Acid-promoted reactions in 1-hydroxy, 1-dimethylaminomethyl and 1-methylene-4-arylmethyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones

Article abstract of DOI:10.1016/S0040-4020(02)00619-1

The 1-dimethylaminomethyl or 1-methylene group of the title compounds was introduced through a Mannich or a tandem of Mannich-Hofmann reactions as the final step of a protocol that is shorter than other previously described for these precursors of N-acyliminium species. In these compounds, the acid-promoted intramolecular cyclizations of Pictet-Spengler-type were restricted to the N(2)-unsubstituted compounds, while their N(2)-methyl substituted analogues gave instead dimerization products. The cyclization was effective with 1-hydroxy-1,2-disubstituted compounds, which were obtained through addition of a Grignard reagent to 2H,4H-pyrazino[2,1-b]quinazoline-1,3,6-triones.

Full text of DOI:10.1016/S0040-4020(02)00619-1

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 6163±6170
Acid-promoted reactions in 1-hydroxy, 1-dimethylaminomethyl
and 1-methylene-4-arylmethyl-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-diones
p
Â
Marõa Luisa Heredia, Elena de la Cuesta and Carmen AvendanÄo
  Â
Departamento de Quõmica Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 2 May 2002; revised 22 May 2002; accepted 17June 2002
AbstractÐThe 1-dimethylaminomethyl or 1-methylene group of the title compounds was introduced through a Mannich or a tandem of
Mannich±Hofmann reactions as the ®nal step of a protocol that is shorter than other previously described for these precursors of N-acyli-
minium species. In these compounds, the acid-promoted intramolecular cyclizations of Pictet±Spengler-type were restricted to the
N(2)-unsubstituted compounds, while their N(2)-methyl substituted analogues gave instead dimerization products. The cyclization was
effective with 1-hydroxy-1,2-disubstituted compounds, which were obtained through addition of a Grignard reagent to 2H,4H-pyrazino[2,1-b]-
quinazoline-1,3,6-triones. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Several fungal metabolites such as glyantripine,1 fumi-
quinazolines F and G,2,3 ®scalin B,4,5 N-acetylardeemin,6,7
and some spiro compounds such as fumiquinazoline C,2,3
spiroquinazoline8 and alantrypinone9 (Fig. 1), contain a
pyrazino[2,1-b]quinazoline-3,6-dione moiety and an indole
ring. With the exception of N-acetylardeemin, the
N(2)-nitrogen atom in all these natural products is unsubsti-
tuted, this circunstance being relevant for their synthetic
approaches.
(1)-Dehydrofumiquinazoline G, which is the 1-methylene
derivative of (1)-glyantrypine, was ®rst prepared by Snider
in a thirteen-step protocol, in which the methylene group
was originated in a preliminar step by acid-promoted
cyclization of N-pyruvyl-N0-dimethoxybenzyl-2,3-dihydro-
N-tri¯uoroacetyl-l-tryptophanamide.10
Dehydrofumiquinazoline G and other 1-methylene ana-
logues (A, Scheme 1), were also obtained following a
simpler protocol in which the methylene group was elabo-
rated by elimination of an HXR portion in 1-RX±CH2-
substituted pyrazino[2,1-b]quinazoline-3,6-diones. These
compounds were obtained through a Mazurkiewicz±
Ganesan cyclyzation11±14 of `tripeptides' having tryptophan
(or the adequate indole modi®ed derivative), anthranilic
acid, and N-Fmoc protected dehydroalanine precursors
Keywords: N-acyliminium; Pictet±Spengler-type reaction; dehydrofumi-
quinazoline; alantrypinone.
p
Corresponding author. Fax: 134-91-3941822;
e-mail: avendano@farm.ucm.es
Figure 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00619-1

6164
M. L. Heredia et al. / Tetrahedron 58 (2002) 6163±6170
(O-acetyl or O-tosylserine, S-methylcysteine and phenyl-
selenylalanine), as the ®rst, second and N-terminal residues,
respectively. The electrophilic species generated by proto-
nation of the double bond (B) were trapped by a nucleo-
philic position of the `indole' substituent or by methanol to
give precursors of (1)-alantrypinone and fumiquinazolines
C, E and H (Scheme 1).15,16
We have previously described that 2,4-disubstituted pyra-
zino[2,1-b]quinazoline-3,6-diones behave as nucleophilic
glycine templates in which a 1-dimethyl-aminomethyl or
1-methylene group can be introduced through a Mannich
or a tandem of Mannich±Hofmann reactions, respec-
tively.17,18 Attempts to use these compounds as precursors
of N-acyliminium species (N-alkyl substituted B), by
protonation and elimination of dimethylamine or by direct
protonation, to be trapped by the ortho-position of a
2-phenethyl substituent failed. However, this acid promoted
Pictet±Spengler cyclization worked for 1-substituted
1-hydroxy-2-phenethylpyrazino-[2,1-b]quinazoline-3,6-
diones, which were obtained from oxidation at C(1) and
subsequent addition of organometallics.19
Here, we extend this study to the 4-arylmethyl compounds
(1±5).
Scheme 1.
2. Results and discussion
Compounds 1±5 were prepared following standard
methods20,21 (Scheme 2).
Compound 3 gave, as expected, the corresponding 1-methyl-
ene derivative 6, but this compound dimerized in TFA to
give 7 instead of a cyclization product arising from a Pictet±
Spengler-type reaction.
This result can be explained by assuming that the steric
constraints imposed by the N(2)-substituent prevent the
stabilization of the carbocation I formed by protonation of
Scheme 2.
Scheme 3.

M. L. Heredia et al. / Tetrahedron 58 (2002) 6163±6170
6165
Scheme 6.
the exocyclic double bond, giving instead protonated
species at N(11) (II, Scheme 3).17,18
In order to obtain alternative precursors of the desired
N-acyliminium species, compound 3 was treated with
PCC to give 8 which, after organometallic addition to the
more electrophilic C(1)-carbonyl group, gave 9. Its 1R,4S-
stereochemistry was unequivocally established by NOE
experiments, and was in accordance to the expected syn
addition.19 This compound was cyclized in TFA to give
the Pictet±Spengler reaction product 10 (Scheme 4).
