A polymer-assisted solution-phase strategy for the synthesis of fused [2,1-b]quinazolinones and the preparation of optically active vasicinone

Article abstract of DOI:10.1055/s-2006-951482

An efficient preparation of fused [2,1-b]quinazolinones has been developed utilizing polymer-supported reagents. (±)- Vasicinone was converted into its dione by oxidation with poly (4-vinylpyridiniumdichromate). An efficient method has been developed for the synthesis of (d)- and (l)-vasicinone via asymmetric reduction of pyrrolo[2,1-b]quinazoline-3,9-dione by employing NaBH₄/Me₃SiCl as the reducing agent and polymer-supported chiral sulfonamide as catalyst. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951482

LETTER
2609
A Polymer-Assisted Solution-Phase Strategy for the Synthesis of Fused
[2,1-b]Quinazolinones and the Preparation of Optically Active Vasicinone
Polymer-Assisted
h
Strategies tow
m
ards
F
used [2,1-
b
]
e
Q
uinazolin
dones Kamal,* V. Devaiah, N. Shankaraiah, K. Laxma Reddy
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27193189; E-mail: ahmedkamal@iict.res.in
Received 21 June 2006
anthelmintic,6d and antianaphylactic6e activities. More-
over, it is used extensively as a remedy to cold, cough,
bronchitis and asthma6f in the Indian Ayurvedic System of
Medicine. 3S-(–)-Vasicinone has been claimed to have
Abstract: An efficient preparation of fused [2,1-b]quinazolinones
has been developed utilizing polymer-supported reagents. ( )-
Vasicinone was converted into its dione by oxidation with poly
(4-vinylpyridiniumdichromate). An efficient method has been de-
veloped for the synthesis of (d)- and (l)-vasicinone via asymmetric better bronchodilatory activity than its racemic form and
has been synthesized in this laboratory4a by a chemoenzy-
matic method and lipase-catalyzed resolution of the
racemic mixture. An approach developed by Argade and
reduction of pyrrolo[2,1-b]quinazoline-3,9-dione by employing
NaBH4/Me3SiCl as the reducing agent and polymer-supported
chiral sulfonamide as catalyst.
co-workers4b employed (S)-acetoxysuccinic anhydride as
Key words: polymer-supported reagents, fused [2,1-b]quinazoli-
nones, oxidations, vasicinone
one of the starting materials.
O
N
O
A major role has been played by solid-phase chemistry in
revolutionizing certain areas of chemistry, particularly
combinatorial synthesis. Solid-phase synthesis is instru-
mental in building compound libraries efficiently. How-
ever, progress of the reaction and compound loading
determination on the polymer usually require specialized
techniques and analytical equipment. Furthermore, cleav-
age of the compound from the polymer at the final step is
also a requirement. Therefore, an attractive alternative is
the use of polymer-supported material as reagents instead
as anchors for the substrates. Polymer-assisted solution-
phase (PASP)1 synthesis has many advantages over con-
ventional solution-phase and solid-phase chemistry.
Some of these include monitoring of the reaction in real-
time by conventional methods, easy reaction optimiza-
tion, and no residual functionality from bead attachment
in the final product.
N
N
n
N
OH
n = 1: Deoxyvasicinone (6a)
n = 2: 6,7,8,9-Tetrahydropyrido-
[2,1-b]quinazolin-11-one (7a)
( )-Vasicinone (10)
α-OH, (d)-Vasicinone (10S)
β-OH, (l)-Vasicinone (10R)
Figure 1 Biologically active fused [2,1-b]quinazolinones
Enantiopure or enantioenriched sec-alcohols are impor-
tant building blocks for the synthesis of natural products,
chiral ligand auxiliaries, biologically active compounds
and catalysts. However, a method for their preparation,
which usually involves an asymmetric reduction of
prochiral ketones, that does not need the use of column
chromatography is highly desirable.
