Efficient synthesis of 1,3-disubstituted 1,3-dihydro-2H-imidazo[5,1-b]quinazolin-9-ones by an intramolecular Mannich-type reaction

Article abstract of DOI:10.1055/s-0034-1378675

A general and efficient method has been developed for the synthesis of 1,3-disubstituted 1,3-dihydroimidazo[5,1-b]quinazolin-9-ones. The process involves an intramolecular Mannich-type reaction of a 2-aminomethylquinazolin-4-one derivative with an aldehyde, and gives diastereomeric mixtures of the minor cis- and major trans-cycloadducts.

Full text of DOI:10.1055/s-0034-1378675

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 377–386
paper
377
J. Leclercq et al.
Paper
Synthesis
Efficient Synthesis of 1,3-Disubstituted 1,3-Dihydro-2H-imid-
azo[5,1-b]quinazolin-9-ones by an Intramolecular Mannich-Type
Reaction
1,3-Disubstituted 1,3-Dihydro-2H-imidazo[5,1-b]quinazolin-9-ones
Julien Leclercq
O
H
O
R2
O
N
R2
O
N
Moshine Driowya
Nathalie Flouquet
Pascal Berthelot
Nicolas Lebegue*
R2
NH
N
N
NH
NH
R1
+
NH2
MeOH, reflux
N
R1
R1
R1 = isopropyl, isobutyl, benzyl, 3-methylindole
Laboratoire de Chimie Thérapeutique, UFR Pharmacie,
Université Lille Nord de France, 59000 Lille, France
nicolas.lebegue@univ-lille2.fr
R
2 = dimethoxymethyl, ethyl, benzyl, benzyloxymethyl
O
N
O
Received: 22.07.2014
Accepted after revision: 19.09.2014
Published online: 13.11.2014
N
N
NH
DOI: 10.1055/s-0034-1378675; Art ID: ss-2014-t0457-op
N
N
H
1
2
Abstract A general and efficient method has been developed for the
synthesis of 1,3-disubstituted 1,3-dihydroimidazo[5,1-b]quinazolin-9-
ones. The process involves an intramolecular Mannich-type reaction of
a 2-aminomethylquinazolin-4-one derivative with an aldehyde, and
gives diastereomeric mixtures of the minor cis- and major trans-
cycloadducts.
Figure 1 Structure of 2,3-fused quinazolinone systems
The
2,3-dihydro-1H-imidazo[2,1-b]quinazolin-5-one
tricyclic system 1 is well documented and it is known to ex-
hibit activities as an antihypertensive,5 a bronchodilator,6 a
cyclic AMP phosphodiesterase inhibitor,7 and an α1-adre-
noceptor antagonist.8 On the other hand, the only report of
a synthesis of the 1,3-dihydro-2H-imidazo[5,1-b] regioiso-
mer 2 appeared in a patent describing compounds used in
the treatment of platelet-derived growth factor-related dis-
orders, such as cancers.9 Five compounds derived from
structure 2 were reported in the patent, and these were
prepared by the method shown in Scheme 1. The synthetic
strategy involves the initial formation of a Schiff base be-
tween a benzaldehyde derivative and benzylamine. The
Schiff base then reacts as an acceptor in a Mannich-type re-
action with the lactim tautomer form of a quinazolin-4-
one. In the presence of a catalytic amount of pyridine, the
secondary amine group in the nonisolated intermediate in-
teracts with the tosyl leaving group to give the desired 1,3-
dihydro-2H- imidazo[5,1-b]quinazolin-9-one derivative.
This Mannich-type reaction using a quinazolin-4-one scaf-
fold has also been described for condensation with formal-
dehyde and aniline derivatives10 or with triazole deriva-
tives,11 leading to the corresponding 3-(aminometh-
yl)quinazolin-4-ones as byproducts. The quinazolin-4-one
can be then considered as an excellent enolizable carbox-
amide heterocycle.
Key words Mannich reactions, heterocycles, cycloadditions, diaste-
reoselectivity, spectroscopy
Quinazolin-4-one is a naturally occurring alkaloid that
also forms a core structural subunit of a growing class of
bioactive natural products and synthetic compounds.1
Moreover, the quinazolinone moiety has been extensively
utilized as a drug-like scaffold in medicinal chemistry, and
as such it is considered to be a privileged structure.2 Thera-
peutic agents containing the quinazolinone core structure
have been marketed or are undergoing clinical trials for the
treatment of cancer.3
In our laboratory, we became interested in the synthesis
of tricyclic quinazolin-4-one derivatives in which the
quinazoline ring is fused to an imidazole ring, and we re-
cently described a synthesis of 1,3-disubstituted imid-
azo[1,5-a]quinazolin-5-(4H)-ones.4 In our continuing
search, we have concentrated on the synthesis of 2,3-con-
densed quinazolin-4-ones bearing a dihydroimidazole core,
as present in structures 1 and 2, which might be used as in-
termediates in syntheses of compounds expected to display
bioactivity (Figure 1).
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Synthesis
O
N
O
1) isobutyl chloroformate
NMM, THF
CHO
H2N
2-OH, 3-OH, 4-OH
3,4-(OH)
b
R
R =
–15 °C to reflux
NH
NH2
HOOC
NHBoc
R1
2
+
3,4,5-(OH)
NHBoc
3
2) 5.4 M NaOMe
MeOH, reflux
+
NH2
3a–d
R1
H
N
a R1 = isopropyl
b R1 = isobutyl
c R1 = benzyl
O
N
O
N
O
a
R
NH
NH
N
d R1 = methyindole
+
HCl (g), CH2Cl2
N
OH
OTs
OTs
c
H
O
N
O
O
N
(a)
R2
R2
MeOH
NH2
NH
NH
N
(b)
R
N
N
N
O
N
O
N
R
5
4a–d
6
R1
R1
R1
+
N
N
N
N
H
R2
CHO
(a): top side
R2
(b): bottom side
a R2 = dimethoxymethyl
b R2 = ethyl
OTs
R2
O
N
O
N
N
c R2 = benzyl
Scheme 1 Available approach for the synthesis of 1,3-dihydro-2H-im-
idazo[5,1-b]quinazolin-9-ones. Reaction conditions: (a) TsCl, Et3N,
CH2Cl2; (b) EtOH, reflux; (c) EtOH, py, reflux.
N
d R2 = benzyloxymethyl
NH
R1
NH
R1
7(a–d)(a–d)dia1
7(a–d)(a–d)dia2
Scheme 2 Synthetic strategy for 1,3-dihydro-2H-imidazo[5,1-
b]quinazolin-9-ones 7
However, we required a general method for the synthe-
sis of 1,3-disubstituted 1,3-dihydro-2H-imidazo[5,1-
b]quinazolin-9-ones to permit the investigation of their
chemical space through variation of the substituents on the
imidazole core to include a diverse range of aliphatic, ben-
zylic, or aromatic groups. Intramolecular Mannich reac-
tions have a significantly wider range of applications than
do their intermolecular counterparts. Their high value has
long been recognized and used in biomimetic syntheses of
natural products,12 as well as in other applications. The syn-
thesis of (–)-strychnine by Overman et al. is an excellent ex-
ample of the intramolecular Mannich-reaction strategy.13 In
our approach to a synthetic strategy (Scheme 2), we used
the 2-(aminomethyl)quinazolin-4(3H)-ones 4 as previously
described key intermediates4 that reacted with various al-
dehydes to give the corresponding nonisolated imines 5.
Cyclization to give the desired 1,3-dihydro-2H-imidazo[5,1-
b]quinazolin-9-ones 7 was based on an intramolecular
Mannich-type reaction between the enol tautomer 6 of
imines 5 and the Schiff base moiety. This mode of cycliza-
tion gave mixtures of diastereomers 7(a-d)(a-d)dia1 and
7(a-d)(a-d)dia2, the ratio of which was determined by
whether top-side (a) or bottom-side (b) attack was pre-
ferred.
(3S)-7aa and trans-(3S)-7aa, respectively, by means of two-
dimensional COSY, HMBC, and HSQC NMR experiments, as
described in detail in the Supporting Information. The abso-
lute configurations were assigned by means of one-dimen-
sional NOESY NMR experiments in which the H-3 proton of
each of the diastereomers was irradiated (Figure 2). In com-
pound (1R,3S)-7aa, the H-3 proton showed strong dipolar
couplings with the dimethylacetal group (protons H-6, H-7,
and H-5), suggesting a conformer with substituents in a
trans arrangement. (1S,3S)-7aa, on the other hand, showed
a strong NOE enhancement between H3 and H5 but a weak
enhancement with the dimethylacetal group, suggesting a
cis-relationship. These results confirmed that the stereoiso-
mer derived from trans-cyclization, with a lower-energy
conformation and less steric hindrance than its ciscounter-
part, is formed predominantly.