Scheme 4.
The N(2)-unsubstituted compounds 1 and 2 could not be
conveniently derived to their 1-dimethylaminomethyl or
1-methylene analogues because they over-react with bis(di-
methylamino) methane in anhydrous tri¯uoroacetic acid. In
the case of 1, only traces of 11 were obtained,22 being 12 the
main reaction product. This compound may be formed by
addition of the Mannich reagent to the enamide 11.
Compound 2 gave in the same reaction conditions a mixture
of compounds 13, its N-alkyl derivative 14, and the cyclized
products 15 (precursor of (2)-alantrypinone) and 16
(Scheme 5).
A possible rationalization to explain formation of
compound 16 is shown in Scheme 6.
Scheme 5.
Scheme 7.

6166
M. L. Heredia et al. / Tetrahedron 58 (2002) 6163±6170
To diminish the unexpected reactivity towards the Mannich
reagent of the N-unsubstituted enamides, the N-Boc
protected compounds 4 and 5 were used as starting
materials, giving mixtures of dimethylaminomethyl
compounds 17 and 19 and 1-methylene derivatives 18 and
20. One-pot treatment of the mixture of compounds 19 and
20 with tri¯uoroacetic acid produced the N-Boc-deprotec-
tion and the cyclization of 20 to give 15 in 40% yield. In
these conditions compound 19 must give 20 through a
Hofmann elimination (Scheme 7).
1.0 Hz), 5.72 (t, 1H, Jˆ4.6 Hz), 4.56 (d, 1H, Jˆ17.1 Hz),
3.48 (dd, 1H, Jˆ4.9 and 4.6 Hz), 2.78 (d, 1H, Jˆ17.1 Hz),
1.52 (s, 9H); dC (63 MHz, CDCl3) 166.8, 160.4, 150.2,
148.5, 147.5, 135.4, 135.1, 129.9, 129.5, 128.6, 127.7,
127.5, 127.4, 120.5, 85.3, 59.0, 47.5, 38.1, 28.3.
3.1.2. (2)-(4R)-2,10-Bis(t-butyloxycarbonyl)-4-(30indolyl-
methyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione (5). To a solution of glyantrypine [(4R)-2] (100 mg,
0.3 mmol) in dry CH2Cl2 (5 mL) was added, under nitrogen,
a solution of DMAP (74 mg, 0.6 mmol), Et3N (0.08 mL)
and di-t-butyldicarbonate (197mg, 0.9 mmol) in dry
CH2Cl2 (5 mL). The resulting solution was stirred for 3 h
at room temperature, quenched with 5% HCl and extracted
with CH2Cl2. The organic extracts were dried over MgSO4
and concentrated in vacuo. Chromatography separation
(EtOAc/hexane 1:2, silica gel) gave compound 5 as a
white solid (155 mg, 95%) [found: C, 65.90; H, 6.04; N,
10.40. C30H32N4O6 requires: C, 66.16; H, 5.92; N, 10.28];
In conclusion, we have developed an alternative protocol
to prepare 1-dimethylaminomethyl, 1-mehylene and 1-hy-
droxy-4-arylmethylpyrazino[2,1-b]quinazoline-3,6-diones
and have shown their ability to give Pictet±Spengler-type
cyclizations through N-acyliminium species.
3. Experimental
3.1. General
25
mp 170±718C; [a]D ˆ231 (c 0.33, CHCl3); nmax (KBr)
1732, 1686 cm21; dH (250 MHz, CDCl3) 8.30 (dd, 1H,
Jˆ8.0 and 1.5 Hz), 8.05 (d, 1H, Jˆ8.3 Hz), 7.77 (ddd,
1H, Jˆ7.6, 7.4 and 1.5 Hz), 7.56 (d, 1H, Jˆ7.4 Hz), 7.52
(ddd, 1H, Jˆ8.0, 7.6 and 1.1 Hz), 7.30 (d, 1H, Jˆ7.8 Hz),
7.24 (dt, 1H, Jˆ8.2 and 1.1 Hz), 7.10 (s, 1H), 7.03 (dt, 1H,
Jˆ7.6 and 0.9 Hz), 5.75 (dd, 1H, Jˆ5.7and 3.8 Hz), 4.58
(d, 1H, Jˆ17.2 Hz), 3.61 (dd, 1H, Jˆ14.8 and 3.8 Hz), 3.53
(dd, 1H, Jˆ14.8 and 5.7Hz), 3.30 (d, 1H, Jˆ17.2 Hz), 1.51
(s, 9H), 1.44 (s, 9H); dC (63 MHz, CDCl3) 166.7, 160.2,
149.6, 149.3, 147.9, 147.3, 135.5, 135.2, 129.6, 127.5,
127.1, 127.0, 125.2, 125.1, 123.2, 120.3, 118.6, 115.5,
113.8, 85.0, 84.9, 57.7, 47.6, 28.2, 27.9, 27.6.
All reagents were of commercial quality (Aldrich, Fluka,
SDS, Probus) and were used as received. Solvents (SDS,
Scharlau) were dried and puri®ed using standard techniques.