In conjunction with our earlier studies on the use of poly-
mer-supported reagents for the preparation of the pyr-
rolo[2,1-c][1,4]benzodiazepine ring system,7 we herein
investigated the synthesis of fused [2,1-b]quinazolinones
and related analogues, including vasicinone, employing
polymer-supported reagents. In the first step 2-azidoben-
zoic acids (1a–c) were coupled with different lactams 2
employing N-cyclohexylcarbodiimide N'-methyl poly-
styrene (A)8a,b to give N-(2-azidobenzoyl)lactams (3–5)
(Scheme 1).9 Convieniently, the excess of acid and the
urea by-products can be simply filtered off from the azido
lactams 3–5. Upon intramolecular azidoreductive cycliza-
tion of the azido-lactams employing polymer-supported
triphenylphosphine (B),8c the fused [2,1-b]quinazolinones
are formed in good overall yields (Table 1, 6–8, 90–
98%).10
A number of quinazolinone alkaloids have been isolated
from various plants, animals, and microorganisms and
also synthesized because of their well-known biological
properties.2 The development of a new, practical, synthet-
ic strategy employing polymer-supported reagents to the
synthesis of such bioactive quinazolinone alkaloids is an
important and challenging task. Deoxyvasicinone (6a)
and vasicinone (10) and pyrido[2,1-b]quinazolinone (7a)
alkaloids (Figure 1) have been isolated from the aerial
parts of Adhatoda vasica3 (from the family Acanthacea,
Sankrit-Vasaka), an evergreen subherbaceous bush. Some
synthetic routes have been reported for the preparation of
deoxyvasicinone,4 which possesses antimicrobial, antiin-
flammatory and antidepressant activities.5 Vasicinone ex-
hibits antitumour,6a,b bronchodilatory, hypotensive,6c
Bromination of deoxyvasicinones 6a–c by employing the
polymer-bound brominating agent C (Amberlyst A-26,
SYNLETT 2006, No. 16, pp 2609–2612
0
4
.1
0
.2
0
0
6
Br3 form)8d gives allylic monobromo derivatives 9a–c11
–
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-951482; Art ID: D17806ST
© Georg Thieme Verlag Stuttgart · New York
in excellent yields (>98%). These bromo-substituted

2610
A. Kamal et al.
LETTER
deoxyvasicinones gave the acetylated derivatives upon
treatment with the AcO– form of Amberlyst A-26 (D).
Racemic vasicinones (10a–c)12 were then obtained by
treatment of these acetylated intermediates with boro-
hydride exchange resin E in the presence of Pd(OAc)2.8e
Oxidation of the racemic vasicinones 10a–c was then
effected by using poly(vinylpyridinium dichromate) (F)
to give diones 11a–c.8f,13 Enantioselective reduction of the
diones 11a–c by using polymer-supported chiral sulfon-
amide H in the presence of NaBH4/Me3SiCl8g afforded the
optically active (l)-vasicinones (10S)a–c.14 Alternatively,
enantioselective reduction of the diones by using
polymer-supported chiral sulfonamide G afforded the (d)-
vasicinones (10R)a–c14 in good yield (Scheme 2) with
>90% of ee as determined by chiral HPLC.15 All results
are illustrated in Table 2. These polymer-supported chiral
reagents have been recovered and reused.
