Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids

Article abstract of DOI:10.1016/j.tetlet.2006.10.123

Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids has been developed for the preparation of vasicinone and deoxyvasicinone by two approaches. The derivative of polymer-supported p-nitrophenyl carbonate was attached to anthranilic acid and then coupled with various bromo-lactams. This resin-linked bromo intermediate upon acetylation, hydrolysis and resin cleavage gave the cyclized [2,1-b]quinazolinones (vasicinone). Alternatively, resin-linked azido-benzoic acids were coupled with bromo-substituted lactams followed by cyclization in an aza-Wittig reductive cyclization process giving the bromo-substituted quinazolinone intermediates, with subsequent acetylation, hydrolysis and resin cleavage affording the fused [2,1-b]quinazolinones.

Full text of DOI:10.1016/j.tetlet.2006.10.123

Tetrahedron Letters 47 (2006) 9025–9028
Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids
Ahmed Kamal,* N. Shankaraiah, V. Devaiah and K. Laxma Reddy
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 2 August 2006; revised 5 October 2006; accepted 23 October 2006
Abstract—Solid-phase synthesis of fused [2,1-b]quinazolinone alkaloids has been developed for the preparation of vasicinone and
deoxyvasicinone by two approaches. The derivative of polymer-supported p-nitrophenyl carbonate was attached to anthranilic acid
and then coupled with various bromo-lactams. This resin-linked bromo intermediate upon acetylation, hydrolysis and resin cleavage
gave the cyclized [2,1-b]quinazolinones (vasicinone). Alternatively, resin-linked azido-benzoic acids were coupled with bromo-substi-
tuted lactams followed by cyclization in an aza-Wittig reductive cyclization process giving the bromo-substituted quinazolinone
intermediates, with subsequent acetylation, hydrolysis and resin cleavage affording the fused [2,1-b]quinazolinones.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Combinatorial chemistry has become an extremely
powerful technique for the generation of drug-like small
organic molecule libraries in medicinal chemistry pro-
grammes.1 Solid-phase organic synthesis (SPOS) is espe-
cially useful in creating large numbers of hit and lead
compounds2 in combinatorial libraries for use in high-
throughput screening.3 As a result, an increasing range
and number of pharmaceutically useful heterocyclic
compounds have been prepared.4 In this investigation,
we have developed new solid-phase strategies for synthe-
sizing nitrogen-containing heterocyclic compounds
based on fused [2,1-b]quinazolinones, employing Wang
resin and polymer-supported (PS) 4-nitrophenyl carbon-
ate linkers.
O
N
N
N
n
N
OH
OH
( )-vasicine 3
( )-vasicinone 1
6-Hydroxy-6,8,9,11-tetrahydro-
-7H-pyrido[2,1-b]quinozolin-11-one 2
n = 1;
n = 2;
O
O
N
HO
N
n
N
N
OH
n = 1; deoxyvasicinone 5
n = 2; 6,7,8,9-Tetrahydropy-
( )-vasicinolone 4
-rido[2,1-b]quinozolin-11-one 6
Vasicinone is a fused [2,1-b]quinazolinone alkaloid iso-
lated from the aerial parts of Adhatoda vacica (family:
Acanthacea; Sanskrit-Vasaka), which is an evergreen
subherbaceous bush used extensively in indigenous
medicine for treatment of colds, coughs, bronchitis
and asthma.5 The related alkaloids, ( )-vasicinone 1,
( )-vasicine 3, ( )-vasicinolone 4 and deoxyvasicinone
5 have also been isolated from the above types of plants6
(Fig. 1).
Figure 1.
towards the preparation of a racemate, including carbon-
ylation catalyzed by palladium,8 coupling O-methyl
butyrolactam with anthranilic acid9 and an intra-
molecular aza-Wittig reaction using PPh3 and PBu3.10
( )-Vasicinone has also been synthesized from deoxyva-
sicinone by bromination with NBS followed by acetyl-
ation with NaOAc–AcOH and lead tetraacetate free
radical oxidation.9 Notably, (3S)-(À)-vasicinone has
been claimed to have better bronchodilation activity
than the racemic form and has been recently synthe-
sized10 via asymmetric hydroxylation using the Davis
reagent. In this laboratory we have developed a chemo-
enzymatic method employing a lipase-catalyzed resolu-
tion process of racemic vasicinone.11 Recently, another
The synthesis of vasicinone and deoxyvasicinone has
been reported,7 however, most methods were targeted
Keywords: Solid-phase synthesis; Fused [2,1-b]quinazolinones; Vasici-
none; Aza-Wittig reductive cyclization.
