Investigation of the enantioselective synthesis of 2,3- Dihydroquinazolinones Using Sc(III)- Inda -pybox

Article abstract of DOI:10.1055/s-0033-1339288

Derivatives of 2,3-dihydroquinazolinones (2,3-DHQZs) are prized for their prevalent pharmaceutical applications. Although there are potential applications, methods available for the enantioselective synthesis of these valuable compounds are scarce, since the chiral aminal center is prone to racemization. We have overcome the difficulties in the catalytic enantioselective synthesis of 2,3-DHQZs using Sc(III)-inda-pybox as a catalyst, in a process with a broad substrate scope. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1339288

PAPER
▌2265
paper
Investigation of the Enantioselective Synthesis of 2,3-Dihydroquinazolinones
Using Sc(III)–inda-pybox
Enantioselective Synthesis of 2,3-Dihydroquinazolinones
Muthuraj Prakash, Samydurai Jayakumar, Venkitasamy Kesavan*
Chemical Biology Laboratory, Department of Biotechnology, Bhupat and Jyothi Mehta School of Biosciences Building, Indian Institute of
Technology Madras, Chennai 600036, India
Fax +91(44)22574102; E-mail: vkesavan@iitm.ac.in
Received: 08.03.2013; Accepted after revision: 27.05.2013
showcased the ability of chiral Brønsted acids in the enan-
Abstract: Derivatives of 2,3-dihydroquinazolinones (2,3-DHQZs)
tioselective synthesis of 2,3-DHQZs. The paucity of
are prized for their prevalent pharmaceutical applications. Although
methods to synthesize enantiomerically enriched 2,3-
there are potential applications, methods available for the enantiose-
lective synthesis of these valuable compounds are scarce, since the
DHQZs stimulated us to develop the first metal-catalyzed
chiral aminal center is prone to racemization. We have overcome enantioselective synthesis of 2,3-DHQZs.6 We hypothe-
the difficulties in the catalytic enantioselective synthesis of 2,3-
DHQZs using Sc(III)–inda-pybox as a catalyst, in a process with a
broad substrate scope.
sized that the activation of imines with a suitable chiral
Lewis acid may facilitate the cyclization in an enantiose-
lective manner (Scheme 1).
Key words: asymmetric catalysis, dihydroquinazolinones, enantio-
selectivity, pybox, scandium(III) triflate
O
O
H2NO2S
Cl
NH
NH
The 2,3-dihydroquinazolinone (2,3-DHQZ) structure is
one of the privileged scaffolds known for their important
biological and medicinal properties (Figure 1).1 Although
2,3-DHQZs possess a chiral center, which is susceptible
to racemization, most of the existing pharmacological
studies have been carried out using racemates. It is note-
worthy that stereoisomers of chiral drugs may exhibit dif-
ferent pharmacological activities, because the biological
matrixes present in the human body are chiral in nature.2
Thus, determination of the binding mode and the affinity
of optically pure 2,3-DHQZs is very much needed for im-
proving ADMET properties. In 2008, Brown and co-
workers reported that the S-enantiomer of 2-aryl-2,3-
DHQZs exhibit significantly higher antitumor activity
than the corresponding R-enantiomers.3
N
H
N
H
fenquizone
(diuretic)
NCI substance TID 19143
(anticancer activity)
O
N
O
N
H2NO2S
N
O
Cl
metolazone
N
O
H
Ph
(symporter inhibitor)
(analgesic activity)
O
N
N
N
Although there are many ways to synthesize 2,3-DHQZs
in racemic form,4 accessing the nonracemic form of 2,3-
DHQZs is more challenging.5 Seminal contributions from
List and co-workers5a and Rueping and co-workers5b
H
evodiamine
(chemotherapeutic agent)
Figure 1 Pharmaceutically important 2,3-DHQZ scaffolds1
O
O
O
N
O
chiral Lewis acid
NH2
NH
NH2
+
R
H
*
N
H
R
NH2
R
2
1a
3
M
ligand
reaction proceeds in an
enantioselective manner
Scheme 1 Intramolecular amidation of imines
SYNTHESIS 2013, 45, 2265–2272
Advanced online publication: 10.07.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339288; Art ID: SS-2013-Z0177-OP
© Georg Thieme Verlag Stuttgart · New York

2266
M. Prakash et al.
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Our hypothesis was proven in the enantioselective synthe- ployment of other well-known pybox ligands 6–9 did not
sis of 2,3-DHQZs via the intramolecular amidation of im- realize the desired results (Table 1, entries 8–11).
ines using Sc(III)–inda-pybox.6 Herein, we describe
Table 1 Optimization Studya
various factors which affect the enantioselectivity of the
reaction and application of the protocol for the synthesis
of various 2-alkyl- and 2,3-diaryl-substituted 2,3-DHQZs
with fair to very good enantioselectivity in high yields.
