Microwave-assisted, solvent-free synthesis of several quinazoline alkaloid frameworks

Article abstract of DOI:10.1055/s-2007-990818

Microwave irradiation leads to a considerable improvement of the cyclocondensation between anthranilic acid and lactim ethers derived from piperazine-2,5-diones in terms of reaction times, yields, and stereocenter integrity. This reaction has been used to

Full text of DOI:10.1055/s-2007-990818

3390
PAPER
Microwave-Assisted, Solvent-Free Synthesis of Several Quinazoline Alkaloid
Frameworks
M
icrowave-
A
i
d
l
Q
uinaz
a
oline Alkal
r
oid Synthesis Cledera,a Juan Domingo Sánchez,a Esmeralda Caballero,a Tamara Yates,b Elena G. Ramírez,c
Carmen Avendaño,a Mª Teresa Ramos,a J. Carlos Menéndez*a
a
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax +34(913)941822; E-mail: josecm@farm.ucm.es
Departamento de Farmacia, Facultad de Farmacia, Universidad de Concepción, Casilla 237, Conceptión, Chile
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, México D. F. 04510, Mexico
b
c
Received 4 June 2007; revised 26 July 2007
This paper is dedicated to Professor George A. Olah, on the occasion of his 80th birthday.
Me
HN
Me
N
O
N
Abstract: Microwave irradiation leads to a considerable improve-
ment of the cyclocondensation between anthranilic acid and lactim
ethers derived from piperazine-2,5-diones in terms of reaction
times, yields, and stereocenter integrity. This reaction has been used
to prepare some derivatives of the pyrazino[2,1-b]quinazoline-3,6-
dione system present in many quinazoline alkaloids. It could also be
applied to the synthesis of compounds containing the complete
hexacyclic ring system of the anti-MDR natural product N-acetyl-
ardeemin, and other comprising the pentacyclic framework of cir-
cumdatin E. The microwave-assisted reaction was also much better
than the thermal one when applied to a bis-lactim ether, leading to
the corresponding pentacyclic pyrazino[2,1-b:5,4-b¢]diquinazoline-
8,16-dione in excellent yield.
N
O
N
O
N
HN
luotonin A
fiscalin B
O
N
N
H
Me
Me
HN
N
O
H
Key words: microwave irradiation, lactim ether, alkaloids, antitu-
mor agents, heterocycles
Me
NH
N
N
Me
N
H
O
N
O
O
O
Me
About 150 naturally occurring alkaloids contain a
quinazolin-4-one structural fragment. These quinazoline
alkaloids1 have been isolated from a variety of natural
sources, including fungi, marine organisms, and higher
plants, and the structures of some representative exam-
ples, including luotonin A,2 fiscalin B,3 N-acetylardeem-
in,4 spiroquinazoline,5 and circumdatin E6 are shown in
Figure 1. These compounds have attracted much attention
from synthetic chemists prompted by their challenging
structures and interesting pharmacological properties,
which include, among others, antitumor activity and inhi-
bition of topoisomerase I by the luotonins,7 inhibition of
multidrug resistance8 to antitumor drugs (MDR)4b,9 and
immunosuppression10 by the ardeemins, and finally com-
petitive inhibition of the binding of substance P to the hu-
man NK-1 receptor by spiroquinazoline.5
spiroquinazoline
N-acetylardeemin
MeO
OH
O
N
N
H
N
O
circumdatin E
Figure 1 The structure of some representative quinazoline alkalo-
ids.
protected amino acids that are transformed into pipera-
zine-2,5-diones, which are submitted to acylation with 2-
azidobenzoyl chloride followed by a domino Staudinger–
aza-Wittig process.16 Although this method has the advan-
tage of starting from inexpensive starting materials and
has been widely employed, it has some drawbacks. Thus,
when both NH groups of the piperazinedione system are
free, the acylation step is often troublesome and it is diffi-
cult to avoid diacylation. An additional problem arises
from the generation of a phosphine oxide as a side prod-
uct, which leads to tedious chromatographic procedures.
For these reasons, we decided to investigate an alternative
procedure related to the von Niementowski quinazoline
Extensive synthetic efforts have been devoted to the prep-
aration of quinazoline alkaloids and their analogues.1,11–13
The creation of the pyrazino[2,1-b]quinazoline-3,6-dione
fragment has relied on two strategies: a five-step sequence
starting from Fmoc-protected amino acids based on the
cyclization of N-aminoacylanthranylamides14 via a ben-
zo[d]oxazine intermediate;15 alternatively the Eguchi pro-
tocol comprises four steps and starts from N-Boc-
SYNTHESIS 2007, No. 21, pp 3390–3398
x
x.
x
x
.
2
0
0
7
Advanced online publication: 10.10.2007
DOI: 10.1055/s-2007-990818; Art ID: T09207SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Microwave-Assisted Quinazoline Alkaloid Synthesis
3391
synthesis and based on the direct cyclocondensation of cant, increases in the case of the preparation of 3c and 3d
lactim ethers derived from piperazinediones with anthra- (entries 3 and 4). Due to the presence of an adjacent car-
nilic acid.17 Although the cyclocondensation step normal- bonyl group, it was necessary to confirm the integrity of
ly proceeds in low yield and sometimes leads to the stereocenter in the reactions summarized in Table 1
epimerization of stereocenters adjacent to carbonyl and Scheme 1, especially since, as already mentioned,
groups,17,18 we considered this reaction a good candidate several examples of epimerization processes have been
for optimization by microwave irradiation under solvent- described in the literature for thermal reactions.17,18 Ste-
free conditions,19,20 and sought to study its application to reocenter inversion for microwave reactions was ruled out,
the synthesis of representative quinazolin-4-one com- within the limits of detection of this technique, by 1H NMR
pounds structurally related to the above-mentioned natu- studies of 3c in the presence of Eu(hfc)3, using racemic tri-
ral frameworks. We now report in full21 our studies on this cycle as a reference. Also, no epimerization was observed
subject.
in the preparation of 3e, which bears two stereocenters, ei-
ther under thermal or under microwave-assisted condi-
tions.
