H, OH), 5.00 (q, J = 7
Hz, 1 H, CH), 4.88 (d, J = 4.5 Hz, 1 H, CHOH), 2.98 (m, 1 H, CH),
1.86 (m, 1 H, CHH), 1.43 (d, J = 7 Hz, 3 H, CH3), 1.23 (m, 1 H,
CHH), 0.34 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 171.4 (s, C=O), 159.2 (s, C4), 158.4 (s,
C2), 157.0 (s, C1 of OPh), 146.3 (s, C8a), 144.1 (s, C1 of Ph), 135.0
(d, C7), 129.5 (d, C3 of OPh), 127.9 (d, C3 of Ph), 127.5 (d, C5),
126.9 (d, C2 of Ph), 126.6 (d, C6), 126.3 (d, C8), 126.2 (d, C4 of
Ph), 121.6 (d, C4 of OPh), 120.6 (s, C4a), 115.5 (d, C2 of OPh),
CI–MS: m/z (%) = 408 (93) [MH+], 336 (58), 273 (12), 247 (84),
175 (100).
HRMS: m/z [MH+] calcd for C24H30N3O3: 408.2287; found:
408.2287.
Synthesis 2004, No. 13, 2121–2130 © Thieme Stuttgart · New York

PAPER
Regioselective Lithiation of Chiral 3-Acylamino-2-alkylquinazolin-4(3H)-ones
2129
73.0 (d, CH), 72.2 (d, CH), 50.2 (d, CH), 18.7 (t, CH2), 18.5 (q,
CH3), 11.7 (q, CH3).
CI–MS: m/z (%) = 472 (16) [MH+], 295 (33), 197 (70), 189 (100),
180 (18), 139 (18), 136 (23), 105 (82), 88 (27).
HRMS: m/z [MH+] calcd for C27H30N3O4: 472.2235; found:
472.2230.
2-(1-Ethyl-2-hydroxy-2-phenylpropyl)-3-(2-phenoxypropionyl-
amino)quinazolin-4(3H)-one (24)
Mp 79–81 °C; four diastereoisomers (NMR).
Compound 26a
1H NMR (DMSO-d6): d = 11.35 (br s, exch., 1 H, NH), 8.23–6.78
(m, 14 H, ArH), 6.19, 6.11, 5.98 (3 × s, exch., 1 H, OH), 5.42–5.04
(m, 1 H, CH), 2.67–2.33 (m, 1 H, CH), 1.92–1.87 (m, 1 H, CHH),
1.81, 1.79, 1.75, 1.66 (4 × d, J = 7 Hz, 3 H, CH3), 1.72, 1.70, 1.69,
1.66 (4 × s, 3 H, CH3), 1.17 (m, 1 H, CHH), 0.95, 0.76, 0.51, 0.37
(4 × t, J = 7.5 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 172.4, 171.8, 171.3, 170.8 (4 × s, C=O),
162.1, 162.0, 160.6, 160.2 (4 × s, C4), 159.0, 158.9, 158.8, 158.5 (4
× s, C2), 158.2, 158.1, 157.2, 157.0 (4 × s, C1 of OPh), 149.3, 147.0,
146.7, 146.6 (4 × s, C8a), 146.3, 145.7, 145.6, 145.1 (4 × s, C1 of
Ph), 135.5, 135.3, 135.0, 134.6 (4 × d, C7), 129.6, 129.5, 129.3,
128.1 (4 × d, C3 of OPh), 128.0, 127.9, 127.8, 127.5 (4 × d, C3 of
Ph), 127.4, 127.3, 127.2, 127.1 (4 × d, C5), 126.9, 126.8, 126.7,
126.6 (4 × d, C2 of Ph), 126.4, 126.3, 126.1, 125.9 (4 × d, C6),
125.1, 124.8 (2 × d, C8), 124.7, 124.6 (2 × d, C4 of Ph), 121.7,
121.6, 121.5, 121.1 (4 × d, C4 of OPh), 120.8, 120.6, 120.4, 120.3
(4 × s, C4a), 115.5, 115.2, 115.0, 114.9 (4 × d, C2 of OPh), 76.3,
76.2, 75.5, 75.4 (4 × s, C-OH), 73.4, 72.6, 72.0, 71.2 (4 × d, CH),
53.7, 52.1, 51.4, 50.3 (4 × d, CH), 31.0, 30.8, 30.0, 29.7 (4 × q,
CH3), 22.3, 22.0, 21.4, 20.9 (4 × t, CH2), 19.3, 19.2, 19.0, 18.7 (4 ×
q, CH3), 13.7, 13.5, 12.3, 12.0 (4 × q, CH3).