O
O
N
N C N
R1
R2
R1
R2
OH
+
( )
A
N
( )
n
HN
n
N3
CH2Cl2, r.t., 95–98%
3O
O
1a–c
a R1 = R2 = H
b R1 = H, R2 = Me
c R1 = Cl, R2 = H
n = 1–3
n = 1: 3a–c
n = 2: 4a–c
n = 3: 5a–c
2
PPh2
B
CH2Cl2, r.t.,
96–98%
O
N
R1
R2
N
( )
n
n = 1: 6a–c
n = 2: 7a–c
n = 3: 8a–c
Scheme 1 PASP synthesis of fused [2,1-b]quinazolinones
NMe3+AcO–
D
MeOH, r.t.,
O
N
O
–
O
NMe3+Br3
C
i)
R1
R2
R1
R2
R1
R2
N
N
N
–
NMe3+BH4
THF, r.t.,
>99%
ii)
N
N
E
Br
OH
Pd(OAc)2/MeOH
reflux, 1 h, 90%
6a–c
9a–c
10a–c
+
–2
NH Cr2O7
2
DMF, 70 °C,
18 h, 93%
F
O
O
N
O
R1
R1
R2
R1
R2
NaBH4/Me3SiCl
NaBH4/Me3SiCl
N
N
N
O
O
R
R2
N
O
S
S
O
N
S
N
N
OH
OH
O
10a–c
10a–c
(l)-Vasicinone (10S)
11a–c
Ph
HO
Ph
Ph
HO
Ph
G
H
THF, reflux,
3 h, 95%
(d)-Vasicinone (10R)
THF, reflux,
3 h, 93%
Scheme 2 PASP synthesis of optically active vasicinones
Table 1 Yields and Observed Molecular Ions for Fused [2,1-b]quinazolinones 6–8
Compound
R1
H
R2
H
n
1
1
1
2
2
2
3
3
3
Time (h)
3.5
Yield (%)a
95
MSb
186
200
220
200
214
234
214
228
248
6a
6b
H
Me
H
4.0
93
90
96
92
91
97
98
92
6c
Cl
H
6.0
7a
H
4.0
7b
H
Me
H
5.0
7c
Cl
H
6.0
8a
H
5.0
8b
H
Me
H
5.2
8c
Cl
6.0
a Isolated Yields.
b Determined by EI mass spectrometry.
Synlett 2006, No. 16, 2609–2612 © Thieme Stuttgart · New York

LETTER
Polymer-Assisted Strategy towards Fused [2,1-b]Quinazolinones
2611
Table 2 Products and Yields for the Preparation of Optically Active
Vasicinones
(3) (a) Amin, A. H.; Mehta, D. R. Nature 1959, 183, 1317.
(b) Mehta, D. R.; Naravane, J. S.; Desai, R. M. J. Org. Chem.
1963, 28, 445. (c) Jain, M. P.; Koul, S. K.; Dhar, K. L.; Atal,
C. K. Phytochemistry 1980, 19, 1880.
Substrate
PS-Reagent
Product,a Yield (%)b
(4) (a) Kamal, A.; Ramana, K. V.; Rao, M. V. J. Org. Chem.
2001, 66, 997. (b) Mhaske, S. B.; Argade, N. P. J. Org.
Chem. 2001, 66, 9098. (c) Kamal, A.; Ramana, A. V.;
Reddy, K. S.; Ramana, K. V.; Babu, A. H.; Prasad, B. R.
Tetrahedron Lett. 2004, 45, 8187.
(5) (a) Al-Shamma, A.; Drake, S.; Flynn, D. L.; Mitscher, L. A.;
Park, Y. H.; Rao, G. S. R.; Simpson, A.; Swayze, J. K.;
Veysoglu, T.; Wu, S. T. S. J. Nat. Prod. 1981, 44, 745.
(b) Koizumi, M.; Matsuura, I.; Murakami, Y. Japan Kokai
7,777,093, 1977; Chem. Abstr. 1978, 88, 6930.
(6) (a) Duan, J.; Zhou, R.; Zhao, S.; Wang, M.; Che, C.
Zhongguo Yaoke Daxue Xuebao 1998, 29, 21. (b) Fan, Z.;
Yao, X.; Gu, L.; Wang, J.; Wang, J.; He, A.; Zhang, B.;
Wang, X.; Wang, H. Shenyang Yaoxueyuan Xuebao 1993,
10, 136. (c) Rahman, A. U.; Sultana, N.; Akhter, F.; Nighat,
F.; Choudhary, M. I. Nat. Prod. Lett. 1997, 10, 249. (d) D'
Cruz, J. L.; Nimbkar, A. Y.; Kokate, C. K. Indian Drugs
1980, 17, 99. (e) Bhide, M. B.; Mahajani, S. S. Bull.
Haffkine Inst. 1975, 3, 128. (f) Choudhury, M. K.
6a–c
C
9a (>99)
9b (98)
9c (99)
9a–c
D+E
F
10a (95)
10b (86)
10c (89)
10a–c
11a–c
11a–c
11a (92)
11b (90)
11c (87)
H
(10S)a (93)
(10S)b (90)
(10S)c (90)
G
(10R)a (95)
(10R)b (91)
(10R)c (90)
Naturwissenschaften 1979, 66, 205.
a Characterized by 1H NMR and EI mass spectra.
b Isolated yields.