We started our study with the preparation of some deriva-
tives 3 of the pyrazino[2,1-b]quinazoline-3,6-dione sys-
tem, related to the fiscalins and related alkaloids After establishing suitable microwave reaction conditions
(fumiquinazolines and glyantrypine).22 Thus, treatment of for the synthesis of the pyrazino[2,1-b]quinazolin-3,6-di-
the known23 1,3-disubstituted piperazine-2,5-diones 1 one system, we set out for the study of more challenging
with triethyloxonium tetrafluoroborate (Meerwein’s salt) examples. Lactim ethers with a conjugated, exocyclic
in the presence of potassium carbonate24 afforded lactim double bond had proved in the past to be troublesome sub-
ethers 2. As shown in Table 1, their reaction with anthra- strates for the thermal reaction with anthranilic acid.25
nilic acid in the absence of solvent and under thermal con- Hence, we undertook the study of this case under our mi-
ditions (120–140 °C for 2 h) gave the expected crowave-assisted conditions. The starting materials for
cyclocondensation products 3, albeit in modest yields this study were lactim ethers 7, which were prepared from
(16–46%). These results were considerably improved the corresponding piperazine-2,5-diones, two of which,
when the reactions were carried out under microwave ir- 6a,b, had been previously described,25 while the prepara-
radiation at 600 W, with the samples introduced in an alu- tion of 6c is shown in Scheme 1. A base-catalyzed aldol
mina bath as a heat sink. Thus, microwave irradiation was condensation between 1,4-diacetylpiperazine-2,5-dione
associated with a dramatic decrease in reaction time (3–5 derivative 4 and 1-tosyl-1H-indole-3-carbaldehyde gave a
minutes under microwave irradiation, compared to 2 h for moderate yield of a mixture of 5c and 6c, through a mech-
the conventional heating conditions). Two- to threefold anism involving neighboring group assistance to the aldol
increases in yield were observed for 3a (entry 1), 3b (en- reaction by the acetyl group adjacent to the reaction
try 2), and 3e (entry 5) and smaller, but also very signifi-
Table 1 Microwave-Assisted Synthesis of Fiscalin-Related Compounds
H2N
O
OEt
BF4– Et3O+, CH2Cl2,
K2CO3
CO2H
no solvent
N
O
R2
R1
R2
R1
NH
Me
R2
R1
N
N
O
N
N
Me
N
Me
O
O
1
2
3
Entry 2, 3
R1
R2
Yield (%) of 2 Synthesis of 3
Conventional heating
Microwave irradiation
Conditions
Conditions
120 °C, 2 h
140 °C, 2 h
140 °C, 2 h
140 °C, 2 h
140 °C, 2 h
Yield (%)
3817b
22a
Yield (%)
1
2
3
4
5
a
b
c
Me
H
H
H
H
5617b
76
84
83
–
600 W, 3 min
600 W, 5 min
600 W, 5 min
600 W, 3 min
600 W, 6 min
63
58
51
58
48b
4-MeOC6H4
CH2CH2Ph
39
d
e
2-naphthylmethyl
1H-indol-3-ylmethyl
48
Me
16b
a This yield was mistakenly given as 40% in our preliminary report.21
b Overall yield from 1e. The thermal reaction has been previously described.23c
Synthesis 2007, No. 21, 3390–3398 © Thieme Stuttgart · New York

3392
P. Cledera et al.
PAPER
O
O
O
O
CHO
R
N
N
Me
KOtBu, DMF, r.t., 16 h
+
HN
Me
N
N
Me
Me
N
SO2
SO2
O
O
Me
4
5c
6c
R = COMe (15%)
+
Me
NH2NH2, r.t., 3 h
(75%)
R = H (16%)
Scheme 1
site.25,26 Deacetylation of 5c with hydrazine hydrate at ilarly, treatment of the known tetracyclic ardeemin frag-
room temperature gave an additional amount of 6c.
ment 1118 with anthranilic acid at 600 W for three minutes
gave a 6:1 mixture of the diastereomeric deprenylardeem-
ins 12 and 13, in 48% overall yield, where the cyclocon-
densation is accompanied by partial epimerization of the
tryptophan stereocenter. Besides the improved yield and
shorter reaction time, this result was also better in terms of
stereochemical integrity than the one obtained under con-
ventional conditions, which led to a 34% overall yield of
a 7:2:1 mixture of three compounds, namely 12, retaining
the configuration of the starting material, 13, epimerized
at the tryptophan stereocenter and 14, epimerized at both
the tryptophan and alanine stereocenters.18 This result
again showcases the mildness and higher efficiency of the
microwave-assisted conditions in comparison with the
traditional, thermal conditions.
As shown in Table 2, compounds 6 were transformed into
the corresponding lactim ethers 7 by exposure to Meer-
wein’s salt. Microwave irradiation of the latter com-
pounds in the presence of anthranilic acid led to moderate,
but still much improved, yields of the desired pyrazi-
no[2,1-b]quinazolines 8a–c with regard to the results ob-
tained under thermal conditions. In this case, the reaction
required relatively long reaction times (9 min), reflecting
the lowered reactivity of the lactim ether function associ-
ated with its conjugation.
The results obtained in the application of our methodolo-
gy to the synthesis of compounds containing the complete
ardeemin framework is summarized in Scheme 2. While
the thermal reaction of anthranilic acid with lactim ether
9, containing the tetracyclic ABCD ardeemin fragment,
required melting both compounds together at 140 °C for
six hours and gave 10 in 44% yield,18 we found that the
same transformation could be carried out in only three
minutes and in 58% yield by microwave irradiation. Sim-
In a further development, we showed that the microwave-
assisted synthesis could also be applied to the preparation
of compounds where the quinazolinone moiety is fused to
a seven-membered ring,27 as shown by the one-step trans-
formation of the known lactim ether 1528 into pentacyclic
Table 2 Microwave-Assisted Synthesis of Fiscalin-Related Compounds Bearing an Arylmethylene Chain
H2N
O
OEt
BF4– Et3O+, CH2Cl2,
K2CO3
CO2H
no solvent
N
Ar
NH
Ar
N
Ar
N
O
N
N
H
R
N
H
R
H
R
O
O
O
6
7
8
Entry
6, 7, 8
Ar
R
Yield (%) of 7
Synthesis of 8
Conventional heating
Microwave irradiation
Yield (%) Conditions
Conditions
120 °C, 2 h
not assayed
not assayed
Yield (%)
1
2
3
a
b
c
4-MeOC6H4
4-MeOC6H4
Me
i-Pr
Me
6524
–
1525
–
600 W, 9 min
600 W, 9 min
600 W, 9 min
26
25a
19
86
–
N
Ts
a Overall yield from 6b.