Reactions were monitored by thin layer chromatography, on
aluminium plates coated with silica gel or aluminium oxide
with ¯uorescent indicator (Merck 60 F254). Separations by
¯ash chromatography were performed on silica gel (Merck
60, 230±400 mesh) or aluminium oxide (Merck 90, 70±230
mesh). Melting points were uncorrected and were deter-
mined either using recrystallized samples or samples
which crystallized during concentration of the chroma-
tography eluents. Infrared spectra were recorded with
solid compounds compressed into KBr pellets. NMR
3.1.3. (1)-(4S)-4-Benzyl-2-methyl-2,4-dihydro-1H-pyra-
zino-[2,1-b]quinazoline-3,6-dione (3). To a stirred solution
of 3 g (11.3 mmol) of N-Boc-(l)-phenylalanine in 50 mL
dry CH2Cl2, under argon, methyl N-(methyl)glycinate
1
spectra were obtained at 250 or 300 MHz for H and at 63
Â
13
or 75 MHz for C (Servicio de Resonancia Magnetica
0
(2 g, 14.7mmol) and EDC [1-ethyl-3-(3 -(dimethylamino)
Nuclear, Universidad Complutense). When necessary,
assignments were aided by DEPT, COSY and 13C±1H corre-
lation experiments. Mass spectra were carried out by the
Â
Servicio de Espectroscopõa, Universidad Complutense.
Elemental analyses were determined by the Servicio de
Â
Microanalisis Elemental, UCM. Optical rotations were
measured at 258C on a 1 mL cell in CHCl3 or MeOH at
589 nm, concentrations being given in g/100 mL.
propyl] carbodiimide] (2.4 g, 13.56 mmol) were added and
stirring was continued overnight. The solution was washed
with 1N aqueous HCl (15 mL) and 1N aqueous NaHCO3
(15 mL), dried over Na2SO4 and evaporated to yield
(1)-Methyl-N0-(t-butyloxycarbonyl)-l-phenylalanyl-N-
methylglycinate as a syropous residue (3 g, 75%) [found: C,
61.38; H, 7.15; N, 7.82. C18H26N2O5 requires: C, 61.69; H,
25
7.47; N, 7.99]; [a]D ˆ114 (c 0.13, CHCl3); nmax (KBr)
2977, 1751, 1710 cm21; dH (250 MHz, CDCl3) 7.19±7.07
(m, 5H), 5.45 (d, 1H, Jˆ8.6 Hz), 4.79 (dd, 1H, Jˆ15.2 and
7.0 Hz), 4.02 (m, 2H), 3.59 (s, 3H), 2.94 (dd, 1H, Jˆ13.4
and 7.0 Hz), 2.83 (dd, 1H, Jˆ13.4 and 6.5 Hz), 1.29 (s, 9H);
dC (63 MHz, CDCl3) 172.2, 169.1, 154.9, 136.2, 129.4,
128.2, 126.6, 79.3, 51.9, 51.3, 49.3, 39.3, 36.0, 28.1.
3.1.1. (1)-(4S)-4-Benzyl-2-t-butyloxycarbonyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione (4). To a solu-
tion of 1 (100 mg, 0.3 mmol) in dry CH2Cl2 (10 mL) was
added, under nitrogen, a solution of DMAP (60 mg, 0.49
mmol) and di-t-butyldicarbonate (107mg, 0.49 mmol) in
dry CH2Cl2 (5 mL). The resulting solution was stirred for
3 h at room temperature, quenched with 5% HCl and
extracted with CH2Cl2. The organic extracts were dried
over MgSO4 and concentrated in vacuo. Chromatography
separation (EtOAc/hexane 1:2, silica gel) gave 4 as a white
solid (114 mg, 85%) [found: C, 68.11; H, 5.69; N, 10.26.
C23H23N3O4 requires: C, 68.13; H, 5.71; N, 10.36]; mp 158±
The above Boc-protected dipeptide (3 g, 8.56 mmol) was
heated at 2008C under a stream of argon for 3±4 h. After
cooling, the residue was washed with ethyl acetate and the
precipitate formed was removed by ®ltration yielding
(2)-(3S)-3-benzyl-1-methyl-2,5-piperazinedione as a white
solid (1.5 g, 80%) [found: C, 65.83; H, 6.52; N, 12.51.
C12H14N2O2 requires: C, 66.04; H, 6.46; N, 12.84]; mp
25
598C; [a]D ˆ119 (c 0.145, CHCl3); nmax (KBr) 1784,
1732, 1683 cm21; dH (250 MHz, CDCl3) 8.31 (dd, 1H,
Jˆ8.0 and 1.5 Hz), 7.79 (ddd, 1H, Jˆ7.7, 7.6 and 1.5 Hz),
7.61 (d, 1H, Jˆ7.7 Hz), 7.53 (ddd, 1H, Jˆ8.0, 7.6 and
1.1 Hz), 7.31±7.16 (m, 3H), 6.93 (dd, 2H, Jˆ7.5 and
25
169±708C; [a]D ˆ232 (c 0.13, CHCl3); nmax (KBr)
3250, 1683, 1665 cm21; dH (250 MHz, CDCl3) 7.29±7.25
(m, 3H), 7.18±7.14 (m, 2H), 4.26 (m, 1H), 3.46 (d, 1H,

M. L. Heredia et al. / Tetrahedron 58 (2002) 6163±6170
6167
Jˆ17.6 Hz), 3.19 (dd, 1H, Jˆ13.6 and 5.4 Hz), 3.05 (dd,
1H, Jˆ13.6 and 4.1 Hz), 2.81 (d, 1H, Jˆ17.6 Hz), 2.78 (s,
3H); dC (63 MHz, CDCl3) 166.3, 165.5, 135.1, 129.9, 128.6,
127.5, 56.3, 50.7, 40.7, 33.4.
6 was obtained from 3 (EtOAc/hexane, 2:1) as a white solid;
(194 mg, 65%) [found: C, 72.13; H, 4.98; N, 12.77.