(7) (a) Kamal, A.; Reddy, K. L.; Devaiah, V.; Shankaraiah, N.
Synlett 2004, 2533. (b) Kamal, A.; Devaiah, V.; Reddy, K.
L.; Shankaraiah, N. Adv. Synth. Catal. 2006, 348, 249.
(8) (a) Weinshenker, N. M.; Shen, C. M.; Wong, J. Y. Org.
Synth., Coll. Vol. VI; John Wiley & Sons: London, 1988,
951. (b) Wolman, Y.; Kivity, S.; Frankel, M. J. Chem. Soc.,
Chem. Commun. 1967, 629. (c) Grieder, A.; Thomas, A. W.
Synthesis 2003, 1707. (d) Ploypradith, P.; Kagan, R. K.;
Ruchirawat, S. J. Org. Chem. 2005, 70, 5119. (e) Choi, J.;
Yoon, N. M. Synth. Commun. 1995, 25, 2655. (f)Frechet,J.
M. J.; Darling, P.; Farrall, M. J. J. Org. Chem. 1981, 46,
1728. (g) Hu, J.-B.; Zhao, G.; Ding, Z.-D. Angew. Chem. Int.
Ed. 2001, 40, 1109.
(9) Typical Procedure: Preparation of Compound 3a.
N-Cyclohexylcarbodiimide N-methyl polystyrene A (1.32
mmol, 1.30 mmol/g) was added to a dry reaction vessel.
Compound 1a (163 mg, 1.0 mmol) in CH2Cl2 (10 mL) was
added to the dry resin and the resulting mixture was stirred
at r.t. for 5 min before the corresponding lactam 2 (56 mg,
0.66 mmol) in CH2Cl2 (2 mL) was added and the stirring
continued at r.t. for 10 h. The resin was removed by filtration
and washed with CH2Cl2. Evaporation of the filtrate
provided 3a in 97% yield. Mp 81–83 °C; IR (KBr): 2150,
1750, 1680 cm–1; 1H NMR (200 MHz, CDCl3): d = 2.19 (q,
J = 6.8 Hz, 2 H), 2.62 (t, J = 7.5 Hz, 2 H), 4.0 (t, J = 7.5 Hz,
2 H), 7.2 (m, 3 H), 7.5 (t, J = 7.5 Hz, 1 H); MS (EI): m/z =
230 [M+].
(10) Typical Procedure: Preparation of Compound 6a.
Triphenylphosphine-impregnated polystyrene B (3.2 mmol,
3 mmol/g) was suspended in anhydrous CH2Cl2 (10 mL) and
the 2-azidobenzoyl lactam 3a (150 mg, 0.65 mmol) was
added and the suspension was stirred for 5 h at r.t. The resin
was removed by filtration and washed with CH2Cl2 and
evaporation of the filtrate afforded 6a in 98% yield. Mp 104–
106 °C; IR (KBr): 1675 cm–1; 1H NMR (200 MHz, CDCl3):
d = 2.32 (q, J = 7.5 and 8.0 Hz, 2 H), 3.22 (t, J = 8.0 Hz, 2
H), 4.19 (t, J = 7.5 Hz, 2 H), 7.5 (t, J = 7.4 Hz, 1 H), 7.6–7.8
(m, 2 H), 8.31 (d, J = 8.0 Hz, 1 H); MS (EI): m/z = 186 [M+].
(11) Typical Procedure: Preparation of Compound 9a. To a
stirred solution of compound 6a (115 mg, 0.61 mmol) in dry
THF was added the Br3– form of Amberlyst A-26 C (515 mg,
0.65 mmol, 1.26 mmol/g). The mixture was allowed to stir at
r.t. for 18–20 h. After completion of the reaction as indicated
In conclusion, a clean preparation of fused [2,1-
b]quinazolinones and enantioselective preparations of
(d)- and (l)-vasicinone has been developed by employing
polymer-supported reagents. This synthetic strategy is
readily amenable for designing and preparing a combina-
torial library. It is noteworthy that in the entire process,
the work-up has been simplified to filtration and evapora-
tion for all the steps and all the reagents could be reused,
thus addressing the problems of environmental and
economical sustainability.