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Microwave-Assisted Quinazoline Alkaloid Synthesis
3393
OEt
H
N
N
H
H
N
H
N
O
+
H2N
N
Me
Me
N
H
CO2H
O
N
H
O
Me
Me
O
O
9
10
Conditions
140 °C, 6 h
Yield (%)
44
58
MW, 600 W, 3 min
N
H
N
O
H2N
OEt
H
N
H
CO2H
H
H
H
N
O
N
O
N
+
+
N
N
Me
Me
Me
N
H
N
H
N
H
O
O
Me
Me
Me
O
O
O
13
12
11
N
N
H
Conditions
140 °C, 6 h
12 (%) 13 (%)
14 (%)
H
O
23
41
8
7
3
0
N
Me
O
MW, 600 W, 3 min
N
H
Me
14
O
Scheme 2
compound 16 in 40% yield, which contains the complete
framework of circumdatin E (Scheme 3). Although this
yield is moderate, it is noteworthy that alternative meth-
ods for circumdatin synthesis often give poor yields or
product mixtures.29
H2N
OCH3
H
O
HO2C
N
N
H
N
MW, 600 W, 5 min
N
N
As a final check of the versatility of our method, we stud-
ied its application to a double von Niementowski-type cy-
clocondensation from bis-lactim ether 17. We found that
microwave irradiation provides an excellent entry to the
linear pentacyclic framework of 18, which was isolated in
89% yield compared to a 54% yield in the literature30 for
a similar reaction at 150–200 °C (Scheme 3).
O
O
15
16 (40%)
OEt
N
O
N
EtO
N
N
N
17
In conclusion, we have shown that microwave irradiation
significantly improves the reaction of lactim ethers with
anthranilic acid. This reaction provides a useful alterna-
tive to existing methods for the preparation of complex
heterocyclic frameworks related to the quinazoline alka-
loids.
N
H2N
2
O
18
HO2C
Conditions
Yield (%)
54
150–200 °C, 1 h
(ref. 29)
600 W, 6 min
89
All reagents (Aldrich, Fluka, SDS, Probus) and solvents (SDS)
were of commercial quality and were used as received. Reactions
were monitored by TLC [aluminum plates coated with silica gel
with fluorescent indicator (SDS CCM221254)]. Separations by
flash chromatography were performed on silica gel (SDS 60 ACC
Scheme 3
Synthesis 2007, No. 21, 3390–3398 © Thieme Stuttgart · New York

3394
P. Cledera et al.
PAPER
40–63 mm). Melting points were measured on a Reichert 723 hot
stage microscope, and are uncorrected. IR spectra were recorded on
a Perkin Elmer Paragon 1000 FT-IR spectrophotometer, with solid
compounds compressed into KBr pellets and liquid compounds ex-
amined as films on NaCl disks. NMR spectra were obtained on a
Bruker Avance 250 spectrometer operating at 250 MHz for 1H and
63 MHz for 13C (CAI de Resonancia Magnética Nuclear, Univer-
sidad Complutense). Polarimetric measurements were carried out
on a Perkin Elmer 240 polarimeter operating at the emission wave-
length of a Na lamp; concentrations for these measurements are giv-
en in g/100 mL. Elemental analyses were determined by the CAI de
Microanálisis Elemental, Universidad Complutense, using a Leco
932 CHNS combustion microanalyzer. Microwave-assisted reac-
tions were performed in a Moulinex domestic microwave oven. The
reactants were thoroughly mixed and placed in a round-bottomed
flask, which was completely submerged in alumina, contained in a
beaker. The reaction was irradiated at 600 W for up to 9 × 1 min pe-
riods (see individual reactions), with 1 min cooling intervals be-
tween each pulse. The temperatures of the alumina at the end of
each of these irradiation periods were 110 °C, 128 °C, 143 °C, 153
°C, 161 °C, 163 °C, 165 °C, 166 °C, and 167 °C, respectively.
1H NMR (250 MHz, CDCl3): d = 7.30–7.16 (m, 5 H, Ar-H), 4.12–
4.03 (m, 3 H, OCH2CH3, H3), 3.77–3.60 (m, 3 H, H6,
PhCH2CH2N), 3.49–3.39 (m, 1 H, PhCH2CH2N), 2.87 (t, J = 7.7
Hz, 2 H, PhCH2CH2N), 1.33 (d, J = 7.2 Hz, 3 H, C3-CH3), 1.23 (t,
J = 7.1 Hz, 3 H, OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 170.1 (C2), 160.0 (C5), 138.5
(C1¢), 128.8, 128.7, 126.7, 61.6 (OCH2CH3), 55.6 (C3), 48.1 (C6),
47.3 (PhCH2CH2N), 33.3 (PhCH2CH2N), 20.9 (C3-CH3), 14.2
(OCH2CH3).
Anal. Calcd for C15H20N2O2 (260): C, 69.20; H, 7.74; N, 10.76.
Found: C, 68.80; H, 7.31; N, 11.02.
(3S)-5-Ethoxy-3-methyl-1-(2-naphthylmethyl)-3,6-dihydropy-
razin-2(1H)-one (2d)
Following the general procedure for 2 using 1d (1 g, 3.73 mmol)
and triethyloxonium tetrafluoroborate (2.48 g, 13.05 mmol) gave 2d
(0.92 g, 83%) as an oil.
IR (NaCl): 3054, 2977, 1698, 1655, 1488 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.82–7.23 (m, 7 H, Ar-H), 4.76–
4.70 (AB system, J = 14.5 Hz, 2 H, naphthyl-CH2N), 4.30–4.00 (m,
3 H, OCH2CH3, H3), 3.97 (d, J = 16.9 Hz, 1 H, C6), 3.73 (d,
J = 16.9 Hz, 1 H, C6), 1.47 (d, J = 7.2 Hz, 3 H, C3-CH3), 1.20 (t,
J = 7.1 Hz, 3 H, OCH2CH3).
