An efficient and selective access to 1-substituted and 3-substituted derivatives of luotonin A Dedicated with best wishes to Professor Gottfried Heinisch on the occasion of his 75th birthday

Article abstract of DOI:10.1016/j.tet.2013.06.040

A method for the selective introduction of a substituent into position 1 or position 3 of the antitumour alkaloid, luotonin A, is described. The protocol involves a base-catalysed intramolecular [4+2] cycloaddition reaction of an arylpropargyl unit with a

Full text of DOI:10.1016/j.tet.2013.06.040

Tetrahedron 69 (2013) 7066e7072
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An efficient and selective access to 1-substituted and 3-substituted
derivatives of luotonin A
y
*
Norbert Haider , Ge Meng , Sabine Roger, Sigrid Wank
Department of Drug and Natural Product Synthesis, Faculty of Life Sciences, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 May 2013
Received in revised form 7 June 2013
Accepted 11 June 2013
Available online 21 June 2013
A method for the selective introduction of a substituent into position 1 or position 3 of the antitumour
alkaloid, luotonin A, is described. The protocol involves a base-catalysed intramolecular [4þ2] cycload-
dition reaction of an arylpropargyl unit with a carbonitrile as the key step. These educts are conveniently
accessible in two steps from a known precursor. The newly developed route is orthogonal to a previously
used cycloaddition approach, which gave access to 2- or 4-substituted luotonin A derivatives.
Ó 2013 Elsevier Ltd. All rights reserved.
Dedicated with best wishes to Professor
Gottfried Heinisch on the occasion of his
75th birthday
Keywords:
Luotonin A
[4þ2] Cycloaddition
Sonogashira coupling
Amide dehydration
1. Introduction
modification of luotonin A in order to identify more potent con-
geners. In particular, the substitution pattern of ring A has been
As reflected by a recent review article,1 there is increasing in-
terest in the chemistry of luotonin A, a pentacyclic alkaloid, which
had been isolated in 1997 from Peganum nigellastrum Bunge
(Zygophyllaceae) by Ma and co-workers.2 This compound was
found to be a topoisomerase I poison, acting by a similar mecha-
nism as camptothecin.3 Its activity is not surprising in view of the
structural similarity between these two natural products (Fig. 1):
they share the same ABC ring fragment, ring D is slightly different
(a pyridone in camptothecin and a pyrimidone in luotonin A),
whereas ring E differs markedly (see Fig. 1). Nevertheless, the
binding mode of luotonin A to the topoisomerase-IeDNA binary
complex might differ to some extent from that of camptothecin.4
Luotonin A lacks both the sensitive hydroxylactone structure and
the chiral centre of camptothecin, therefore it offers some advan-
tage in terms of chemical stability as well as synthetic accessibility.
On the other hand, cytotoxic activity of unmodified luotonin A is
considerably lower than that of camptothecin,3 and this has stim-
ulated a number of investigations directed towards the structural
found to be a promising target for systematic variation,1 and several
A-ring-substituted derivatives of the alkaloid have been found to
exhibit higher activity than the lead compound.5e8 Recently, we
reported an improved variant of Yao’s9 total synthesis of luotonin A,
which enabled us to obtain not only the parent compound in high
yield, but also various 2-substituted, 4-substituted and identically
1,3-disubstituted derivatives (Scheme 1).
As a consequence of the fact that the final step in this sequence
is an intramolecular [4þ2] cycloaddition reaction between an
anilide-derived imidoyl unit (acting as the azadiene) and a prop-
argyl residue (as the dienophile), this route is perfectly suited for
such educts where no isomer mixtures can arise from rotation
around the aniline CeN bond (i.e., starting from 4-substituted or 2-
14
1
13
O
O
2
3
A
B
C
N
N
11
12
10
D
N
N
4
5
N
E
9
6
O
7
8
OH
O
Luotonin A
Camptothecin
* Corresponding author. E-mail address: norbert.haider@univie.ac.at (N. Haider).
Permanent address: Faculty of Pharmacy, School of Medicine, Xi’an Jiaotong
University, Xi’an 710061, PR China.
y
Fig. 1. Structures of luotonin A and camptothecin.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.040

N. Haider et al. / Tetrahedron 69 (2013) 7066e7072
7067
R1
1. ArNH2 / AlMe3
O
N
2. propargyl
R2
R1
O
Ph3PO, Tf2O
bromide
NH
N
O
OEt
N
H
R3
N
O
R1
R3
R1
R3
O
N
R2
R1
R2
R1
[4+2]
O
N
cycloaddition
N
N
O
N
- Ph3PO,
- TfOH
N
P+
-
TfO
Ph
Ph
Ph
R1 = OMe, H; R2 = H, Cl, NO2, CN; R3 = H, Me
Scheme 1.
substituted or symmetrically 3,5-disubstituted anilines as building
blocks). However, this strategy intrinsically fails to provide access
to 1-substituted and 3-substituted products in a regioselective
manner,10 and so far there are only very few examples of such 1- or
3-monosubstituted luotonin A derivatives known, which had been
prepared from halogen-substituted 2-aminobenzaldehydes as
starting materials.6 In order to close this gap, we now developed
a complementary cycloaddition pathway, which enabled us to ob-
tain a series of hitherto unknown 1-substituted and 3-substituted
luotonin A derivatives in a concise, flexible and efficient manner.
a variety of aryl iodides under standard Sonogashira conditions,
affording the arylpropargyl amides 3aef in satisfactory yields
(Scheme 2). The subsequent dehydration reaction of the primary
amides 3 into the nitriles 4 then proved to be more challenging
than expected, as some of these compounds are more sensitive
towards decomposition than the prototype 1, which had been
easily dehydrated under relatively harsh conditions, as described
above. Finally, we could accomplish this transformation by one
of three different methods, depending on the respective educt:
the desired carbonitriles 4aef thus were obtained either by
refluxing in phosphorus oxychloride/chloroform (method A),
treatment with trifluoroacetic anhydride/triethylamine in dry
dichloromethane at 0 ꢀC (method B),12 or reaction with ethyl
dichlorophosphate/DBU in dry dichloromethane at room tem-
perature (method C).13 In all cases, the successful dehydration
was indicated by the appearance of a less polar spot on TLC, and
the products in their mass spectra expectedly show a molecular
ion peak of 18 units less than for the educts 3, together with the
disappearance of the two distinct NH resonances in the 1H NMR
spectra and the appearance of a typical nitrile carbon signal at
around 110 ppm in the 13C NMR spectra.