Acknowledgment
The authors VD, NS and KLR are grateful to CSIR, New Delhi for
the award of Research fellowships.
References and Notes
(1) For recent reviews, see: (a) Kirschning, A.; Monenschein,
H.; Wittenberg, R. Angew. Chem. Int. Ed. 2001, 40, 650.
(b) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P.
S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1
2000, 3815. (c) Storer, R. I.; Takemoto, T.; Jackson, P. S.;
Ley, S. V. Angew. Chem. Int. Ed. 2003, 42, 2521.
(d) Jaunzems, J.; Hofer, E.; Jesberger, M.; Sourkouni-
Argirusi, G.; Kirschning, A. Angew. Chem. Int. Ed. 2003, 42,
1166. (e) Storer, P. I.; Takemoto, T.; Jackson, P. S.; Brown,
D. S.; Baxendale, I. R.; Ley, S. V. Chem. Eur. J. 2004, 10,
2529. (f) Wang, Y.; Sauer, D. R. Org. Lett. 2004, 6, 2793.
(g) Siu, J.; Baxendale, I. R.; Lewthwaite, R. A.; Ley, S. V.
Org. Biomol. Chem. 2005, 3, 3140.
(2) (a) Johne, S.; Groger, D. Pharmazie 1970, 25, 22.
(b) Coppola, M. Synthesis 1980, 505. (c) Johne, S. Prog.
Drug Res. 1982, 26, 259. (d) Johne, S. Prog. Chem. Org.
Nat. Prod. 1984, 46, 159. (e) Michael, J. P. Nat. Prod. Rep.
2000, 17, 603; and references cited therein.
Synlett 2006, No. 16, 2609–2612 © Thieme Stuttgart · New York

2612
A. Kamal et al.
LETTER
(14) Typical Procedures: Preparations of (d)-Vasicinone
by TLC the reaction was filtered and the resin washed with
CH2Cl2 and EtOH. The filtrate was concentrated under
reduced pressure to afford 9a in >99% yield. Mp 141–
142 °C; IR (KBr): 1684, 776 cm–1; 1H NMR (200 MHz,
CDCl3): d = 2.50–2.90 (m, 2 H), 4.10–4.30 (m, 1 H), 4.30–
4.50 (m, 1 H), 5.20 (dd, J = 4.6, 1.8 Hz, 1 H), 7.40–7.60 (m,
2 H), 7.60–7.80 (m, 1 H), 8.30 (d, J = 8.0 Hz, 1 H); MS (EI):
m/z = 264 [M+].
(10R)a and (l)-Vasicinone (10S)a. A solution of Me3SiCl
(132 mg, 1.2 mmol) was added to a suspension of NaBH4 (45
mg, 1.2 mmol) in THF (10 mL) and the resulting suspension
held at reflux for 1 h. The polymer-supported chiral
sulfonamide G (50 mg, 0.12 mmol) was added and the
suspension was treated with a solution of compound 11a
(100 mg, 0.5 mmol) in THF (10 mL) at rate of 3 mL h–1.
After completion of the reaction, the mixture was treated
with water and filtered. The resulting aqueous solution was
extracted with CH2Cl2. The organic phase was dried
(Na2SO4) and evaporated to afford the (10R)a in 93% yield
and 94% ee (as determined by chiral HPLC15). Mp 202–
203 °C; [a]D22 +102 (c 1, CHCl3), Lit.16a [a]D22 +148 (c 1.35,
EtOH); IR (KBr): 3140, 1668 cm–1; 1H NMR (200 MHz,
CDCl3): d = 2.21–2.42 (m, 1 H), 2.63–2.79 (m, 1 H), 3.92–
4.11 (m, 1 H), 4.30–4.49 (m, 1 H), 4.82 (s, 1 H), 5.19 (t,
J = 7.35 Hz, 1 H), 7.43–7.62 (m, 1 H), 7.68–7.77 (m, 2 H),
8.33 (d, J = 7.35 Hz, 1 H); MS (EI): m/z = 202 [M+].