5-Ethoxy-3-methyl-3,6-dihydropyrazine-2(1H)-ones 2; General
Procedure
Triethyloxonium tetrafluoroborate (3.5 equiv) was added to a soln
of 123 (1 g, 1 equiv) in CH2Cl2 (50 mL) in the presence of anhyd
Na2CO3 (1.3 g) and the mixture was stirred at r.t. under argon for 24
h. The mixture was then poured onto crushed ice, the organic phase
was separated, and the aqueous phase was extracted with CH2Cl2
(3 × 50 mL). The combined organic layers were dried (Na2SO4) and
evaporated to yield the crude compound, which could be used for
the next reaction with no further purification. For analytical purpos-
es, samples could be purified by column chromatography (silica gel,
CH2Cl2). Compound 2a17 is known in the literature and 2e was not
isolated. Data for 2b–d are given.
13C NMR (63 MHz, CDCl3): d = 169.9 (C2), 156.5 (C5), 133.1,
132.8, 128.8, 127.6, 127.3, 126.3, 126.1, 125.9, 61.3 (OCH2CH3),
55.4 (C3), 49.2 (C6), 45.5 (naphthyl-CH2N), 21.1 (C3-CH3), 14.1
(OCH2CH3).
Anal. Calcd for C18H20N2O2 (296): C, 72.95; H, 6.80; N, 9.45.
Found: C, 72.45; H, 6.70; N, 9.13.
Pyrazinoquinazolines 3; General Procedures
Conventional Heating; Method A
A mixture of 2 (1 equiv) and anthranilic acid (2.2 equiv) was heated
at 140 °C for 2 h under argon. After cooling, the mixture was treated
with 25% NH4OH soln and extracted with CHCl3. The organic layer
was dried (Na2SO4) and concentrated to give crude product that was
purified by column chromatography (silica gel, CH2Cl2). Com-
pounds 3a17 and 3e23c are known in the literature. Data for 3b–d are
given.
(3S)-5-Ethoxy-1-(4-methoxybenzyl)-3-methyl-3,6-dihydropy-
razin-2(1H)-one (2b)
Following the general procedure for 2 using 1b (1 g, 4.03 mmol)
and triethyloxonium tetrafluoroborate (2.68 g, 14.1 mmol) gave 2b
(0.84 g, 76%) as an oil.
[a]D25 +3.7 (c 0.29, CHCl3).
IR (NaCl): 2975, 1700, 1653, 1512, 1489 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.15 (d, J = 8.8 Hz, 2 H, H2¢, H6¢),
6.83 (d, J = 8.8 Hz, 2 H, H3¢, H5¢), 4.51 (d, J = 14.3 Hz, 1 H, Ar-
CH2N), 4.47 (d, J = 14.3 Hz, 1 H, Ar-CH2N), 4.20–4.00 (m, 3 H,
OCH2CH3, H3), 3.80 (s, 3 H, OCH3), 3.77 (d, J = 16.9 Hz, 1 H, H6),
3.67 (d, J = 16.9 Hz, 1 H, H6), 1.42 (d, J = 7.3 Hz, 3 H, C3-CH3),
1.21 (t, J = 7.1 Hz, 3 H, OCH2CH3).
Microwave-Assisted Conditions; Method B
A 10-mL flask containing a mixture of 2 (1 equiv) and anthranilic
acid (1.1 equiv) was completely submerged in alumina, contained
in a beaker, and irradiated for 1 min at 600 W in a domestic micro-
wave oven. The reaction was left to cool for 1 min and submitted to
2 additional irradiation–cooling cycles. The solid thus obtained was
chromatographed (silica gel, petroleum ether–EtOAc gradients) to
yield 3.
13C NMR (63 MHz, CDCl3): d = 169.91 (C2), 159.40 (C5), 156.72
(C4¢), 129.81 (C3¢, C5¢), 127.9 (C1¢), 114.3 (C2¢, C6¢), 61.6
(OCH2CH3), 55.5, 55.4 (CH3O, C3), 48.6, 45.5 (C6, Ar-CH2N),
21.3 (C3-CH3), 14.2 (OCH2CH3).
(4S)-2,4-Dimethyl-2H-pyrazino[2,1-b]quinazoline-3,6(1H,4H)-
dione (3a)
Following the general procedure for 3, method A (literature
procedure17) gave 3a in 38% yield; method B using 2a17 (100 mg,
0.59 mmol) and anthranilic acid (88 mg, 0.65 mmol) gave 3a (90
mg, 63%) as a white solid.
Anal. Calcd for C15H20N2O3 (276): C, 65.20; H, 7.30; N, 10.14.
Found: C, 65.14; H, 6.94; N, 9.81.
(3S)-5-Ethoxy-3-methyl-1-phenethyl-3,6-dihydropyrazin-
2(1H)-one (2c)
Following the general procedure for 2 using 1c (1 g, 4.31 mmol) and
triethyloxonium tetrafluoroborate (2.87 g, 15.1 mmol) gave 2c
(0.94 g, 84%) as a syrup.
[a]D25 –2.5 (c 0.11, CHCl3).
IR (NaCl): 3027, 2978, 1698, 1653, 1493 cm–1.
(4S)-2-(4-Methoxybenzyl)-4-methyl-2H-pyrazino[2,1-
b]quinazoline-3,6(1H,4H)-dione (3b)
Following the general procedure for 3, method A using 2b (300 mg,
1.08 mmol) and anthranilic acid (340 mg, 2.42 mmol) gave 3b (80
mg, 22%) as a colorless syrup; method B using 2b (195 mg, 0.71
mmol) and anthranilic acid (116 mg, 0.85 mmol) gave 3b (143 mg,
58%) as a colorless syrup.
[a]D25 –56.14 (c 0.34, CH2Cl2).
