Synthesis of 2,3-dihydro-4(1H)-quinazolinones

Article abstract of DOI:10.3987/COM-04-10130

An improved procedure for the synthesis of 2-substituted 2,3-dihydro-4(1H)-quinazolinones through diastereomer separation of the corresponding quinazolinones derivatives is presented. The determination of their absolute configurations was obtained by X-Ra

Full text of DOI:10.3987/COM-04-10130

HETEROCYCLES, Vol. 63, No. 9, 2004, pp. 2019 - 2032
Received, 25th May, 2004, Accepted, 22nd July, 2004, Published online, 26th July, 2004
SYNTHESIS OF 2,3-DIHYDRO-4(1H)-QUINAZOLINONES
Jaime Escalante,* Patricia Flores, and Jaime M. Priego
Chemical Research Center, Morelos Autonomous State University
Av. Universidad No. 1001, Col. Chamilpa, C.P. 62210 Cuernavaca, Mor., Mexico,
E-mail: jaime@ciq.uaem.mx
Abstract – An improved procedure for the synthesis of 2-substituted
2,3-dihydro-4(1H)-quinazolinones through diastereomer separation of the
corresponding quinazolinones derivatives is presented. The determination of their
absolute configurations was obtained by X-Ray diffraction.
INTRODUCTION
Preparation of quinazolinones are in demand because of their potential biological and pharmaceutical
activities.1 Unfortunately, synthetic methods for the elaboration of this bicyclic system are not general in
scope, and often low-yielding. Here we wish to describe the preparation of eight new 2-substituted
2,3-dihydro-4(1H)-quinazolinones according to the literature procedures.2
RESULTS AND DISCUSSION
In continuation of our studies of asymmetric synthesis of β-amino acids,3 we synthesized a series of
2-substituted 2,3-dihydro-4(1H)-quinazolinones derivatives. There are numerous methods available for
the synthesis of quinazolinones and their derivatives.2 We adapted the reaction of isatoic anhydride with
different amines to prepare our starting materials,4 aminobenzamides (3, 4, 11 and 15), and finally the
procedure of direct cyclocondensation dehydrogenation with different aldehydes.5 We then used X-Ray
crystal-structure determinations to elucidate the stereochemical outcome of the reactions studied.
I. Synthesis of 2,3-dihydro-4(1H)-quinazolinones.
A. Synthesis of 2,3-dihydro-3-[(1R,2S,5R)-menthoxycarbonylmethyl]-4(1H)-quinazolinone (7) and
2,3-dihydro-3-[(1R,2S,5R)-menthoxycarbonylethyl]-4(1H)-quinazolinone (8).
The benzamides (1) and (2) were obtained through treatment of isatoic anhydride with glycine methyl
ester hydrochloride and β-alanine menthyl ester respectively in presence of Et3N (Scheme 1).7
Cyclocondensation with trimethyl orthoformate and p-TsOH in toluene yielded the cyclized compounds

(3) and (4) in good yields. Hydrolysis of 3 with aqueous NaOH in THF-MeOH gave product (5). The
4(3H)-quinazolinone (6) was obtained with DCC and (-)-menthol in 52 % overall yield conversion.
Finally, the 2,3-dihydro-4-(1H)-quinazolinone (7) and (8) were formed by hydrogenation.
Scheme 1
O
O
OR
HC(OMe)3
p-TsOH
Toluene
isatoic anhydride / Et3N
Toluene / AcOEt
n
N
H2N
H
OR
O
n
NH2
n = 1, R = Me
1, n = 1, R = Me
n = 2, R = Menthyl
2, n = 2, R = Menthyl
O
O
O
O
N
NaOH
THF / MeOH
DCC, DMAP
OH
N
O
(-)-Menthol
N
N
O
O
5
6
N
OR
n
H2, PtO2
MeOH
N
O
O
O
O
3, n = 1, R = Me
4, n = 2, R = Menthyl
O
O
N
N
H2, PtO2
MeOH
N
H
N
H
8
7
B. Synthesis of 2-substituted 2,3-dihydro-4(1H)-quinazolinone derivatives.
The benzamides (9) and (10) were prepared with isatoic anhydride and (S)-α–phenylethylamine and
(S)-(+)-alanine methyl ester hydrochloride respectively. Subsequently, the cyclocondensation
with different aldehydes in benzene or CH2Cl2, and p-TsOH yielded the diastereomers (S,R)- and
1
(S,S)-(11-16). Assessment of diasteromeric product ratios (ds) was achieved by H-NMR spectroscopic
analysis of the crude products (Table 1). Final confirmation of the absolute configuration of the newly
created stereogenic center at C(2) was carried out by analysis of solid-state structure for each.
II. X-Ray diffraction study of 2,3-dihydro-4(1H)-quinazolinone derivatives.
This study afforded relevant information on the conformation in the 4(1H)-quinazolinone derivatives. See
Figures 1 and 2 for a view of the solid-state structures of 6 and 8. It is interesting to note how the
conformation of the amino acid segment changes. When the amino acid is β-alanine, this group is in the
plane, meanwhile with glycine is above to the face to quinazolinone, and this contrasting behavior is
explained by the approach of the menthol group.

