TBAHS-catalyzed synthesis of 2-dihydroquinazolin-2-ylquinoline: An efficient and practical synthesis of naturally occurring alkaloids luotonin A, B, and e

Article abstract of DOI:10.1055/s-0032-1316537

A synthesis of 2-dihydroquinazolin-2-ylquinoline using a phase-transfer catalyst (TBAHS) in semi-aqueous phase, followed by Mitsunobu cyclization as key steps for an efficient and practical synthesis of naturally occurring alkaloids luotonin A, B, and E starting from o-nitrobenzaldehyde is reported. The new approach presents the advantage of a shorter route with high overall yield (57%, 45%, and 37%, respectively) and ease of operation.

Full text of DOI:10.1055/s-0032-1316537

LETTER
▌1775
letter
TBAHS-Catalyzed Synthesis of 2-Dihydroquinazolin-2-ylquinoline: An Effici-
ent and Practical Synthesis of Naturally Occurring Alkaloids Luotonin A, B,
and E
Luotonins A, B, and E
Lingaiah Nagarapu,* Hanmant K. Gaikwad, Rajashaker Bantu
Organic Chemistry Division-II, Indian Institute of Chemical Technology (CSIR), Tarnaka, Hyderabad 500607, India
Fax +91(40)27193382; E-mail: lnagarapuiict@yahoo.com; E-mail: nagarapu@iict.res.in
Received: 04.04.2012; Accepted after revision: 19.05.2012
Tetrabutylammonium hydrogen sulfate (TBAHS) was
Abstract: A synthesis of 2-dihydroquinazolin-2-ylquinoline using
used as a phase-transfer catalyst in our earlier report7 on
a phase-transfer catalyst (TBAHS) in semi-aqueous phase, followed
the synthesis of 4H-pyrimido[2,1-b]benzothiazole. The
by Mitsunobu cyclization as key steps for an efficient and practical
synthesis of naturally occurring alkaloids luotonin A, B, and E start-
TBAHS catalyst is acidic in nature, water-soluble, ther-
ing from o-nitrobenzaldehyde is reported. The new approach pres- mally stable, mild, and inexpensive.8 The synthesis of di-
hydroquinazolinone had been reported9 and our effort is
ents the advantage of a shorter route with high overall yield (57%,
45%, and 37%, respectively) and ease of operation.
directed towards a more efficient method. In continuation
of our studies10 on the synthesis of bioactive compounds,
Key words: luotonins, 2-dihydroquinazolin-2-ylquinoline, tetrabu-
tylammonium hydrogen sulfate (TBAHS), Mitsunobu
herein we report on an improved and reliable approach for
the synthesis of a 2-dihydroquinazolin-2-ylquinoline us-
ing TBAHS catalyst and then Mitsunobu cyclization to
Luotonin A–F, six natural alkaloids possess the pyrrolo- render direct and easy access to naturally occurring alka-
quinazolinoquinoline ring system, were first isolated by loids, luotonins A, B, and E, in overall high yields.
Nomura and co-workers1 in 1997 from an aerial part of the
Chinese medicinal plant, Peganum nigellastrum Bunge
(luo-tuo-hao, Figure 1). Luotonins are used in traditional
Chinese medicine and are reported to exhibit diverse ac-
tivities against a range of ailments including rheumatism,
inflammation, influenza, hepatitis, and leukemia. Luo-
tonin A is cytotoxic towards the murine leukemia P-388
cell line (IC50, 1.8 μg/mL).1 It has received increased at-
tention in the last few decades, due to its structural simi-
larity with the well-known cytotoxic alkaloid
camptothecin (CPT).2 Hecht and co-workers3a demon-
strated that luotonin A stabilizes the human DNA topo-
isomerase I–DNA covalent binary complex and mediates
topisomerase I dependent cytotoxicity in intact cells, like
camptothecin and its analogues.3 After the first report of
its isolation, several synthetic routes of luotonin A have
been reported using a variety of elegant synthetic strate-
gies.1,4 Most of the multistep synthesis of linear pentacy-
clic alkaloid luotonin A have been completed using two
suitable building blocks for the construction of ring B and
D. These methods typically suffered from either the low