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PAPER
Microwave-Assisted Quinazoline Alkaloid Synthesis
3395
IR (KBr): d = 2947, 1675, 1607, 1555, 1508, 1472 cm–1.
with triethyloxonium tetrafluoroborate (246 mg, 1.29 mmol). The
crude 2e thus obtained was mixed with anthranilic acid (66 mg, 0.48
mmol). After cooling, the mixture was subjected to column chroma-
tography (silica gel) to afford 3e23c (66 mg, 48%) as a white solid.
1H NMR (250 MHz, CDCl3): d = 8.22 (d, J = 8 Hz, 1 H, H7), 7.74
(t, J = 7.2 Hz, 1 H, H9), 7.54 (d, J = 8.0 Hz, 1 H, H10), 7.46 (t,
J = 8.0 Hz, 1 H, H8), 7.21 (d, J = 6.8 Hz, 2 H, H2¢, H6¢), 6.85 (d,
J = 6.8 Hz, 2 H, H3¢, H5¢), 5.50 (q, J = 7.2 Hz, 1 H, H4), 4.81 (d,
J = 14.4 Hz, 1 H, Ar-CH2N), 4.47 (d, J = 14.4 Hz, 1 H, Ar-CH2N),
4.44 (d, J = 16.9 Hz, 1 H, C1), 4.33 (d, J = 16.9 Hz, 1 H, H1), 3.77
(s, 3 H, OCH3), 1.57 (d, J = 7.2 Hz, 3 H, C4-CH3).
13C NMR (63 MHz, CDCl3): d = 167.45 (C3), 159.7 (C6), 151.1
(C4¢), 148.1 (C11a), 147.2 (C10a), 134.9, 129.9, 129.4, 127.4,
127.3, 127.2, 127.0, 120.6, 115.2, 114.6, 55.4 (CH3O), 52.2 (C4),
49.2 (Ar-CH2-N), 49.1 (C1), 17.2 (CH3).
6-Methyl-3-[(1-tosyl-1H-indol-3-yl)methylene]piperazine-2,5-
diones 5c and 6c
To a cooled (0 °C), stirred soln of (3S)-1,4-diacetyl-3-methylpiper-
azine-2,5-dione (4,25 488 mg, 2.3 mmol) and 1-tosyl-1H-indole-3-
carbaldehyde (1 g, 3.4 mmol) in anhyd DMF (5 mL), maintained
under argon, was added dropwise t-BuOK (1 M in t-BuOH; 2.4 mL,
2.4 mmol). The soln was stirred at r.t. for 16 h, neutralized with
AcOH and poured onto ice (25–50 g), giving a precipitate which
was filtered. The filtrate was extracted with EtOAc (3 × 50 mL),
which was dried (Na2SO4) and evaporated. The residue was mixed
with the precipitate initially obtained and this mixture was purified
by column chromatography (silica gel, petroleum ether–EtOAc,
gradient starting from 5:1) to give 5c (153 mg, 15%) and 6c (152
mg, 16%).
Anal. Calcd for C20H19N3O3 (349): C, 68.75; H, 5.48; N, 12.03.
Found: C, 68.46; H, 6.01; N, 11.89.
(4S)-4-Methyl-2-phenethyl-2H-pyrazino[2,1-b]quinazoline-
3,6(1H,4H)-dione (3c)
Following the general procedure for 3, method A using 2c (90 mg,
3.46 mmol) and anthranilic acid (1.09 g, 7.95 mmol) gave 3c (450
mg, 39%) as a white solid; method B using 2c (290 mg, 1.11 mmol)
and anthranilic acid (193 mg, 1.41 mmol) gave 3c (190 mg, 51%)
as a colorless syrup; mp 106–08 °C.
(6S,3Z)-1-Acetyl-6-methyl-3-[(1-tosyl-1H-indol-3-yl)methyl-
ene]piperazine-2,5-dione (5c)
Mp 211–213 °C.
[a]D25 –3.8 (c 0.13, CHCl3).
IR (KBr): 3083, 1693, 1380, 1175 cm–1.
[a]D25 +59.64 (c 0.34, CH2Cl2).
IR (KBr): d = 3428, 2979, 1682, 1667, 1598 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.91 (s, 1 H, H4), 8.00 (d, J = 8.0
Hz, 1 H, H7¢), 7.89 (s, 1 H, H2¢), 7.83 (d, J = 8.4 Hz, 2 H, H2¢¢,
H6¢¢), 7.61 (d, J = 7.1 Hz, 1 H, H4¢), 7.41–7.24 (m, 5 H, H5¢, H6¢,
H3¢¢, H5¢¢, Ha), 5.19 (q, J = 7.1 Hz, 1 H, H6), 2.59 (s, 3 H, COCH3),
2.35 (s, 3 H, C6H4CH3), 1.21 (d, J = 6.9 Hz, 3 H, C6-CH3).
13C NMR (63 MHz, CDCl3): d = 172.0 (COCH3), 167.5 (C5), 160.8
(C2), 145.8 (C1¢¢), 134.8 (C7a¢), 134.7 (C4¢¢), 130.3 (C3¢¢, C5¢¢),
129.4 (C3a¢), 127.2 (C2¢¢, C6¢¢), 126.1 (C2¢), 125.8 (C3), 125.5 and
124.2 (C4¢ and C5¢), 119.7 (C6¢), 114.7 (C3¢), 113.9 (C7¢), 110.7
(Ca), 53.0 (C6), 27.0 (COCH3), 21.8 (C6H4CH3), 19.9 (C6-CH3).
1H NMR (250 MHz, CDCl3): d = 8.25 (d, J = 8 Hz, 1 H, H7), 7.74
(t, J = 8.4 Hz, 1 H, H9), 7.55 (d, J = 8.1 Hz, 1 H, H10), 7.47 (t,
J = 7.1 Hz, 1 H, H8), 7.22–7.09 (m, 5 H, Ph), 5.41 (q, J = 7.2 Hz, 1
H, H4), 4.32 (d, J = 16.7 Hz, 1 H, H1), 4.14 (d, J = 16.7 Hz, 1 H,
H1), 4.12 (m, 1 H, PhCH2CH2N), 3.51 (m, 1 H, PhCH2CH2N),
3.01–2.91 (m, 2 H, PhCH2CH2N), 1.47 (d, J = 7.2 Hz, 3 H, C4-
CH3).