Entry
Ligand
Lewis acid
Yieldb (%) of 3a erc (R/S)
1
2
4
4
4
5
5
5
5
6
7
8
9
CuOTf
20
10
10
15
10
10
90
80
82
89
90
rac
Our exploration began with the screening of various sub-
stituted bis(oxazoline)s derived from amino alcohols in
combination with various Lewis acids. The model reac-
tion was carried out between anthranilamide (2-amino-
benzamide, 1a) and benzaldehyde (2a) at 25 °C in the
presence of 5 mol% of various Lewis acids [CuOTf,
Cu(OTf)2 or Zn(OTf)2], 10 mol% of bis(oxazoline) ligand
4 and powdered 4 Å molecular sieves (Scheme 2). All of
these catalytic systems failed to promote the cyclization;
imine was observed as a major product and less than 20%
of the desired product was isolated with no chiral induc-
tion (Table 1, entries 1–3). After these unsuccessful ex-
periments, we focused on the tridentate pyridine–
bis(oxazoline)s 5–9 (Scheme 2), and the reactions were
performed under similar conditions. Metal triflates (Cu,
Zn) in combination with pybox 5 were not efficient
enough to catalyze the intramolecular amidation of imine
to form 2,3-DHQZ 3a (Table 1, entries 4–6). In our con-
tinued effort to identify a suitable Lewis acid, we explored
rare earth metal triflates in combination with pybox 5,
since the catalytic efficiency of such complexes is well
known.7,8 The scandium(III)–pybox complex promoted
intramolecular amidation of imine to form 2,3-DHQZ 3a
in excellent yield with non-neglectable enantioselectivity
(Table 1, entry 7). Encouraged by this observation, efforts
were dedicated to improve the enantioselectivity. The em-
Cu(OTf)2
Zn(OTf)2
CuOTf
rac
3
rac
4
rac
5
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
rac
6
rac
7
62:38
50:50
68:32
58:42
65:35
8
9
10
11
a Reaction conditions: Lewis acid (5 mol%), ligand 4–9 (10 mol%),
powdered 4 Å MS (50 mg), CH2Cl2 (1 mL), r.t., 3 h; anthranilamide
(0.3 mmol, 1 equiv), benzaldehyde (0.36 mmol, 1.2 equiv), CH2Cl2
(1 mL).
b Isolated yield after column purification.
c Determined by HPLC (Chiralpak AD-H column).
These results indicate that pybox ligands derived from
amino alcohols do not provide optimal encircling of acti-
vated imine to induce very good asymmetric induction.
We hoped that pybox derived from (1R,2S)-1-amino-2-in-
danol would provide such an environment around imine
leading to the formation of enantiomerically enriched 2,3-
DHQZs. It is evident from Table 1 that pybox ligands de-
rived from (S)-amino alcohols are responsible for forma-
tion of the R-isomer of 2,3-DHQZ 3a. Hence, inda-pybox
(10) (Scheme 2) was synthesized from (1R,2S)-1-amino-
2-indanol in order to obtain the most-wanted S-isomer of
2,3-DHQZ 3a. As expected, the most-wanted S-stereoiso-
mer of 2,3-DHQZ 3a was isolated with very good enanti-
O
O
O
NH
NH2
H
metal, ligand
*
+
N
H
CH2Cl2, 4 Å MS
NH2
1a
2a
3a
O
O
O
O
N
Table 2 Influence of Metal Triflates on the Enantioselectivitya
N
N
(S)
(S)
N
N
(S)
(S)
4
R1
R1
Entry
Metal
Yieldb (%) of 3a
erc (R/S)
5 R1 = t-Bu
6 R1 = i-Pr
7 R1 = Ph
8 R1 = Bn
1
2
3
4
Sc3+
Yb3+
Y3+
94
72
65
20
8:92
12:88
18:82
rac
Ph
Ph
Ph
Ph
O
O
N
N
N
(S)
(S)
9
La3+
O
O
(S)
(S)
N
a Reaction conditions: M(OTf)3 (5 mol%), ligand 10 (10 mol%), pow-
dered 4 Å MS (50 mg), CH2Cl2 (1 mL), r.t., 3 h; anthranilamide (0.3
mmol, 1 equiv), benzaldehyde (0.36 mmol, 1.2 equiv), CH2Cl2
(1 mL).
N
N
(R)
(R)
10
b Isolated yield after column purification.
c Determined by HPLC (Chiralpak AD-H column).
Scheme 2 Enantioselective synthesis of 2-phenyl-2,3-DHQZ 3a
Synthesis 2013, 45, 2265–2272
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Synthesis of 2,3-Dihydroquinazolinones
2267
oselectivity (84% ee) under the previously established of any competitive, achiral background reaction by effi-
conditions (Table 2, entry 1).
cient complexation, resulted in the achievement of an ex-
cellent level of enantioselection (98% ee) at room
temperature (Table 4, entry 4).
Other rare earth metal triflates were evaluated in an at-
tempt to further improve the enantioselectivity (Table 2,
entries 2–4); however, it is beyond any doubt that scandi-
um(III) triflate is the most suitable rare earth metal, cata-
lyzing the intramolecular amidation of imine to afford
2,3-DHQZ 3a in very good enantioselectivity.
Table 4 Optimization of the Metal/Ligand Ratioa
Entry
Metal/ligand
Yieldb
erc (S/R)
(mol%:mol%)
(%) of 3a
An optimization study of the reaction medium was carried
out with various solvents, including acetonitrile, chloro-
form, dichloromethane, methyl tert-butyl ether, tetrahy-
drofuran, benzene and toluene. Use of acetonitrile and
tetrahydrofuran, as well as nonpolar solvents such as ben-
zene and toluene, yielded the product 3a with moderate
enantioselectivity and conversion (Table 3, entries 3–6).