Table 1. Diastereoselectivity of cyclocondensation of the benzamides (9) and (10) with different
aldehydes.
O
Me
O
Me
Me
N
H
NH2
R
isatoic anhydride
R
AcOEt
N
R
R´CHO
Solvent
p-TsOH
H2N
N
H
R´
R = Ph
R = CO2Me
9, R = Ph
10, R = CO2Me
11-(S,R) and 11-(S,S), R= R´= Ph
12-(S,R) and 12-(S,S), R = Ph, R´= Cy
13-(S,R) and 13-(S,S), R = Ph, R´= o-MeO-Ph
14-(S,R) and 14-(S,S), R = CO2Me, R´ = Ph
15-(S,R) and 15-(S,S), R = CO2Me, R´ = t-Bu
16-(S,R) and 16-(S,S), R = CO2Me, R´ = o-NO2-Ph
R
Ph
Ph
R´CHO
PhCHO
CyCHO
Solvent
Benzene
CH2Cl2
Benzene
CH2Cl2
CH2Cl2
CH2Cl2
Yielda (%)
ds: (S,S)/(S,R)
90:10
88
71
51
80
58
52
53:47
75:25
47:53
85:15
Ph
o-MeOPhCHO
PhCHO
t-BuCHO
o-NO2PhCHO
CO2Me
CO2Me
CO2Me
25:75
a Yield after flash chromatography.
Figure 2. Structure and solid-state conformation
of 2,3-dihydro-3-[(1R,2S,5R)-menthoxycarbonyl-
ethyl]-4(1H)-quinazolinone (8).
Figure 1. Structure and solid-state conformation
of 3-[(1R,2S,5R)-menthoxycarbonylmethyl]-
4(3H)-quinazolinone (6).

On the another hand, there is relevant information on the conformation at C(2) in the 2-substituted
2,3-dihydro-4(1H)-quinazolinones (S,R)-(11), (S,R)-(12), and (S,S)-(13). Here, we have the astonishing
feature of the phenyl, cyclohexyl, and o-methoxyphenyl groups in quasi-axial or quasi-flagpole position!
(Figures 3, 4, and 5). It is a clearly consequence of the powerful A1,3-strain effect.7 In addition to this effect,
in the compound (11), is the stabilization between aromatic ring π- interaction crystal packing.8 In
particular, one wonders what role intramolecular hydrogen bonding/crystal packing might play in the
conformation of these compounds. Analysis of these molecules precisely reveals the existence of an
intramolecular hydrogen bonding between C(15)-H and the carbonyl adjacent (r = 2.16 Å), and anchor the
phenylethyl segment in the quinazolinone.
Figure 4. Structure and solid-state conformation
of 2,3-dihydro-2(R)-cyclohexyl-3- [(S)-α-phenyl-
ethyl]- 4(1H)-quinazolinone (12).
Figure 3. Structure and solid-state conformation
of 2,3-dihydro-2(R)-phenyl-3-[(S)-α-phenylethyl]-
4(1H)-quinazolinone (11).
With the segment methyloxycarbonylethyl in quinazolinones [(S,S)-(14), (S,S)-(15), and (S,R)-(16)] the
most interesting feature of the crystallographic structure of (S,R)-16 is that the o-nitrophenyl group at
C(2) adopts a pseudo equatorial conformaction, which can be explained by an intramolecular hydrogen
bonging between oxygen(NO2) and the protons in C(2)-H and N(1)-H (r = 2.20 Å), while with phenyl and
t-butyl groups in (S,S)-14 and (S,S)-15 respectively, a pseudo axial oriented conformation at C(2) is
expected (Figures 6, 7, and 8).

Figure 6. Structure and solid-state conformation
of 2,3-dihydro-2(S)-phenyl-3-[(S)-methyloxy-
carbonylethyl]-4(1H)- quinazolinone (14).
Figure 5. Structure and solid-state conformation
of 2,3-dihydro-2(S)-(o-methoxyphenyl)-3-
[(S)-α-phenylethyl]-4(1H)-quinazolinone (13).
Figure 8. Structure and solid-state conformation
Figure 7. Structure and solid-state conformation
of 2,3-dihydro-2(S)-tert-butyl-3-[(S)-methoxy-
carbonylethyl]-4(1H)-quinazolinone (15).
of
2,3-dihydro-2(R)-(o-nitrophenyl)-3-[(S)-
methoxycarbonylethyl]-4(1H)-quinazolinone (16).
EXPERIMENTAL
General. For a description of general experimental part for 1, see ref.9 Microanalyses were performed
by Elementar Vario EL III.
The compound β-alanine methyl ester and glycine menthyl esters hydrochloride were prepared from
β-alanine and glycine according to the literature.10