13C NMR (63 MHz, CDCl3): d = 167.4 (C3), 160.0 (C6), 148.0
(C11a), 147.2 (C10a), 138.0, 134.9, 128.9, 128.9, 127.4, 127.1,
127.0, 126.9, 120.5, 52.3 (C4), 51.1 (PhCH2CH2N), 48.7 (C1), 33.7
(PhCH2CH2N), 16.8 (CH3).
Anal. Calcd for C23H21N3O5S (451): C, 61.19; H, 4.69; N, 9.31.
Found: C, 60.80; H, 4.67; N, 9.07.
Anal. Calcd for C20H19N3O2 (333): C, 72.05; H, 5.74; N, 12.60.
Found: C, 72.31; H, 6.06; N, 12.95.
(3S,6Z)-3-Methyl-6-[(1-tosyl-1H-indol-3-yl)methylene]piper-
azine-2,5-dione (6c)
Mp 261–263 °C.
[a]D25 –32.5 (c 0.08, DMSO).
IR (KBr): 3205, 3062, 1674, 1372, 1168 cm–1.
1H NMR (250 MHz, CDCl3): d = 10.18 (br s, 1 H, H1), 8.52 (br s, 1
H, H4), 8.34 (s, 1 H, H2¢), 7.98 (d, J = 8.3 Hz, 2 H, H2¢¢, H6¢¢), 7.89
(d, J = 7.8 Hz, 1 H, H7¢), 7.66 (d, J = 7.9 Hz, 1 H, H4¢), 7.39 (d,
J = 8.2 Hz, 2 H, H3¢¢, H5¢¢), 7.32–7.28 (m, 2 H, H5¢, H6¢), 6.70 (s, 1
H, Ha), 4.19 (q, J = 7.0 Hz, 1 H, H3), 2.30 (s, 3 H, C6H4CH3), 1.36
(d, J = 6.9 Hz, 3 H, C3-CH3).
13C NMR (63 MHz, CDCl3): d = 167.9 (C5), 159.8 (C2), 145.6
(C1¢¢), 133.8 (C7a¢), 133.4 (C4¢¢), 130.2 (C3¢¢, C5¢¢), 129.8 (C3a¢),
127.4 (C2¢), 126.9 (C2¢¢, C6¢¢), 125.7 (C3), 125.2 (C4¢), 123.7 (C5¢),
119.4 (C6¢), 114.1 (C3¢), 113.0 (C7¢), 103.0 (Ca), 50.3 (C6), 21.00
(C6H4CH3), 19.2 (C3-CH3).
(4S)-4-Methyl-2-(2-naphthylmethyl)-2H-pyrazino[2,1-
b]quinazoline-3,6(1H,4H)-dione (3d)
Following the general procedure for 3, method A using 2d (0.30 g,
1.01 mmol) and anthranilic acid (0.31 g, 2.26 mmol) gave 3d (0.18
g, 48%) as a white solid. Method B using 2d (166 mg, 0.56 mmol)
and anthranilic acid (95 mg, 0.70 mmol) gave 3d (121 mg, 58%) as
a white solid; mp 140–42 °C.
IR (KBr): 3428, 2979, 1682, 1667, 1598 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.24 (d, J = 7.9 Hz, 1 H, H7),
7.89–7.67 (m, 5 H Ar), 7.54–7.36 (m, 5 H, Ar), 5.55 (q, J = 7.2 Hz,
1 H, H4), 5.02 (d, J = 14.4 Hz, 1 H, ArCH2N), 4.69 (d, J = 14.4 Hz,
1 H, ArCH2N), 4.47 (d, J = 16.9, 1 H, H1), 4.36 (d, J = 16.9, 1 H,
H1), 1.60 (d, J = 7.2 Hz, 3 H, C4-CH3).
13C NMR (63 MHz, CDCl3): d = 167.5 (C3), 160.0 (C6), 151.1
(C2¢), 148.1 (C11a), 147.2 (C10a), 136.3, 134.8, 127.3, 127.2,
126.9, 126.9, 122.4, 122.2, 120.5, 119.7, 118.5, 112.3, 111.4, 52.3
(C4), 51.1 (Ar-CH2-N), 48.2 (C1), 16.8 (C4-CH3).
Anal. Calcd for C23H21N3O5S (409): C, 61.60; H, 4.68; N, 10.26.
Found: C, 61.36; H, 4.60; N, 10.10.
Anal. Calcd for C23H19N3O2 (369): C, 74.78; H, 5.18; N, 11.37.
Found: C, 75.19; H, 5.49; N, 11.08.
Formation of 6c by Deacetylation of 5c with Hydrazine Hydrate
To a soln of 5c (0.250 g, 0.554 mmol) in DMF (5 mL), cooled to 0
°C and kept under argon, was added 80% hydrazine monohydrate
(25 mL, 1.031 mmol). The mixture was stirred at r.t. for 3 h and
poured onto crushed ice. 6c (170 mg, 75%) precipitated as a white
(1S,4S)-2-(1H-Indol-3-ylmethyl)-1,4-dimethyl-2H-pyrazi-
no[2,1-b]quinazoline-3,6(1H,4H)-dione (3e)
Method A: This procedure has been previously described23c and was
used to give 3e in 16% overall yield from 1e. Method B: Following
the general procedure for 2, 1e23c (100 mg, 0.37 mmol) was treated
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3396
P. Cledera et al.
PAPER
solid that was filtered and dried overnight in vacuo in the presence
of P2O5.
Anal. Calcd for C28H22N4O4S (510): C, 65.87; H, 4.34; N, 10.97.
Found: C, 65.50; H, 4.63; N, 10.59.
(3S,6Z)-5-Ethoxy-3-methyl-6-(1-tosyl-1H-indol-3-ylmethyl-
ene]piperazin-2-one (7c)
Following the general procedure for 2 using 6c (100 mg, 0.24
mmol), triethyloxonium tetrafluoroborate (55 mg, 0.29 mmol),
Na2CO3 (154 mg), and CH2Cl2 (3.5 mL), followed by chromatogra-
phy (silica gel, petroleum ether–EtOAc, 4:1) gave 7c (92 mg, 86%)
as a colorless viscous oil.