When ethanol was used as the solvent, complete racemi-
zation of the product occurred (Table 3, entry 7). Methyl
tert-butyl ether did not play any important role in further
improving the enantioselectivity (Table 3, entry 8). This
study identified dichloromethane or chloroform as the
most suitable reaction medium for the synthesis of 2,3-
DHQZ 3a in an enantioselective manner using Sc(III)–
(1R,2S)-inda-pybox (Table 3, entries 1 and 2).
1
2
3
4
10:20
5:10
1:2
96
94
92
92
88:12
93:7
96:4
99:1
1:2.5
a Reaction conditions: Sc(OTf)3 (1–10 mol%), ligand 10 (2–20
mol%), powdered 4 Å MS (50 mg), CH2Cl2 (1 mL), r.t., 3 h; anthra-
nilamide (0.3 mmol, 1 equiv), benzaldehyde (0.36 mmol, 1.2 equiv),
CH2Cl2 (1 mL).
b Isolated yield after column purification.
c Determined by HPLC (Chiralpak AD-H column).
To prove that the cyclization occurs through an imine in-
termediate,
(E)-2-[(4-bromobenzylidene)amino]benz-
amide (11) was treated with Sc(III)–inda-pybox. The
corresponding 2,3-dihydroquinazolinone 3f was isolated
in very good yield and enantioselectivity (Scheme 3), thus
demonstrating that imine 11 is the intermediate that un-
dergoes cyclization to afford the 2,3-DHQZ.
Table 3 Impact of the Reaction Mediuma
Entry
Solvent
Yieldb (%) of 3a erc (S/R)
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
THF
94
92
78
81
60
54
74
30
92:8
92:8
O
O
83:17
88:12
81:19
76:24
rac
NH2
NH
MeCN
toluene
benzene
EtOH
Sc(III)–inda-pybox
H
N
CH2Cl2, 4 Å MS, r.t.
N
H
11
3f
Br
Br
94% ee
90% yield
Scheme 3 Enantioselective cyclization of (E)-2-[(4-bromobenzyli-
dene)amino]benzamide (11)
MTBE
67:33
a Reaction conditions: Sc(OTf)3 (5 mol%), ligand 10 (10 mol%),
powdered 4 Å MS (50 mg), solvent (1 mL), r.t., 3 h; anthranilamide
(0.3 mmol, 1 equiv), benzaldehyde (0.36 mmol, 1.2 equiv), solvent
(1 mL).
After studying the influence of various parameters, we ex-
perienced difficulties in reproducing the results with the
same enantioselectivity. The only parameter which had
not been fixed was the molecular sieves, so more attention
was given to optimizing the amount of molecular sieves.
The purpose of molecular sieves is to absorb the water
molecules produced during the course of the reaction. Al-
though scandium(III) triflate is a water-tolerant Lewis
acid, molecular sieves need to be added to obtain an
enantiomerically enriched compound because the genera-
tion of a trace amount of triflic acid is sufficient enough to
catalyze the cyclization, which may lead to poor enantio-
selection. The quantity and the nature of the molecular
sieves has a profound effect on the enantioselectivity and
yield of the reaction. Under our standard conditions, a
clean reaction occurred when 200 mg of molecular sieves
were used as beads instead of in powdered form, but a
b Isolated yield after column purification.
c Determined by HPLC (Chiralpak AD-H column).
The ratio of metal to ligand was studied in order to im-
prove the efficiency and selectivity of the reaction. Per-
haps the most interesting observation was that a higher
loading of metal ion resulted in a negative effect on the en-
antioselectivity (Table 4, entry 1); the enantioselectivity
was strongly affected when excess Lewis acid was used.
Hence, we performed the reaction with a low catalyst
loading of 1 mol% of Lewis acid and 2 mol% of ligand 10.
These conditions provided a significant increase in the en-
antioselectivity while maintaining a high yield within four
hours (Table 4, entry 3). Employment of an excess of the
ligand (2.5 mol%), which ensures complete suppression
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2265–2272

2268
M. Prakash et al.
PAPER
poor enantioselection of 32% was observed. This implies entry 6). Hence, we performed the reaction at low temper-
that the nature of the molecular sieves plays a crucial role. ature. Cyclization occurred with the maximum enantiose-
The presence of an excess amount of molecular sieves in lectivity (86% ee) at –20 °C (Table 7, entry 7). Further
powdered form promotes the formation of imine rather lowering of the temperature failed to enhance the enantio-
than generation of the product through the catalytic cycle; selectivity nor the yield of the reaction (Table 7, entry 8).
this retards the rate of the reaction and, even after longer
Table 6 Substrate Scope (Aromatic Aldehydes)a
reaction time, a poor yield of 2,3-DHQZ 3a was isolated
(Table 5, entries 1–3).