We then applied our optimized conditions to the syn-
thesis of a range of 1,3-disubstituted 1,3-dihydro-2H-imid-
azo[5,1-b]quinazolin-9-ones (Table 1). Various 2-(amino-
methyl)quinazolin-4-one derivatives 4a–d were synthe-
sized from the D- or L-stereoisomers or racemic mixtures of
N-protected amino acids, including valine, leucine, phenyl-
alanine, and tryptophan. Derivatives 4a–d were subjected
to intramolecular Mannich-type reaction with a range of al-
dehydes containing aliphatic, aromatic, or alkoxy substitu-
ents. Regardless of the nature of the reactants, the reaction
gave mixtures of diastereomeric products containing 65–
90% of the predominant trans-cyclized derivatives, as char-
acterized by HPLC analysis on a column with a chiral sta-
tionary phase.14 Except for compounds (3S)-7aa and (3R)-
The first dihydroimidazoquinazolinone to be synthe-
sized was (3S)-7aa, prepared by using L-valine as a starting
amino acid and dimethoxyacetaldehyde as the aldehyde
component. The 1H NMR spectra of the crude reaction mix-
ture showed two sets of signals with an integration ratio of
70:30, indicating the formation of cis- and trans-diastereo-
mers, one of which was strongly predominant. The two dia-
stereomers were isolated by chromatography on silica gel
and their stereochemical structures were shown to be cis-
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Figure 2 One-dimensional NOESY NMR studies
7aa, for which the enantiomers could be readily separated
by column chromatography, the tricyclic cycloadducts were
isolated as diastereomeric mixtures. When a racemic mix-
ture of the starting amino acid was used (Table 1; entries 3
and 6), the four possible diastereomers were obtained,
whereas optically pure D- or L-stereoisomers (entries 1, 2, 4,
5, and 7), gave two diastereomers in the same ratio as their
racemic cycloadduct counterparts, indicating that no race-
mization had occurred and that the intramolecular cycliza-
tion was weakly diastereoselective. Surprisingly, purifica-
tion of compound (3S)-7dc by column chromatography led
to degradation, whereas reactions involving the tryptophan
derivative (3S)-4d and each of the others aldehyde reac-
tants gave good yields of the desired imidazoquinazoli-
nones 7da, 7db, and 7dd, respectively.
Table 1 1,3-Disubstituted 1,3-Dihydroimidazo[5,1-b]quinazolin-9-ones 7(a–d)(a–d) Prepared by Mannich-Type Reactions of 2-(Aminometh-
yl)quinazolin-4(3H)-ones with Aldehydes
Entry Substrate
(MeO)2CHCHO
Yield (%) EtCHO
dra
Yield (%) BnCHO
dra
Yield (%) BnOCH2CHO
dra
Yield (%)
dra
MeO
O
N
O
N
O
N
OMe
O
N
NH
N
80b
67:25
68
65:35
65
70:30
65
80:20
O
O
N
NH
1
NH
NH2
N
NH
N
NH
(S)-4a
(3S)-7ab
(3S)-7aa
N
(3S)-7ac
(3S)-7ad
MeO
N
O
N
O
N
O
N
OMe
O
N
80b
68:29
76
68:32
60
70:30
62
80:20
NH
N
O
O
NH
2
NH
NH2
N
NH
N
NH
(R)-4a
(3R)-7ab
(3R)-7aa
N
(3R)-7ac
(3R)-7ad
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Synthesis
Table 1 (continued)
Entry Substrate
(MeO)2CHCHO
Yield (%) EtCHO
dra
Yield (%) BnCHO
dra
Yield (%) BnOCH2CHO
dra
Yield (%)
dra
MeO
O
O
N
O
N
OMe
O
N
NH
N
O
O
N
NH
NH
87
72:28
60
68:32
56
82:18
61
79:21
NH2
N
3
N
NH
N
NH
N
(3RS)-7bb
(RS)-4b
(3RS)-7ba
(3RS)-7bc
(3RS)-7bd
MeO
O
O
O
N
OMe
O
NH
NH
NH
N
O
O
N
NH
85
81:19
63
69:31
49
58
79:21
NH
NH2
N
4
N
NH 79:21
N
N
NH
N
N
(R)-4b
(3R)-7bb
(3R)-7ba
(3R)-7bc
(3R)-7bd
MeO
N
O
N
O
N
O
N
OMe
O
N
N
O
N
O
NH
79
81:19
55
69:31
57
79:21
61
79:21
NH
N
NH2
5
NH
N
NH
(S)-4b
(3S)-7ba
(3S)-7bb
(3S)-7bc
(3S)-7bd
MeO
N
O
N
O
N
O
N
OMe
O
N
O
O
NH
NH
N
NH2
NH
84
76:24
55
71:29
63
70:30
N
62
72:28
6
NH
N
N
(RS)-4c
(3RS)-7cb
(3RS)-7ca
(3RS)-7cc
(3RS)-7cd
O
N
MeO
O
O
OMe
NH
N
O
O
N
NH
NH2
NH
N
N
N
68
70:30
68
62:38
(3S)-7dc
degradation
–
–
70
70:30
NH
7
HN
N
HN
HN
HN
(3S)-7db
(3S)-7da
(3S)-4d
(3S)-7dd
a By chiral HPLC analysis.
b Isolated yield of purified product.
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In conclusion, we have developed an efficient intramo-
lecular Mannich-type reaction of 2-aminomethyl-
quinazolin-4-one derivatives with various aldehydes for the
synthesis of 1,3-disubstituted 1,3-dihydro-2H-imidazo[5,1-
b]quinazolin-9-ones, few of which have previously been de-
scribed in the literature. This reaction proceeded with weak
diastereoselection to produce the trans-stereoisomers pre-
dominantly, as determined by one-dimensional NOESY
NMR experiments. We intend to adapt the method to the
synthesis of libraries of related dihydroimidazoquinazoli-
nones, potentially useful as intermediates for syntheses of
putative bioactive compounds; results of these studies will
be published in due course.
LC/MS (APCI+): m/z = 318.1 [M + H]+.
Anal. Calcd for C17H23N3O3: C, 64.33; H, 7.30; N, 13.24. Found: C,
64.41; H, 7.18; N, 13.36.
tert-Butyl [(1S/1R/1RS)-3-Methyl-1-(4-oxo-3,4-dihydroquinazolin-
2-yl)butyl]carbamate [(R)-3b, (S)-3b, and (RS)-3b]
Prepared according to the general procedure from N-Boc-D-leucine,
N-Boc-L-leucine, or N-Boc-DL-leucine, respectively, as colorless solids;
yields: 2.0 g (61%) [(R)-3b], 2.2 g (66%) [(S)-3b], 2.3 g (69%) [(RS)-3b];
mp 178–180 °C [(R)-3b and (S)-3b], 176–178 °C [(RS)-3b].
1H NMR (300 MHz, DMSO-d6): δ = 0.89 (m, 6 H), 1.35 (s, 9 H), 1.58 (m,
3 H), 4.48 (m, 1 H), 7.13 (d, J = 8.2 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.60
(d, J = 8.1 Hz, 1 H), 7.78 (t, J = 7.6 Hz, 1 H), 8.08 (d, J = 8.1 Hz, 1 H),
12.15 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 21.9, 23.3, 24.9, 28.6, 42.4, 52.8,
87.7, 121.5, 126.2, 126.7, 127.4, 134.9, 155.7, 159.0, 162.2.
All reagents and solvents were purchased and used without further
purification. Melting points were determined on a Büchi B-540 appa-
ratus and are uncorrected. NMR spectra were acquired using a Bruker
Avance NMR spectrometer operating at 300 MHz (1H) or 75 MHz
LC/MS (APCI+): m/z = 332.4 [M + H]+.
Anal. Calcd for C18H25N3O3: C, 65.23; H, 7.60; N, 12.68. Found: C,
65.49; H, 7.51; N, 12.83.