General Procedure for the Reaction of Isatoic Anhydride with Amines (GP1).
1.1 Equiv of the amine was added to a suspension of isatoic anhydride (1 equiv.) in a mixture of
o
toluene/ethyl acetate (1:1, 0.62 M). The reaction mixture was warmed to 35-40 C during 40 min. The
solution was then concentrated under reduced pressure. The crude product was purified by FC.
General Procedure for the Preparation of Quinazolinones (GP2).
A solution of the aminobenzamide (1 equiv.) in benzene or CH2Cl2 (0.11 M) was treated with the
aldehyde (1.1 equiv.) and p-toluenesulfonic acid monohydrate (0.1 equiv.), and the reaction mixture was
heated to 40 oC for 2 h with azeotropic removal of water. The organic layer was then treated with 15 mL
of saturated sodium bisulfide solution. The organic layer was dried (MgSO4) and concentrated under
reduced pressure. The crude product was purified by FC.
2-Amine-N-(methoxycarbonylmethyl)benzamide (1).
A suspension of glycine methyl ester hydrochloride (4.0 g, 32 mmol) was treated with Et3N (5.8 mL, 41
mmol), and isatoic anhydride (5.8 g, 35.2 mmol) according to GP1. The triethylamine hydrochloride was
removed by filtration, and the filtrate was concentrated on a rotary evaporator. Recrystallization
o
1
(CH2Cl2/Hexane) of the benzamide (1) produced 5.9 g (88 %) as a yellow solid: mp 71-73 C, H NMR
(400 MHz, CDCl3): δ 3.68 (3H, s), 4.09 (2H, d, J = 6.0 Hz), 5.54 (2H, br s), 7.91 (1H, br s), 7.27-7.32
13
(2H, m), 7.78 (1H, td, Jortho = 7.2 and Jmeta = 1.2 Hz), 7.99 (1H, dd, Jortho = 8.0 and Jmeta = 1.2 Hz); C
NMR (100 MHz CDCl3): δ 41.8, 52.2, 116.2, 116.2, 117.8, 128.7, 133.1, 151.1, 170.4, 171.4. Anal. Calcd
for C10H12N2O3: C, 57.68; H, 5.81; N, 13.45. Found: C, 57.35; H, 5.62; N, 13.52.
2-Amine-N-[(1R,2S,5R)-menthoxycarbonylethyl]benzamide (2).
β-Alanine menthyl ester (2.0 g, 8.8 mmol) was treated with isatoic anhydride (1.6 g, 9.7 mmol) according
to GP1. Filtration of the mixture through charcoal and concentration on a rotary evaporator afforded 2.7 g
(91 %) of the desired benzamide (2) as a yellow oil. For analytical purposes a sample was purified by FC
[hexane-ethyl acetate (50:50)]: [α]D24 -50.6 o (c = 0.50, CHCl3), 1H NMR (400 MHz, CDCl3): δ 0.71-2.03
(18H, m), 2.60 (2H, m), 3.67 (2H, dd, J1 = 6.0 and J2 = 12.4 Hz), 4.70 (1H, dt, J1 = 10.8 and J2 = 4.4 Hz),
5.53 (2H, br s), 6.74 (1H, br s), 6.60-6.67 (2H, m), 7.18 (1H, td, Jortho = 7.6 and Jmeta = 1.2 Hz), 7.27 (1H,
dd, Jortho = 7.2 and Jmeta = 1.2 Hz); 13C NMR (100 MHz, CDCl3): δ 16.6, 20.9, 22.7, 23.7, 26.8, 31.8, 34.5,
34.6, 35.4, 41.2, 47.3, 75.1, 116.0, 116.8, 117.5, 127.4, 132.5, 149.1, 169.4, 172.6. HRMS calcd for
C20H30N2O3 346.2256, found 346.2254.
3-Methoxycarbonylmethyl-3,4-dihydro-4(1H)-quinazolinone (3).

Compound (1) (3 g, 14.3 mmol) was treated with trimethyl orthoformate (3.6 mL, 21.5 mmol) according
to GP2. Purification of the crude product by FC [hexane-ethyl acetate (50:50)] yielded (3) (2.47 g, 77 %)
as a white solid. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): mp 158-160 ºC,
1H NMR (400 MHz, CDCl3): δ 3.80 (3H, s), 4.74 (2H, s), 7.52 (1H, dt, Jortho = 8.0 and Jmeta = 1.6 Hz),
13
7.72 - 7.87 (2H, m), 8.00 (1H, s), 8.11 (1H, dd, Jortho = 7.2 and Jmeta = 1.6 Hz); C NMR (100 MHz,
CDCl3): δ 47.3, 53.0, 122.0, 127.0, 127.6, 127.8, 134.6, 146.2, 148.3, 161.0, 167.8. Anal. Calcd for
C11H10N2O3: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.38; H, 4.66; N, 12.71.
3,4-Dihydro-3-[(1R,2S,5R)-menthoxycarbonylethyl]-4(1H)-quinazolinone (4).
Compound (2) (2.0 g, 5.8 mmol) was treated with trimethyl orthoformate (0.97 mL, 6.3 mmol) according
to GP2. Purification of the crude product by FC [hexane-ethyl acetate-methanol (60:38:2)] yielded (5)
(1.98 g, 96 %) as a white solid. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): mp
98-99 oC, [α]D24 -54.5 o (c = 0.50, CHCl3), 1H NMR (200 MHz, CDCl3): δ 0.61-1.96 (18H, m), 2.90 (2H,
dt, J1 = 6.2 and J2 = 2.8 Hz), 4.27 (2H, t, J = 6.2 Hz), 4.69 (1H, dt, J1 = 11.0 and J2 = 4.4 Hz), 7.51 (1H,
13
td, Jortho = 7.9 and Jmeta = 1.5 Hz), 7.79-7.82 (2H, m), 8.31 (1H, dd, Jortho = 8.1 and Jmeta = 1.5 Hz); C
NMR (50 MHz, CDCl3): δ 16.5, 20.8, 22.3, 23.6, 26.6, 31.7, 33.5, 34.4, 41.1, 43.8, 47.1, 75.2, 121.9,
126.5, 127.2, 127.5, 134.3, 147.2, 148.1, 161.0, 170.6. Anal. Calcd for C21H28N2O3: C, 70.76; H, 7.92; N,
7.86. Found: C, 70.87; H, 7.94; N, 7.89.
3-Carboxymethyl-3,4-dihydro-4(1H)-quinazolinone (5).
1 g (4.4 mmol) of the quinazolinone (3), 20 mL of tetrahydrofuran and 20 mL of methanol was placed in
a flask with a magnetic stirrer. This mixture was treated with 4 mL of a 2.5 N solution sodium hydroxide,
and the mixture was stirred for 1 h. Then HCl (1N) was added to adjust pH = 2, and then extracted with
ethyl acetate (x 3). The organic layer was dried (MgSO4) and evaporated. FC [hexane-ethyl
acetate-methanol (60:38:2)] yielded a solid of 5 (0.77g, 86%). For analytical purposes a sample was
recrystallized (CH2Cl2/Hexane): mp 215 ºC (decomp), 1H NMR (400 MHz, CD3OD): δ 4.83 (2H, s), 7.59
(1H, dt, Jortho = 8.0 and Jmeta = 1.2 Hz), 7.72 (1H, d, Jortho = 8.4 Hz), 7.87 (1H, dt, Jortho = 7.2 and Jmeta = 1.6
13
Hz), 8.25 (1H, dd, Jortho = 8.0 and Jmeta = 1.6 Hz), 8.37 (1H, s); C NMR (100 MHz, CD3OD): δ 49.8,
122.9, 127.7, 127.8, 129.0, 136.2, 148.8, 149.6, 162.6, 170.9. HRMS calcd for C10H8N2O3 204.0535,
found 204.0537.
3,4-Dihydro-3-[(1R,2S,5R)-menthoxycarbonylmethyl]- 4(1H)-quinazolinone (6).
A stirred solution of 5 (1.0 g, 4.8 mmol) in 100 mL of CH2Cl2 was treated with 1.54 g (6.3 mmol) of
DCC, 0.06 g (0.4 mmol) of DMAP, and 1.54 g (6.3 mmol) of (1R,2S,5R)-(-)-menthol. The mixture was