With the key synthons 4 now conveniently available, the stage
was set for the final cycloaddition step, which should simulta-
neously assemble rings B and C of the luotonin A skeleton. By
employing Wang’s conditions (heating in 1,2-dichlorobenzene at
110e120 ꢀC in the presence of 5 mol % DBU), we found that all of the
compounds, almost regardless of electronic and steric properties of
the different substituents, cyclised very smoothly into the target
luotonin A derivatives 5aef (Scheme 3). The latter were isolated in
excellent yields simply by filtration after dilution of the reaction
mixtures with diethyl ether.
2. Results and discussion
We envisaged that rearranging the topology of diene and
dienophile, by attaching the aryl moiety to the propargyl unit and
placing the requisite nitrogen atom into the dienophile, should
open an access to the desired 1- and 3-substituted luotonin A de-
rivatives. This approach appeared quite promising in view of
a previous report by Wang and co-workers who had successfully
performed an intramolecular cycloaddition reaction of 1-(3-
arylprop-2-yn-1-yl)-1,6-dihydro-6-oxo-2-pyridinecarbonitriles to
yield the ABCD ring fragment of camptothecin and some methoxy
derivatives thereof. In order to apply this concept to the synthesis of
the pentacyclic quinolino[20,30:3,4]pyrrolo[2,1-b]quinazoline skel-
eton of luotonin A, an appropriate 4-oxo-3-(3-arylprop-2-yn-1-yl)-
3,4-dihydroquinazoline-2-carbonitrile would be required as the
key intermediate. Thus, we first developed a convenient and flex-
ible method for the preparation of such synthons.
In order to introduce diversity as late as possible in the en-
visaged reaction sequence, we first attempted to generate the
requisite arylpropargyl-substituted quinazolinonecarbonitriles (4)
by Sonogashira coupling of appropriate aryl iodides with 4-oxo-
3-(prop-2-yn-1-yl)-3,4-dihydroquinazoline-2-carbonitrile (2), a b
uilding block, which could be conveniently prepared from the
known carboxamide (1) by dehydration using phosphorus oxy-
chloride in boiling chloroform. However, it turned out that the
Pd-catalysed cross-coupling reaction gives very poor results with
this alkyne synthon, leading mainly to resinification and pro-
ducing the desired coupling products in less than 10% yield after
chromatographic separation of the complex reaction mixtures.
But in contrast, we found that the corresponding carboxamide 1
does not suffer from this drawback and smoothly couples with
The [4þ2] cycloaddition reaction presumably takes place after
an initial alkyne/allene isomerisation, which is mediated by the
base DBU, as proposed previously,11 but also a stepwise mecha-
nism involving a biradicalic intermediate14 cannot be ruled out. A
1,5-hydrogen shift in the primary cycloadduct then produces the
fully aromatic quinoline scaffold (rings A and B). Reaction times
typically are 24 h with the exception of the ortho-tolyl substrate 4a
(48 h) and the electron-poor ester 4f (12 h). Thus, the method is
perfectly suitable for the selective introduction of electron-
donating as well as electron-withdrawing substituents into posi-
tion 1 or position 3 of the alkaloid. Moreover, our route is rather

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N. Haider et al. / Tetrahedron 69 (2013) 7066e7072
1. NH3 / MeOH
2. propargyl
O
N
O
N
O
bromide,
POCl3 / CHCl3
N
K2CO3 / DMF
N
NH
OEt
NH2
N
CN
O
O
R
2
1
R
I
Pd(PPh3)2Cl2
CuI, NEt3
(<10%)
R1
R1
O
N
O
Method
R2
R2
A, B,or C
N
NH2
CN
N
N
A: POCl3 / CHCl3
B: (CF3CO)2O / NEt3
C: EtOPOCl2 / DBU
O
3a-f
4a-f
Scheme 2.
O
N
O
N
1,2-dichlorobenzene,
5 mol% DBU
R1
[4+2]
cycloaddition
R1
110-120°C
N
N
N
R2
N
R2
4a-f
R1
R1
O
O
[1,5]-H shift
N
N
R2
N
R2
N
H
N
N
5a-f (72-98%)
Scheme 3.
short, consisting of only three steps from the known amide 1 (the
latter, in turn, is conveniently accessible from commercially
available anthranilamide by proven protocols9,15,16). The struc-
tures of the new compounds are in full agreement with their an-
alytical and spectroscopic data. The 1H NMR signal patterns, in
particular those of the quinoline protons, can be easily assigned by
NOE techniques, making use of the spatial proximity of 14-H and
the methylene protons at 13-C as the starting point. The mass
spectra of compounds 5, although they have the same molecular
masses as their precursors 4, show marked differences compared
to the latter in terms of significantly less fragmentation, with the
molecular ion representing the base peak in all cases.

N. Haider et al. / Tetrahedron 69 (2013) 7066e7072
7069
3. Conclusion
After consecutive addition of the appropriate aryl iodide
(1.5 mmol), 2,6-di-tert-butyl-4-methylphenol (55 mg, 0.25 mmol),
CuI (38 mg, 0.2 mmol), Pd(PPh3)2Cl2 (70 mg, 0.1 mmol) and trie-
thylamine (243 mg, 2.4 mmol), the mixture was again flushed with
argon, then it was stirred in a closed vessel for 3 h at room tem-
perature (TLC monitoring: CH2Cl2/EtOH, 9:1). The dark mixture was
diluted with CH2Cl2 (10 mL) and filtered through a short pad of
silica gel, eluting with CH2Cl2 (100 mL). The solution was washed
with 0.5 N HCl and water, dried (Na2SO4) and evaporated. The
residue was subjected to column chromatography, eluting first with
CH2Cl2 (to give some unchanged aryl iodide) and then with CH2Cl2/
ethyl acetate (4:1), followed by recrystallisation, to afford the pure
products.
With the described synthetic route, a gap in the systematic
variation of the substitution pattern in ring A of the antitumour
alkaloid, luotonin A, could be closed, thus enabling further studies
of structureeactivity relationships within this class of compounds.
As demonstrated, the method is compatible both with electron-rich
and electron-poor substituents, which can be selectively in-
troduced either into position 1 or position 3 of the pentacyclic
skeleton. Together with the previously reported approach,8,9 there
are now two orthogonal cycloaddition pathways available, which
allow the selective introduction of various substituents into all
available positions at ring A of luotonin A.