Alternatively, polymer-supported chiral sulfonamide H (98
mg, 0.25 mmol) suspension was treated with compound 11a
(200 mg, 1.0 mmol) to give (10S)a in 95% yield and 94% ee
(12) Typical Procedure: Preparation of Compound 10a. To a
stirred solution of 3-bromo-3-deoxyvasicinone 9 (134 mg,
0.50 mmol) in MeOH (5 mL) was added Amberlyst A-26 in
the AcO– form D (275 mg, 1.00 mmol, 3.65 mmol/g). The
mixture was stirred at r. t. for 1 h then a MeOH (5 mL)
solution of Pd(OAc)2 (56 mg, 0.25 mmol) and boron hydride
exchange resin E (500 mg, 1.5 mmol) was added to the
reaction flask under a nitrogen atmosphere and the mixture
was held at reflux for 1 h. After completion of the reaction
as indicated by TLC the reaction was filtered the resin was
washed with CH2Cl2 and EtOH. The filtrate was concen-
trated under reduced pressure to afford 10a in 95% yield. Mp
203–204 °C; 1H NMR (200 MHz, CDCl3): d = 2.30–2.50
(m, 1 H), 2.60–2.80 (m, 1 H), 4.00–4.20 (m, 1 H), 4.30–4.50
(m, 1 H), 5.10–5.30 (m, 2 H), 7.50–7.60 (m, 1 H), 7.70–7.80
(m, 2 H), 8.40 (d, J = 8.1 Hz, 1 H). MS (EI): m/z = 202 [M+].
(13) Typical Procedure: Preparation of Compound 11. To a
stirred solution of compound 10a (75 mg, 0.036 mmol) in
DMF (5 mL) was added poly(vinylpyridinium dichromate)
F (190 mg, 0.14 mmol). The reaction mixture was stirred at
70 °C until the completion of the reaction. The resin was
removed by filtration and washed with CH2Cl2. Evaporation
of the filtrate provided 11a in 92% yield. Mp 165–170 °C;
IR (KBr): 1744, 1656, 1600 cm–1; 1H NMR (200 MHz,
CDC13): d = 3.05 (t, J = 6.7 Hz, 2 H), 4.41 (t, J = 6.7 Hz, 2
H) 7.63 (ddd, J = 7.8, 7.6, 1.5 Hz, l H), 7.85 (d, J = 7.8, 1.5
Hz, 1 H), 7.98 (ddd, J = 8.3, 7.6, 1.5 Hz, 1 H), 8.37 (dd,
J = 8.3, 1.5 Hz, lH); MS (EI): m/z = 200 [M+].
22
(as determined by chiral HPLC15). Mp 200–202 °C; [a]D
–85 (c 0.5, CHCl3), Lit.16b [a]D22 –90 (c 0.5, CHCl3); IR
(KBr): 3135, 1648 cm–1; 1H NMR (200 MHz, CDCl3):
d = 2.21–2.39 (m 1 H), 2.62–2.83 (m, 1 H), 4.0–4.1 (m, 1 H),
4.32–4.53 (m, 1 H), 4.75 (s, 1 H), 5.19 (t, J = 7.15 Hz, 1 H),
7.39–7.58, (m, 1 H), 7.71–7.82 (m, 2 H), 8.29 (d, J = 7.15
Hz, 1 H); MS (EI): m/z = 202 [M+].
(15) Conditions: Chiracel OD column employing hexane-2-
propanol (85:15) as the mobile phase at 0.7 mL/min flow
rate and monitored at 254 nm wavelength.
(16) (a) Rajlakshmi, P.; Aditya, N. C. J. Ind. Chem. Soc. 1988,
65, 814. (b) Mehta, D. R.; Naravane, J. S.; Desai, R. M. J.
Org. Chem. 1963, 28, 445.
Synlett 2006, No. 16, 2609–2612 © Thieme Stuttgart · New York