(
13C). Chemical shifts are given in ppm relative to the solvent. HPLC-
tert-Butyl [(1RS)-1-(4-Oxo-3,4-dihydroquinazolin-2-yl)-2-phenyl-
ethyl]carbamate [(RS)-3c]
MS analyses were performed by using a Waters HPLC instrument
(ODS-30 column; H2O–MeCN–HCO2H mobile phase, gradient mode)
in combination with a Surveyor MSQ mass spectrometer (Thermo
Electron) equipped with an APCI source. Elemental analyses were
performed by using an UMR CNRS8181 analyzer, and were in agree-
ment with the calculated values within ±0.4%. Analytical chiral HPLC
was performed on a Waters HPLC system equipped with a HPLC 600
pump and a 2996 photodiode array detector. The HPLC analyses were
performed on a Daicel Chiralpak AD or ODI Column (250 × 4.6 mm)
with elution by hexane–i-PrOH at 1 mL/min.
Prepared according to the general procedure from N-Boc-DL-phenyl-
alanine as a colorless solid; yield: 3.55 g (97%); mp 211–213 °C.
1H NMR (300 MHz, DMSO-d6): δ = 1.30 (s, 9 H), 2.93 (m, 1 H), 3.10 (m,
1 H), 4.63 (m, 1 H), 7.19–7.35 (m, 6 H), 7.51 (t, J = 7.8 Hz, 1 H), 7.2 (d,
J = 7.9 Hz, 1 H), 7.81 (t, J = 7.7 Hz, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 12.38
(s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 28.6, 55.9, 78.7, 121.6, 126.3, 126.8,
127.3, 128.5, 129.8, 134.9, 138.2, 155.8, 162.2.
LC/MS (APCI+): m/z = 366.4 [M + H]+.
2-{[N-(tert-Butoxycarbonyl)amino]methyl}quinazolin-4-(3H)-
ones 3a–d; General Procedure
Anal. Calcd for C21H23N3O3: C, 69.02; H, 6.34; N, 11.50. Found: C,
69.18; H, 6.24; N, 11.65.
A solution of i-BuO2CCl (11 mmol) in THF (10 mL) was added drop-
wise to a solution of the appropriate N-(tert-butoxycarbonyl)amino
acid (11 mmol) and NMM (11 mmol) in THF (30 mL) at –15 °C under
N2, and the mixture was stirred for 1 h. A soln of 2-aminobenzamide
(10 mmol) in THF (15 mL) was added dropwise, and the mixture was
stirred at r.t., then refluxed for 10 h. The mixture was cooled and then
a 30% soln of NaOMe in MeOH (20 mmol) and MeOH (20 mL) were
added. The the mixture was refluxed for 3 h then cooled and concen-
trated under reduced pressure to give a residue that was dissolved in
H2O (50 mL). The pH was adjusted to 3 with 10% aq oxalic acid (10
mL) and the resulting precipitate was collected by filtration, washed
with H2O (2 × 10 mL), and recrystallized from EtOH.
tert-Butyl [(1S)-2-(1H-Indol-3-yl)-1-(4-oxo-3,4-dihydroquin-
azolin-2-yl)ethyl]carbamate [(S)-3d]
Prepared according to the general procedure from N-Boc-L-trypto-
phan as a colorless solid; yield: 3.5 g (87%); mp 202–204 °C.
1H NMR (300 MHz, DMSO-d6): δ = 1.29 (s, 9 H), 3.11 (m, 1 H), 3.25 (m,
1 H), 4.68 (m, 1 H), 6.92 (t, J = 7.5 Hz, 1 H), 7.00–7.14 (m, 3 H), 7.30 (d,
J = 8.0 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.63 (m, 2 H), 7.79 (t, J = 8.2 Hz,
1 H), 8.09 (d, J = 6.9 Hz, 1 H), 10.88 (s, 1 H), 12.32 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 28.5, 29.5, 55.2, 78.7, 110.0, 111.7,
118.6, 119.0, 121.3, 121.5, 124.5, 126.2, 126.7, 127.4, 127.7, 134.9,
136.4, 149.1, 155.6, 158.5, 162.2.
tert-Butyl [(1S/1R)-2-Methyl-1-(4-oxo-3,4-dihydroquinazolin-2-
yl)propyl]carbamate [(S)-3a and (R)-3a]
LC/MS (APCI+): m/z = 405.1 [M + H]+.
Prepared according to the general procedure from N-Boc-L-valine and
N-Boc-D-valine, respectively, as colorless solids; yields: 2.15 g (68%)
[(S)-3a] and 2.25 g (71%) [(R)-3b]; mp 136–138 °C.
Anal. Calcd for C23H24N4O3: C, 68.30; H, 5.98; N, 13.85. Found: C,
68.42; H, 5.81; N, 13.97.
1H NMR (300 MHz, DMSO-d6): δ = 0.81 (d, J = 6.7 Hz, 3 H), 0.90 (d,
J = 6.7 Hz, 3 H), 1.34 (s, 9 H), 2.05 (m, 1 H), 4.22 (t, J = 8.75 Hz, 1 H),
6.99 (d, J = 8.6 Hz, 1 H), 7.47 (t, J = 7.9 Hz, 1 H), 7.62 (d, J = 7.85 Hz, 1
H), 7.78 (t, J = 8.4 Hz, 1 H), 8.08 (dd, J = 1.15, 7.9 Hz, 1 H), 11.55 (s, 1
H).
13C NMR (75 MHz, DMSO-d6): δ = 19.1, 19.7, 28.6, 31.9, 59.9, 78.8,
121.5, 126.2, 126.8, 127.4, 134.9, 148.9, 155.8, 157.9, 162.0.
2-(Aminomethyl)quinazolin-4-(3H)-ones 4a–d; General Procedure
A solution of the appropriate carbamate 3a–d (5 mmol) in CH2Cl2
(150 mL) was saturated with HCl gas, and the mixture was stirred at
r.t. for 12 h. The mixture was then concentrated under reduced pres-
sure. The residue was dissolved in H2O (25 mL) and the solution was
basified with 10% aq NH3. The resulting precipitate was collected by
filtration, washed with H2O (2 × 10 mL), dried in vacuo, and recrystal-
lized from MeOH.
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2-[(1S/1R)-1-Amino-2-methylpropyl]quinazolin-4(3H)-one [(S)-4a
and (R)-4a]
1,3-Dihydroimidazo[5,1-b]quinazolin-9-one Derivatives 7(a–d)(a–
d); General Procedure
Colorless solids; yields: 820 mg (75%) [(S)-4a] and 880 mg (81%) [(R)-
4a]; mp 109–111 °C.
1H NMR (300 MHz, DMSO-d6): δ = 0.84 (d, J = 6.8 Hz, 3 H), 0.89 (d,
J = 6.7 Hz, 3 H), 1.97 (m, 1 H), 3.39 (d, J = 6.8 Hz, 1 H), 5.39 (s, 2 H),
7.45 (td, J = 1.2, 8.15 Hz, 1 H), 7.61 (dd, J = 0.8, 8.2 Hz, 1 H), 7.77 (td,
J = 1.55, 8.4 Hz, 1 H), 8.08 (dd, J = 1.65, 8.3 Hz, 1 H).
A solution of the appropriate 2-(aminomethyl)quinazolin-4-one de-
rivative 4a–d (1 mmol) and aldehyde (1.5 mmol) in MeOH (7 mL) was
refluxed for 12 h. The mixture was then evaporated under reduced
pressure to give a residue that was purified by column chromatogra-
phy [silica gel, PE–EtOAc (1:1)].
(1R,3S)-1-(Dimethoxymethyl)-3-isopropyl-2,3-dihydroimid-
azo[5,1-b]quinazolin-9(1H)-one [(1R,3S)-7aa]
13C NMR (75 MHz, DMSO-d6): δ = 18.4, 20.3, 33.2, 60.8, 121.4, 126.2,
126.5, 127.3, 134.8, 149.0, 161.2, 162.3.
LC/MS (APCI+): m/z = 218.1 [M + H]+.
Prepared according to the general method from (S)-4a and
(MeO)2CHCHO as a yellow oil; yield: 205 mg (67%).
Anal. Calcd for C12H15N3O: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.47;
H, 6.79; N, 19.22.