Deprenylardeemin Analogue 10
Following the general procedure for 3, method B using 931 (110 mg,
0.34 mmol) and anthranilic acid (138 mg, 1.00 mmol) gave 1018 (78
mg, 58%) as a white solid.
Deprenylardeemin Analogues 12 and 13
Following the general procedure for 3, method B using 1131 (90 mg,
0.27 mmol) and anthranilic acid (81 mg, 0.59 mmol) gave 1218 (45
mg, 41%) and 1318 (8 mg, 7%), both as white solids.
IR (KBr): 3117, 1679, 1637 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.02 (d, J = 8.1 Hz, 2 H, H2¢¢,
H6¢¢), 7.81 (d, J = 8.4 Hz, 2 H, H3¢¢, H5¢¢), 7.69 (s, 1 H, H2¢), 7.58
(br s, 1 H, H1), 7.55–7.24 (m, 4 H, H4¢, H5¢, H6¢, H7¢), 6.51 (s, 1 H,
Ha), 4.43–4.20 (m, 3 H, H3, OCH2CH3), 2.35 (s, 3 H, C6H4CH3),
1.55 (d, J = 8.1 Hz, 3 H, C3-CH3), 1.39 (q, J = 7.0 Hz, 3 H,
OCH2CH3).
13C NMR (63 MHz, CDCl3): d = 170.5 (C5), 152.3 (C2), 145.3
(C1¢¢), 134.7 (C7a¢), 134.7 (C4¢¢), 129.9 (C3¢¢, C5¢¢), 129.4 (C2¢),
126.8 (C2¢¢, C6¢¢), 125.5 (C3a¢), 124.8 (C6¢), 123.7 (C4¢, C5¢), 119.7
(C7¢), 115.0 (C6), 113.7 (C3¢), 99.8 (Ca), 62.0 (OCH2CH3), 55.8
(C3), 21.4 (OCH2CH3), 21.4 (C6H5CH3), 14.1 (C3-CH3).
(5bS)-5b,6,7,8-Tetrahydropyrrolo[2,1-c]quinazolino[3,2-
a][1,4]benzodiazepin-10,16-dione (16)
Following the general procedure for 3, method B using 1528 (100
mg, 0.43 mmol) and anthranilic acid (66 mg, 0.47 mmol) and 5 × 1
min irradiation gave 16 (55 mg, 40%) as a white solid; mp 239–41
°C.
1H NMR (250 MHz, CDCl3): d = 8.32 (dd, J = 7.8, 1.4 Hz, 1 H,
H1), 8.00 (dd, J = 6.8, 1.6 Hz, 1 H, H11), 7.79 (dt, J = 6.8, 1.8 Hz,
1 H, H2), 7.71 (dd, J = 7.5, 0.8 Hz, 1 H, H14), 7.60–7.45 (m, 4 H,
H3, H4, H12, H13), 4.54 (d, J = 6.2 Hz, 1 H, H5b), 3.85–3.74 (m, 1
H, H8), 3.69–3.57 (m, 1 H, H8), 3.23–3.15 (m, 1 H, H6), 2.36–1.90
(m, 3 H, H6, H7).
Anal. Calcd for C23H23N3O4S (437): C, 63.14; H, 5.30; N, 9.60.
Found: C, 62.83; H, 5.45; N, 9.31.
13C NMR (63 MHz, CDCl3): d = 164.9 (C10), 162.1 (C16), 154.0
(C10a), 146.5 (C16a), 135.2 (C2), 133.6 (C14a), 132.7 (C4a), 131.2
(C12), 130.3 (C11), 129.1 (C13), 128.7 (C3), 128.0 (C4), 128.0
(C14), 127.9 (C1), 59.3 (C5), 46.9 (C8), 27.4 (C6), 24.1 (C7).
1-(Arylmethylene)pyrazinoquinazolines 8; General Procedures
Following the general procedures for 3, methods A and B, the mi-
crowave-assisted reactions required 9 × 1 min irradiation pulses,
with intermediate 1 min cooling periods. 8a and 8b are known in the
literature.25
Anal. Calcd for C19H15N3O2 (317): C, 71.91; H, 4.76; N, 13.24.
Found: C, 71.62; H, 5.03; N, 12.99.
(4S,1Z)-1-(4-Methoxybenzylidene)-4-methyl-2H-pyrazino[2,1-
b]quinazoline-3,6(1H,4H)-dione (8a)
Following the general procedure for 3, method A, the preparation of
8a has been previously described;25 method B using 7a25 (15 mg,
0.054 mmol) and anthranilic acid (8 mg, 0.060 mmol) with 9 × 1
min irradiation gave 8a (5 mg, 26%) as a white solid.
6,14-Dihydropyrazino[2,1-b:5,4-b¢]diquinazoline-8,16-dione
(18)
2,5-Diethoxy-3,6-dihydropyrazine (17)
To a suspension of piperazine-2,5-dione (1 g, 8.77 mmol) in anhyd
CH2Cl2 (100 mL) under argon, was added triethyloxonium tetraflu-
oroborate (3.019 g, 15.89 mmol). The suspension was stirred at r.t.
for 48 h and then poured on a buffer soln prepared from Na2HPO4·2
H2O (4.688 g, 26.31 mmol), NaH2PO4·H2O (1.21 g. 8.77 mmol),
and H2O (30 mL). The CH2Cl2 phase was separated and the aqueous
layer was extracted with CH2Cl2 (3 × 25 mL). The combined organ-
ic layers were dried (Na2SO4) and evaporated, giving 17 (956 mg,
64%) as a colorless oil that solidified upon cooling at –18 °C.32
IR (KBr): 1709 cm–1.
1H NMR (250 MHz, CDCl3): d = 4.02 (s, 4 H, H3, H6), 4.12 (q,
J = 7.1 Hz, 4 H, 2 OCH2CH3), 1.30 (t, J = 7.1 Hz, 6 H, 2 OCH2CH3).