C20H17N3O2 requires: C, 72.49; H, 5.17; N, 12.68]; mp
25
54±558C; [a]D ˆ1242 (c 0.13, CHCl3); nmax (KBr)
1684, 1624 cm21; dH (250 MHz, CDCl3) 8.30 (dd, 1H, Jˆ
7.8 and 1.6 Hz), 7.76 (ddd 1H, Jˆ7.9, 7.6 and 1.6 Hz), 7.63
(dd, 1H, Jˆ7.9 and 1.3 Hz), 7.49 (ddd, 1H, Jˆ7.8, 7.6 and
1.3 Hz), 7.17 (m, 1H), 7.05 (dt, 2H, Jˆ6.2 and 1.2 Hz), 6.69
(dd, 2H, Jˆ7.7 and 1.4 Hz), 5.76 (t, 1H, Jˆ4.2 Hz), 5.50 (d,
1H, Jˆ1.6 Hz), 4.40 (d, 1H, Jˆ1.6 Hz), 3.34 (d, 2H, Jˆ
4.2 Hz), 3.06 (s, 3H); dC (63 MHz, CDCl3) 164.4, 160.3,
147.4, 144.9, 136.8, 134.9, 134.0, 129.7, 128.7, 127.9,
127.8, 127.3, 126.9, 120.3, 101.3, 56.3, 38.3, 30.2.
A solution of the above described piperazinedione (220 mg,
1.01 mmol), triethyloxonium tetra¯uoroborate (250 mg,
1.31 mmol) and anhydrous Na2CO3 (154 mg, 1.1 mmol) in
3 mL of dry CH2Cl2 was stirred overnight, under argon at rt,
poured on ice water, extracted with CH2Cl2, dried (Na2SO4)
and evaporated. Column chromatography (EtOAc, alu-
minium oxide) of the residue afforded (1)-(3S)-3-benzyl-
5-ethoxy-1-methyl-3,6-dihidro-1H-2-pirazinone (150 mg,
60%) as a colorless oil [found: C, 67.99; H, 7.51; N,
11.25. C14H18N2O2 requires: C, 68.27; H, 7.37; N, 11.37.];
;
3.2.2. (1)-(4S)-4-Benzyl-1-dimethylaminoethyliden-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione (12).
Compound 12 was obtained from 1 (EtOAc/CH3OH;
95:5) as a white solid, (152 mg, 45%) [found: C, 70.65;
H, 5.87; N, 14.78. C22H22N4O2 requires: C, 70.56; H,
[a]D ˆ155 (c 0.19, CHCl3); nmax (KBr) 1696, 1657cm 21
25
dH (250 MHz, CDCl3) 7.17±7.10 (m, 3H), 7.04±6.99 (m,
2H), 4.39 (m, 1H), 4.11 (m, 2H), 3.26 (d, 1H, Jˆ16.5 Hz),
3.25 (d, 1H, Jˆ16.5 Hz), 2.96 (dd, 1H, Jˆ13.5 and 4.3 Hz),
2.66 (s, 3H), 2.44 (dd, 1H, Jˆ13.5 and 2.1 Hz), 1.21 (t, 3H,
Jˆ7.1 Hz); dC (63 MHz, CDCl3) 168.5, 157.6, 136.4, 130.0,
127.7, 126.6, 61.3, 60.1, 47.7, 40.2, 32.8, 14.1.
25
5.92; N, 14.96]; mp 76±778C; [a]D ˆ1176 (c 0.09,
CHCl3); nmax (KBr) 1683, 1581 cm21; dH (250 MHz,
CDCl3) 8.33 (dd, 1H, Jˆ8.0 and 1.4 Hz), 7.76 (dd 1H,
Jˆ7.7 and 1.4 Hz), 7.62 (d, 1H, Jˆ7.7 Hz), 7.52 (dd, 1H,
Jˆ8.0 and 7.7 Hz), 7.17±7.06 (m, 3H), 6.83 (dd, 2H, Jˆ7.5
and 1.5 Hz), 5.86 (dd, 1H, Jˆ5.7and 4.3 Hz), 5.71 (dd, 1H,
Jˆ4.8 and 3.7Hz), 3.42 (d, 1H, Jˆ4.8 Hz), 3.41 (d, 1H,
Jˆ3.7Hz), 3.0 (dd, 1H, Jˆ16.2 and 4.3 Hz), 2.85 (dd,
1H, Jˆ16.2 and 5.7Hz), 2.16 (s, 6H); dC (63 MHz,
CDCl3) 164.4, 161.0, 147.5, 144.0, 135.2, 134.6, 130.9,
130.3, 128.8, 127.8, 127.4, 127.3, 120.5, 109.9, 57.4, 56.8,
45.5, 38.1.
A mixture of the above described iminoether (115 mg,
0.47mmol) and anthranilic acid (90 mg, 0.66 mmol) was
melted at 1208C under a stream of argon and kept at this
temperature for 3 h. The cooled melt was triturated with 3N
ammonium hydroxide, and the mixture was extracted with
CH2Cl2 (5£5 mL). The combined organic layers were dried
over Na2SO4 and evaporated. The residue was chromato-
graphed on silica gel eluting with EtOAc affording
compound 3 (145 mg, 97%) [found: C, 71.69; H, 5.11; N,
13.34. C19H17N3O2 2r5equires: C, 71.46; H, 5.36; N, 13.16];
mp 56±578C; [a]D ˆ1267( c 0.33, CHCl3); nmax (KBr)
1673, 1603 cm21; dH (250 MHz, CDCl3) 8.33 (dd, 1H,
Jˆ7.9 and 1.5 Hz), 7.77 (ddd, 1H, Jˆ7.4, 7.0 and 1.5 Hz),
7.56 (d, 1H, Jˆ7.4 Hz), 7.51 (ddd, 1H, Jˆ7.9, 7.6 and
1.1 Hz), 7.30±7.14 (m, 3H), 6.87 (dd, 2H, Jˆ7.6 and
1.5 Hz), 5.60 (t, 1H, Jˆ4.0 Hz), 3.74 (d, 1H, Jˆ17.0 Hz),
3.62 (dd, 1H, Jˆ14.0 and 3.5 Hz), 3.41 (dd, 1H, Jˆ14.0 and
4.5 Hz), 2.86 (s, 3H), 2.59 (d, 1H, Jˆ17.0 Hz); dC (63 MHz,
CDCl3) 165.9, 160.2, 148.1, 147.1, 134.9, 134.8, 129.6,
128.7, 127.9, 127.0, 126.9, 126.8, 120.0, 56.9, 51.0, 37.5,
33.3.