stirred overnight and then filtered and concentrated in vacuo. FC [hexane–ethyl acetate (70:30)] afforded
the pure quinazolinone (6) as a solid white (1.5 g, 90 %). For analytical purposes a sample was
24
o
1
recrystallized (CH2Cl2/Hexane): mp 89-90º. [α]D -26.8 (c = 0.50, CHCl3), H NMR (200 MHz,
CDCl3): δ 0.75-2.08 (18H, m), 4.69 (1H, s), 4.78 (1H, dt, J1 = 11.0 and J2 = 4.8 Hz), 7.52 (1H, td, Jortho
=
6.2 and Jmeta = 1.8 Hz), 7.71-7.79 (2H, m,), 7.99 (1H, s), 8.31 (1H, d, Jortho = 8.2 Hz); 13C NMR (50 MHz,
CDCl3): δ 16.5, 20.87, 22.1, 23.6, 26.5, 31.6, 34.2, 40.7, 47.1, 47.7, 76.8, 122.1, 127.0, 127.6, 127.8,
134.7, 146.4, 148.3, 161.1, 167.0. Anal. Calcd for C20H26N2O3: C, 70.15; H, 7.65; N, 8.18. Found: C,
70.10; H, 7.71; N, 8.21. X-Ray crystallographic structure in Figure 2.11
2,3-Dihydro-3-[(1R,2S,5R)-menthoxycarbonylmethyl]- 4(1H)-quinazolinone (7).
A mixture of 0.1 g (0.29 mmol) of 6, 20 mL of methanol and 0.01 g of PtO2 catalyst was stirred and
pressurized to 30 lb of hydrogen for 2.5 h. Filtration of the mixture through Celite and concentration on a
rotary evaporator afforded 0.098 g (95 %) of the desired quinazolinone (7) as a white solid. For analytical
purposes a sample was recrystallized (CH2Cl2/Hexane): mp 118-120 ºC, [α]D24 - 56.3 o (c = 1.0, MeOH),
1H NMR (400MHz, CDCl3): δ 0.74-2.08 (18H, m), 4.26 (2H, s), 4.45 (1H, br s), 4.65-4.8 (3H, m), 6.67
(1H, d, Jortho = 8.2 Hz), 6.87 (1H, td, Jortho = 8.0 and Jmeta = 1.2 Hz), 7.28 (1H, td, Jortho = 8.0 and Jmeta = 1.2
13
Hz), 7.92 (1H, dd, Jortho = 7.6 and Jmeta = 1.2 Hz); C NMR (100 MHz, CDCl3): δ 16.7, 21.1, 22.3, 23.7,
26.5, 31.7, 34.4, 41.1, 47.2, 47.6, 60.8, 75.8, 115.4, 117.2, 119.9, 128.9, 133.3, 147.6, 163.9, 168.6. Anal.
Calcd for C20H28N2O3: C, 69.78; H, 8.19; N, 8.13. Found: C, 69.66; H, 8.12; N, 8.19.
2,3-Dihydro-3-[(1R,2S,5R)-menthoxycarbonylethyl]- 4(1H)-quinazolinone (8).
A mixture of 0.5 g (1.4 mmol) of 4, 20 mL of methanol and 0.05 g of PtO2 catalyst was stirred and
pressurized to 30 lb of hydrogen for 2.5 h. Filtration of the mixture through Celite and concentration on a
rotary evaporator produced 0.46 g (92 % yield) of the desired quinazolinone (8) as a white solid. For
analytical purposes a sample was recrystallized (CH2Cl2/Hexane): mp 111-112 ºC, [α]D24 -62.2 o (c = 0.50,
CHCl3), 1H NMR (400MHz, CDCl3): δ 0.62-1.98 (18H, m), 2.72 (2H, dt, J1 = 6.4 and J2 = 3.2 Hz), 3.75
(2H, t, J = 6.4 Hz), 4.69 (1H, dt, J1 = 10.8 and J2 = 4.4 Hz), 4.71 (2H, s), 6.69 (1H, d, Jortho = 8.4 Hz), 6.89
(1H, td, Jortho = 8.0 and Jmeta = 1.2 Hz), 7.29 (1H, td, Jortho = 8.0 and Jmeta = 1.2 Hz), 7.92 (1H, dd, Jortho
=
7.6 and Jmeta = 1.2 Hz); 13C NMR (100 MHz, CDCl3): δ 16.4, 20.9, 22.2, 23.5, 26.3, 31.6, 33.8, 34.3, 41.0,
42.4, 47.0, 61.0, 74.8, 115.2, 117.9, 120.0, 128.9, 133.3, 147.8, 164.0, 172.2. Anal. Calcd for
C21H30N2O3: C, 70.36; H, 8.44; N, 7.81. Found: C, 70.16; H, 8.46; N, 7.78. X-Ray crystallographic
structure in Figure 1.11
2-Amine-N-[(S)-α-phenylethyl]benzamide (9).