1H NMR (DMSO-d6): d = 11.26 (br s, exch., 1 H, NH), 8.13–6.97
(m, 15 H, ArH, OH), 5.11 (d, J = 4 Hz, 1 H, CHOH), 4.94 (t, J = 7
Hz, 1 H, CH), 3.08 (m, 1 H, CH), 2.14–1.38 (m, 4 H, 2 × CH2), 1.17
(t, J = 7 Hz, 3 H, CH3), 0.58 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 171.3 (s, C=O), 159.6 (s, C4), 158.8 (s,
C2), 157.5 (s, C1 of OPh), 145.9 (s, C8a), 143.9 (s, C1 of Ph), 135.2
(d, C7), 129.6 (d, C3 of OPh), 127.7 (d, C3 of Ph), 127.3 (d, C5),
126.9 (d, C2 of Ph), 126.6 (d, C6), 126.4 (d, C8), 126.3 (d, C4 of
Ph), 121.6 (d, C4 of OPh), 120.4 (s, C4a), 115.4 (d, C2 of OPh),
78.2 (d, CH), 72.1 (d, CH), 48.4 (d, CH), 26.1 (t, CH2), 20.5 (t,
CH2), 15.5 (q, CH3), 10.5 (q, CH3).
Compound 26b
1H NMR (DMSO-d6): d = 11.42 (br s, exch., 1 H, NH), 8.13–6.97
(m, 15 H, ArH, OH), 5.34 (d, J = 4 Hz, 1 H, CHOH), 4.98 (t, J = 7
Hz, 1 H, CH), 3.12 (m, 1 H, CH), 2.14–1.38 (m, 4 H, 2 × CH2), 1.09
(t, J = 7 Hz, 3 H, CH3), 0.54 (t, J = 7.5 Hz, 3 H, CH3)
13C NMR (DMSO-d6): d = 170.7 (s, C=O), 159.2 (s, C4), 158.4 (s,
C2), 157.5 (s, C1 of OPh), 146.3 (s, C8a), 144.0 (s, C1 of Ph), 135.0
(d, C7), 129.5 (d, C3 of OPh), 127.9 (d, C3 of Ph), 127.5 (d, C5),
127.0 (d, C2 of Ph), 126.7 (d, C6), 126.4 (d, C8), 126.3 (d, C4 of
Ph), 121.7 (d, C4 of OPh), 120.6 (s, C4a), 115.7 (d, C2 of OPh),
77.3 (d, CH), 72.9 (d, CH), 50.1 (d, CH), 25.6 (t, CH2), 18.5 (t,
CH2), 11.7 (q, CH3), 9.4 (q, CH3).
EI–MS: m/z (%) = 323 (7), 230 (22), 173 (18), 160 (40), 121 (32),
105 (49), 94 (22), 77 (100).
CI–MS: m/z (%) = 472 (5) [MH+], 352 (17), 309 (18), 189 (76), 138
(100), 122 (22), 91 (49).
HRMS: m/z [MH+] calcd for C27H30N3O4: 472.2235; found:
472.2235.
2-(1-Ethyl-2-hydroxy-2-phenylpropyl)-3-(2-phenoxybutyryl-
amino)quinazolin-4(3H)-one (27)
Mp 105–107 °C; 27a/27b = 4:5 (1H NMR).
EI–MS: m/z (%) = 365 (19), 337 (25), 272 (10), 244 (53), 230 (100),
214 (24), 202 (27).
EI–MS: m/z (%) = 486 (33) [MH+], 366 (15), 309 (100).
2-(1-Diphenylhydroxymethylpropyl)-3-(2-phenoxybutyrylami-
no)quinazolin-4(3H)-one (25)
Mp 139–140 °C; four diastereoisomers (NMR)
1H NMR (DMSO-d6): d = 11.55, 11.51, 11.45, 11.28 (4 × s, exch.,
1 H, NH), 8.10–6.85 (m, 20 H, ArH, OH), 5.11, 5.02 (2 × t, J = 7
Hz, 1 H, CH), 4.26, 4.05, 3.93, 3.82 (4 × t, J = 7.5 Hz, 1 H, CH),
2.22–1.43 (m, 4 H, 2 × CH2), 1.20, 1.09 (2 × t, J = 7 Hz, 3 H, CH3),
0.68, 0.34, 0.30, 0.28 (4 × t, J = 7.5 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 172.8, 171.7, 171.6 (3 × s, C=O), 161.8,
161.3 (2 × s, C4), 158.2, 158.0 (2 × s, C2), 157.7, 157.6 (2 × s, C1
of OPh), 148.6, 148.5 (2 × s, C8a), 145.7, 144.4 (2 × s, C1 of 2 ×
Ph), 135.5, 135.4 (2 × d, C7), 129.9, 129.7 (2 × d, C3 of OPh),
128.3, 128.1 (2 × d, C3 of 2 × Ph), 127.9, 127.5 (2 × d, C5), 126.8,
126.7 (2 × d, C6), 126.4, 125.5 (2 × d, C8), 126.1, 125.5 (2 × d, C4
of 2 × Ph), 125.3, 125.1 (2 × d, C2 of 2 × Ph), 121.7, 121.6 (2 × d,
C4 of OPh), 119.9 (s, C4a), 115.5, 114.7 (2 × d, C2 of OPh), 79.7,
79.2 (2 × s, C-OH), 78.7, 76.9 (2 × d, CH), 47.9, 47.8, 47.7 (3 × d,
CH), 26.3, 25.8 (2 × t, CH2), 22.8, 22.7 (2 × t, CH2), 12.7, 12.0 (2 ×
q, CH3), 9.7, 9.6, 9.5, 9.4 (4 × q, CH3).