efficiency or the lack of generality and low overall yields.
Argade and Mhaske5 reported the synthesis of luotonins
using ortho lithiation of quinoline moiety. Recently, Chu
and co-workers6 reported the synthesis of luotonin A and
its analogues in a one-pot, self-directed chemical process
with the aid of a single metal triflate for the construction
of quinazoline and pyrroloquinoline rings (B, C, and D).
R
O
A
B
N
N
C
D
N
E
luotonin A (1a): R = H
luotonin B (1b): R = OH
luotonin E (1c): R = OMe
Figure 1 Structure of luotonins 1a–c
Syntheses of luotonins A, B, and E were achieved from
the commercially available o-nitrobenzaldehye (2). The
quinoline 3 was synthesized in one step by condensation
of o-nitrobenzaldehyde (2) with ethyl acetoacetate (EAA)
in presence of SnCl2 and ZnCl2 with 96% yield, followed
by oxidation with SeO2 in 1,4-dioxane at a reflux temper-
ature to give aldehyde 4 with 95% yield (Scheme 1).
COOEt
COOEt
CHO
CHO
NO2
i
ii
N
N
2
3
4
Scheme 1 Reagents and conditions: i) EAA, SnCl2, ZnCl2, 4 Å MS,
70 °C, 3 h, 96%; ii) SeO2, 1,4-dioxane, reflux, 2 h, 95%.
To investigate the use of phase-transfer catalyst for the
synthesis of a 2-dihydroquinazolin-2-ylquinoline in a fac-
ile and convenient manner, the reaction of the two compo-
nents
o-aminobenzamide
(5)
and
ethyl
2-
formylquinoline-3-carboxylate (4) was initially examined
(Scheme 2).11 To optimize the reaction conditions, differ-
ent solvents and catalysts were screened. The results
SYNLETT 2012, 23, 1775–1778
Advanced online publication: 29.06.2012
DOI: 10.1055/s-0032-1316537; Art ID: ST-2012-D0305-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1776
L. Nagarapu et al.
LETTER
showed that 95% of the desired product 6a was obtained NMR spectrum which showed a peak at δ = 71.79 ppm,
predominantly using TBAHS (30 mol%) in MeOH–H2O and its HRMS data which gave an m/z value of 370.1173
(1:1, semi-aqueous phase) at 80 °C. When the amount of [M + H]+.
TBAHS was increased to 50 mol%, the yield slightly de-
Based on our observation for the synthesis of 2-dihydro-
creased from 95% to 91% (Table 1, entries 2–5). Several
quinazolin-2-ylquinoline, we used TBAHS as the phase-
other catalysts were tested (Table 1, entries 8–11) and a
transfer catalyst for the dehydration and cyclization steps.
mixture of products 6a, 6b, and 6c were observed. Com-
The desired product 6a was obtained in almost quantita-
pound 6a was identified by its 1H NMR spectrum which
tive yield (95%) with the reaction of aldehyde 4 and
showed a characteristic methine proton at δ = 6.53, its 13C
o-aminobenzamide (5) in the presence of TBAHS (30
O
N
O
O
O
N
TBAHS (30 mol%)
NH2
NH2
NH
NH
+
R
CHO
+
+
MeOH–H2O (1:1)
80 °C, 0.5 h
R
NH2
N
H
R
R
5
4
6b
6c
6a (95%)
N
R =
EtOOC
Scheme 2 Synthesis of 2-dihydroquinazolin-2-ylquinoline 6a
COOEt
H
OH
O
N
H
N
O
ii
N
O
i
iii
N
6a
N
N
N
N
N
6b
7
1a
iv
N
OMe
N
OH
N
O
O
v
N
N
N
1c
1b
Scheme 3 Reagents and conditions: i) KMnO4, acetone, reflux, 0.5 h, 93%; ii) NaBH4, CaCl2, MeOH, r.t., 12 h, 86%; iii) a) Ph3P, DEAD, THF,
r.t., 1 h, 81%; or b) 60% ethanolic H2SO4, reflux, 3 h, 83%; iv) PCC, 4 Å MS, CH2Cl2, r.t., 1 h, 65%; v) PTSA, MeOH, reflux, 3 h, 82%.
Table 1 Reaction of 5 and 4 under Different Reaction Conditions and Catalysts
Entry
Catalyst (mol%)
Solvent
Time (h)
Yield of 6a (%)a
Yield of 6b (%)a
Yield of 6c (%)a
1
2
–
MeOH
12
0.5
0.5
0.5
0.5
12
12
12
12
12
12
–
–
76
–
TBAHS (10)
TBAHS (20)
TBAHS (30)
TBAHS (50)
TBAHS (30)
TBAHS (30)
PTSA (30)
TBAB (10)
Yb(OTf)3 (30)
FeCl3 (50)
MeOH–H2O (1:1)
MeOH–H2O (1:1)
MeOH–H2O (1:1)
MeOH–H2O (1:1)
MeOH
75
87
95
91
68
50
38
43
18
55
10
4
3
–
4
1
–
5
2
–
6
–
23
–
7
H2O
–
8
MeOH
10
19
32
5
17
–
9
MeOH
10
11
MeOH
–
H2O
–
a Isolated yields obtained after column chromatography.
Synlett 2012, 23, 1775–1778
© Georg Thieme Verlag Stuttgart · New York