4. Experimental
4.1. General
4.2.2.1. 3-[3-(2-Methylphenyl)prop-2-yn-1-yl]-4-oxo-3,4-
dihydroquinazoline-2-carboxamide (3a). Yield: 213 mg (67%); pale
yellow needles, mp 199e203 ꢀC (toluene/ethyl acetate). 1H NMR
(400 MHz, DMSO-d6)
d
8.54 (br s, 1H, NH), 8.23 (dd, J¼7.9, 1.5 Hz,
Melting points (uncorrected) were determined on a Kofler hot-
stage microscope (Reichert). 1H NMR and 13C NMR spectra were
recorded on a Varian UnityPlus 300 spectrometer at 300 MHz and
75 MHz, respectively, and on a Bruker Avance III 400 spectrometer at
400 MHz and 100 MHz, respectively. Mass spectra were obtained on
a Shimadzu QP5050A DI 50 instrument, high-resolution mass spectra
were recorded on a Finnigan MAT 8230 spectrometer or on a Bruker
maXis spectrometer at the Institute of Organic Chemistry, University
of Vienna, or on a Shimadzu LCMS-IT-TOF instrument at the Institute
of Chemical Technologies and Analytics, Vienna University of Tech-
nology. Column chromatography was carried out on Merck Kieselgel
60, 0.063e0.200 mm, thin layer chromatography was done on Merck
aluminium sheets pre-coated with Kieselgel 60F254. Microanalyses
were performed at the Microanalytical Laboratory, Faculty of Chem-
istry, University of Vienna. Ethyl 4-oxo-3,4-dihydroquinazoline-2-
carboxylate,9,15 4-oxo-3,4-dihydroquinazoline-2-carboxamide,15,17 4-
oxo-3-(prop-2-yn-1-yl)-3,4-dihydroquinazoline-2-carboxamide16 an
d ethyl 2-iodobenzoate18 were prepared according to literature
procedures.
1H, 5-H), 8.22 (br s, 1H, NH), 7.92 (ddd, J¼8.2, 7.2, 1.5 Hz, 1H, 7-H),
7.77 (dd, J¼8.2, 1.0 Hz, 1H, 8-H), 7.65 (ddd, J¼8.0, 7.2, 1.2 Hz, 1H, 6-
H), 7.37 (d, J¼7.6 Hz, 1H, phenyl 60-H), 7.29e7.23 (m, 2H, phenyl 30-
H, 40-H), 7.19e7.13 (m, 1H, phenyl 50-H), 5.34 (s, 2H, CH2), 2.32 (s,
3H, CH3); 13C NMR (100 MHz, DMSO-d6)
d 163.3, 160.0, 148.9, 145.9,
140.1, 135.1, 131.8, 129.5, 128.8, 128.3, 127.6, 126.5, 125.7, 121.5, 121.0,
88.4, 81.8, 33.8, 20.1; MS (EI, 70 eV) m/z 317 (Mþ, 32%), 273 (14), 144
(13), 129 (28), 128 (100), 127 (30), 102 (16), 77 (14), 63 (9). HRMS
(ESI) m/z 318.1240 ([MþH]þ calcd for C19H16N3O2: 318.1237).
4.2.2.2. 3-[3-(2-Methoxyphenyl)prop-2-yn-1-yl]-4-oxo-3,4-
dihydroquinazoline-2-carboxamide (3b). Yield: 270 mg (81%); pale
yellow crystals, mp 179e182 ꢀC (toluene/ethyl acetate). 1H NMR
(400 MHz, DMSO-d6) d 8.53 (br s,1H, NH), 8.22 (br s,1H, NH), 8.22 (dd,
J¼8.0, 1.5 Hz, 1H, 5-H), 7.92 (ddd, J¼8.2, 7.2, 1.5 Hz, 1H, 7-H), 7.77 (m,
1H, 8-H), 7.65 (ddd, J¼8.0, 7.2, 1.2 Hz, 1H, 6-H), 7.36e7.32 (m, 2H,
phenyl 40-H, 60-H), 7.02 (dd, J¼8.9, 1.0 Hz, 1H, phenyl 30-H), 6.89 (td,
J¼7.5, 1.0 Hz, 1H, phenyl 50-H), 5.33 (s, 2H, CH2), 3.78 (s, 3H, OCH3); 13C
NMR (100 MHz, DMSO-d6)
d 163.3, 160.0, 159.8, 148.9, 145.9, 135.1,
133.5, 130.4, 128.3, 127.6, 126.5, 121.0, 120.3, 111.3, 110.6, 88.0, 79.8,
55.5, 33.7; MS (EI, 70 eV) m/z 333 (Mþ, 21%), 289 (8), 275 (8),145 (31),
144 (100), 116 (23), 115 (88), 102 (25), 91 (21), 76 (23), 63 (22). HRMS
(ESI) m/z 334.1192 ([MþH]þ calcd for C19H16N3O3: 334.1186).
4.2. Procedures
4.2.1. 4-Oxo-3-(prop-2-yn-1-yl)-3,4-dihydroquinazoline-2-
carbonitrile (2). To a suspension of 4-oxo-3-(prop-2-yn-1-yl)-3,4-
dihydroquinazoline-2-carboxamide (1136 mg, 5.0 mmol) in dry
CHCl3 (30 mL) was added POCl3 (10 mL) and the mixture was refluxed
for 8 h with exclusion of moisture, then it was stirred at room tem-
perature for another 16 h. The dark-brown solution was chilled and
slowly poured into ice-water (200 mL). The two-phase system was
vigorously stirred for 30 min, then the phases were separated and the
aqueous layer was repeatedly extracted with CH2Cl2. The combined
organic phases were washed with water and brine, dried over Na2SO4
and passed through a short silica column. Evaporation in vacuo, fol-
lowed by recrystallisation of the residue from EtOH afforded the ni-
trile 2 as colourless crystals (649 mg, 62%), mp 141e143 ꢀC. 1H NMR
4.2.2.3. Ethyl 2-[3-(2-carbamoyl-4-oxoquinazolin-3(4H)-yl)prop-
1-yn-1-yl]benzoate (3c). Yield: 180 mg (48%); pale yellow needles,
mp 183e185 ꢀC (EtOH). 1H NMR (400 MHz, DMSO-d6)
d 8.50 (br s,
1H, amide-NH), 8.22 (dd, J¼8.0, 1.5 Hz, 1H, 5-H), 8.21 (br s, 1H,
amide-NH), 7.94e7.90 (m, 1H, 7-H), 7.81 (td, J¼7.6, 1.0 Hz, 1H,
phenyl 30-H), 7.77 (dd, J¼8.2, 0.6 Hz, 1H, 8-H), 7.67e7.63 (m, 1H, 6-
H), 7.57e7.54 (m, 2H, phenyl 50-H, 60-H), 7.51e7.46 (m, 1H, phenyl
40-H), 5.35 (s, 2H, NCH2), 4.21 (q, J¼7.1 Hz, 2H, OCH2CH3), 1.18 (t,
J¼7.1 Hz, 3H, OCH2CH3); 13C NMR (100 MHz, DMSO-d6)
d 165.6,
163.2, 160.0, 148.8, 145.9, 135.2, 134.0, 132.2, 131.9, 129.8, 128.8,
128.3, 127.6, 126.5, 121.5, 121.0, 89.2, 81.5, 60.9, 33.9, 13.9. MS (EI,
70 eV) m/z 375 (Mþ, 60%), 346 (24), 329 (13), 303 (28), 287 (15), 175
(52), 174 (39), 157 (71), 145 (100), 130 (87), 129 (83), 102 (66), 77
(51), 69 (40). Anal. Calcd for C21H17N3O4$0.5H2O: C, 65.62; H, 4.72;
N, 10.93. Found: 65.59; H, 4.32; N, 10.66. HRMS (ESI) m/z 376.1294
([MþH]þ calcd for C21H18N3O4: 376.1292).