1H NMR (300 MHz, CDCl3): δ = 0.80 (d, J = 6.8 Hz, 3 H), 1.05 (d, J = 6.8
Hz, 3 H), 2.29 (m, 1 H), 2.53 (s, 1 H), 3.25 (s, 3 H), 3.53 (s, 3 H), 4.45
(dd, J = 1.35, 3.4 Hz, 1 H), 4.96 (d, J = 1.45 Hz, 1 H), 5.48 (t, J = 1.5 Hz, 1
H), 7.40 (td, J = 1.95, 8.15 Hz, 1 H), 7.67 (m, 2 H), 8.22 (dd, J = 1.5, 8.7
Hz, 1 H).
2-[(1S/1R/1RS)-1-Amino-3-methylbutyl]quinazolin-4(3H)-one
[(R)-4b, (S)-4b, and (RS)-4b]
Colorless solids; yields: 800 mg (69%) [(R)-4b], 820 mg (71%) [(S)-4b],
1.0 g (86%) [(RS)-4b]; mp 145–147 °C [(R)-4b and (S)-4b], 143–145 °C
[(RS)-4b].
1H NMR (300 MHz, DMSO-d6): δ = 0.86 (d, J = 6.5 Hz, 3 H), 0.90 (d,
J = 6.5 Hz, 3 H), 1.55 (m, 2 H), 1.69 (m, 1 H), 3.69 (dd, J = 2.1, 6.35 Hz, 1
H), 5.40 (s, 2 H), 7.45 (t, J = 7.05 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.77
(td, J = 1.45, 8.25 Hz, 1 H), 8.08 (dd, J = 1.05, 7.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 15.9, 19.4, 31.6, 57.1, 58.1, 66.2, 74.8,
103.4, 120.4, 126.3, 126.4, 127.3, 134.4, 149.5, 159.4, 160.1.
Anal. Calcd for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C,
63.45; H, 7.08; N, 13.73.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (95:5); tR = 15.13 min.
(1S,3S)-1-(Dimethoxymethyl)-3-isopropyl-2,3-dihydroimid-
azo[5,1-b]quinazolin-9(1H)-one [(1S,3S)-7aa]
13C NMR (75 MHz, DMSO-d6): δ = 22.4, 23.4, 24.7, 44.9, 53.5, 121.5,
126.2, 126.5, 127.3, 134.8, 149.1, 161.5, 162.3.
LC/MS (APCI+): m/z = 232.1 [M + H]+.
Prepared according to the general method from (S)-4a and (MeO)2CH-
CHO as a yellow oil; yield: 75 mg (25%).
1H NMR (300 MHz, CDCl3): δ = 1.01 (d, J = 6.8 Hz, 3 H), 1.22 (d, J = 6.8
Hz, 3 H), 2.57 (m, 2 H), 3.40 (s, 3 H), 3.60 (s, 3 H), 4.01 (d, J = 4.0 Hz, 1
H), 5.32 (m, 1 H), 5.59 (d, J = 1.7 Hz, 1 H), 7.43 (td, J = 1.9, 8.1 Hz, 1 H),
7.69 (m, 2 H), 8.24 (dd, J = 1.35, 8.4 Hz, 1 H).
Anal. Calcd for C13H17N3O: C, 67.51; H, 7.41; N, 18.17. Found: C, 67.68;
H, 7.31; N, 18.25.
2-[(1RS)-1-Amino-2-phenylethyl]quinazolin-4(3H)-one [(RS)-4c]
Colorless solid; yield: 1.0 g (76%); mp 198–200 °C.
13C NMR (75 MHz, CDCl3): δ = 16.6, 19.5, 29.6, 29.7, 57.3, 57.7, 65.6,
76.2, 101.3, 120.7, 126.3, 127.2, 134.4, 149.4, 159.3, 160.9.
1H NMR (300 MHz, DMSO-d6): δ = 2.90 (dd, J = 5.4, 8.2 Hz, 1 H), 3.15
(dd, J = 6.0, 7.2 Hz, 1 H), 4.00 (dd, J = 1.8, 6.3 Hz, 1 H), 6.32 (s, 2 H),
7.23 (m, 5 H), 7.48 (t, J = 7.9 Hz, 1 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.79 (td,
J = 1.5, 8.4 Hz, 1 H), 8.10 (dd, J = 1.2, 8.0 Hz, 1 H).
Anal. Calcd for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C,
63.48; H, 6.81; N, 13.82.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (95:5); tR = 26.18 min.
13C NMR (75 MHz, DMSO-d6): δ = 41.8, 56.3, 121.5, 126.2, 126.7,
127.3, 128.6, 129.8, 134.9, 138.4, 148.9, 159.9, 162.1.
LC/MS (APCI+): m/z = 266.1 [M + H]+.
(1S,3R)-1-(Dimethoxymethyl)-3-isopropyl-2,3-dihydroimid-
azo[5,1-b]quinazolin-9(1H)-one [(1S,3R)-7aa]
Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N, 15.84. Found: C, 72.56;
H, 5.55; N, 15.76.
Prepared according to the general method from (R)-4a and
(MeO)2CHCHO as a yellow oil; yield: 206 mg (68%).
The 1H and 13C NMR spectra were identical to those of (1R,3S)-7aa.
2-[(1S)-1-Amino-2-(1H-indol-3-yl)ethyl]quinazolin-4(3H)-one
[(S)-4d]
Anal. Calcd for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C,
63.44; H, 7.05; N, 13.92.
Colorless solid; yield: 1.25 g (84%); mp 185–187 °C.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (95:5); tR = 21.97 min.
1H NMR (300 MHz, DMSO-d6): δ = 3.01 (dd, J = 6.6, 7.5 Hz, 1 H), 3.24
(dd, J = 6.3, 7.8 Hz, 1 H), 4.00 (t, J = 7.4 Hz, 1 H), 5.37 (s, 2 H), 6.89 (td,
J = 0.9, 7.85 Hz, 1 H), 7.01 (td, J = 1.1, 8.05 Hz, 1 H), 7.08 (d, J = 2.3 Hz,
1 H), 7.28 (d, J = 7.8 Hz, 1 H), 7.45 (td, J = 1.1, 8.05 Hz, 1 H), 7.52 (d,
J = 7.9 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.76 (td, J = 1.6, 8.5 Hz, 1 H),
8.07 (dd, J = 1.25, 8.0 Hz, 1 H), 10.77 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 55.9, 67.5, 110.8, 111.7, 118.6,
121.3, 124.2, 125.3, 126.2, 126.5, 127.3, 127.9, 134.8, 136.5, 139.6,
149.1, 161.1, 162.2.
(1R,3R)-1-(Dimethoxymethyl)-3-isopropyl-2,3-dihydroimid-
azo[5,1-b]quinazolin-9(1H)-one [(1R,3R)-7aa]
Prepared according to the general method from (R)-4a and
(MeO)2CHCHO as a yellow oil; yield: 87 mg (29%).
The 1H and 13C NMR spectra were identical to those of (1S,3S)-7aa.
Anal. Calcd for C16H21N3O3: C, 63.35; H, 6.98; N, 13.85. Found: C,
63.47; H, 6.91; N, 13.79.
LC/MS (APCI+): m/z = 305.1 [M + H]+.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (95:5); tR = 13.35 min.
Anal. Calcd for C18H16N4O: C, 71.04; H, 5.30; N, 13.41. Found: C, 71.19;
H, 5.17; N, 13.53.
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Synthesis
(1R,3S)- and (1S,3S)-1-Ethyl-3-isopropyl-2,3-dihydroimidazo[5,1-
b]quinazolin-9(1H)-one [(3S)-7ab]
(1R,3S)- and (1S,3S)-1-[(Benzyloxy)methyl]-3-isopropyl-2,3-dihy-
droimidazo[5,1-b]quinazolin-9(1H)-one [(3S)-7ad]
Prepared according to the general method from (S)-4a and EtCHO as a
mixture of diastereomers; colorless oil; yield: 174 mg (68%).
Prepared according to the general method from (S)-4a and
BnOCH2CHO as a mixture of diastereomers; colorless solid; yield: 225
mg (65%); mp 87–88 °C.