The same reaction conditions, but using 2 as starting
material and EtOAc/methanol (3:2) as eluent for the silica
gel chromatography gave compounds 13±16. Compound 15
is described later.
3.2.3. (2)-(4R)-4-(30-Indolylmethyl)-1-(20-dimethylamino-
ethyliden)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-
3,6-dione (13). Yellow solid, (12 mg, 10%) [found: C,
69.77; H, 5.58; N, 16.96. C24H23N5O2 requires: C, 69.72;
25
H, 5.61; N, 16.94]; mp 128±1298C; [a]D ˆ2230 (c 0.09,
CHCl3); nmax (KBr) 3142, 1683 cm21; dH (250 MHz,
CDCl3) 8.32 (dd, 1H, Jˆ8.0 and 1.5 Hz), 7.98 (ws, 1H),
7.74 (ddd, 1H, Jˆ8.0, 7.6 and 1.5 Hz), 7.63 (d, 1H, Jˆ
7.9 Hz), 7.57 (d, 1H, Jˆ8.0 Hz), 7.47 (ddd, 1H, Jˆ8.0,
7.6 and 1.1 Hz), 7.24 (d, 1H, Jˆ8.0 Hz), 7.13 (dt, 1H,
Jˆ6.9 and 1.1 Hz), 7.01 (dt, 1H, Jˆ7.9 and 1.1 Hz), 6.27
(d, 1H, Jˆ2.3 Hz), 5.72 (dd, 1H, Jˆ5.0 and 2.5 Hz), 5.50
(dd, 1H, Jˆ6.2 and 3.6 Hz), 3.72 (dd, 1H, Jˆ14.8 and
2.5 Hz), 3.45 (dd, 1H, Jˆ14.8 and 5.0 Hz), 2.31 (dd, 1H,
Jˆ16.0 and 6.2 Hz), 1.89 (s, 6H), 1.77 (dd, 1H, Jˆ16.0 and
3.6 Hz); dC (63 MHz, CDCl3) 165.2, 160.6, 147.4, 144.7,
136.3, 134.8, 130.5, 128.0, 127.4, 127.1, 126.9, 124.2,
122.4, 120.2, 119.8, 119.5, 110.8, 108.8, 108.7, 56.1, 55.7,
44.8, 28.2.
3.2. General procedure for the Mannich reactions
Method A. To a stirred and cooled (ice-salt bath) anhydrous
tri¯uoroacetic acid (0.348 mL, 4.5 mmol), bis(dimethyl-
amino)methane (0.12 mL, 0.905 mmol) was added slowly.
The temperature of the resulting solution was kept below
2158C and the substituted pyrazino quinazolinedione
(0.905 mmol) disolved in dry CH2Cl2 (6 mL) was then
added. The cooling bath was removed and the solution
was heated at 658C for 3.5 h. To the cooled solution H2O
(5 mL) was added, neutralized with saturated solution of
NaHCO3 and extracted with CH2Cl2. The combined organic
extracts were dried over Na2SO4, ®ltered and concentrated.
Flash column chromatography (silica gel) afforded pure
products.
3.2.4. (2)-(4R)-1-(20-Dimethylaminoethyliden)-4-(10-di-
methyl-aminomethyl-30-indolylmethyl)-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione (14). Yellow solid,
(14 mg, 10%) [found: C, 68.89; H, 6.44; N, 17.90.
C27H30N6O2 requires: C, 68.92; H, 6.43; N, 17.86]; mp
3.2.1. (1)-(4S)-4-Benzyl-2-methyl-1-methylene-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione (6). Compound
25
80±818C; [a]D ˆ2195 (c 0.49, CHCl3); nmax (KBr)

6168
M. L. Heredia et al. / Tetrahedron 58 (2002) 6163±6170
3135, 1683 cm21; dH (250 MHz, CDCl3) 8.32 (dd, 1H,
Jˆ7.9 and 1.6 Hz), 7.73 (ddd, 1H, Jˆ7.7, 6.9 and 1.6 Hz),
7.66 (d, 1H, Jˆ7.8 Hz), 7.52 (d, 1H, Jˆ6.9 Hz), 7.48 (ddd,
1H, Jˆ7.9, 7.6 and 1.6 Hz), 7.30 (d, 1H, Jˆ8.2 Hz), 7.15
(dt, 1H, Jˆ7.0 and 1.0 Hz), 7.02 (dt, 1H, Jˆ7.4 and 1.0 Hz),
6.20 (s, 1H), 5.72 (dd, 1H, Jˆ5.2 and 2.4 Hz), 5.52 (dd, 1H,
Jˆ6.2 and 3.5 Hz), 4.63 (d, 1H, Jˆ13.0 Hz), 4.36 (d, 1H,
Jˆ13.0 Hz), 3.72 (dd, 1H, Jˆ14.8 and 2.4 Hz), 3.44 (dd,
1H, Jˆ14.8 and 5.2 Hz), 2.32 (dd, 1H, Jˆ16.0 and 6.2 Hz),
2.11 (s, 6H), 1.91 (s, 6H), 1.78 (dd, 1H, Jˆ16.0 and 3.5 Hz);
dC (63 MHz, CDCl3) 164.9, 160.4, 147.1, 144.2, 137.5,
134.6, 130.4, 128.5, 128.4, 127.0, 126.9, 126.7, 121.9,
120.0, 119.4, 109.6, 108.9, 107.4, 62.3, 55.9, 55.5, 44.7,
42.2, 28.1.