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40
27193189; e-mail addresses: ahmedkamal@iict.res.in; ahmedkamal@
iictnet.org
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.123

9026
A. Kamal et al. / Tetrahedron Letters 47 (2006) 9025–9028
approach was developed by Argade and co-workers12
employing (S)-acetoxysuccinic anhydride as one of the
starting materials. However, there are no reports of
solid-phase synthesis for these compounds. Therefore,
in this letter we report two strategies for the solid-phase
synthesis of fused [2,1-b]quinazolinones for the first
time. This will allow the method to be used for the pro-
duction of libraries, as different anthranilic acid and azi-
do benzoic acid derivatives could be anchored to the
solid support and coupled to a diverse range of C-ring
precursors.
A stirred solution of anthranilic acid 8 was coupled to
the PS-p-nitrophenyl carbonate 7 using 1-hydroxy-
benzotriazole (HOBt) and diisopropylethylamine (DI-
PEA) in DMF–CH2Cl2 (1:2) to give 9. Then, 9 was
coupled to various lactams 1013 utilizing dicyclohexyl-
carbodiimide (DCC) and 4-dimethylaminopyridine
(DMAP) in CH2Cl2 to afford 11 and 13. Bromides 13
were reacted with potassium acetate and catalytic 18-
crown-6-ether in dry CH3CN at reflux for 6 h or DMF
at room temperature for 8 h to afford acetates 15. These
upon deacetylation with K2CO3 in THF–MeOH (1:1)
gave 17. Finally, 11 and 17 were treated with 50%
TFA–CH2Cl2 (1:1) to effect cleavage from the resin fol-
lowed by cyclization to produce [2,1-b]quinazolinones
Table 1. Yields and molecular ions observed for fused [2,1-b]-
quinazolinones
1
15 and 516 in good yields as shown in Table 1. Similarly,
Entry
R1
R2
n
Yield (%)a
EIMSb
(Scheme 2) the Wang resin was attached to methyl-2-
azido-4-hydroxy-5-methoxybenzoate under Mitsunobu
conditions,14a,b this upon hydrolysis and coupling with
22 gave 23 as indicated by IR spectra, which showed a
strong azide stretching vibration in the range
2115 cmÀ1. Azides 23 were cyclized by an aza-Wittig
mediated reductive cyclization using triphenylphosphine
(TPP) in dry toluene to give 24. Intermediate 24 was
converted into 2717 by employing reactions similar to
those described in Scheme 1. These transformations
were monitored by FT-IR spectroscopy of the resin
beads.
1a
1b
1c
H
H
H
OBn
Cl
H
H
OBn
Cl
H
OBn
H
1
1
1
1
2
2
2
2
1
1
2
2
1
2
88
85
85
88
86
84
85
87
90
88
87
90
82
80
202
216
338
236
216
230
352
250
186
322
200
336
248
262
Me
OMe
H
1d
2a
2b
2c
H
Me
OMe
H
H
OMe
H
OMe
OMe
OMe
2d
5a
5b
6a
6b
27a
27b
OBn
OH
OH
In a typical synthesis, a suspension of PS-p-nitrophenyl
carbonate 7 (1.00 g, 0.93 mmol/g, 100–200 mesh and 1%
DVB) in CH2Cl2–DMF (2:1, 10 mL) was stirred for
30 min, then a solution of anthranilic acid 8 (0.64 g,
a Based on initial loading of the Wang resin and PS-p-nitrophenyl
carbonate.
b Parent ion observed as (M+).
O
R1
R2
COOH
NH2
O
X
O
O
O
HN
R1
R2
R1
R2
10
COOH
n
n
N
8
(ii)
X = H, Br
n =1, 2
X
(i)
NH
O
NH
O
R1 = H, OBn, Cl
NO2
R2 = H, Me, OMe
O
O
O
7
9
11a-b; n = 1
12a-b; n = 2
X= H
(v)
13a-d; n = 1
14a-d; n = 2
X = Br
O
N
N
R1
R2
n
(iii)
5a-b; n = 1
6a-b; n = 2
O
O
O
N
R1
R2
R1
R2
R1
R2
n
n
(v)
(iv)
N
N
n
OH
OAc
N
NH
NH
O
O
OH
O
O
O
O
1a-d; n = 1
2a-d; n = 2
17a-d; n = 1
18a-d; n = 2
15a-d; n = 1
16a-d; n = 2
Scheme 1. Reagents and conditions: (i) HOBt, DIPEA, CH2Cl2–DMF (2:1), 6 h, rt; (ii) DCC, DMAP, CH2Cl2, 0 ꢁC, 12 h, rt; (iii) KOAc, 18-crown-
6-ether, CH3CN, 80 ꢁC, 6 h or DMF, 8 h, rt; (iv) K2CO3, THF–MeOH (1:1), rt, 6 h; (v) TFA, CH2Cl2 (1:1), 2 h.