1H NMR (300 MHz, CDCl3): δ = 0.89 (d, J = 6.8 Hz, 2.5 H), 1.00 (d,
J = 6.8 Hz, 0.5 H), 1.14 (d, J = 6.8 Hz, 2.5 H), 1.23 (d, J = 6.8 Hz, 0.5 H),
2.39 (m, 1 H), 2.60 (m, 1 H), 3.87 (dd, J = 2.15, 10.4 Hz, 0.8 H), 3.98 (dd,
J = 2.0, 10.5 Hz, 0.2 H), 4.05 (d, J = 3.85 Hz, 0.2 H), 4.26 (dd, J = 3.3, 10.4
Hz, 0.8 H), 4.39 (d, J = 3.3 Hz, 0.8 H), 4.45–4.55 (m, 2 H), 4.64 (dd,
J = 3.2, 10.5 Hz, 0.2 H), 5.32 (m, 0.2 H), 5.54 (m, 0.8 H), 7.17–7.27 (m, 5
H), 7.46 (td, J = 1.6, 8.1 Hz, 1 H), 7.72 (m, 1 H), 8.26 (m, 1 H).
1H NMR (300 MHz, CDCl3): δ = 0.90 (d, J = 7.0 Hz, 2.2 H), 0.99 (m, 3.2
H), 1.15 (d, J = 7.0 Hz, 1.7 H), 1.21 (m, 1.9 H), 1.88 (m, 1.2 H), 2.15 (m,
1.6 H), 2.44 (m, 1.2 H), 4.07 (d, J = 4.95 Hz, 0.35 H), 4.26 (d, J = 3.65 Hz,
0.65 H), 5.30 (dd, J = 2.4, 8.2 Hz, 0.35 H), 5.44 (dd, J = 2.6, 7.8 Hz, 0.65
H), 7.44 (m, 1 H), 7.70 (m, 2 H), 8.28 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 8.3, 8.6, 16.3, 17.3, 19.5, 19.8, 26.3, 26.7,
26.9, 29.7, 30.9, 65.4, 65.7, 120.9, 121.1, 126.2, 126.3, 126.4, 126.5,
127.1, 127.2, 124.1, 134.2, 149.6, 159.1, 160.0, 160.5.
13C NMR (75 MHz, CDCl3): δ = 16.3, 16.6, 19.6, 19.7, 29.5, 29.7, 31.5,
65.5, 66.9, 68.3, 73.4, 73.5, 74.9, 75.2, 120.8, 121.0, 126.2, 126.3,
126.4, 127.1, 127.2, 127.5, 127.6, 127.8, 128.4, 134.2, 134.3, 137.5,
137.6, 149.5, 149.6, 159.3, 159.6, 160.2, 161.0.
Anal. Calcd for C15H19N3O: C, 70.01; H, 7.44; N, 16.33. Found: C, 70.12;
H, 7.33; N, 16.36.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (90:10); tR = 14.83 min
(65%), 17.11 min (35%).
Anal. Calcd for C21H23N3O2: C, 72.18; H, 6.63; N, 12.03. Found: C,
72.30; H, 6.57; N, 12.08.
(1R,3R)- and (1S,3R)-1-Ethyl-3-isopropyl-2,3-dihydroimidazo[5,1-
b]quinazolin-9(1H)-one [(3R)-7ab]
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (85:15); tR = 11.60 min
(80%), 16.37 min (20%).
Prepared according to the general method from (R)-4a and EtCHO as a
mixture of diastereomers; colorless oil; yield: 195 mg (76%).
The 1H and 13C NMR spectra were identical to those of (3S)-7ab.
(1R,3R)- and (1S,3R)-1-[(Benzyloxy)methyl]-3-isopropyl-2,3-dihy-
droimidazo[5,1-b]quinazolin-9(1H)-one [(3R)-7ad]
Anal. Calcd for C15H19N3O: C, 70.01; H, 7.44; N, 16.33. Found: C, 70.08;
H, 7.47; N, 16.38.
Prepared according to the general method from (R)-4b and
BnOCH2CHO as a mixture of diastereomers; colorless solid; yield: 215
mg (62%); mp 87–88 °C.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (90:10); tR = 12.61 min
(68%), 20.95 min (32%).
The 1H and 13C NMR spectra were identical to those of (3S)-7ad.
Anal. Calcd for C21H23N3O2: C, 72.18; H, 6.63; N, 12.03. Found: C,
72.27; H, 6.68; N, 11.98.
(1R,3S)- and (1S,3S)-1-Benzyl-3-isopropyl-2,3-dihydroimid-
azo[5,1-b]quinazolin-9(1H)-one [(3S)-7ac]
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (85:15); tR = 10.00 min
(80%), 11.95 min (20%).
Prepared according to the general method from (S)-4a and PhCH2CHO
as a mixture of diastereomers; colorless oil; yield: 207 mg (65%).
1H NMR (300 MHz, CDCl3): δ = 0.87 (d, J = 6.7 Hz, 3 H), 1.08 (d, J = 6.9
Hz, 3 H), 2.35 (m, 1 H), 3.34 (m, 1.4 H), 3.52 (dd, J = 6.5, 13.6 Hz, 0.34
H), 3.64 (dd, J = 2.95, 13.7 Hz, 0.33 H), 3.88 (d, J = 3.7 Hz, 0.7 H), 4.04
(d, J = 4.4 Hz, 0.3 H), 5.55 (dd, J = 3.1, 6.7 Hz, 0.3 H), 5.74 (dd, J = 3.1,
5.9 Hz, 0.7 H), 7.24 (m, 5 H), 7.50 (m, 1 H), 7.69 (m, 1 H), 7.76 (m, 1 H),
8.36 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 16.2, 16.6, 19.5, 19.6, 29.7, 30.4, 30.8,
38.7, 38.8, 65.2, 65.5, 75.6, 75.6, 120.9, 121.1, 126.4, 126.5, 126.9,
127.1, 127.2, 127.3, 128.5, 128.6, 128.7, 130.0, 130.1, 134.3, 135.2,
135.4, 149.4, 149.5, 158.9, 159.0, 160.2, 161.0.
(1R,3R)-, (1R,3S)-, (1S,3R)-, and (1S,3S)-1-(Dimethoxymethyl)-3-
isobutyl-2,3-dihydroimidazo[5,1-b]quinazolin-9(1H)-one [(RS)-
7ba]
Prepared according to the general method from (RS)-4b and
(MeO)2CHCHO as a mixture of diastereomers; yellow oil; yield: 275
mg (87%).
1H NMR (300 MHz, CDCl3): δ = 0.94 (m, 6 H), 1.44 (m, 0.8 H), 1.89 (m,
2.2 H), 2.45 (s, 1 H), 3.23 (s, 2.2 H), 3.32 (s, 0.8 H), 3.51 (s, 2.4 H), 3.53
(s, 0.6 H), 4.09 (d, J = 10.4 Hz, 0.25 H), 4.49 (dd, J = 3.0, 10.4 Hz, 0.75
H), 4.87 (d, J = 1.5 Hz, 0.75 H), 5.33 (m, 0.25 H), 5.39 (d, J = 1.75 Hz,
0.25 H), 5.45 (m, 0.75 H), 7.35 (td, J = 2.2, 8.2 Hz, 1 H), 7.63 (m, 2 H),
8.18 (d, J = 7.8 Hz, 1 H).
Anal. Calcd for C20H21N3O: C, 75.21; H, 6.63; N, 13.16. Found: C, 75.36;
H, 6.58; N, 13.21.
Chiral HPLC: Chiralpak ODI; hexane–i-PrOH (95:5); tR = 8.02 min
(70%), 10.14 min (30%).
13C NMR (75 MHz, CDCl3): δ = 21.3, 21.5, 23.5, 23.6, 25.0, 25.1, 42.1,
43.4, 57.1, 57.3, 57.8, 58.0, 59.1, 59.8, 74.4, 101.0, 120.5, 126.3, 126.4,
126.5, 127.1, 127.3, 134.1, 134.4, 149.5, 160.1, 160.6.
(1R,3R)- and (1S,3R)-1-Benzyl-3-isopropyl-2,3-dihydroimid-
azo[5,1-b]quinazolin-9(1H)-one [(3R)-7ac]
Anal. Calcd for C17H23N3O3: C, 64.33; H, 7.30; N, 13.24. Found: C,
64.39; H, 7.21; N, 13.25.
Prepared according to the general method from (R)-4a and
PhCH2CHO as a mixture of diastereomers; colorless oil; yield: 191 mg
(60%).
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (90:10); tR = 13.00 min
(37%), 17.38 min (14%), 24.70 min (14%), 34.61 min (35%).
The 1H and 13C NMR spectra were identical to those of (3S)-7ac.