The isatoic anhydride (4.9 g, 30.0 mmol) was treated with (S)-phenylethylamine (4.2 g, 35.0 mmol)
according to GP1. Filtration of the mixture through charcoal and concentration on a rotary evaporator
produced 7.2 g (97 %) of the desired benzamide (9), as white solid. For analytical purposes a sample was
o
24
o
1
recrystallized (CH2Cl2/Hexane): mp 136–138 C, [α]D +110.9 (c = 1.0, CHCl3), H NMR (400 MHz,
CDCl3): δ 1.59 (3H, d, J = 7.0 Hz), 5.28 (1H, dq, J1 = J2 = 7.0 Hz), 6.29 (1H, d, J = 6.2 Hz), 6.62 (1H, d,
J
ortho = 7.3 Hz), 6.66 (1H, t, Jortho = 8.4 Hz), 7.20 (1H, td, Jortho = 7.7 and Jmeta = 1.5 Hz), 7.26–7.40 (6H,
13
m); C NMR (100 MHz, CDCl3): δ 22.0, 48.9, 116.6, 116.6, 117.4, 126.1, 127.1, 127.4, 128.8, 132.2,
143.4, 148.8, 168.4. Anal. Calcd for C15H16N2O: C, 74.97; H, 6.71; N, 11.66. Found: C, 74.22; H, 6.78; N,
11.32.
2-Amine-N-[(S)-methoxycarbonylethyl)]benzamide (10).
The isatoic anhydride (4.9 g, 30.0 mmol) was treated with (S)-alanine methyl ester hydrochloride (4.8 g,
35.0 mmol) according to GP1. Filtration of the mixture through charcoal and concentration on a rotary
evaporator produced 5.6 g (82 %) of the desired benzamide (10) as white solid. For analytical purposes a
sample was recrystallized (CH2Cl2/Hexane): mp 90-91 °C, [α]D24 + 4.5 o (c = 0.52, CHCl3). 1H NMR (200
MHz, CDCl3): δ 1.49 (3H, d, J = 7.0 Hz), 3.76 (3H, s), 4.72 (1H, dq, J1 = J2 = 7.1 Hz), 5.50 (1H, br s),
6.60 (1H, dd, Jmeta = 1.2 and Jortho= 7.6 Hz), 6.64 (1H, d, Jortho = 7.6 Hz), 7.18 (1H, ddd, Jmeta = 1.3 Hz,
Jortho = Jortho = 7.4 Hz), 7.37 (1H, dd, Jmeta = 1.4 and Jortho = 8.2 Hz); 13C NMR (50 MHz, CDCl3): δ 18.9,
48.5, 52.8, 115.2, 116.6, 117.3, 127.4, 132.5, 148.8, 168.5, 173.6. Anal. Calcd for C11H14N2O3: C, 59.45;
H, 6.35; N, 12.61. Found: C, 59.35; H, 6.28; N, 12.47.
2,3-Dihydro-2(R)- and 2,3-dihydro-2(S)-phenyl-3-[(S)-α-phenylethyl]-4(1H)-quinazolinone [(S,R)-
and (S,S)-11].
Compound (9) (0.67 g, 2.8 mmol) was treated with p-toluenesulfonic acid (76 mg, 0.4 mmol) and
benzaldehyde (0.31 g, 3 mmol) in benzene according to GP2. The crude products were purified by FC
[hexane: ethyl acetate: CH2Cl2 (75:15:10)] to produce both diastereoisomers (0.80 g, 88 %).
(S,S)-11. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp
182–184 °C, [α]D24 +301.0 o (c = 0.52, CHCl3), 1H NMR (400 MHz, CDCl3): δ 1.22 (3H, d, J = 7.2 Hz),
4.54 (1H, s), 5.37 (1H, s), 6.24 (1H, q, J = 7.2), 6.39 (1H, d, Jortho = 8.4 Hz), 6.82 (1H, td, Jmeta = 1.2 Hz
13
and Jortho = 8.2 Hz), 7.15–7.41 (11H, m), 8.01 (1H, d, Jortho = 8.0 Hz); C NMR (100 MHz, CDCl3): δ
17.5, 51.4, 68.0, 115.1, 117.1, 119.5, 125.7, 127.6, 127.7, 128.7, 128.8, 128.8, 129.0, 133.6, 140.8, 142.5,
144.5, 163.1. Anal. Calcd for C22H20N2O: C, 80.48; H, 6.09; N, 8.54. Found: C, 80.41; H, 6.11; N, 8.57.
(R,S)-11. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp
24
o
1
156–158 °C, [α]D -350.5 (c = 0.53, CHCl3). H NMR (200 MHz, CDCl3): δ 1.70 (3H, d, J = 7.4 Hz),