A. Kamal et al. / Tetrahedron Letters 47 (2006) 9025–9028
9027
O
O
Br
OH
H3CO
O
COOH
N3
H3CO
O
HN
22
H3CO
HO
COOCH3
N3
n
N
20
n
(ii)
n = 1, 2
N3
(i)
Br
O
21
23a; n = 1
23b; n = 2
19
(iii)
O
N
N
O
N
N
O
H3CO
O
H3CO
O
H3CO
O
(v)
(iv)
N
n
n
n
N
OH
Br
OAc
26a; n = 1
26b; n = 2
25a; n = 1
25b; n = 2
24a; n = 1
24b; n = 2
(vi)
O
N
H3CO
HO
N
n
OH
27a; n = 1
27b; n = 2
Scheme 2. Reagents and conditions: (i) (a) TPP, DIAD, NMP, 16 h, rt; (b) 1 N NaOH, 1,4-dioxane, 100 ꢁC, 12 h; (ii) DCC, DMAP, CH2Cl2, 12 h,
0 ꢁC–rt; (iii) TPP, toluene, 3 h, rt; (iv) KOAc, 18-crown-6-ether, CH3CN, 80 ꢁC, 6 h or DMF, 8 h, rt; (v) K2CO3, THF–MeOH (1:1), 6 h, rt; (vi) TFA,
CH2Cl2, (1:1) 1 h, rt.
4.70 mmol), HOBt (0.38 g, 2.80 mmol), DIPEA
(0.97 mL, 5.50 mmol) in CH2Cl2–DMF (2:1, 10 mL)
was added to the swollen resin and the mixture stirred
at rt for 6 h. The derivatized resin 9 was then filtered,
rinsed with DMF (2 · 15 mL), CH2Cl2 (2 · 15 mL),
MeOH (2 · 15 mL), ether (2 · 15 mL) and dried in
vacuo. To a suspension of resin 9 in CH2Cl2 (10 mL),
DCC (0.77 g, 3.72 mmol) and DMAP (8 mg) were added
at 0 ꢁC and the reaction allowed to stir at the same
temperature for 30 min. Lactam 10 (0.61 g, 3.72 mmol)
in CH2Cl2 (5 mL) was added to the above reaction mix-
ture, which was slowly stirred at rt for 12 h to gives 11
and 13. This resin was then filtered and washed with
CH2Cl2 (2 · 15 mL), MeOH–water (9:1, 2 · 15 mL),
MeOH (2 · 15 mL) and ether (2 · 15 mL) and then
dried in vacuo. To a suspension of resin 13 in dry
CH3CN (15 mL) or DMF (10 mL) was added KOAc
(0.73 g, 7.44 mmol), and a catalytic amount of 18-
crown-6-ether and the reaction mixture was slowly
stirred at 80 ꢁC for 6 h, or in DMF at rt for 8 h. On cool-
ing, resin 15 was filtered, washed with CH3CN
(2 · 15 mL), DMF (2 · 15 mL), MeOH–water (8:2,
2 · 15 mL), MeOH (2 · 15 mL), CH2Cl2 (2 · 15 mL)
and ether (2 · 15 mL) and then dried in vacuo. To resin
15 in THF–MeOH (1:1, 10 mL), K2CO3 was added
(0.39 g, 2.80 mmol) and the slurry was stirred at rt
for 6 h. The derivatized resin was then filtered and
washed with water (2 · 15 mL), THF (2 · 15 mL),
MeOH (2 · 15 mL), CH2Cl2 (2 · 15 mL) and ether
(2 · 15 mL), then dried in vacuo. Finally, a suspension
of resin 17 or 11 in (10 mL) TFA–CH2Cl2 (1:1) was stir-
red at rt for 2 h. This procedure was repeated to ensure a
complete cleavage of the product from the resin. The
combined supernatant was saturated with aqueous
NaHCO3 solution, the organic layer was then separated
and dried over Na2SO4. This, upon evaporation in
vacuo, afforded crude products 1 and 5, which were
purified by column chromatography (silica gel, 60–120
mesh) employing ethyl acetate–hexane (6:4).