HRMS: m/z [MH+] calcd for C29H32N3O4: 486.2393; found:
486.2394.
Compound 27a
1H NMR (DMSO-d6): d = 11.34 (br s, exch., 1 H, NH), 8.21–6.94
(m, 14 H, ArH), 5.27 (s, exch., 1 H, OH), 5.06–5.00 (m, 1 H, CH),
3.44–3.41 (m, 1 H, CH), 2.15–1.56 (m, 4 H, 2 × CH2), 1.19 (s, 3 H,
CH3), 0.85 (t, J = 7 Hz, 3 H, CH3), 0.23 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (DMSO-d6): d = 172.2 (s, C=O), 160.0 (s, C4), 158.4 (s,
C2), 157.5 (s, C1 of OPh), 147.0 (s, C8a), 145.7 (s, C1 of Ph), 135.3
(d, C7), 129.7 (d, C3 of OPh), 127.9 (d, C3 of Ph), 127.4 (d, C5),
127.2 (d, C6), 126.6 (d, C8), 124.7 (d, C2 of Ph), 121.5 (d, C4 of
Ph), 120.3 (d, C4 of OPh), 119.4 (s, C4a), 115.1 (d, C2 of OPh),
76.9 (d, CH), 75.3 (s, C-OH), 50.2 (d, CH), 29.5 (q, CH3), 25.9 (t,
CH2), 21.9 (t, CH2), 11.9 (q, CH3), 9.7 (q, CH3).
Compound 27b
EI–MS: m/z (%) = 365 (51), 337 (100), 308 (20), 277 (38).
CI–MS: m/z (%) = 548 (41) [MH+], 371 (89), 366 (100).
HRMS: m/z [MH+] calcd for C34H34N3O4: 548.2549; found:
1H NMR (DMSO-d6): d = 11.34 (br s, exch., 1 H, NH), 8.21–6.94
(m, 14 H, ArH), 6.01 (s, exch., 1 H, OH), 5.06–5.00 (m, 1 H, CH),
3.10–3.08 (m, 1 H, CH), 2.15–1.56 (m, 4 H, 2 × CH2), 1.28 (s, 3 H,
CH3), 1.15 (t, J = 7 Hz, 3 H, CH3), 0.33 (t, J = 7.5 Hz, 3 H, CH3).
548.2549.
13C NMR (DMSO-d6): d = 170.6 (s, C=O), 162.1 (s, C4), 158.6 (s,
C2), 157.6 (s, C1 of OPh), 146.7 (s, C8a), 145.1 (s, C1 of Ph), 135.5
(d, C7), 129.5 (d, C3 of OPh), 128.0 (d, C3 of Ph), 127.5 (d, C5),
127.1 (d, C6), 126.5 (d, C8), 125.1 (d, C2 of Ph), 121.5 (d, C4 of
Ph), 120.6 (d, C4 of OPh), 120.4 (s, C4a), 115.4 (d, C2 of OPh),
2-(1-Phenylhydroxymethylpropyl)-3-(2-phenoxybutyrylami-
no)quinazolin-4(3H)-one (26)
Mp 136–137 °C; 26a/26b = 3:5 (1H NMR).
EI–MS: m/z (%) = 365 (62), 337 (100), 308 (22), 272 (45).
Synthesis 2004, No. 13, 2121–2130 © Thieme Stuttgart · New York

2130
K. Smith et al.
PAPER
78.2 (d, CH), 75.5 (s, C-OH), 52.1 (d, CH), 30.8 (q, CH3), 26.5 (t,
CH2), 23.6 (t, CH2), 11.3 (q, CH3), 9.5 (q, CH3).
(5) Rathman, T. L.; Sleevi, M. C.; Krafft, M. F.; Wolfe, J. F. J.
Org. Chem. 1980, 45, 2169.
(6) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M.
A. Collect. Czech. Chem. Commun. 1999, 64, 515.
(7) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M.
A. J. Org. Chem. 1996, 61, 656.
(8) El-Hiti, G. A. Monatsh. Chem. 2004, 135, 323.
(9) Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M.
A. J. Org. Chem. 1996, 61, 647.
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F. J. Chem. Soc., Perkin Trans. 1 1995, 1029.
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Tetrahedron 1997, 53, 2871.
Acknowledgment
We thank the EPSRC Mass Spectroscopy Service, University of
Wales Swansea, for recording the mass spectra. We also thank the
EPSRC, the Higher Education Funding Council for Wales (ELWa-
HEFCW) and the University of Wales Swansea for grants that ena-
bled the purchase and upgrading of NMR equipment used in the
course of this work. G. A. El-Hiti thanks the University of Wales
Swansea for financial support and the Royal Society of Chemistry
for an international author grant.
(12) Dai, X.; Virgil, S. Tetrahedron: Asymmetry 1999, 10, 25.
(13) Chapoulaud, V. G.; Salliot, I.; Plé, N.; Turck, A.; Quéguiner,
G. Tetrahedron 1999, 55, 5389.
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Synthesis 2004, No. 13, 2121–2130 © Thieme Stuttgart · New York