O
O
R1
R1
O
Sc(OTf)3, ligand 10
Table 5 Role of Molecular Sieves (MS)a
NH
NH2
+
H
R2
CH2Cl2, 4 Å MS
*
R2
H
N
H
NH2
Entry
Powdered 4 Å MS Yieldb
erc (S/R)
(mg)
(%) of 3a
1a–o
2
3a–o
1
2
3
4
5
200
150
100
50
30
52
76
92
93
99:1
99:1
99:1
99:1
rac
Entry
1
R1
H
R2
Yieldb (%) erc (S/R)
3a: 94
99:1
–
2
3
H
H
3b: 92
3c: 91
99:1
99:1
a Reaction conditions: Sc(OTf)3 (1 mol%), ligand 10 (2.5 mol%),
powdered 4 Å MS (0–200 mg), CH2Cl2 (1 mL), r.t., 3 h; anthranil-
amide (0.3 mmol, 1 equiv), benzaldehyde (0.36 mmol, 1.2 equiv),
CH2Cl2 (1 mL).
F
b Isolated yield after column purification.
Br
c Determined by HPLC (Chiralpak AD-H column).
4
5
H
3d: 94
3e: 92
3f: 90
3g: 88
3h: 95
3i: 91
3j: 95
3k: 90
3l: 95
3m: 93
3n: 95
90:10
95:5
97:3
95:5
98:2
93:7
95:5
95:5
95:5
96:4
97:3
Molecular sieves not only act as a desiccant, which in
powdered form in larger amounts affects the yield of the
reaction, in their absence complete racemization of the
product was observed (Table 5, entry 5). This clearly in-
dicates that the water molecules produced in the reaction
mixture are efficiently trapped with an adequate amount
of molecular sieves (Table 5, entry 4).
H
F
6
H
Br
7
H
After investigating the influence of various parameters on
the enantioselectivity, we started surveying the substrate
scope. Simple aromatic aldehydes like benzaldehyde and
2-naphthaldehyde provided excellent enantioselectivity
and yield (Table 6, entries 1 and 2). The cyclization of var-
ious meta- and para-substituted aldehydes was also
achieved with excellent enantioselectivity and yield (Ta-
ble 6, entries 3–9). 3,4-Disubstituted aldehydes were suc-
cessfully employed as substrates; the corresponding
cyclized products were isolated in admirable yield and en-
antioselectivity (Table 6, entries 10–13). The presence of
a free hydroxy group did not pose any negative effect on
the enantioselectivity (Table 6, entry 11). Substituted an-
thranilamides were also found to be suitable substrates un-
der our catalytic conditions (Table 6, entries 14 and 15).
NC
Ph
8
H
9
H
Et
O
10
11
12
13
14
H
O
MeO
H
HO
MeO
H
After achieving the cyclization of various aromatic alde-
hydes, and to highlight the efficiency of our catalytic pro-
tocol, aliphatic aldehydes were investigated, for which
butyraldehyde (12b) was chosen as a model substrate (Ta-
ble 7). Initial screening experiments revealed that the use
of various ligands under the standard conditions failed to
induce good enantioselectivity in cyclized product 13b
and only 10% enantiomeric excess was obtained when
inda-pybox (10) was used as the chiral ligand (Table 7,
MeO
Br
H
MeO
Ph
OCF3
Synthesis 2013, 45, 2265–2272
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Synthesis of 2,3-Dihydroquinazolinones
2269
Table 6 Substrate Scope (Aromatic Aldehydes)a (continued)
Table 8 Substrate Scope (Aliphatic Aldehydes)a
O
O
O
O
R1
R1
O
O
Sc(OTf)3, ligand 10
NH
NH2
Sc(OTf)3, ligand 10
NH
NH2
+
H
+
H
R
CH2Cl2, 4 Å MS
*
R2
H
R
H CH2Cl2, 4 Å MS, –20 °C
*
N
H
R2
NH2
N
H
NH2
1a–o
2
1a
12a–i
13a–i
3a–o
R1
Cl
R2
Yieldb (%) erc (S/R)
Entry Aldehyde 12
Yieldb (%)
13a: 80
erc (S/R)
Entry
15
1
2
3
4
5
6
7
8
9
propionaldehyde (12a)
butyraldehyde (12b)
89:11
93:7
3o: 95
98:2
13b: 82
13c: 79
13d: 84
13e: 78
13f: 81
13g: 77
13h: 87
Ph
hexaldehyde (12c)
88:12
96:4
a Reaction conditions: Sc(OTf)3 (1 mol%), ligand 10 (2.5 mol%),
powdered 4 Å MS (50 mg), CH2Cl2 (1 mL), r.t., 3 h; amide (0.3 mmol,
1 equiv), aldehyde (0.36 mmol, 1.2 equiv), CH2Cl2 (1 mL), r.t., 3–8 h.
b Isolated yield after column purification.
heptaldehyde (12d)
isobutyraldehyde (12e)
isovaleraldehyde (12f)
phenylacetaldehyde (12g)
hydrocinnamaldehyde (12h)
82:18
83:17
82:18
93:7
c Determined by HPLC (Chiralpak AD-H column).