4.78 (1H, s), 5.60 (1H, d, J = 2.2), 5.87 (1H, q, J = 7.4 Hz), 6.44 (1H, d, Jortho = 8.0 Hz), 6.78–7.05 (9H,
m), 7.15–7.41 (3H, m), 7.96 (1H, dd, Jmeta = 1.4 and Jortho = 7.8 Hz); 13C NMR (50 MHz, CDCl3): δ 17.4,
53.0, 69.2, 114.8, 117.6, 119.4, 125.7, 127.5, 128.0, 128.1, 128.3, 128.4, 128.6, 133.5, 139.2, 141.1, 144.8,
163.0. Anal. Calcd for C22H20N2O: C, 80.48; H, 6.09; N, 8.54. Found: C, 80.43; H, 6.13; N, 8.50. X-Ray
crystallographic structure in Figure 3.11
2,3-Dihydro-2(R)- and 2,3-dihydro-2(S)-cyclohexyl-3-[(S)-α-phenylethyl]-4(1H)-quinazolinone
[(S,R)- and (S,S)-12].
Compound (9) (0.67 g, 2.8 mmol) was treated with p-toluenesulfonic acid (76 mg, 0.4 mmol) and
cyclohexanecarboxaldehyde (0.33 g, 3 mmol) in benzene according to GP2. The crude products were
purified by FC [hexane: ethyl acetate: CH2Cl2 (80:10:10)] to produce both diastereoisomers (0.66 g,
71 %).
(S,R)-12. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp
144–145 °C, [α]D24 -39.2 o (c = 0.49, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.58–0.61 (2H, m), 0.81-89
(5H, m), 1.23–1.27 (2H, m), 1.44–1.46 (2H, m), 1.72 (3H, d, J = 7.2 Hz), 4.49 (1H, d, J = 1.8 Hz), 5.29
(1H, s), 5.91 (1H, q, J = 7.2 Hz), 6.53 (1H, dd, Jmeta = 0.8 and Jortho = 8.0 Hz), 6.77 (1H, ddd, Jmeta = 1.0
Hz, Jortho = Jortho = 7.2 Hz), 7.21 (1H, dd, Jmeta = 1.6 Hz, Jortho = Jortho = 7.2 Hz), 7.25–7.48 (5H, m), 7.86
(1H, dd, Jmeta = 1.2 and Jortho = 8.0 Hz); 13C NMR (100 MHz, CDCl3): δ 17.3, 26.2, 26.3, 26.4, 27.4, 29.3,
45.4, 53.3, 70.8, 113.8, 117.8, 118.7, 127.8, 128.0, 128.6, 128.7, 133.3, 141.6, 146.4, 163.3. Anal. Calcd
for C22H26N2O: C, 79.04; H, 7.78; N, 8.38. Found: C, 78.69; H, 8.48; N, 7.44. X-Ray crystallographic
structure in Figure 4.11
(S,S)-12. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp
24
o
1
147–149 °C, [α]D -59.1 (c = 0.51, CHCl3), H NMR (400 MHz, CDCl3): δ 0.71–0.79 (1H, m),
0.83–0.88 (2H, m), 1.00–1.65 (8H, m), 1.67 (3H, d, J = 7.2 Hz), 4.17 (1H, dd, J1 = 3.6 Hz, J2 = 7.2 Hz),
4.34 (1H, d, J = 2.4 Hz), 6.06 (1H, q, J = 7.2 Hz), 6.51 (1H, dd, Jmeta = 0.8 and Jortho = 7.6 Hz), 6.77 (1H,
ddd, Jmeta = 1.0 Hz, Jortho = Jortho = 7.4 Hz), 7.22 (1H, ddd, Jmeta = 1.6 Hz, Jortho = Jortho = 8.0 Hz),
7.25–7.40 (5H, m), 7.85 (1H, dd, Jmeta = 1.6 Hz and Jortho = 8.0 Hz); 13C NMR (100 MHz, CDCl3): δ 18.7,
26.3, 26.6, 27.8, 29.7, 47.1, 52.8, 69.9, 113.8, 117.5, 118.6, 127.7, 127.7, 128.7, 128.9, 133.4, 141.1,
146.3, 163.7. Anal. Calcd for C22H26N2O: C, 79.00; H, 7.84; N, 8.38. Found: C,78.85; H,7.90; N,8.38.
2,3-Dihydro-2(R)- and 2,3-dihydro-2(S)-(o-methoxyphenyl)-3-[(S)-α-phenylethyl]-4(1H)-
quinazolinone [(S,R)- and (S,S)-13].
Compound (9) (0.67 g, 2.8 mmol) was treated with p-toluenesulfonic acid (76 mg, 0.4 mmol) and
o-methoxybenzaldehyde (0.40 g, 3 mmol) in benzene according to GP2. The crude products were purified