(300 MHz, CDCl3)
d 8.37e8.31 (m, 1H, 5-H), 7.91e7.84 (m, 1H, 7-H),
7.83e7.79 (m, 1H, 8-H), 7.71e7.63 (m, 1H, 6-H), 5.07 (d, J¼2.4 Hz, 2H,
CH2), 2.44 (t, J¼2.4 Hz, 1H, C^CH); 13C NMR (75 MHz, CDCl3)
d 159.1,
146.1, 135.3, 130.6, 130.3, 128.6, 127.3, 122.6, 111.1, 75.8, 74.2, 35.0; MS
(EI, 70 eV) m/z 209 (Mþ, 100%), 154 (50), 77 (44), 76 (76), 64 (69), 63
(68), 51 (46), 50 (71). Anal. Calcd for C12H7N3O: C, 68.89; H, 3.37; N,
20.09. Found: C, 68.77; H, 3.30; N, 19.98.
4.2.2.4. 3-[3-(4-Methylphenyl)prop-2-yn-1-yl]-4-oxo-3,4-
dihydroquinazoline-2-carboxamide (3d). Yield: 141 mg (44%); pale
yellow needles, mp 221e223 ꢀC (toluene).1H NMR (300 MHz, DMSO-
4.2.2. 3-(3-Arylprop-2-yn-1-yl)-4-oxo-3,4-dihydroquinazoline-2-
carboxamides (3aef). General procedure. A solution of 4-oxo-3-
(prop-2-yn-1-yl)-3,4-dihydroquinazoline-2-carboxamide16
(227 mg, 1.0 mmol) in dry dimethylformamide (1.0 mL) was diluted
with dry CH2Cl2 (15 mL) and the mixture was flushed with argon.
d6)
d 8.57 (br s, 1H, amide-H), 8.22 (br s, 1H, amide-H), 8.19 (dd,
3J¼8.0 Hz, 4J¼1.2 Hz,1H, 5-H), 7.90 (dt, 3J¼7.7 Hz, 4J¼1.5 Hz,1H, 7-H),
7.75 (d, J¼7.8 Hz,1H, 8-H), 7.63 (dt, 3J¼7.6 Hz, 4J¼1.1 Hz,1H, 6-H), 7.28
(d, J¼8.1 Hz, 2H, phenyl 20-H, 60-H), 7.14 (d, J¼7.8 Hz, 2H, phenyl 30-H,

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N. Haider et al. / Tetrahedron 69 (2013) 7066e7072
50-H), 5.25 (s, 2H, CH2), 2.26 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6)
stirred for 30 min. The phases were separated and the aqueous
layer was extracted with CH2Cl2 (3ꢁ15 mL). The combined organic
layers were washed with 0.5 N HCl, water and brine and dried over
Na2SO4. The dried solution was passed through a short column of
silica, eluting with CH2Cl2/ethyl acetate (95:5). Evaporation gave
the pure product as a colourless solid.
d
163.6, 160.3, 149.1, 146.1, 138.9, 135.4, 131.7, 129.4, 128.6, 127.8, 126.7,
121.1,118.8, 84.0, 83.5, 33.9, 21.2; MS (EI, 70 eV) m/z 317 (Mþ, 73%), 273
(25),198 (19),144 (23),129 (84),128 (100),127 (47),102 (40), 77 (35),
76 (28), 63 (31). Anal. Calcd for C19H15N3O2: C, 71.91; H, 4.76; N,13.24.
Found: 71.58; H, 4.56; N, 12.88.
4.2.2.5. 3-[3-(4-Methoxyphenyl)prop-2-yn-1-yl]-4-oxo-3,4-
dihydroquinazoline-2-carboxamide (3e). Yield: 142 mg (45%); pale
yellow needles, mp 215e217 ꢀC (EtOH).1H NMR (300 MHz, DMSO-d6)
4.2.3.1. 3-[3-(2-Methylphenyl)prop-2-yn-1-yl]-4-oxo-3,4-
dihydroquinazoline-2-carbonitrile (4a). Preparation from 3a by
method B; yield: 78 mg (87%); colourless crystals, mp 126e127 ꢀC
d
8.55 (br s, 1H, amide-H), 8.22 (br s, 1H, amide-H), 8.20 (d, J¼8.7 Hz,
(EtOH). 1H NMR (300 MHz, CDCl3)
d
8.37 (d, J¼8.1 Hz, 1H, 5-H),
1H, 5-H), 7.96e7.86 (m, 1H, 7-H), 7.75 (d, J¼8.1 Hz, 1H, 8-H), 7.64 (t,
J¼7.5 Hz, 1H, 6-H), 7.35 (d, J¼8.4 Hz, 2H, phenyl 20-H, 60-H), 6.90 (d,
J¼8.4 Hz, 2H, phenyl 30-H, 50-H). 5.26 (s, 2H, CH2), 3.74 (s, 3H, OCH3);
7.90e7.80 (m, 2H, 7-H, 8-H), 7.70e7.64 (m, 1H, 6-H), 7.42 (d,
J¼7.4 Hz, 1H, phenyl 60-H), 7.25e7.16 (m, 2H, phenyl 30-H, 40-H), 7.11
(t, J¼7.4 Hz, 1H, phenyl 50-H), 5.34 (s, 2H, CH2), 2.43 (s, 3H, CH3); 13C
13C NMR (75 MHz, DMSO-d6)
d
163.3, 159.9, 159.5, 149.0, 145.9, 135.1,
NMR (75 MHz, CDCl3) d 159.3, 146.4, 141.1, 135.4, 132.6, 131.1, 130.4,
133.1, 128.2, 127.5, 126.5, 120.9, 114.2, 113.5, 83.1, 82.9, 55.2, 33.5; MS
(EI, 70 eV) m/z 333 (Mþ, 45%), 275 (20), 145 (100), 144 (69), 135 (27),
130(24),102(58), 76 (44), 75(29), 63(32). Anal. Calcd for C19H15N3O3:
C, 68.46; H, 4.54; N, 12.61. Found: 68.29; H, 4.37; N, 12.44.