(1R,3R)- and (1S,3R)-1-(Dimethoxymethyl)-3-isobutyl-2,3-dihy-
droimidazo[5,1-b]quinazolin-9(1H)-one [(3R)-7ba]
Anal. Calcd for C20H21N3O: C, 75.21; H, 6.63; N, 13.16. Found: C, 75.39;
H, 6.70; N, 13.20.
Prepared according to the general method from (R)-4b and
(MeO)2CHCHO as a mixture of diastereomers; yellow oil; yield: 269
mg (85%).
Chiral HPLC: Chiralpak ODI; hexane–i-PrOH (95:5); tR = 6.85 min
(70%), 13.89 min (30%).
The 1H and 13C NMR spectra were identical to those of (RS)-7ba.
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Synthesis
Anal. Calcd for C17H23N3O3: C, 64.33; H, 7.30; N, 13.24. Found: C,
64.42; H, 7.24; N, 13.18.
(1R,3R)-, (1R,3S)-, (1S,3R)-, and (1S,3S)-1-Benzyl-3-isobutyl-2,3-di-
hydroimidazo[5,1-b]quinazolin-9(1H)-one [(3RS)-7bc]
Prepared according to the general method from (RS)-4b and
PhCH2CHO as a mixture of diastereomers; colorless solid; yield: 186
mg (56%); mp 80–82 °C.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (90:10); tR = 17.26 min
(19%), 33.46 min (81%).
(1R,3S)- and (1S,3S)-1-(Dimethoxymethyl)-3-(2-methylpropyl)-
1,3-dihydroimidazo[5,1-b]quinazolin-9-one [(3S)-7ba]
1H NMR (300 MHz, CDCl3): δ = 0.97 (t, J = 6.0 Hz, 6 H), 1.21 (m, 0.25
H), 1.43 (m, 0.75 H), 1.94 (m, 2 H), 2.11 (s, 1 H), 3.29 (m, 1.6 H), 3.49
(m, 0.4 H), 3.73 (dd, J = 2.85, 10.15 Hz, 0.8 H), 4.19 (dd, J = 3.65, 10.9
Hz, 0.2 H), 5.62 (dd, J = 3.0, 6.4 Hz, 0.2 H), 5.73 (t, J = 4.7 Hz, 0.8 H),
7.23 (m, 5 H), 7.50 (t, J = 7.05 Hz, 1 H), 7.69–7.78 (m, 2 H), 8.37 (d,
J = 8.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 21.2, 22.6, 23.4, 25.3, 29.7, 38.7, 41.7,
44.7, 58.6, 75.2, 120.8, 126.4, 126.5, 127.1, 127.2, 128.5, 128.8, 130.0,
134.3, 134.8, 135.7, 149.6, 160.1, 160.3.
Prepared according to the general method from (S)-4b and
(MeO)2CHCHO as a mixture of diastereomers; yellow oil; yield: 250
mg (79%).
The 1H and 13C NMR spectra were identical to those of (RS)-7ba.
Anal. Calcd for C17H23N3O3: C, 64.33; H, 7.30; N, 13.24. Found: C,
64.39; H, 7.18; N, 13.27.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (90:10); tR = 13.31 min
(81%), 25.53 min (19%).
Anal. Calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60. Found: C, 75.71;
H, 6.84; N, 12.71.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (70:30); tR = 6.52 min
(41%), 8.69 min (9%), 13.89 min (9%), 21.65 min (41%).
(1R,3R)-, (1R,3S)-, (1S,3R)-, and (1S,3S)-1-Ethyl-3-isobutyl-2,3-di-
hydroimidazo[5,1-b]quinazolin-9(1H)-one [(3RS)-7bb]
Prepared according to the general method from (RS)-4b and EtCHO as
a mixture of diastereomers; colorless oil; yield: 162 mg (60%).
(1R,3R)- and (1S,3R)-1-Benzyl-3-isobutyl-2,3-dihydroimidazo[5,1-
b]quinazolin-9(1H)-one [(3R)-7bc]
1H NMR (300 MHz, CDCl3): δ = 1.05 (m, 9 H), 1.55 (m, 1 H), 1.63 (s, 1
H), 1.79 (m, 1 H), 1.90–2.15 (m, 2.7 H), 2.45 (m, 0.3 H), 4.22 (dd,
J = 2.9, 10.55 Hz, 0.3 H), 4.30 (dd, J = 3.3, 10.1 Hz, 0.7 H), 5.33 (dd,
J = 2.5, 8.25 Hz, 0.3 H), 5.44 (dd, J = 3.0, 8.5 Hz, 0.7 H), 7.46 (td, J = 1.65,
8.15 Hz, 1 H), 7.72 (m, 2 H), 8.29 (m, 1 H).
Prepared according to the general method from (R)-4b and
PhCH2CHO as a mixture of diastereomers; colorless solid; yield: 163
mg (49%); mp 80–82 °C.
The 1H and 13C NMR spectra were identical to those of (3RS)-7bc.
13C NMR (75 MHz, CDCl3): δ = 8.4, 9.3, 21.4, 21.5, 22.6, 23.4, 23.5, 25.3,
26.0, 26.9, 41.9, 43.4, 58.8, 59.1, 76.2, 77.2, 121.0, 126.3, 126.4, 127.0,
127.1, 134.2, 149.6, 159.9, 160.2.
Anal. Calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60. Found: C, 75.73;
H, 7.01; N, 12.56.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (70:30); tR = 9.01 min
(11%), 23.86 min (89%).
Anal. Calcd for C16H21N3O: C, 70.82; H, 7.80; N, 15.49. Found: C, 70.90;
H, 7.74; N, 15.54.
(1R,3S)- and (1S,3S)-1-Benzyl-3-isobutyl-2,3-dihydroimidazo[5,1-
b]quinazolin-9(1H)-one [(3S)-7bc]
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (80:20); tR = 9.53 min
(35%), 11.54 min (17%), 13.51 min (15%), 21.58 min (33%).
Prepared according to the general method from (S)-4b and PhCH2CHO
as a mixture of diastereomer; colorless solid; yield: 189 mg (57%); mp
80–82 °C.
The 1H and 13C NMR spectra were identical to those of (3RS)-7bc.
(1R,3R)- and (1S,3R)-1-Ethyl-3-isobutyl-2,3-dihydroimidazo[5,1-
b]quinazolin-9(1H)-one [(3R)-7bb]
Prepared according to the general method from (R)-4b and EtCHO as
a mixture of diastereomers; colorless oil; yield: 170 mg (63%).
The 1H and 13C NMR spectra were identical to those of (3RS)-7bb.
Anal. Calcd for C21H23N3O: C, 75.65; H, 6.95; N, 12.60. Found: C, 75.72;
H, 6.88; N, 12.69.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (70:30); tR = 6.64 min
(79%), 15.44 min (21%).
Anal. Calcd for C16H21N3O: C, 70.82; H, 7.80; N, 15.49. Found: C, 70.92;
H, 7.76; N, 15.46.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (80:20); tR = 11.63 min
(31%), 20.76 min (69%).
(1R,3R)-, (1R,3S)-, (1S,3R)-, and (1S,3S)-1-[(Benzyloxy)methyl]-3-
isobutyl-2,3-dihydroimidazo[5,1-b]quinazolin-9(1H)-one [(3RS)-
7bd]
(1R,3S)- and (1S,3S)-1-Ethyl-3-isobutyl-2,3-dihydroimidazo[5,1-
b]quinazolin-9(1H)-one [(3S)-7bb]
Prepared according to the general method from (RS)-4b and
BnOCH2CHO as a mixture of diastereomers; light-yellow solid; yield:
221 mg (61%); mp 71–73 °C.
1H NMR (300 MHz, CDCl3): δ = 1.05 (t, J = 5.8 Hz, 6 H), 1.52–1.67 (m, 2
H), 2.00 (m, 2 H), 3.87 (dd, J = 2.15, 10.25 Hz, 1 H), 4.19 (dd, J = 3.5,
10.35 Hz, 1 H), 4.46–4.65 (m, 3 H), 5.35 (m, 0.2 H), 5.57 (m, 0.8 H),
7.20 (m, 5 H), 7.46 (td, J = 1.6, 8.05 Hz, 1 H), 7.73 (m, 2 H), 8.26 (m, 1
H).
Prepared according to the general method from (S)-4b and EtCHO as a
mixture of diastereomers; colorless oil; yield: 149 mg (55%).
The 1H and 13C NMR spectra were identical to those of (3RS)-7bb.