After optimizing the reaction conditions for the formation
of 2-propyl-2,3-DHQZ 13b, we synthesized various 2-al-
kyl-substituted 2,3-DHQZs 13a–i in an enantioenriched
manner (Table 8). Linear as well as branched aliphatic al-
dehydes were subjected to cyclization with anthranil-
amide (2-aminobenzamide, 1a). Reaction proceeded
smoothly with good yield and enantioselectivity when lin-
ear aliphatic aldehydes were employed as substrates (Ta-
ble 8, entries 1–4). In the case of branched aldehydes like
isobutyraldehyde (12e) and isovaleraldehyde (12f), fair
enantioselectivity and good yield was achieved (Table 8,
cyclohexanecarboxaldehyde (12i) 13i: 79
82:18
a Reaction conditions: Sc(OTf)3 (1 mol%), ligand 10 (2.5 mol%),
powdered 4 Å MS (50 mg), CH2Cl2 (1 mL), r.t., 3 h; anthranilamide
(0.3 mmol, 1 equiv), aldehyde (0.36 mmol, 1.2 equiv), CH2Cl2 (1
mL), –20 °C, 48–80 h.
b Isolated yield after column purification.
c Determined by HPLC (Chiralcel OD-H or Chiralpak AD-H col-
umn).
entries 5 and 6). Improvement in enantioselectivity and
yield was obtained when aromatic substitution was pres-
ent at the β-position (Table 8, entry 8) rather than at the α-
position (Table 8, entry 7) of the chain. When cyclohex-
anecarboxaldehyde (12i) was employed as the substrate,
the corresponding cyclized product 13i was isolated with
moderate enantioselectivity and yield (Table 8, entry 9).
Table 7 Influence of Temperaturea
O
O
Sc(OTf)3
O
NH2
ligand
NH
+
H
CH2Cl2
4 Å MS
NH2
N
H
13b
1a
12b
After achieving the enantioselective synthesis of various
2-aryl- and 2-alkyl-substituted 2,3-DHQZs, we proceeded
to optimize the reaction conditions for 2,3-diaryl-2,3-
DHQZs, which are potent analgesic and antimicrobial
agents.1e To the best of our knowledge, there is no general
synthetic method available for obtaining enantiomerically
enriched 2,3-diaryl-2,3-DHQZ analogues, because they
are more sterically hindered and less nucleophilic than 2-
substituted 2,3-DHQZs. The importance of these valuable
2,3-diaryl-2,3-DHQZs, as well as the lack of methods for
their enantioselective synthesis, stimulated us to develop
a catalytic protocol for the asymmetric synthesis of such
compounds. We initially carried out the condensation re-
action between N-phenylanthranilamide (14) and benzal-
dehyde (2a) with scandium(III) triflate (5 mol%) and
inda-pybox (10 mol%) in dichloromethane at room tem-
perature. No chiral induction was observed at room tem-
perature, hence the reactions were performed at –20 °C.
Various substituted pybox ligands 5–10 were tested at this
low temperature and the results are shown in Table 9. This
screening revealed that ligand 10 induces the best asym-
Entry
Ligand
Temp (°C) Yieldb (%) of 13b erc (S/R)
1
2
3
4
5
6
7
8
5
6
25
25
80
78
80
83
75
88
85
79
rac
rac
7
25
rac
8
25
rac
9
25
rac
10
10
10
25
55:45
93:7
92:8
–20
–40
a Reaction conditions: Sc(OTf)3 (1 mol%), ligand 5–10 (2.5 mol%),
powdered 4 Å MS (50 mg), CH2Cl2 (1 mL), r.t., 3 h; anthranilamide
(0.3 mmol, 1 equiv), butyraldehyde (0.36 mmol, 1.2 equiv), CH2Cl2
(1 mL), at the given temperature, 48 h.
b Isolated yield after column purification.
c Determined by HPLC (Chiralpak AD-H column).
© Georg Thieme Verlag Stuttgart · New York
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M. Prakash et al.
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Table 10 Enantioselective Synthesis of 2-Aryl-3-phenyl-2,3-DHQZsa
Table 9 Screening of pybox Ligandsa
O
O
Entry
Ligand
Yieldb (%) of 15a erc (S/R)
Sc(OTf)3
O
ligand 10
N
N
1
2
3
4
5
6
5
6
60
57
54
60
64
72
68:32
53:47
84:16
86:14
67:33
90:10
H
+
H
R
R
H
CH2Cl2
4 Å MS
–20 °C
*
N
H
15a–f
NH2
14
2
7
Entry
1
R
Time (d)
Yieldb (%) erc (S/R)
8
9
4
15a: 74
90:10
10
a Reaction conditions: Sc(OTf)3 (5 mol%), ligand 5–10 (10 mol%),
powdered 4 Å MS (50 mg), CH2Cl2 (1 mL), r.t., 3 h; N-phenylanthra-
nilamide (0.3 mmol, 1 equiv), benzaldehyde (0.36 mmol, 1.2 equiv),
CH2Cl2 (1 mL), –20 °C.
2
3
4
6
15b: 78
15c: 70
87:13
81:19
b Isolated yield after column purification.
c Determined by HPLC (Chiralcel OD-H or Chiralpak AD-H col-
umn).
F
4
5
6
4
7
7
15d: 92
15e: 70
15f: 73
91:9
Ph
O
metric induction (Table 9, entry 6). Further lowering of
the temperature, as well as the mole ratio of the metal, sig-
nificantly lowered the rate of the reaction.