(dd, 1H, Jˆ8.0 and 1.5 Hz), 7.80 (ddd, 1H, Jˆ7.9, 7.6 and
1.5 Hz), 7.68 (dd, 1H, Jˆ7.9 and 1.2 Hz), 7.53 (ddd, 1H,
Jˆ8.0, 7.6 and 1.2 Hz), 7.22±7.09 (m, 3H), 6.87 (dd, 2H,
Jˆ7.6 and 1.5 Hz), 5.81 (t, 1H, Jˆ4.8 Hz), 5.64 (d, 1H, Jˆ
1.8 Hz), 4.75 (d, 1H, Jˆ1.8 Hz), 3.39 (d, 2H, Jˆ4.8 Hz),
1.58 (s, 9H); dC (63 MHz, CDCl3) 163.7, 160.4, 149.4,
147.6, 144.8, 135.3, 133.7, 132.9, 130.4, 129.1, 128.2,
128.1, 127.9, 127.3, 120.5, 105.2, 86.7, 57.0, 38.3, 27.9.
3.2.8. (2)-(1S,4R)-2,10-Bis(t-butyloxycarbonyl)-4-(30indo-
lyl-methyl)-1-dimethylaminomethyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione (19). Compound 19
was obtained from 5 (HCCl3/EtOAc, 9:1) (15 mg, 14%)
[found: C, 65.91; H, 6.50; N, 11.65. C33H39N5O6 requires:
25
C, 65.87; H, 6.53; N, 11.64]; mp 89±908C; [a]D ˆ220 (c
0.12, CHCl3); nmax (KBr) 1781, 1735, 1686 cm21; dH
(250 MHz, CDCl3) 8.30 (dd, 1H, Jˆ8.0 and 1.5 Hz), 8.05
(d, 1H, Jˆ8.1 Hz), 7.78 (ddd, 1H, Jˆ7.6, 7.5 and 1.5 Hz),
7.64 (d, 1H, Jˆ7.6 Hz), 7.56 (d, 1H, Jˆ7.8 Hz), 7.50 (ddd,
1H, Jˆ8.0, 7.5 and 1.2 Hz), 7.28 (s, 1H), 7.27 (m, 1H), 7.1
(dt, 1H, Jˆ7.5 and 1.9 Hz), 5.63 (dd, 1H, Jˆ7.3 and 4.0 Hz),
5.25 (dd, 1H, Jˆ8.0 and 4.1 Hz), 3.66 (dd, 1H, Jˆ14.6 and
7.3 Hz), 3.50 (dd, 1H, Jˆ14.6 and 4.0 Hz), 2.52 (d, 1H, Jˆ
13.2 and 4.1 Hz), 2.05 (s, 6H), 2.02 (d, 1H, Jˆ13.0 Hz), 1.62
(s, 9H), 1.49 (s, 9H); dC (63 MHz, CDCl3) 164.8, 160.5,
150.6, 149.5, 149.4, 147.1, 135.1, 134.8, 130.3, 127.1,
126.9, 126.7, 124.7, 124.5, 122.7, 120.0, 119.2, 115.1,
115.0, 84.2, 83.5, 64.8, 57.7, 45.8, 28.5, 28.0, 27.6.
3.2.5. (2)-(1R,4R)-1,4-(2,3)-Indolmethane-1-dimethyl-
aminomethyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazo-
line-3,6-dione (16). Yellow solid, (12 mg, 10%) [found: C,
69.22; H, 5.27; N, 17.55. C23H21N5O2 requires: C, 69.16; H,
25
5.30; N, 17.53]; mp 141±428C; [a]D ˆ2162 (c 0.18,
CHCl3); nmax (KBr) 3194, 1684 cm21; dH (250 MHz,
CDCl3) 8.24 (dd, 1H, Jˆ7.9 and 1.5 Hz), 7.67 (dt, 1H,
Jˆ8.2 and 1.5 Hz), 7.56 (d, 1H, Jˆ7.4 Hz), 7.46±7.38 (m,
2H), 7.29 (d, 1H, Jˆ8.0 Hz), 7.16 (dt, 1H, Jˆ6.9 and
1.2 Hz), 7.06 (dt, 1H, Jˆ7.4 and 1.1 Hz), 6.03 (dd, 1H,
Jˆ4.7and 2.6 Hz), 3.55 (dd, 1H, Jˆ17.3 and 2.6 Hz),
3.39 (dd, 1H, Jˆ17.3 and 4.7 Hz), 2.91±2.78 (m, 2H),
2.34 (s, 6H); dC (63 MHz, CDCl3) 170.1, 160.2, 153.4,
146.8, 134.9, 134.4, 132.1, 127.7, 127.4, 127.1, 126.8,
123.0, 120.6, 120.1, 118.2, 111.3, 107.7, 58.6, 54.7, 54.2,
44.8, 25.7.
3.2.9. (2)-(4R)-2,10-Bis(t-butyloxycarbonyl)-4-(30indolyl-
methyl)-1-methylene-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-dione (20). (HCCl3/EtOAc, 9:1), (35 mg,
35%) [found: C, 66.93; H, 5.77; N, 10.03. C31H32N4O6
requires: C, 66.89; H, 5.79; N, 10.06]; mp 66±678C;
Method B. It was the same as Method A but starting by
N-Boc protected compounds 4 (139 mg, 0.34 mmol) or 5
(100 mg, 0.18 mmol) and solution stirring at room tempera-
ture for 24 h. Flash column chromatography (silica gel) of
the residue afforded pure compounds.
25
[a]D ˆ220 (c 0.12, CHCl3); nmax (KBr) 1772, 1734,
1684 cm21; dH (250 MHz, CDCl3) 8.30 (dd, 1H, Jˆ7.9
and 1.5 Hz), 8.02 (d, 1H, Jˆ8.3 Hz), 7.75 (ddd, 1H, Jˆ
8.4, 7.7 and 1.5 Hz), 7.56 (d, 1H, Jˆ8.4 Hz), 7.50 (ddd,
1H, Jˆ7.9, 7.1 and 1.1 Hz), 7.19±7.12 (m, 2H), 7.08 (s,
1H), 6.87(dt, 1H, Jˆ7.5 and 0.9 Hz), 5.84 (dd, 1H, Jˆ5.7
and 3.7Hz), 5.51 (d, 1H, Jˆ1.6 Hz), 4.65 (d, 1H, Jˆ
1.6 Hz), 3.53 (dd, 1H, Jˆ14.7and 5.7Hz), 3.44 (d, 1H,
3.2.6.