Calcd for C16H21N3O: C, 70.82; H, 7.80; N, 15.49. Found: C, 70.89; H,
7.85; N, 15.53.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (80:20); tR = 9.64 min
13C NMR (75 MHz, CDCl3): δ = 21.4, 23.5, 25.3, 42.4, 59.6, 68.9, 73.4,
74.0, 120.8, 126.3, 126.4, 127.2, 127.5, 127.7, 128.4, 134.3, 137.6,
149.6, 160.1, 160.8.
(72.5%), 13.69 min (27.5%).
Anal. Calcd for C22H25N3O2: C, 72.70; H, 6.93; N, 11.56. Found: C,
72.81; H, 6.84; N, 11.51.
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Synthesis
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (85:15); tR = 12.03 min
(34%), 13.04 min (11%), 22.31 min (11%), 24.86 min (44%).
13C NMR (75 MHz, CDCl3): δ = 7.7, 9.1, 26.1, 26.4, 37.6, 39.3, 60.9, 61.7,
76.2, 120.9, 121.0, 126.4, 126.4, 126.5, 126.9, 127.0, 127.1, 127.2,
128.6, 128.7, 129.5, 129.6, 129.7, 134.2, 136.3, 137.1, 149.3, 149.4,
158.8, 159.0, 159.8, 160.3.
(1R,3R)- and (1S,3R)-1-[(Benzyloxy)methyl]-3-isobutyl-2,3-dihy-
droimidazo[5,1-b]quinazolin-9(1H)-one [(3R)-7bd]
Anal. Calcd for C19H19N3O: C, 74.73; H, 6.27; N, 13.76. Found: C, 74.82;
H, 6.19; N, 13.81.
Prepared according to the general method from (R)-4b and
BnOCH2CHO as a mixture of diastereomers; light-yellow solid; yield:
210 mg (58%); mp 71–73 °C.
The 1H and 13C NMR spectra were identical to those of (3RS)-7bd.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (70:30); tR = 10.99 min
(13%), 11.56 min (33%), 12.22 min (38%), 14.66 min (16%).
(1R,3R)-, (1R,3S)-, (1S,3R)-, and (1S,3S)-1,3-Dibenzyl-2,3-dihydro-
imidazo[5,1-b]quinazolin-9(1H)-one [(3RS)-7cc]
Anal. Calcd for C22H25N3O2: C, 72.70; H, 6.93; N, 11.56. Found: C,
72.76; H, 6.91; N, 11.48.
Prepared according to the general method from (RS)-4c and
PhCH2CHO as a mixture of diastereomers; colorless oil; yield: 231 mg
(63%).
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (85:15); tR = 13.04 min
(22%), 24.64 min (78%).
1H NMR (300 MHz, CDCl3): δ = 2.24 (s, 1 H), 2.81 (dd, J = 8.25, 14.15
Hz, 0.3 H), 3.11–3.35 (m, 3.7 H), 3.56 (dd, J = 2.95, 13.8 Hz, 0.3 H), 4.12
(dd, J = 5.1, 6.95 Hz, 0.7 H), 4.44 (dd, J = 4.05, 8.45 Hz, 0.3 H), 5.55 (m,
1 H), 7.16–7.27 (m, 5 H), 7.53 (td, J = 1.35, 8.0 Hz, 1 H), 7.78 (m, 2 H),
8.37 (d, J = 7.95 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 37.7, 38.8, 39.2, 39.3, 60.7, 61.7, 75.3,
76.1, 120.9, 121.1, 126.6, 127.0, 127.05, 127.1, 127.3, 128.5, 128.6,
128.7, 129.4, 129.5, 130.0, 130.1, 134.4, 135.6, 136.3, 136.4, 149.3,
149.4, 158.8, 158.9, 160.0, 160.7.
(1R,3S)- and (1S,3S)-1-[(Benzyloxy)methyl]-3-isobutyl-2,3-dihy-
droimidazo[5,1-b]quinazolin-9(1H)-one [(3S)-7bd]
Prepared according to the general method from (S)-4b and
BnOCH2CHO as a mixture of diastereomers; light-yellow solid; yield:
221 mg (61%); mp 71–73 °C.
The 1H and 13C NMR spectra were identical to those of (3RS)-7bd.
Anal. Calcd for C22H25N3O2: C, 72.70; H, 6.93; N, 11.56. Found: C,
72.82; H, 6.89; N, 11.60.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (85:15); tR = 12.06 min
(79%), 22.66 min (21%).
Anal. Calcd for C24H21N3O: C, 78.45; H, 5.76; N, 11.44. Found: C, 78.55;
H, 5.71; N, 11.40.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (70:30); tR = 13.31 min
(31%), 16.41 min (30%), 18.04 min (39%).
(1R,3R)-, (1R,3S)-, (1S,3R)-, and (1S,3S)-3-Benzyl-1-(dimethoxy-
methyl)-2,3-dihydroimidazo[5,1-b]quinazolin-9(1H)-one [(3RS)-
7ca]
(1R,3R)-, (1R,3S)-, (1S,3R)-, and (1S,3S)-3-Benzyl-1-[(benzyl-
oxy)methyl]-2,3-dihydroimidazo[5,1-b]quinazolin-9(1H)-one
[(3RS)-7cd]
Prepared according to the general method from (RS)-4c and
(MeO)2CHCHO as a mixture of diastereomers; light-yellow solid;
yield: 294 mg (84%); mp 126–128 °C.
1H NMR (300 MHz, CDCl3): δ = 2.57 (s, 1 H), 3.26 (m, 1 H), 3.29 (s, 0.6
H), 3.33 (s, 2.4 H), 3.47 (dd, J = 3.7, 14.05 Hz, 1 H), 3.55 (s, 0.6 H), 3.58
(s, 2.4 H), 4.48 (dd, J = 3.7, 9.2 Hz, 0.8 H), 4.85 (dd, J = 4.5, 6.9 Hz, 0.2
H), 4.89 (d, J = 1.55 Hz, 0.2 H), 5.29 (d, J = 1.7 Hz, 0.8 H), 5.38 (m, 0.2
H), 5.45 (m, 0.8 H), 7.26 (d, J = 4.6 Hz, 2 H), 7.35 (m, 3 H), 7.49 (td,
J = 2.15, 8.15 Hz, 1 H), 7.77 (m, 2 H), 8.29 (d, J = 8.6 Hz, 1 H).
Prepared according to the general method from (RS)-4c and
BnOCH2CHO as a mixture of diastereomers; colorless oil; yield: 246
mg (62%).
1H NMR (300 MHz, CDCl3): δ = 2.57 (s, 1 H), 3.21 (m, 1 H), 3.42 (dd,
J = 4.35, 14.25 Hz, 0.7 H), 3.54 (dd, J = 4.0, 14.25 Hz, 0.3 H), 3.82 (td,
J = 2.0, 12.45 Hz, 1 H), 4.13 (dd, J = 3.2, 10.25 Hz, 0.7 H), 4.41–4.53 (m,
2.6 H), 4.80 (dd, J = 4.45, 6.9 Hz, 0.7 H), 5.36 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 29.7, 38.3, 38.4, 61.6, 61.9, 66.9, 68.8,
73.4, 74.0, 75.3, 120.8, 121.0, 126.5, 127.0, 127.2, 127.5, 127.7, 128.0,
128.3, 128.7, 129.4, 129.6, 134.3, 136.5, 136.9, 137.4, 149.5, 159.3,
160.0.
13C NMR (75 MHz, CDCl3): δ = 38.9, 39.1, 57.0, 57.1, 57.5, 58.0, 62.0,
62.3, 74.2, 75.9, 101.1, 103.7, 120.5, 120.7, 126.5, 126.8, 127.1, 127.3,
128.7, 129.4, 129.7, 134.5, 136.7, 137.1, 149.4, 159.1, 160.5.
Anal. Calcd for C20H21N3O3: C, 68.36; H, 6.02; N, 11.96. Found: C,
68.43; H, 5.97; N, 12.01.
Anal. Calcd for C25H23N3O2: C, 75.54; H, 5.83; N, 10.57. Found: C,
75.62; H, 5.87; N, 10.46.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (80:20); tR = 11.48 min
(11%), 14.78 min (13%), 20.44 min (35%), 22.6 min (41%).
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (90:10); tR = 25.39 min
(33%), 31.33 min (14%), 33.74 min (39%), 43.68 min (14%).