78:22
76:24
O
With the optimized conditions for the formation of 2,3-di-
phenyl-2,3-DHQZ 15a in hand, we started investigating
the substrate scope. Cyclization occurred smoothly with
good yield and enantioselectivity when benzaldehyde or
2-naphthaldehyde was employed as the substrate in the re-
action with N-phenylanthranilamide (Table 10, entries 1
and 2). The presence of fluoro substitution at the para po-
sition of the aldehyde yielded the desired product 15c with
moderate enantioselectivity (Table 10, entry 3); better
yield and enantioselectivity were observed when 4-phe-
nyl-substituted benzaldehyde was employed as the sub-
strate (Table 10, entry 4). In the case of disubstituted
aldehydes, the cyclized products 15e and 15f were isolat-
ed with good yields and moderate enantioselectivities
(Table 10, entries 5 and 6).
MeO
MeO
a Reaction conditions: Sc(OTf)3 (5 mol%), ligand 10 (10 mol%),
powdered 4 Å MS (50 mg), CH2Cl2 (1 mL), r.t., 3 h; N-phenylanthra-
nilamide (0.3 mmol, 1 equiv), aldehyde (0.36 mmol, 1.2 equiv),
CH2Cl2 (1 mL), –20 °C.
b Isolated yield after column purification.
c Determined by HPLC (Chiralcel OD-H or Chiralpak AD-H column)
zene and THF were dried over sodium/benzophenone; CH2Cl2 and
CHCl3 were dried over CaH2. Solvents for HPLC analysis were
bought as HPLC grade and used without further purification. TLC
was performed on precoated Merck silica gel 60 aluminum plates
with F254 indicator, which were visualized by irradiation with UV
light. Column chromatography was performed using Merck silica
gel 60–100 mesh. Melting points were determined by the open glass
In summary, we have accomplished the first metal-cata-
lyzed enantioselective synthesis of 2-aryl-, 2-alkyl- and
2,3-diaryl-substituted 2,3-DHQZs, in a process with a
broad substrate scope. Detailed experimental studies have
revealed the influence of various factors, such as the mole
ratio of the chiral catalyst, temperature and molecular
sieves, which are prone to affect the enantioselective syn-
thesis of 2,3-DHQZs. This work will pave the way to find-
ing better lead compounds, in optically enriched form,
against various drug targets. Currently, we are expanding
this methodology to the synthesis of cyclothiazides in an
enantioselective manner.
capillary method and are uncorrected. H and 13C NMR spectra
1
were recorded on a Bruker AV 500-MHz instrument using DMSO-
d6 or CDCl3 as solvent and TMS as internal standard. High-resolu-
tion mass spectra were obtained by ESI using a Waters Micromass
Q-TOF mass spectrometer. IR spectra were recorded on a Perkin El-
mer FT/IR-420 spectrometer. Enantiomeric excesses were obtained
by HPLC analysis on a chiral stationary phase column (Chiralpak
AD-H, Chiralpak AS-H or Chiralcel OD-H). Optical rotations were
recorded on a Jasco DIP polarimeter with a sodium lamp at λ = 589
nm and are reported as [α]DT (T = temperature in °C).
2-Alkyl-, 2-Aryl- and 2,3-Diaryl-2,3-dihydroquinazolinones;
General Procedure
In an oven-dried flask, pybox ligand 10 (7.5 μmol) and Sc(OTf)3 (3
μmol) were taken up in anhyd CH2Cl2 (1 mL) [5 mol% metal/10
mol% ligand was employed in the case of N-phenylanthranilamide
(14)]. Powdered 4 Å molecular sieves (50 mg) were added to the so-
lution and the resulting mixture was stirred for a further 3 h. Then,
anthranilamide (1) or N-phenylanthranilamide (14) (300 μmol) sol-
ubilized in CH2Cl2 (1 mL) was added at the indicated temperature
Chiral ligands 4–10 were synthesized according to reported proce-
dures.9 Amino alcohols required for the synthesis of ligands, anthra-
nilamide and aldehydes were purchased from Aldrich Chemicals
and used without further purification. N-Phenylanthranilamide was
obtained from Alfa Aesar. All reactions were carried out in a flame-
dried flask. Solvents used for reactions and column chromatography
were of commercial grade and distilled prior to use. Toluene, ben-
Synthesis 2013, 45, 2265–2272
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Synthesis of 2,3-Dihydroquinazolinones
2271
(see tables), followed by aldehyde (360 μmol), and the mixture was
stirred until the reaction was complete as ascertained by TLC. The
product was purified by using a small pad of silica gel (60–100
mesh) with PE–EtOAc (1:1) as eluent to afford the corresponding
2,3-dihydroquinazolinone as a colorless solid. Analytical data for
all new compounds (13a, 13c, 15e) are provided below, and charac-
terization data for other reported compounds are provided in detail
in the Supporting Information.
HRMS (ESI): m/z [M + H]+ calcd for C21H16N2O3: 345.1239;
found: 345.1233.
Acknowledgment
We acknowledge DST (SR/S1/OC-60/2006), Government of India,
New Delhi for financial support. M.P. thanks CSIR for a research
fellowship. We thank Sophisticated Analytical Instrument Facility
(SAIF) and the Department of Chemistry, IIT Madras for the analy-
tical data.
(S)-2-Ethyl-2,3-dihydroquinazolin-4(1H)-one (13a)
Colorless solid; yield: 42 mg (80%); mp 148 °C.
[α]D25 +75.2 (c 1.0, THF).