In conclusion, we have demonstrated a solid-phase syn-
thesis of fused [2,1-b]quinazolinones, namely vasicinone
and deoxyvasicinone, for the first time. One of the
methods involves a resin attached to an amino function-
ality while the other is an aza-Wittig reductive cycliza-
tion process. These methodologies are amenable to the
generation of libraries with diversity in both the
A- and C-rings to afford the fused [2,1-b]quinazolinones.
Acknowledgements
The authors N.S., V.D. and K.L.R. are grateful to
CSIR, New Delhi, for the award of Research
Fellowships.
References and notes
1. (a) Hermakens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
Tetrahedron 1997, 53, 5643–5678; (b) Gordon, E. M.;
Barrett, R. W.; Dower, W. J.; Foder, S. P. A.; Gallop, M.
A. J. Med.Chem. 1994, 37, 1385–1401.

9028
A. Kamal et al. / Tetrahedron Letters 47 (2006) 9025–9028
17. Preparation of compound 27a: To
2. (a) Krchoak, V.; Holladay, M. V. Chem. Rev. 2002, 102,
a
solution of
61–92; (b) Nfzi, A.; Ostresh, J. M.; Houghten, R. A.
Chem. Rev. 1997, 97, 449–472; (c) Thompson, L. A.;
Ellman, J. A. Chem. Rev. 1996, 96, 555–600; (d) Terrett,
N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.;
Steele, J. Tetrahedron 1995, 51, 8135–8173.
methyl-2-azido-4-hydroxy-5-methoxybenzoate 19 (0.39 g,
4.00 mmol) in NMP (15 mL) was added Wang resin 20
(1 g, 0.8–1.0 mmol/g, 4-benzyloxybenzyl alcohol, polymer-
supported; polystyrene, 2% crosslinked, 200–400 mesh),
TPP (1.05 g, 4.00 mmol), DIAD (0.79 mL, 4.00 mmol) and
the reaction mixture was slowly stirred at rt for 16 h. The
derivatized resin was filtered, rinsed with THF
(2 · 15 mL), MeOH (2 · 15 mL) and dried in vacuo. This
resin-coupled ester was hydrolyzed with 1 N NaOH
(5 mL) in 1,4-dioxane (10 mL) and refluxed for 12 h.
Filtration, washing with water (3 · 15 mL), water–dioxane
(1:9, 3 · 15 mL), MeOH (3 · 15 mL), CH2Cl2 (3 · 15 mL)
and ether (3 · 15 mL) then drying in vacuo gave resin 21.
To a suspension of 21 in CH2Cl2 (10 mL), DCC (0.83 g,
4.00 mmol) and DMAP (8 mg) were added at 0 ꢁC and the
reaction allowed to stir at the same temperature for
30 min. Bromo-lactam 22 (0.67 g, 4.00 mmol) in CH2Cl2
(5 mL) was added, and the reaction mixture was slowly
stirred at rt for 12 h to give 23a. This resin was then
filtered and washed with CH2Cl2 (2 · 15 mL), MeOH–
water (9:1, 2 · 15 mL), MeOH (2 · 15 mL) and ether
(2 · 15 mL) and then dried in vacuo. To resin 23a in dry
toluene (10 mL) was added TPP (1.31 g, 5.00 mmol) and
the mixture allowed stirred for 5 h at rt to give reductive
cyclized product 24a. The resin was filtered, and washed
with toluene (2 · 15 mL), CH2Cl2 (2 · 15 mL) and ether
(2 · 15 mL), then dried in vacuo. To a suspension of resin
24a in dry CH3CN (15 mL) or DMF (10 mL) was added
KOAc (0.79 g, 8.00 mmol) and a catalytic amount of 18-
crown-6-ether and the reaction mixture was slowly stirred
at 80 ꢁC for 6 h, or in DMF at rt for 8 h. On cooling, resin
25a was filtered, washed with CH3CN (2 · 15 mL), DMF
(2 · 15 mL), MeOH–water (8:2, 2 · 15 mL), MeOH
(2 · 15 mL), CH2Cl2 (2 · 15 mL) and ether (2 · 15 mL),
and then dried in vacuo. To resin 25a in THF–MeOH (1:1,
10 mL), K2CO3 (0.42 g, 3.00 mmol) was added and the
mixture was stirred at rt for 6 h. The derivatized resin 26a
was then filtered and washed with water (2 · 15 mL), THF
(2 · 15 mL), MeOH (2 · 15 mL), CH2Cl2 (2 · 15 mL) and
ether (2 · 15 mL), then dried in vacuo. Finally, a suspen-
sion of resin 26a in (10 mL) TFA–CH2Cl2 (1:1) was stirred
at rt for 1 h. This procedure was repeated to ensure a
complete cleavage of the product from the resin. The
combined supernatant was saturated with aqueous
NaHCO3 solution, the organic layer was then separated
and dried over Na2SO4. This upon evaporation in vacuo
afforded the crude product, which was purified by column
chromatography (silica gel, 60–120 mesh) with ethyl
acetate–methanol (95:5) to give 27a in good yields as
shown in Table 1. 1H NMR (200 MHz, CDCl3+DMSO) d
7.47 (s, 1H), 7.02 (s, 1H), 5.34–5.31 (d, 1H, J = 5.72 Hz),
4.36–4.25 (m, 1H), 4.14–4.01 (m, 3H), 3.96 (s, 3H), 2.89–
2.73 (m, 1H), 2.57–2.47 (m, 1H); EIMS m/z 248 (M+);
HRMS calcd for C12H12N2O4 248.2368, found 248.2371.