129.6, 129.2, 128.8, 127.5, 125.7, 122.9, 121.5, 111.5, 85.1, 85.0, 36.1,
20.8.; MS (EI, 70 eV) m/z 299 (Mþ, 46%), 298 (15), 129 (36), 128
(100), 127 (33), 102 (11), 77 (14), 63 (12). Anal. Calcd for C19H13N3O:
C, 76.24; H, 4.38; N, 14.04. Found: C, 76.31; H, 4.18; N, 13.81.
4.2.2.6. Ethyl 4-[3-(2-carbamoyl-4-oxoquinazolin-3(4H)-yl)prop-
1-yn-1-yl]benzoate (3f). Yield: 224 mg (60%); colourless needles,
4.2.3.2. 3-[3-(2-Methoxyphenyl)prop-2-yn-1-yl]-4-oxo-3,4-
dihydroquinazoline-2-carbonitrile (4b). Preparation from 3b by
method B; yield: 91 mg (97%); colourless crystals, mp 135e136 ꢀC
mp 209e211 ꢀC (EtOH). 1H NMR (300 MHz, CDCl3)
d 8.37 (dd,
3J¼4.1 Hz, J¼0.9 Hz, 1H, 5-H), 7.96e7.92 (BB0 part of an AA0BB0
system, 2H, phenyl 30-H, 50-H), 7.87e7.77 (m, 1H, 7-H), 7.74 (d,
J¼7.5 Hz, 1H, 8-H), 7.66e7.50 (m, 2H, 6-H, amide-H), 7.48e7.43 (AA0
part of an AA0BB0 system, 2H, phenyl 20-H, 60-H), 5.80 (br s, 1H,
amide-H), 5.78 (s, 2H, CH2), 4.36 (q, J¼7.2 Hz, 2H, OCH2CH3), 1.38 (t,
(EtOH). 1H NMR (300 MHz, CDCl3)
d
8.36 (ddd, J¼8.0, 1.5, 0.7 Hz, 1H, 5-
4
H), 7.89e7.79 (m, 2H, 7-H, 8-H), 7.66 (ddd, J¼8.0, 6.7, 1.7 Hz, 1H, 6-H),
7.41 (dd, J¼7.6,1.7 Hz,1H, phenyl 60-H), 7.33e7.27 (m, 1H, phenyl 40-H),
6.90e6.83 (m, 2H, phenyl 30-H, 50-H), 5.35 (s, 2H, CH2), 3.86 (s, 3H,
OCH3); 13C NMR (75 MHz, CDCl3)
d 160.8, 159.3, 146.4, 135.4, 134.1,
J¼7.2 Hz, 3H, OCH2CH3); 13C NMR (75 MHz, CDCl3)
d
166.0, 162.9,
131.3,130.7,130.3,128.8,127.5,122.9,120.5,111.4,111.0,110.8, 85.3, 82.6,
55.9, 36.2; MS (EI, 70 eV) m/z 315 (Mþ, 54%), 272 (66),196 (23),145 (31),
144 (78),116 (24),115 (100), 91 (27), 76 (27). Anal. Calcd for C19H13N3O2:
C, 72.37; H, 4.16; N, 13.33. Found: C, 72.42; H, 4.03; N, 13.27.
161.2, 145.3, 145.1, 134.8, 131.8, 130.1, 129.3, 128.9, 127.9, 127.4, 127.0,
121.9, 87.3, 82.9, 61.1, 34.0, 14.3; MS (EI, 70 eV) m/z 375 (Mþ, 100%),
159 (27), 130 (28), 129 (33), 114 (42), 113 (33), 102 (38), 77 (30), 76
(27), 63 (40), 44 (25). Anal. Calcd for C21H17N3O4: C, 67.19; H, 4.56;
N, 11.19. Found: C, 67.06; H, 4.38; N, 11.12.
4.2.3.3. Ethyl 2-[3-(2-cyano-4-oxoquinazolin-3(4H)-yl)prop-1-
yn-1-yl]benzoate (4c). Preparation from 3c by method B; yield:
93 mg (87%); colourless needles, mp 129e131 ꢀC (EtOH). 1H NMR
4.2.3. 3-(3-Arylprop-2-yn-1-yl)-4-oxo-3,4-dihydroquinazoline-2-
carbonitriles (4aef). General procedure. Method A. To a solution of
the amide 3 (0.3 mmol) in dry CHCl3 (15 mL) was added POCl3
(5 mL) and the mixture was refluxed for 24 h. After cooling, it was
slowly poured into ice-water (50 mL) and the mixture was vigor-
ously stirred for 30 min. The phases were separated and the
aqueous layer was extracted with CH2Cl2 (3ꢁ15 mL). The combined
organic layers were washed with water and brine and dried over
Na2SO4. The dried solution was passed through a short column of
silica, eluting with CH2Cl2/ethyl acetate (95:5). Evaporation gave
a solid residue, which was further purified by recrystallisation from
an appropriate solvent.