HPLC (OD-H column; n-hexane–i-PrOH, 80:20; flow rate = 0.8
mL·min–1): tR = 11.32 (minor enantiomer), 9.77 min (major enan-
tiomer); er 89:11.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Rf = 0.3 (PE–EtOAc, 1:1).
References
FTIR (KBr): 3294, 3081, 2958, 1654, 1613, 1506, 1385, 1264,
1153, 755, 699 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.89 (dd, J = 8, 1.5 Hz, 1 H),
7.34–7.30 (m, 1 H), 6.88–6.85 (m, 1 H), 6.69 (d, J = 8.0 Hz, 1 H),
6.43 (br s, 1 H), 4.88–4.85 (m, 1 H), 1.86–1.81 (m, 2 H), 1.08 (t,
J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 165.43, 147.44, 133.85, 128.57,
119.34, 115.86, 114.69, 66.43, 28.59, 8.28.
HRMS (ESI): m/z [M + Na]+ calcd for C10H12N2O: 199.0847;
found: 119.0845.
(1) (a) Russel, H. E.; Alaimo, R. J. J. Med. Chem. 1972, 15, 335.
(b) Neil, G. L.; Li, L. H.; Buskirk, H. H.; Moxley, T. E.
Cancer Chemother. Rep. 1972, 56, 163. (c) Cooper, E. R. A.;
Jackson, H. J. Reprod. Fertil. 1973, 34, 445.
(d) Kozhevnikov, Y. V.; Smirrnova, N. N.; Zalesov, V. S.;
Gradel, I. I. Pharm. Chem. J. 1981, 15, 403.
(e) Sadanandam, Y. S.; Ram Mohan Reddy, K.; Bhaskar
Rao, A. Eur. J. Med. Chem. 1987, 22, 169. (f) Kuo, S. C. H.;
Lee, Z.; Juang, J. P.; Lin, Y. T.; Wu, T. S.; Chang, J. J.;
Lednicer, D.; Paull, K. D.; Lin, C. M.; Hamel, E.; Lee, K. H.
J. Med. Chem. 1993, 36, 1146. (g) Levin, J. I.; Chan, P. S.;
Bailey, T.; Katocs, A. S.; Venkatesan, A. M. Bioorg. Med.
Chem. Lett. 1994, 4, 1141. (h) Hamel, E.; Lin, M.; Plowman,
C. J.; Wang, H. K.; Lee, K. H.; Paull, K. D. Biochem.
Pharmacol. 1996, 51, 53. (i) Hour, M. J.; Huang, L. J.; Kuo,
S. C.; Xia, Y.; Bastow, K.; Nakanishi, Y.; Hamel, E.; Lee, K.
H. J. Med. Chem. 2000, 43, 4479. (j) Xu, Z.; Zhang, Y.; Fu,
H.; Zhong, H.; Hong, K.; Zhu, W. Bioorg. Med. Chem. Lett.
2011, 21, 4005.
(S)-2-Pentyl-2,3-dihydroquinazolin-4(1H)-one (13c)
Colorless solid; yield: 52 mg (79%); mp 154 °C.
[α]D25 +79.7 (c 1.0, THF).
HPLC (OD-H column; n-hexane–i-PrOH, 90:10; flow rate = 0.8
mL·min–1): tR = 23.45 (minor enantiomer), 20.66 min (major enan-
tiomer); er 88:12.
Rf = 0.35 (PE–EtOAc, 1:1).
(2) (a) Agranat, I.; Caner, H.; Caldwell, J. Nat. Rev. Drug
Discovery 2002, 1, 753. (b) Kasprzyk-Hordern, B. Chem.
Soc. Rev. 2010, 39, 4466. (c) Agranat, I.; Wainschtein, S. R.
Drug Discovery Today 2010, 15, 163.
(3) Chinigo, G. M.; Paige, M.; Grindrod, S.; Hamel, E.;
Dakshanamurthy, S.; Chruszcz, M.; Minor, W.; Brown, M.
L. J. Med. Chem. 2008, 51, 4620.
(4) Selected references for the synthesis of 2,3-DHQZs:
(a) Chen, J. X.; Wu, H.; Hua, Y.; Su, W. K. Chin. Chem.
Lett. 2007, 18, 536. (b) Chen, J.; Su, W.; Wu, H.; Liu, M.;
Jin, C. Green Chem. 2007, 9, 972. (c) Chen, J.; Wu, D.; He,
F.; Liu, M.; Huayue, D.; Ding, J.; Su, W. Tetrahedron Lett.
2008, 49, 3814. (d) Allameh, S.; Heravi, M. M.; Hashemi,
M. M.; Bamoharram, F. F. Chin. Chem. Lett. 2011, 22, 131;
and references cited therein.
(5) (a) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am.
Chem. Soc. 2008, 130, 15786. (b) Rueping, M.; Antonchick,
A. P.; Sugiono, E.; Grenader, K. Angew. Chem. Int. Ed.
2009, 48, 908.
FTIR (KBr): 3329, 3206, 3069, 2953, 1643, 1614, 1507, 1387,
1261, 1152, 752, 690 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.91 (d, J = 1.5 Hz, 1 H), 7.35–
7.28 (m, 1 H), 6.90–6.87 (m, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 6.16
(br s, 1 H), 4.91 (t, J = 6 Hz, 1 H), 1.80–1.77 (m, 2 H), 1.38–1.36
(m, 5 H), 0.95–0.92 (m, 4 H).