(1)-(4S)-4-Benzyl-1-dimethylaminomethyl-2-t-
butyloxycarbonyl-2,4-dihydro-1H-pyrazino[2,1-b]quin-
azoline-3,6-dione (17). Compound 17 was obtained from 4
(EtOAc/CH3OH; 95:5) as a white solid, (71 mg, 45%)
[found: C, 67.39; H, 6.46; N, 12.07. C26H30N4O4 requires:
Jˆ14.7and 3.7Hz), 1.55 (s, 9H), 1.50 (s, 9H);
dC
25
(63 MHz, CDCl3) 163.5, 160.1, 149.2, 148.7, 147.1,
144.4, 135.2, 134.8, 133.0, 130.1, 127.6, 127.4, 126.7,
125.4, 124.4, 122.5, 120.4, 118.0, 114.8, 112.6, 105.2,
86.1, 83.9, 56.0, 27.9, 27.4, 27.2.
C, 67.51; H, 6.53; N, 12.11]; mp 62±638C; [a]D ˆ195 (c
0.1, CHCl3); nmax (KBr) 2996, 1779, 1732, 1688 cm21; dH
(250 MHz, CDCl3) 8.30 (dd, 1H, Jˆ7.7 and 1.5 Hz), 7.80
(ddd, 1H, Jˆ7.9, 7.6 and 1.5 Hz), 7.67 (dd, 1H, Jˆ7.9 and
1.2 Hz), 7.52 (ddd, 1H, Jˆ7.7, 7.6 and 1.2 Hz), 7.30±7.20
(m, 5H), 5.33 (dd, 1H, Jˆ7.1 and 3.8 Hz), 5.27 (dd, 1H, Jˆ
7.7 and 4.3 Hz), 3.54 (dd, 1H, Jˆ13.8 and 7.1 Hz), 3.41 (dd,
1H, Jˆ13.8 and 3.8 Hz), 2.61 (dd, 1H, Jˆ13.3 and 4.3 Hz),
2.09 (dd, 1H, Jˆ13.3 and 7.7 Hz), 2.19 (s, 6H), 1.54 (s, 9H);
dC (63 MHz, CDCl3) 165.6, 160.9, 151.1, 149.9, 147.5,
136.7, 135.3, 130.4, 129.1, 127.7, 127.5, 127.4, 127.2,
120.5, 84.6, 64.7, 59.2, 58.9, 46.4, 39.5, 28.1.
3.3. Oxidation at C-1 and subsequent Grignard addition
3.3.1. (1)-(4S)-4-Benzyl-2-methyl-2,4-dihydropyrazino-
[2,1-b]quinazoline-1,3,6-trione (8).
A mixture of 3
(262 mg, 0.82 mmol) and PCC (371 mg, 1.72 mmol) in
dry CH2Cl2 (20 mL) was stirred under nitrogen at room
temperature overnight. After evaporation in vacuo of the
solvent, the crude was chromatographed in silica gel.
(EtOAc/hexane, 2:1) as a white solid (164 mg, 60%)
[found: C, 68.41; H, 4.79; N, 12.56. C19H15N3O32r5equires:
C, 68.46; H, 4.53; N, 12.61]; mp 163±648C; [a]D ˆ1390
(c 0.11, CHCl3); nmax (KBr) 1742, 1685, 1595 cm21; dH
(250 MHz, CDCl3) 8.32 (dd, 1H, Jˆ7.9 and 1.0 Hz), 7.91
(dd, 1H, Jˆ7.8 and 0.8 Hz), 7.84 (m, 1H), 7.63 (m, 1H),
7.18 (m, 1H), 7.08 (t, 2H, Jˆ7.5 Hz), 6.59 (dd, 2H, Jˆ7.6
3.2.7. (1)-(4S)-4-Benzyl-1-methylene-2-t-butyloxycarbo-
nyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
(18). Compound 18 was obtained from 4 (EtOAc/CH3OH;
95:5) as a white solid, (64 mg, 45%) [found: C, 68.94; H,
5.36; N, 9.98. C24H23N3O4 requires: C, 69.05; H, 5.55; N,
25
10.06]; mp 64±658C; [a]D ˆ1105 (c 0.095, CHCl3); nmax
(KBr) 1772, 1685, 1473 cm21; dH (250 MHz, CDCl3) 8.32

M. L. Heredia et al. / Tetrahedron 58 (2002) 6163±6170
6169
and 1.2 Hz), 5.84 (t, 1H, Jˆ4.0 Hz), 3.46 (dd, 2H, Jˆ14.0
and 4.7Hz), 3.36 (dd, 1H, Jˆ14.0 and 3.3 Hz), 3.07(s, 3H);
dC (63 MHz, CDCl3) 167.5, 159.5, 156.3, 146.4, 139.3,
135.5, 132.7, 129.7, 129.2, 129.1, 128.7, 126.9, 121.4,
57.0, 38.8, 27.3.
127.6, 127.5, 127.3, 127.2, 127.1, 120.2, 117.9, 62.1, 60.4,
57.3, 56.5, 37.9, 37.7, 32.9, 32.8, 31.2.
3.4.2.
(1)-(1R,4S)-1-Phenyl-1,4(1,2)benzenemethane-
2,4-dihydro-(1H)-pyrazino[2,1-b]quinazoline-3,6-dione
(10). It was obtained from 9 (EtOAc/hexane, 1:3) as a white
solid, (155 mg, 48%) [found: C, 76.29; H, 4.91; N, 10.65.