(300 MHz, CDCl3)
d
8.36 (ddd, J¼8.0, 1.5, 0.6 Hz, 1H, 5-H), 7.91 (dd,
J¼7.8, 1.5 Hz, 1H, phenyl 30-H), 7.89e7.84 (m, 1H, 7-H), 7.82 (ddd, J¼8.2,
1.5, 0.6 Hz,1H, 8-H), 7.68e7.64 (m,1H, 6-H), 7.57 (dd, J¼7.7, 1.4 Hz, 1H,
phenyl 60-H), 7.44 (dt, J¼7.6, 1.5 Hz, 1H, phenyl 50-H), 7.38 (dt, J¼7.6,
1.5 Hz, 1H, phenyl 40-H), 5.35 (s, 2H, NCH2), 4.30 (q, J¼7.1 Hz, 2H,
OCH2), 1.32 (t, J¼7.1 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d 165.9,
159.4, 146.4, 135.4, 134.5, 132.9, 131.7, 131.2, 130.5, 130.3, 128.8, 128.8,
127.5,122.9,122.1, 111.5, 86.1, 84.8, 61.4, 36.2, 14.4.; MS (EI, 70 eV) m/z
357 (Mþ, 42%), 329 (28), 328 (40), 312 (19), 284 (21), 159 (41), 157
(100),154 (67),129 (39),102 (48), 77 (53). Anal. Calcd for C21H15N3O3:
C, 70.58; H, 4.23; N, 11.76. Found: C, 70.52; H, 3.93; N, 11.62.
Method B. To an ice-cooled solution of the amide 3 (0.3 mmol)
and triethylamine (2.0 mL) in dry CH2Cl2 (2 mL) was slowly added
trifluoroacetic anhydride (1.0 mL) with stirring. The cooling bath
was removed and stirring was continued for 1 h (TLC monitoring:
CH2Cl2/EtOH, 9:1). The mixture was poured into ice-water (20 mL)
and stirred for 30 min. The phases were separated and the aqueous
phase was extracted with CH2Cl2 (3ꢁ15 mL). The combined organic
phases were washed with 0.5 N HCl, 10% aq NaHCO3 and water. The
solution was dried (Na2SO4) and evaporated. The residue was pu-
rified by column chromatography, eluting with CH2Cl2/ethyl ace-
tate (95:5). Evaporation gave a solid residue, which was further
purified by recrystallisation from an appropriate solvent.
Method C. To a solution of the amide 3 (0.3 mmol) in dry CH2Cl2
(5 mL) was added DBU (137 mg, 0.9 mmol) and the mixture was
stirred at room temperature for 10 min. Then, ethyl dichlor-
ophosphate (97 mg, 0.6 mmol) was added and stirring was con-
tinued for 3 h. Further portions of DBU and ethyl dichlorophosphate
(0.3 mmol each) were added and the mixture was stirred for 24 h. It
was then slowly poured into ice-water (50 mL) and vigorously
4.2.3.4. 3-[3-(4-Methylphenyl)prop-2-yn-1-yl]-4-oxo-3,4-
dihydroquinazoline-2-carbonitrile (4d). Preparation from 3d by
method A; yield: 43 mg (47%); colourless needles, mp 167e168 ꢀC
(EtOH). 1H NMR (300 MHz, CDCl3)
d
8.38 (d, J¼7.8 Hz, 1H, 5-H),
7.92e7.80 (m, 2H, 7-H, 8-H), 7.72e7.63 (m, 1H, 6-H), 7.36 (d,
J¼8.1 Hz, 2H, phenyl 20-H, 60-H), 7.11 (d, J¼7.8 Hz, 2H, phenyl 30-H,
50-H), 5.30 (s, 2H, CH2), 2.34 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d
159.2, 146.3, 139.3, 135.3, 132.0, 131.0, 130.2, 129.1, 128.6, 127.4,
122.7, 118.5, 111.3, 86.0, 80.5, 35.9, 21.5; MS (EI, 70 eV) m/z 299 (Mþ,
91%), 270 (21),129 (87),128 (100),102 (29), 77 (45), 71 (44), 69 (85),
63 (50), 57 (85), 55 (52). Anal. Calcd for C19H13N3O: C, 76.24; H,
4.38; N, 14.04. Found: C, 75.99; H, 4.19; N, 13.83.
4.2.3.5. 3-[3-(4-Methoxyphenyl)prop-2-yn-1-yl]-4-oxo-3,4-
dihydroquinazoline-2-carbonitrile (4e). Preparation from 3e by
method C; yield: 91 mg (96%); colourless crystals, mp 183e184 ꢀC
(EtOH). 1H NMR (300 MHz, CDCl3)
d
8.37 (d, J¼7.8 Hz, 1H, 5-H),
7.90e7.79 (m, 2H, 7-H, 8-H), 7.71e7.63 (m, 1H, 6-H), 7.43e7.38 (BB0

N. Haider et al. / Tetrahedron 69 (2013) 7066e7072
7071
part of an AA0BB0 system, 2H, phenyl 20-H, 60-H), 6.85e6.80 (AA0
part of an AA0BB0 system, 2H, phenyl 30-H, 50-H), 5.28 (s, 2H, CH2),
3.81 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3)
160.2, 159.2, 146.3,
135.3, 133.6, 131.0, 130.2, 128.6, 127.4, 122.8, 114.0, 113.6, 111.3, 85.9,
79.9, 55.3, 36.0; MS (EI, 70 eV) m/z 315 (Mþ, 49%), 272 (63), 145
(100), 144 (46), 115 (25), 102 (59), 101 (30), 90 (22), 76 (60), 75 (48),
63 (50). Anal. Calcd for C19H13N3O2$0.15H2O: C, 71.76; H, 4.22; N,
13.21. Found: C, 71.77; H, 3.93; N, 12.98. HRMS (ESI) m/z 316.1080
([MþH]þ calcd for C19H14N3O2: 316.1081).
(400 MHz, CDCl3)
d
9.76 (s, 1H, 14-H), 8.64 (d, J¼8.6 Hz, 1H, 10-H),
8.44e8.40 (m, 2H, 2-H, 8-H), 8.10 (d, J¼7.8 Hz, 1H, 7-H), 7.87e7.82
d
(m, 2H, 4-H, 9-H), 7.57 (dt, J¼7.5, 1.1 Hz, 1H, 3-H), 7.37 (s, 2H, 5-CH2),
4.51 (q, J¼7.1 Hz, 2H, OCH2CH3), 1.49 (t, J¼7.1 Hz, 3H, OCH2CH3); 13
C
NMR (100 MHz, CDCl3) d 166.4, 160.7, 152.5, 151.5, 149.6, 149.4, 136.1,
134.7, 132.7, 131.0, 130.4, 129.3, 128.9, 127.8, 127.7, 127.3, 126.6, 121.5,
61.8, 47.8, 14.5; MS (EI, 70 eV) m/z 358 (25%), 357 (Mþ, 100), 329 (23),
328 (26), 312 (7), 284 (16), 156 (7), 142 (14), 128 (8). Anal. Calcd for
C21H15N3O3$0.15H2O: C, 70.05; H, 4.28; N, 11.67. Found: C, 70.07; H,
3.99; N, 11.47. HRMS (ESI) m/z 358.1191 ([MþH]þ calcd for
C21H16N3O3: 358.1186).