(4S,1Z)-4-Isopropyl-1-(4-methoxybenzylidene)-2H-pyrazi-
no[2,1-b]quinazoline-3,6(1H,4H)-dione (8b)
Previously prepared using the Eguchi protocol.25 Following the
general procedures for 2 and 3, method B using 6b (100 mg, 0.36
mmol), triethyloxonium tetrafluoroborate (82 mg, 0.431 mmol),
Na2CO3 (230 mg), and CH2Cl2 (5 mL) gave 7b (60 mg, 54%) as a
colorless oil, together with recovered starting material (30 mg,
33%). The microwave-assisted reaction between crude 7b (16 mg,
0.058 mmol) and anthranilic acid (9 mg, 0.067 mmol) using 9 × 1
min irradiation gave 8b (9 mg, 25% overall from 6b) as a pale or-
ange oil.
13C NMR (63 MHz, CDCl3): d = 162.6 (C2, C5), 61.3 (2
OCH2CH3), 46.9 (C3, C6), 14.6 (2 OCH2CH3).
(4S,1Z)-4-Methyl-1-(1-tosyl-1H-indol-3-ylmethylene)-2H-
pyrazino[2,1-b]quinazoline-3,6(1H,4H)-dione (8c)
Anal. Calcd for C8H14N2O2 (170): C, 56.45; H, 8.29; N, 16.46.
Found: C, 56.18; H, 8.27; N, 16.22.
Following the general procedure for 3, method B using 7c (90 mg,
0.206 mmol) and anthranilic acid (35 mg, 0.260 mmol) and 9 × 1
min irradiation gave 8c (20 mg, 19%) as a white solid.
[a]D25 –80.0 (c 0.02, CHCl3).
Three-Component Cyclocondensation of 17 with Two Equiva-
lents of Anthranilic Acid
Following the general procedure for 3, method B using 17 (200 mg,
1.18 mmol) and anthranilic acid (483 mg, 3.53 mmol) with 6 × 1
min irradiation pulses, and washing the mixture with Et2O gave 18
(332 mg, 89%) as a white solid; mp >300 °C.
IR (NaCl): 3400, 1681 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.29 (d, J = 7.9 Hz, 1 H, H7), 8.68
(s, 1 H, NH), 8.01 (d, J = 8.1 Hz, 1 H, H7¢), 7.91 (t, J = 7.8 Hz, 1 H,
H8), 7.83 (d, J = 8.3 Hz, 1 H, H10), 7.78 (d, J = 7.8 Hz, 1 H, H9),
7.67 (d, J = 8.0 Hz, 2 H, H2¢, H6¢), 7.62 (d, J = 6.4 Hz, 1 H, H4¢),
7.45–7.31 (m, 3 H, H2¢, H5¢, H6¢), 7.21 (s, 1 H, Ha), 7.05 (d, J = 8.1
Hz, 2 H, H3¢, H5¢), 5.52 (q, J = 6.7 Hz, 1 H, H4), 2.18 (s, 3 H,
C6H4CH3), 1.59 (d, J = 6.7 Hz, 3 H, C4-CH3).
IR (KBr): 1689, 1607 cm–1.
1H NMR (250 MHz, CDCl3): d = 8.18 (d, J = 7.9 Hz, 2 H, H4, H12),
7.87 (t, J = 7.1 Hz, 2 H, H3, H11), 7.71 (d, J = 7.6 Hz, 2 H, H1, H9),
7.57 (d, J = 8.0 Hz, 2 H, H2, H10), 5.31 (s, 4 H, H6, H14).
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Microwave-Assisted Quinazoline Alkaloid Synthesis
3397
13C NMR (63 MHz, CDCl3): d = 159.8 (C8, C16), 149.9 (C5a,
C13a), 147.4 (C4a, C12a), 135.2 (C3, C11), 127.5 (C1, C9), 127.4
(C2, C10), 126.7 (C4, C12), 120.5 (C8a, C16a), 44.8 (C6, C14).
Menéndez, J. C. J. Org. Chem. 2000, 65, 1743.
(f) Hernández, F.; Lumetzberger, A.; Avendaño, C.;
Söllhuber, M. M. Synlett 2001, 1387. (g) Snider, B. B.;
Zeng, H. Org. Lett. 2002, 4, 1087. (h) Snider, B. B.; Zeng,
H. J. Org. Chem. 2003, 68, 545; see also refs. 14, 15, and 22.
(12) Ardeemins, see: (a) Marsden, S. P.; Depew, K. M.;
Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143.
(b) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski,
A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc.
1999, 121, 11953.
(13) Circumdatins and related natural products, see: (a) Bock,
M. G.; Dipardo, R. M.; Pitzenberger, S. M.; Homnick, C. F.;
Springer, J. P.; Freidinger, R. M. J. Org. Chem. 1987, 52,
1644. (b) He, F.; Foxman, B. M.; Snider, B. B. J. Am. Chem.
Soc. 1998, 120, 6417. (c) Sugimori, T.; Okawa, T.; Eguchi,
S.; Kakehi, A.; Yashima, E.; Okamoto, Y. Tetrahedron
1998, 54, 7997. (d) Snider, B. B.; Busuyek, M. V.
Tetrahedron 2001, 57, 3301. (e) Witt, A.; Bergman, J. J.
Org. Chem. 2001, 66, 2784. (f) Grieder, A.; Thomas, A. W.
Synthesis 2003, 1707; see also ref. 26.
(14) (a) Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432.
(b) Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022.
(15) (a) He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397.
(b) Snider, B. B.; Zeng, H. J. Org. Chem. 2003, 68, 545.
(16) For a review, see: Eguchi, S. ARKIVOC 2005, (ii), 98.
(17) (a) Rajappa, S.; Advani, B. G. Tetrahedron 1973, 29, 1299.
(b) Rajappa, S.; Advani, B. G. J. Chem. Soc., Perkin Trans.
1 1974, 2122.
Anal. Calcd for C18H12N4O2 (316): C, 68.35; H, 3.82; N, 17.71.
Found: C, 68.07; H, 3.85; N, 17.46.
Acknowledgment
We thank MEC (grant CTQ2006-10930/BQU) and CAM-UCM
(Grupos de Investigación, grant 920234) for financial support of
this research. The stays of T.Y. and E.G.R. in Madrid were suppor-
ted, respectively, by fellowships from Universidad de Concepción
and Fundación Carolina, which are also gratefully acknowledged.
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