by FC [hexane: ethyl acetate: CH2Cl2 (75:15:10)] to produce both diastereoisomers (0.51g, 51 %).
(S,S)-13. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp 176–177
°C, [α]D24 +418.0 o (c = 0.525, CHCl3), 1H NMR (400 MHz, CDCl3): δ 1.31 (3H, d, J = 7.2 Hz), 3.84 (3H,
s), 4.99 (1H, s), 5.83 (1H, d, J = 2.4 Hz); 6.29 (1H, q, J = 6.8 Hz), 6.39 (1H, dd, Jmeta = 0.8 and Jortho = 7.2
Hz), 6.75–6.86 (3H, m), 7.13 (1H, ddd, Jmeta = 1.6 Hz, Jortho = Jortho = 8.0 Hz), 7.21 (1H, ddd, Jmeta = 1.6
13
Hz, Jortho = Jortho = 7.6 Hz), 7.26-7.46 (6H, m), 7.98 (1H, dd, Jmeta = 1.2 and Jortho = 8.0 Hz); C NMR
(100 MHz, CDCl3): δ 17.5, 51.3, 55.6, 62.7, 114.9, 110.6, 117.1, 119.2, 120.5, 127.3, 127.6, 127.8,
128.7, 128.9, 128.5, 129.2, 129.6, 133.4, 141.7, 145.8, 155.7, 164.1. Anal. Calcd for C23H22N2O2: C,
77.095; H, 6.145; N, 7.821. Found: C, 76.980; H, 6.246; N, 7.787. X-Ray crystallographic structure in
Figure 5.11
(R,S)-13. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp 138–139
°C, [α]D24 -100.8 o (c = 0.50, CHCl3), 1H NMR (400 MHz, CDCl3): δ 1.31 (3H, d, J = 7.2 Hz), 3.85 (3H,
s), 4.97 (1H, s), 5.98 (1H, q, J = 6.8 Hz), 6.03 (1H, s), 6.40 (1H, dd, Jmeta = 0.4 and Jortho = 8.0 Hz), 6.49
(1H, ddd, Jmeta = 0.8 Hz, Jortho = Jortho = 7.6 Hz), 6.61 (1H, dd, Jmeta = 0.8 and Jortho = 8.0 Hz), 6.77 (1H,
ddd, Jmeta = 0.8 Hz, Jortho = Jortho = 7.8 Hz), 6.82 (1H, dd, Jmeta = 1.4 and Jortho = 7.4 Hz), 6.96–7.04 (4H,
m), 7.12 (1H, ddd, Jmeta = 1.3 and Jortho = Jortho = 7.6 Hz), 7.25–7.29 (2H, m), 7.95 (1H, dd, Jmeta = 1.4 and
Jortho = 7.8 Hz); 13C NMR (100 MHz, CDCl3): δ 17.5, 51.3, 55.6, 62.7, 110.0, 114.9, 117.6, 119.3, 120.1,
127.6, 127.7, 127.9, 128.3, 128.6, 128.7, 129.0, 133.3, 139.1, 145.7, 151.4, 163.7. Anal. Calcd for
C23H22N2O2: C, 77.095; H, 6.145; N, 7.821. Found: C, 76.237; H, 6.369; N, 7.297.
2,3-Dihydro-2(R)- and 2,3-dihydro-2(S)-phenyl-3-[(S)-methoxycarbonylethyl]-4(1H)-quinazolinone
[(S,R)- and (S,S)-14].
Compound (10) (0.62 g, 2.8 mmol) was treated with p-toluenesulfonic acid (76 mg, 0.4 mmol) and
benzaldehyde (0.31 g, 3 mmol) in CH2Cl2 according to GP2. The crude products were purified by FC
[hexane: ethyl acetate (80:20 → 60:40)] to produce both diastereoisomers (0.69 g, 80 %).
(S,R)-14. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp
171–173 °C, [α]D24 +118.1 o (c = 0.525, CHCl3) 1H NMR (200 MHz, CDCl3): δ 1.42 (3H, d, J = 6.8 Hz),
3.56 (3H, s), 3.83 (1H, q, J = 7.0 Hz), 3.78 (1H, br s), 5.98 (1H, s), 6.56 (1H, dd, Jmeta = 0.7 and Jortho
=
=
8.2 Hz), 6.83 (1H, ddd, Jmeta = 1.2 Hz, Jortho = Jortho = 7.2 Hz), 7.26 (1H, ddd, Jmeta = 1.4 Hz, Jortho
13
Jortho = 7.7 Hz), 7.37–7.53 (5H, m), 7.90 (1H, dd, Jmeta = 1.4 and Jortho = 7.8 Hz); C NMR (50 MHz,
CDCl3): δ 15.8, 52.4, 54.0, 74.4, 114.1, 115.9, 119.4, 127.8, 128.8, 129.1, 130.0, 133.8, 138.6, 145.8,
163.8, 171.8. Anal. Calcd for C18H18N2O3: C, 69.677; H, 5.806; N, 9.302. Found: C, 69.470; H, 5.900; N,
8.724.
(S,S)-14. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp

187–188 °C, [α]D24 -292.7 o (c = 0.505, CHCl3). 1H NMR (200 MHz, CDCl3): δ 1.31 (3H, d, J = 7.0 Hz),
3.69 (3H, s), 4.55 (1H, q, J = 7.2 Hz), 4.60 (1H, br s), 5.87 (1H, s), 6.52 (1H, dd, Jmeta = 0.7 and Jortho
=
8.2 Hz), 6.82 (1H, ddd, Jmeta = 1.2 Hz, Jortho = Jortho = 7.2 Hz), 7.22 (1H, ddd, Jmeta = 1.4 Hz, Jortho = Jortho
= 8.2 Hz), 7.31–7.46 (5H, m), 7.89 (1H, dd, Jmeta = 1.6 and Jortho = 7.6 Hz); 13C NMR (50 MHz, CDCl3): δ
14.9, 52.6, 52.8, 71.3, 114.9, 116.6, 119.6, 126.8, 128.6, 128.9, 129.4, 133.7, 139.9, 145.0, 162.9, 171.8.
Anal. Calcd for C18H18N2O3: C, 69.677; H, 5.806; N, 9.302. Found: C, 69.420; H, 5.851; N, 8.904. X-Ray
crystallographic structure in Figure 6.11
2,3-Dihydro-2(R)- and 2,3-dihydro-2(S)-tert-butyl-3-[(S)-methyloxycarbonylethyl]-4(1H)-
quinazolinone [(S,R)- and (S,S)-15].
Compound (10) (0.62 g, 0.62 g, 2.8 mmol) was treated with p-toluenesulfonic acid (76 mg, 0.4 mmol)
and trimethylacetaldehyde (3 mmol) in CH2Cl2 according to GP2. The crude products were purified by
FC [hexane: n-Butyl acetate: i-PrOH (75:15:10)] to produce both diastereoisomers (0.47 g, 58 %).
(S,S)-15. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp
162–164 °C, [α]D24 -168.1 o (c = 0.565, CHCl3), 1H NMR (200 MHz, CDCl3): δ 1.01 (9H, s), 1.55 (3H, d,
J = 7.0 Hz), 3.81 (3H, s), 4.38 (1H, d, J = 3.0 Hz), 4.71 (1H, br s), 6.57 (1H, dd, Jmeta = 0.8 and Jortho = 8.2
Hz), 6.71 (1H, ddd, Jmeta = 1.2 Hz, Jortho = Jortho = 7.6 Hz), 7.22 (1H, ddd, Jmeta = 1.4 Hz, Jortho = Jortho
=
7.8 Hz), 7.73 (1H, dd, Jmeta = 1.6 and Jortho = 7.7 Hz); 13C NMR (50 MHz, CDCl3): δ 15.1, 26.0, 41.7, 52.4,
59.8, 78.2, 113.1, 116.6, 118.3, 128.2, 133.8, 146.7, 162.9, 171.3. Anal. Calcd for C16H22N2O3: C, 66.21;
H, 7.59; N, 9.65. Found: C, 66.92; H, 7.47; N, 9.13. X-Ray crystallographic structure in Figure 7.11
(R,S)-15. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp
133-134 °C, [α]D24 +112.2 o (c = 0.51, CHCl3), 1H NMR (200 MHz, CDCl3): δ 0.95 (9H, s), 1.90 (3H, d, J
= 7.0 Hz), 3.71 (3H, s), 3.87 (1H, q, J = 7.0 Hz), 4.38 (1H, s), 4.55 (1H, br s), 6.57 (1H, dd, Jmeta = 0.8
and Jortho = 8.2 Hz), 6.73 (1H, ddd, Jmeta = 0.8 Hz, Jortho = Jortho = 7.8 Hz), 7.20 (1H, ddd, Jmeta = 1.5 Hz,
Jortho = Jortho = 8.0 Hz), 7.71 (1H, dd, Jmeta = 1.6 and Jortho = 7.7 Hz); 13C NMR (50 MHz, CDCl3): δ 17.0,
26.3, 40.8, 52.7, 61.4, 80.2, 113.6, 117.5, 118.5, 128.1, 133.4, 146.2, 164.5, 171.7. Anal. Calcd for
C16H22N2O3: C, 66.21; H, 7.59; N, 9.65. Found: C, 65.99; H, 7.60; N, 9.59.
2,3-Dihydro-2(R)- and 2,3-dihydro-2(S)-(o-nitrophenyl)-3-[(S)-methoxycarbonylethyl]-4(1H)-
quinazolinone [(S,R)- and (S,S)-16].
Compound (10) (0.62 g, 2.8 mmol) was treated with p-toluenesulfonic acid (76 mg, 0.4 mmol) and
o-nitrobenzaldehyde (0.45 g, 3 mmol) in CH2Cl2 according to GP2. The crude products were purified by
FC [hexane: CH2Cl2: ethyl acetate (74:20:6)] to produce both diastereoisomers (0.51 g, 52 %).
(S,R)-16. For analytical purposes a sample was recrystallized (CH2Cl2/Hexane): white solid, mp

156–158 °C, [α]D24 +372.1 o (c = 0.51, CHCl3), 1H NMR (200 MHz, CDCl3): δ 1.48 (3H, d, J = 7.4 Hz),
3.31 (3H, s), 5.09 (1H, q, J = 7.2 Hz), 5.37 (1H, d, J = 2.2 Hz), 6.44 (1H, d, J = 2.6 Hz), 6.50 (1H, d, Jortho
= 8.2 Hz), 6.84 (1H, ddd, Jmeta = 1.2 Hz, Jortho = Jortho = 7.4Hz), 7.24 (1H, ddd, Jmeta = 1.5 Hz, Jortho
=
Jortho = 7.4 Hz), 7.41–7.36 (3H, m), 7.95 (1H, dd, Jmeta = 1.5 and Jortho = 7.6 Hz), 8.03 (1H, dd, Jmeta = 1.7
13
and Jortho = 8.0 Hz); C NMR (50 MHz, CDCl3): δ 15.6, 52.1, 52.7, 64.9, 115.1, 115.9, 119.8, 125.6,
128.7, 128.9, 129.8, 133.7, 134.4, 135.2, 144.2, 147.5, 163.4, 171.1. Anal. Calcd for C18H17N3O5: C,
59.17; H, 4.65; N, 11.50. Found: C, 60.07; H, 4.85; N, 11.73. X-Ray crystallographic structure in Figure
8.11
(S,S)-16: Spectroscopic analysis was not determined because we could not obtain a single
diastereoisomer.
ACKNOWLEDGEMENTS
We thanks CONACYT for financial support (Project No. 38187-E) and for scholarship to P.F and J.P. We
are grateful to Dr. Cirilo García for recording the optical rotation, Prof. Joseph Muchowski for many
important observations, and Claudia Ortiz for technical support.
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11. Crystallographic data are deposited at Cambridge Crystallographic Data Center (CDDC 218246,
218247, 218248, 218249, 218250, 218251, 218252).