4.2.3.6. Ethyl 4-[3-(2-cyano-4-oxoquinazolin-3(4H)-yl)prop-1-
yn-1-yl]benzoate (4f). Preparation from 3f by method A; yield:
78 mg (73%); colourless crystals, mp 169e171 ꢀC (EtOH). 1H NMR
4.2.4.4. 3-Methylquinolino[20,30:3,4]pyrrolo[2,1-b]quinazolin-
11(13H)-one (3-methylluotonin A) (5d). Yield: 44 mg (98%), col-
ourless crystals, mp 288e290 ꢀC (EtOH). 1H NMR (300 MHz, CDCl3)
(300 MHz, CDCl3)
d
8.38 (td, J¼7.8, 0.7 Hz, 1H, 5-H), 7.98 (d,
J¼8.4 Hz, 2H, phenyl 30-H, 50-H), 7.92e7.80 (m, 2H, 7-H, 8-H),
7.53e7.65 (m, 1H, 6-H), 7.52 (d, J¼8.4 Hz, 2H, phenyl 20-H, 60-H),
5.33 (s, 2H, CH2), 4.38 (q, J¼7.2 Hz, 2H, OCH2CH3), 1.39 (t, J¼7.2 Hz,
d
8.42 (d, J¼7.8 Hz, 1H, 10-H), 8.36 (s, 1H, 14-H), 8.22 (s, 1H, 4-H),
8.11 (d, J¼8.1 Hz, 1H, 7-H), 7.85 (t, J¼7.5 Hz, 1H, 8-H), 7.79 (d,
J¼8.4 Hz, 1H, 1-H), 7.63e7.54 (m, 1H, 9-H), 7.47 (d, J¼8.7 Hz, 1H, 2-
H), 5.28 (s, 2H, CH2), 2.62 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3)
3H, OCH2CH3); 13C NMR (75 MHz, CDCl3)
d 165.9, 159.2, 146.3, 135.4,
132.0, 130.8, 130.7, 130.3, 129.4, 128.7, 127.4, 126.0, 122.7, 111.2, 85.0,
83.9, 61.2, 35.8, 14.3; MS (EI, 70 eV) m/z 357 (Mþ, 46%), 284 (40), 187
(38), 159 (42), 114 (47), 113 (44), 76 (50), 69 (73), 63 (100), 57 (67),
55 (65). Anal. Calcd for C21H15N3O3: C, 70.58; H, 4.23; N, 11.76.
Found: C, 70.42; H, 3.97; N, 11.57.
d
160.7, 152.8, 151.1, 149.8, 149.4, 141.3, 134.5, 131.2, 131.0, 129.6,
128.8, 127.5, 127.3, 127.0, 126.4, 121.3, 47.3, 22.0; MS (EI, 70 eV) m/z
299 (Mþ, 100%), 298 (33), 284 (18), 270 (9), 150 (22), 135 (15), 77
(13), 63 (9). Anal. Calcd for C19H13N3O$0.15H2O: C, 75.56; H, 4.44; N,
13.91. Found: C, 75.62; H, 4.13; N, 13.64. HRMS (ESI) m/z 300.1134
([MþH]þ calcd for C19H14N3O: 300.1131).
4.2.4. 1-Substituted and 3-substituted luotonin A derivatives (5aef).
General procedure. To a solution of the appropriate nitrile 4
(0.15 mmol) in dry 1,2-dichlorobenzene (4 mL) was added a 0.1 M
solution of DBU in 1,2-dichlorobenzene (0.08 mL, 0.008 mmol).
After flushing with argon, the vessel was closed and heated to
110e120 ꢀC for 24 h (for compound 5a: 48 h, for compound 5f:
12 h). The mixture was cooled and diluted with diethyl ether. It was
kept in the refrigerator for 2 h, then the precipitate was collected by
filtration and washed with diethyl ether to give the pure product.
4.2.4.5. 3-Methoxyquinolino[20,30:3,4]pyrrolo[2,1-b]quinazolin-
11(13H)-one (3-methoxyluotonin A) (5e). Yield: 40 mg (84%), col-
ourless crystals, mp 310e312 ꢀC (EtOH). 1H NMR (300 MHz, CDCl3)
d
8.43 (dd, J¼7.8, 1.5 Hz, 1H, 10-H), 8.36 (s, 1H, 14-H), 8.11 (d,
J¼8.1 Hz, 1H, 7-H), 7.90e7.82 (m, 1H, 8-H), 7.82e7.76 (m, 2H, 4-H,
1H), 7.58 (t, J¼7.6 Hz, 1H, 9-H), 7.32 (dd, J¼9.0, 2.6 Hz, 1H, 2-H), 5.30
(s, 2H, CH2), 4.00 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3)
d 161.6,
160.7, 152.8, 151.4, 151.2, 149.5, 134.5, 131.1, 128.8, 128.7, 127.7, 127.3,
126.5, 124.4, 122.3, 121.3, 108.1, 55.7, 47.3; MS (EI, 70 eV) m/z 315
(Mþ, 100%), 300 (34), 272 (33), 158 (39), 77 (48), 76 (41), 63 (36), 57
(31), 50 (25). Anal. Calcd for C19H13N3O2$0.2H2O: C, 71.55; H, 4.23;
N, 13.18. Found: C, 71.66; H, 3.97; N, 12.91. HRMS (ESI) m/z 316.1082
([MþH]þ calcd for C19H14N3O2: 316.1081).