(1R,3R)-, (1R,3S)-, (1S,3R)-, and (1S,3S)-3-Benzyl-1-ethyl-2,3-dihy-
droimidazo[5,1-b]quinazolin-9(1H)-one [(3RS)-7cb]
(1R,3S)- and (1S,3S)-1-(Dimethoxymethyl)-3-(1H-indol-3-ylmeth-
yl)-2,3-dihydroimidazo[5,1-b]quinazolin-9(1H)-one [(3S)-7da]
Prepared according to the general method from (RS)-4c and EtCHO as
a mixture of diastereomers; colorless oil; yield: 167 mg (55%).
Prepared according to the general method from (S)-4d and
(MeO)2CHCHO as a mixture of diastereomers; yellow solid; yield: 265
mg (68%); mp 75–77 °C.
1H NMR (300 MHz, CDCl3): δ = 2.59 (s, 0.7 H), 2.72 (s, 0.3 H), 3.24 (s,
0.9 H), 3.30 (s, 2.1 H), 3.46–3.61 (m, 5.3 H), 4.57 (m, 0.3 H), 4.83 (m,
0.7 H), 4.89 (m, 0.7 H), 5.30 (m, 0.7 H), 5.45 (m, 0.3 H), 6.99 (d, J = 2.05
Hz, 0.7 H), 7.04–7.11 (m, 1 H), 7.17 (m, 1.3 H), 7.34 (m, 1 H), 7.50 (m,
1 H), 7.69 (d, J = 7.65 Hz, 0.7 H), 7.81 (m, 2.3 H), 8.06 (s, 0.7 H), 8.12 (s,
0.3 H), 8.29 (m, 1 H).
1H NMR (300 MHz, CDCl3): δ = 0.78 (t, J = 7.6 Hz, 1 H), 0.96 (t, J = 7.6
Hz, 2 H), 1.74 (m, 1 H), 2.05 (m, 0.7 H), 2.26 (m, 0.3 H), 2.35 (s, 1 H),
3.20 (m, 1 H), 3.44 (m, 1 H), 4.43 (dd, J = 4.05, 7.85 Hz, 0.3 H), 4.58 (dd,
J = 4.45, 6.75 Hz, 0.7 H), 5.25 (m, 1 H), 7.21–7.29 (m, 5 H), 7.44 (m, 1
H), 7.74 (m, 2 H), 8.26 (d, J = 7.9 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 377–386

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Synthesis
13C NMR (75 MHz, CDCl3): δ = 27.5, 28.9, 56.8, 57.1, 57.4, 58.0, 61.2,
62.3, 74.4, 76.0, 101.1, 103.9, 109.9, 111.1, 119.0, 119.1, 119.5, 119.7,
120.5, 120.7, 122.1, 123.3, 123.5, 126.5, 127.1, 127.3, 127.6, 127.9,
134.5, 136.0, 149.5, 159.9, 160.0.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (70:30); tR = 10.81 min
(70%), 21.35 min (30%).
Acknowledgment
Anal. Calcd for C22H22N4O3: C, 67.68; H, 5.68; N, 14.35. Found: C,
67.76; H, 5.59; N, 14.30.
We thank Professor Stephanie Delbaere of the Laboratoire d’Applica-
tion de Résonnance Magnétique Nucléaire (LARM) of the University
of Lille 2 for her help in the interpretation of the NMR spectra.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (70:30); tR = 9.30 (70%),
18.52 (30%) min.
(1R,3S)- and (1S,3S)-1-Ethyl-3-(1H-indol-3-ylmethyl)-2,3-dihydro-
imidazo[5,1-b]quinazolin-9(1H)-one [(3S)-7db]
Supporting Information
Prepared according to the general method from (S)-4d and EtCHO as a
mixture of diastereomers; yellow solid; yield: 233 mg (68%); mp 65–
67 °C.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378675.
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1H NMR (300 MHz, CDCl3): δ = 0.55 (t, J = 7.45 Hz, 0.9 H), 0.99 (t,
J = 7.45 Hz, 2.1 H), 1.68–1.85 (m, 1 H), 1.91 (s, 1 H), 2.20 (m, 1 H), 3.58
(m, 2 H), 4.49 (t, J = 6.05 Hz, 0.3 H), 4.67 (t, J = 4.75 Hz, 0.7 H), 5.18
(dd, J = 2.85, 8.5 Hz, 0.7 H), 5.25 (dd, J = 2.2, 7.1 Hz, 0.3 H), 6.98 (d,
J = 2.4 Hz, 0.7 H), 7.09 (m, 1.3 H), 7.18 (m, 1 H), 7.33 (m, 1 H), 7.48 (m,
1 H), 7.71 (m, 1 H), 7.79–7.85 (m, 2 H), 8.28 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 7.1, 9.4, 26.3, 27.9, 60.9, 61.2, 76.2, 76.9,
109.3, 111.3, 118.7, 119.7, 120.9, 122.2, 123.5, 123.7, 126.4, 126.5,
127.0, 127.1, 128.0, 134.3, 136.0, 136.1, 149.4, 149.5, 159.3, 159.7,
159.9, 160.6.
References
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S. In The Alkaloids: Chemistry and Pharmacology; Vol. 29; Brossi,
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(2) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103,
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(3) Examples include raltitrexed (marketed as Tomudex for treat-
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(4) Jankowski, F.; Verones, V.; Flouquet, N.; Carato, P.; Berthelot, P.;
Lebegue, N. Tetrahedron 2010, 66, 128.
Anal. Calcd for C21H20N4O: C, 73.23; H, 5.85; N, 16.27. Found: C, 73.36;
H, 5.74; N, 16.33.
Chiral HPLC: Chiralpak AD; hexane–i-PrOH (75:25); tR = 11.12 min
(62%), 13.54 min (38%).
(5) Jen, T.; Dienel, B.; Bowman, H.; Petta, J.; Helt, A.; Love, B. J. Med.
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(1R,3S)- and (1S,3S)-1-[(Benzyloxy)methyl]-3-(1H-indol-3-ylmeth-
yl)-2,3-dihydroimidazo[5,1-b]quinazolin-9(1H)-one [(3S)-7dd]
Prepared according to the general method from (S)-4d and
BnOCH2CHO as a mixture of diastereomers; yellow solid; yield: 305
mg (70%); mp 61–64 °C.
(8) Chern, J.-W.; Tao, P.-L.; Wang, K.-C.; Gutcait, A.; Liu, S.-W.; Yen,
M.-H.; Chien, S.-L.; Rong, J.-K. J. Med. Chem. 1998, 41, 3128.
(9) Hirth, K. P.; Mann, E.; Shawyer, L. K.; Ullrich, A.; Keri, G.;
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Tang, P. T.; Lammers, R. US 6331555, 2001.
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37, 1044.
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(14) See the experimental section and the Supporting Information
for details.
1H NMR (300 MHz, CDCl3): δ = 2.64 (s, 1 H), 3.47–3.56 (m, 1.3 H), 3.62
(m, 0.7 H), 3.77 (m, 1 H), 4.04 (dd, J = 3.5, 10.2 Hz, 0.7 H), 4.25 (d,
J = 4.7 Hz, 0.7 H), 4.41–4.55 (m, 1.9 H), 4.87 (m, 0.7 H), 5.32 (m, 1 H),
6.97 (m, 2 H), 7.06–7.22 (m, 6 H), 7.34 (d, J = 8.1 Hz, 1 H), 7.48 (m, 1
H), 7.68 (d, J = 7.9 Hz, 0.7 H), 7.73 (d, J = 8.15 Hz, 0.3 H), 7.79 (m, 2 H),
8.00 (s, 1 H), 8.23 (dd, J = 0.9, 8.5 Hz, 0.7 H), 8.28 (dd, J = 0.95, 8.0 Hz,
0.3 H).
13C NMR (75 MHz, CDCl3): δ = 27.0, 29.7, 61.1, 61.9, 66.5, 69.4, 73.2,
73.4, 73.9, 75.5, 109.7, 111.2, 118.8, 119.6, 119.8, 120.8, 122.2, 122.3,
123.3, 123.5, 126.3, 126.5, 127.1, 127.2, 127.4, 127.6, 127.8, 127.9,
128.3, 134.3, 136.0, 137.5, 149.6, 159.9.
Anal. Calcd for C27H24N4O2: C, 74.29; H, 5.54; N, 12.84. Found: C,
74.36; H, 5.47; N, 12.93.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 377–386