13C NMR (125 MHz, CDCl3): δ = 165.37, 147.42, 133.89, 128.63,
119.46, 115.91, 114.74, 65.38, 35.59, 31.45, 23.72, 22.49, 13.91.
HRMS (ESI): m/z [M + Na]+ calcd for C13H18N2O: 241.1317;
found: 241.1311.
(S)-2-(1,3-Benzodioxol-5-yl)-3-phenyl-2,3-dihydroquinazolin-
4(1H)-one (15e)
Colorless solid; yield: 71 mg (70%); mp 239 °C.
[α]D25 +97.1 (c 1.0, THF).
HPLC (OD-H column; n-hexane–i-PrOH, 80:20; flow rate = 0.8
mL·min–1): tR = 32.35 (minor enantiomer), 22.42 min (major enan-
tiomer); er 78:22.
(6) Prakash, M.; Kesavan, V. Org. Lett. 2012, 14, 1896.
(7) Selected references for pybox: (a) Nishiyama, H.;
Sakaguchi, H.; Nakamura, T.; Horlhata, M.; Kondo, M.;
Itoh, K. Organometallics 1989, 8, 846. (b) Evans, D. A.;
Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118,
5814. (c) Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev.
2003, 103, 3119. (d) Poisson, T.; Yamashita, Y.; Kobayashi,
S. J. Am. Chem. Soc. 2010, 132, 7890. (e) Hanhan, N. V.;
Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz, A. K.
Angew. Chem. Int. Ed. 2010, 49, 744. (f) Singh, P. K.; Singh,
V. K. Org. Lett. 2010, 12, 80. (g) Zeng, T.; Yang, L.;
Hudson, R.; Song, G.; Moores, A. R.; Li, C.-J. Org. Lett.
Rf = 0.3 (PE–EtOAc, 3:1).
FTIR (KBr): 3297, 3039, 2928, 1639, 1614, 1500, 1450, 1393,
1244, 1035, 937, 856, 697 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 7.72 (d, J = 7.5 Hz, 1 H), 7.55
(m, 1 H), 7.34 (t, J = 8 Hz, 2 H), 7.30–7.25 (m, 3 H), 7.20 (t, J = 7.5
Hz, 1 H), 6.93 (s, 1 H), 6.81 (s, 2 H), 6.77–6.71 (m, 2 H), 6.20 (d,
J = 2.5 Hz, 1 H), 5.97 (d, J = 4.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 162.73, 147.82, 147.66,
147.02, 141.2, 135.07, 134.23, 129.06, 128.40, 126.72, 126.28,
120.74, 118.00, 115.76, 115.26, 108.26, 107.30, 101.64, 72.85.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2265–2272

2272
M. Prakash et al.
PAPER
2011, 13, 442. (h) Gutierrez, E. G.; Wong, C. J.; Sahin, A. H.
Org. Lett. 2011, 13, 5754; and references cited therein.
(i) Comelles, J.; Pericas, A.; Moreno-Mañas, M.; Vallribera,
A.; Drudis-Solé, G.; Lledos, A.; Parella, T.; Roglans, A.;
García-Granda, S.; Roces-Fernández, L. J. Org. Chem.
2007, 72, 2077. (j) Desimoni, G.; Faita, G.; Toscanini, M.;
Boiocchi, M. Chem. Eur. J. 2008, 14, 3630. (k) Hanhan, N.
V.; Ball-Jones, N. R.; Tran, N. T.; Franz, A. K. Angew.
Chem. Int. Ed. 2011, 50, 1; and references cited therein.
(9) For the synthesis of pybox, see: (a) Gupta, A. D.; Bhuniya,
D.; Singh, V. K. Tetrahedron 1994, 50, 13725. (b) Towers,
M. D. K. N.; Woodgate, P. D.; Brimble, M. A. ARKIVOC
2003, (i), 43. (c) Cornejo, A.; Fraile, J. M.; García, J. I.; Gil,
M. J.; Martínez-Merino, V.; Mayoral, J. A.; Pires, E.;
Villalba, I. Synlett 2005, 2321.
(8) For applications of Sc–pybox, see: (a) Desimoni, G.; Faita,
G.; Guala, M.; Pratelli, C. J. Org. Chem. 2003, 68, 7862.
(b) Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126,
9544. (c) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127,
8006. (d) Evans, D. A.; Aye, Y. J. Am. Chem. Soc. 2006,
128, 11034. (e) Evans, D. A.; Aye, Y.; Wu, J. Org. Lett.
2006, 8, 2071. (f) Desimoni, G.; Faita, G.; Piccinini, F.;
Toscanini, M. Eur. J. Org. Chem. 2006, 5228. (g) Desimoni,
G.; Faita, G.; Toscanini, M.; Boiocchi, M. Chem. Eur. J.
2007, 13, 9478. (h) Desimoni, G.; Faita, G.; Mella, M.;
Piccinini, F.; Toscanini, M. Eur. J. Org. Chem. 2007, 1529.
Synthesis 2013, 45, 2265–2272
© Georg Thieme Verlag Stuttgart · New York