4.2.4.1. 1-Methylquinolino[20,30:3,4]pyrrolo[2,1-b]quinazolin-
11(13H)-one (1-methylluotonin A) (5a). Yield: 33 mg (72%), col-
ourless crystals, mp 310e312 ꢀC (EtOH). 1H NMR (300 MHz, CDCl3)
d
8.61 (d, J¼0.9 Hz, 1H, 14-H), 8.43 (dd, J¼8.0, 1.2 Hz, 1H, 10-H), 8.32
(d, J¼8.7 Hz, 1H, 4-H), 8.11 (d, J¼8.2 Hz, 1H, 7-H), 7.85 (ddd, J¼8.3,
7.1, 1.6 Hz, 1H, 8-H), 7.72 (dd, J¼8.6, 7.0 Hz, 1H, 3-H), 7.58 (ddd,
J¼8.2, 7.2, 1.2 Hz, 1H, 9-H), 7.49 (d, J¼6.9 Hz, 1H, 2-H), 5.35 (d,
J¼1.0 Hz, 2H, CH2), 2.77 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3)
4.2.4.6. Ethyl 11-oxo-11,13-dihydroquinolino[20,30:3,4]pyrrolo[2,1-
b]quinazoline-3-carboxylate (3-ethoxycarbonylluotonin A) (5f). Yield:
52 mg (97%), colourless crystals, mp 291e293 ꢀC (EtOH). 1H NMR
d
160.9, 152.9, 150.9, 150.0, 149.6, 134.9, 134.7, 130.5, 129.3, 129.3,
129.2, 128.9, 128.5, 128.2, 127.6, 126.6, 121.5, 47.7, 18.6; MS (EI,
70 eV) m/z 300 (24%), 299 (Mþ, 100), 298 (28), 284 (25), 150 (13),
135 (18), 77 (15), 63 (13). Anal. Calcd for C19H13N3O$0.1H2O: C,
75.78; H, 4.42; N, 13.95. Found: C, 75.72; H, 4.14; N, 13.72. HRMS
(ESI) m/z 300.1134 ([MþH]þ calcd for C19H14N3O: 300.1131).
(400 MHz, CDCl3) d 9.21 (s, 1H, 4-H), 8.52 (s, 1H, 14-H), 8.44 (d,
J¼7.8 Hz, 1H, 10-H), 8.29 (d, J¼8.7 Hz, 1H, 2-H), 8.14 (d, J¼8.1 Hz, 1H,
7-H), 8.03 (d, J¼8.7 Hz, 1H, 1-H), 7.94e7.84 (m, 1H, 8-H), 7.66e7.57
(m, 1H, 9-H), 5.39 (s, 2H, CH2), 4.49 (q, J¼7.2 Hz, 2H, OCH2CH3), 1.48
(t, J¼7.2 Hz, 3H, OCH2CH3); 13C NMR (100 MHz, CDCl3)
d 165.8, 160.6,
152.4, 152.1, 149.3, 148.9, 134.7, 133.1, 132.5, 131.4, 131.1, 130.9, 128.9,
128.2, 128.0, 127.7, 126.5, 121.4, 61.7, 47.4, 14.3; MS (EI, 70 eV) m/z 357
(Mþ, 100%), 329 (27), 312 (23), 284 (57), 76 (43), 69 (35), 63 (40), 57
(73), 55 (49). Anal. Calcd for C21H15N3O3$0.3H2O: C, 69.53; H, 4.33; N,
11.58. Found: C, 69.56; H, 4.10; N, 11.51. HRMS (ESI) m/z 358.1187
([MþH]þ calcd for C21H16N3O3: 358.1186).
4.2.4.2. 1-Methoxyquinolino[20,30:3,4]pyrrolo[2,1-b]quinazolin-
11(13H)-one (1-methoxyluotonin A) (5b). Yield: 46 mg (96%), col-
ourless crystals, mp 309e311 ꢀC (EtOH). 1H NMR (300 MHz, CDCl3)
d
8.91 (s, 1H, 14-H), 8.44 (dd, J¼7.9, 1.5 Hz, 1H, 10-H), 8.12 (d,
J¼7.7 Hz, 1H, 7-H), 8.05 (d, J¼8.7 Hz, 1H, 4-H), 7.86 (ddd, J¼8.2, 7.2,
1.6 Hz, 1H, 8-H), 7.74 (t, J¼8.2 Hz, 1H, 3-H), 7.65e7.53 (m, 1H, 9-H),
6.99 (d, J¼7.6 Hz, 1H, 2-H), 5.34 (s, 2H, CH2), 4.07 (s, 3H, OCH3); 13
C
Acknowledgements
NMR (75 MHz, CDCl3) d 160.9, 155.3, 152.9, 151.5, 150.5, 149.6, 134.7,
130.8, 129.0, 128.8, 127.6, 126.9, 126.6, 122.9, 121.8,121.5, 106.0, 56.2,
47.7; MS (EI, 70 eV) m/z 316 (21%), 315 (Mþ, 100), 300 (52), 272 (30),
243 (13), 158 (21), 136 (23), 122 (21), 69 (26), 63 (23), 57 (45), 55
(36). Anal. Calcd for C19H13N3O2: C, 72.37; H, 4.16; N, 13.33. Found:
C, 71.98; H, 3.85; N, 13.11.
One of us (G.M.) wishes to thank the Eurasia-Pacific Uninet
network and the Austrian Academic Exchange Service for support
of her stay at the University of Vienna.
Supplementary data
4.2.4.3. Ethyl 11-oxo-11,13-dihydroquinolino[20,30:3,4]pyrrolo[2,1-
b]quinazoline-1-carboxylate (1-ethoxycarbonylluotonin A) (5c). Yield:
49 mg (92%), colourless crystals, mp 307e308 ꢀC (EtOH). 1H NMR
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.06.040.

7072
N. Haider et al. / Tetrahedron 69 (2013) 7066e7072
10. In order to verify this assumed limitation, we performed a control experiment,
employing the meta-substituted anilide, N-(3-methylphenyl)-4-oxo-3-(prop-2-
yn-1-yl)-3,4-dihydroquinazoline-2-carboxamide, as the starting material in the
triphenylphosphine oxide/triflic anhydride mediated cyclisation. Indeed, this
reaction gave an isomer mixture of 1-methylluotonin A (5a) and 3-methyl-
luotonin A (5d) in a ratio of approx. 2:3 (see Supplementary data)
11. Dai, W.; Petersen, J. L.; Wang, K. K. Org. Lett. 2006, 8, 4665e4667.
12. Khanna, I. K.; Yu, Y.; Huff, R. M.; Weier, R. M.; Xu, X.; Koszyk, F. J.; Collins, P. W.;
Cogburn, J. N.; Isakson, P. C.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.;
Seibert, K.; Veenhuizen, A. W.; Yuan, J.; Yang, D.-C.; Zhang, Y. Y. J. Med. Chem.
2000, 43, 3168e3185.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
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