3. Houghten, R. A.; Pinilla, C.; Appel, J. R.; Blondelle, S. E.;
Dooley, C. T.; Eichler, J.; Nefzi, A.; Ostresh, J. M. J. Med.
Chem. 1999, 42, 3743–3778.
4. (a) Solid-Phase Organic Synthesis; Czarnik, A. W., Ed.;
John Wiley & Sons: New York, 2001; (b) Solid-Phase
Organic Synthesis; Burgess, K., Ed.; John Wiley & Sons:
New York, 2000.
5. Amin, A. H.; Mehta, D. R. Nature 1959, 183, 1317.
6. (a) Joshi, B. S.; Newton, M. G.; Lee, D. W.; Barber, A. D.;
Pelletier, S. W. Tetrahedron: Asymmetry 1996, 7, 25–28;
(b) Atal, C. K. In Chemistry and Pharmacology of
Vasicine; Raj Bandu Industrial Co.: Delhi, 1980; (c)
Ghosal, S.; Chauhan, P. S. R. B.; Mehta, R. Phytochemi-
stry 1975, 14, 830–832; (d) Chatterjee, A.; Ganguly, M.
Phytochemistry 1968, 7, 307–311.
7. (a) Onaka, T. Tetrahedron Lett. 1971, 12, 4387–4390; (b)
Kametani, T.; Loc, C. V.; Higa, T.; Koizumi, M.; Ihara,
K.; Fukumoto, K. J. Am. Chem. Soc. 1977, 99, 2306–2309;
(c) Grundon, M. F. Nat. Prod. Rep. 1988, 5, 293.
8. Mori, M.; Kobayashi, H.; Kimura, M.; Ban, Y. Hetero-
cycles 1985, 23, 2803–2806.
9. Morris, R. C.; Hanford, W. E.; Roger, A. J. Am. Chem.
Soc. 1935, 57, 951–954.
10. (a) Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y. J.
Org. Chem. 1996, 61, 7316–7319; (b) Takeuchi, H.;
Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45, 6375–
6386.
11. Kamal, A.; Ramana, K. V.; Rao, M. V. J. Org. Chem.
2001, 66, 997–1001.
12. Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2001, 66,
9038–9040.
13. Kamal, A.; Ramana, K. V.; Ramana, A. V.; Babu, A. H.
Tetrahedron: Asymmetry 2003, 14, 2587–2594.
14. (a) Hamper, B. C.; Dukesherer, D. R.; South, M. S.
Tetrahedron Lett. 1996, 37, 3671–3674; (b) Kamal, A.;
Reddy, G. S. K.; Raghavan, S. Bioorg. Med. Chem. Lett.
2001, 11, 387–389.
15. Compound 1a: 1H NMR (200 MHz, CDCl3) d 8.38 (d,
1H, J = 8.24 Hz), 7.83–7.72 (m, 2H), 7.62–7.52 (m, 1H),
5.35–5.14 (m, 2H), 4.58–4.37 (m, 1H), 4.23–4.05 (m, 1H),
2.87–2.63 (m, 1H), 2.56–2.34 (m, 1H); EIMS m/z 202
(M+); HRMS calcd for C11H10N2O2 202.0742, found
202.0745.
16. Compound 5a: 1H NMR (300 MHz, CDCl3) d 8.24
(dd, 1H, J = 1.5, 8.3 Hz), 7.70–7.57 (m, 2H), 7.52–
7.38 (m, 1H), 4.21–4.16 (t, 2H, J = 7.5 Hz), 3.18–3.12
(t, 2H, J = 7.5 Hz), 2.34–2.24 (m, 2H); EIMS m/z 186
(M+); HRMS calcd for C11H10N2O 186.0793, found
186.0789.