LETTER
Luotonins A, B, and E
1777
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mol%) in a semi-aqueous phase (MeOH–H2O) at 80 °C
(Scheme 2). The oxidation of 6a with KMnO4 in acetone
gave quinolinequinazolinone 6b in quantitative yield. The
regioselective reduction of ester 6b using NaBH4 and
CaCl2 in ethanol gave alcohol 7 with 86% yield, followed
by Mitsunobu cyclization at 80 °C furnished the bioactive
natural product luotonin A in 81% yield. Under acidic
conditions the alcohol 7 also furnished luotonin A in 83%
yield. The PCC oxidation of alcohol 7 in CH2Cl2 fur-
nished luotonin B in 65% yield. Luotonin B (1b) on treat-
ment with PTSA in methanol provided luotonin E in 82%
yield (Scheme 3). Thus using the TBAHS-catalyzed reac-
tion, we accomplished a straightforward synthesis of luo-
tonin A (57%), B (45%), and E (37%), with overall high
yields starting from a commercially available o-nitroben-
zaldehyde. The analytical and spectral data obtained for
all luotonins were in complete agreement with the report-
ed data.1,4,5
In conclusion, we have demonstrated a new approach for
the synthesis of 2-dihydroquinazolin-2-ylquinoline using
TBAHS catalyst, followed by Mitsnuobu cyclization for
the highly efficient, short, and practical synthesis of natu-
rally occurring promising anticancer agents. Luotonin A,
B, and E were accomplished in direct fashion with high
overall yields (57%, 45%, and 37%, respectively). Further
application of this approach for the construction of aryl-
and heteroaryl-substituted quinazolinone system will be
highly useful for the synthesis of a large number of de-
sired complex quinazolinone alkaloids and its analogues
for SAR studies.
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Acknowledgment
(5) Argade, N. P.; Mhaske, S. B. J. Org. Chem. 2004, 69, 4563.
(6) Chu, H.-Y.; Tseng, M.-C.; Chu, Y.-W.; Tsai, H.-P.; Lin,
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(7) Nagarapu, L.; Gaikwad, H. K.; Palem, J. D.; Venkatesh, R.;
Bantu, R.; Sridhar, B. Synth. Commun. 2012, DOI:
10.1080/00397911.2011.592624.
Authors are grateful to the Director and Head, Organic Chemistry
Division-II, IICT for their support. Hanmant K. Gaikwad is thank-
ful to the University Grant Commission (UGC), New Delhi for a re-
search fellowship.
(8) Tripathi, R. P.; Tewari, N.; Dwivedi, N. Tetrahedron Lett.
2004, 45, 9011.
Supporting Information for this article is available online at
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m
iotSrat
ungIifoop
r
t
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1775–1778

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LETTER
over Na2SO4. The organic layer was evaporated under
Bantu, R.; Sheeba Rani, M. Eur. J. Med. Chem. 2011, 2152.
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vacuum, the residue obtained was subjected to chroma-
tography on silica gel. The desired 2-dihydroquinazolin-2-
ylquinoline (6a) was obtained in 95% yield; mp 194–196 °C.
IR (KBr): νmax = 3327, 3247, 2924, 1710, 1653, 1611, 1511,
1137, 1018, 776, 747 cm–1. 1H NMR (300 MHz, DMSO-d6):
δ = 1.48 (t, J = 7.17 Hz, 3 H, CH3), 4.48 (q, J = 7.17 Hz, 2 H,
CH2), 6.47 (br s, 1 H, NH), 6.53 (s, 1 H, CH), 6.66 (t, J = 8.28
Hz, 2 H, ArH), 7.11 (t, J = 7.65 Hz, 1 H, ArH), 7.60 (t, J =
7.36 Hz, 1 H, ArH), 7.65–7.83 (m, 3 H, ArH), 7.90–8.03 (m,
2 H, ArH), 8.89 (s, 1 H, NH). 13C NMR (75 MHz, DMSO-
d6): δ = 14.19, 61.38, 71.79, 120.76, 124.81, 126.52, 126.98,
127.18, 127.69, 127.87, 129.07, 130.16 (2 C), 130.67,
134.18 (2 C), 138.03, 146.84, 158.80, 165.37. HRMS
(ESI+): m/z calcd for C20H17N3O3 [M + Na]+: 370.1167;
found: 370.1173.
(11) General Procedure for the Synthesis of
2-Dihydroquinazolin-2-ylquinoline (6a)
Aldehyde 4 (4 g, 17.46 mmol), o-aminobenzamide (2.38 g,
17.46 mmol), and TBAHS (1.8 g, 5.42 mmol) were added to
MeOH–H2O (5 mL, 1:1) at r.t. The resulting mixture was
heated at 80 °C for 0.5 h, and completion of the reaction was
monitored by TLC (EtOAc–hexane = 7:3). After completion
of the reaction, reaction mixture was allowed to cool, diluted
with H2O, and extracted with EtOAc. The organic layer were
combined and washed thoroughly with sat. aq NaCl, dried
Synlett 2012, 23, 1775–1778
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