C25H19N3O2 requires: C, 76.32; H, 4.87; N, 10.68]; mp 197±
3.3.2. (1)-(1R,4S)-4-Benzyl-1-hydroxy-2-methyl-1-phenyl-
2,4-dihydro-(1H)-pyrazino [2,1-b]quinazoline-3,6-dione
(9). To a solution of 8 (0.39 mmol) in dry THF (7mL)
was added, under nitrogen, a solution of PhMgBr (0.5
mmol) at 2788C. The resulting mixture was stirred for
3 h, quenched by the addition of saturated solution of
NH4Cl (1 mL), and allowed to warm to 208C. Ethyl acetate
was added (10 mL), the organic layer was separated, and the
aqueous phase was extracted with EtOAc (3£10 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo. Flash column chromatography in silica gel
(EtOAc/hexane, 1:2) afforded 9 as a white solid, (130 mg,
84%) [found: C, 73.07; H, 5.09; N, 10.15. C25H21N3O3
requires: C, 72.98; H, 5.26; N, 10.21]; mp 80±818C;
25
988C; [a]D ˆ153 (c 0.12, CHCl3); nmax (KBr) 1668,
1608 cm21; dH (250 MHz, CDCl3) 8.31 (dd, 1H, Jˆ8.3
and 1.6 Hz), 8.0 (dd, 1H, Jˆ8.3 and 1.6 Hz), 7.89 (ddd,
1H, Jˆ8.3, 5.3 and 3.4 Hz), 7.73 (ddd, 1H, Jˆ8.3, 7.5 and
1.6 Hz), 7.54 (dd, 1H, Jˆ6.4 and 3.4 Hz), 7.33 (dd, 1H,
Jˆ8.3 and 7.5 Hz), 7.19±7.13 (m, 2H), 6.89±6.81 (m,
5H), 5.58 (dd, 1H, Jˆ5.3 and 3.9 Hz), 3.54 (s, 3H), 3.42
(dd, 1H, Jˆ13.7and 5.3 Hz), 3.31 (dd, 1H, Jˆ13.7and
3.9 Hz); dC (63 MHz, CDCl3) 163.0, 157.1, 138.4, 135.0,
134.9, 130.1, 129.4, 128.9, 127.9, 127.1, 123.8, 122.5,
122.1, 120.9, 120.5, 117.3, 117.1, 114.6, 113.1, 100.4,
58.6, 37.6, 30.5.
25
[a]D ˆ146 (c 0.17, CHCl3); nmax (KBr) 3372, 1669,
1607cm 21; dH (250 MHz, CDCl3) 8.18 (dd, 1H, Jˆ7.9
and 1.5 Hz), 7.78 (ddd, 1H, Jˆ8.2, 7.4 and 1.5 Hz), 7.73
(dd, 1H, Jˆ8.2 and 1.6 Hz), 7.50 (ddd, 1H, Jˆ7.9, 7.4 and
1.6 Hz), 7.42±7.28 (m, 5H), 7.23±7.18 (m, 3H), 7.08±7.03
(m, 2H), 6.13 (ws, 1H), 5.52 (dd, 1H, Jˆ8.4 and 5.5 Hz),
3.18 (s, 3H), 2.93 (dd, 1H, Jˆ13.6 and 8.4 Hz), 2.79 (dd,
1H, Jˆ13.6 and 5.5 Hz); dC (63 MHz, CDCl3) 165.2, 160.6,
152.8, 145.9, 140.8, 135.9, 135.1, 129.6, 129.1, 128.6,
128.1, 127.3, 127.2, 127.1, 126.4, 120.6, 85.1, 57.8, 37.6,
27.2.
3.4.3. (2)-(1R,4R)-1,4-(2,3)-Indolmethane-1-methyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione (15).
A mixture of 19 (10 mg, 0.016 mmol) and 20 (30 mg,
0.05 mmol) in anhydrous TFA (2 mL) was treated as
described for 10. Compound 15 was obtained (CHCl3/
EtOAc, 3:1) as a white solid, (9.5 mg, 40%) [found: C,
70.71; H, 4.55; N, 15.69. C21H16N4O2 requires: C, 70.77;
25
H, 4.52; N, 15.72]; mp 158±1598C; [a]D ˆ2258 (c 0.243,
EtOAc); nmax (KBr) 3318, 1689 cm21; dH (250 MHz,
CDCl3) 8.24 (dd, 1H, Jˆ7.9 and 1.2 Hz), 8.13 (ws, 1H),
7.75±7.72 (m, 2H), 7.59 (d, 1H, Jˆ7.3 Hz), 7.45 (dd, 1H,
Jˆ7.5 and 1.2 Hz), 7.39 (dt, 1H, Jˆ7.5 and 1.2 Hz), 7.30 (d,
1H, Jˆ8.1 Hz), 7.18 (dt, 1H, Jˆ7.1 and 1.1 Hz), 7.06 (dt,
1H, Jˆ7.5 and 1.1 Hz), 6.06 (ws, 1H), 3.52 (dd, 2H, Jˆ17.4
and 2.8 Hz), 3.40 (dd, 1H, Jˆ17.4 and 4.6 Hz), 2.25 (s, 3H);
dC (63 MHz, CDCl3) 170.5, 160.1, 153.1, 146.9, 134.5,
134.4, 132.2, 127.7, 127.5, 127.3, 126.8, 123.4, 120.6,
120.5, 118.3, 111.2, 107.5, 54.6, 54.4, 25.8, 17.9. EIMS
m/z (rel. intensity) 356 (M1, 57), 341 (M12CH3, 100).
3.4. Cyclization attempts. Synthesis of 7 and 10
A solution of compound 6 or 9 (0.82 mmol), in anhydrous
TFA (5 mL) was re¯uxed with stirring for 4 h. After
evaporation of the solvent, a small amount of EtOAc was
added to the residue, basi®ed with saturated NaHCO3
solution and extracted with EtOAc. The organic layer was
dried over Na2SO4 and concentrated. The solid residue was
chromatographed in silica gel to afford the pure products.
Acknowledgements
3.4.1. (1)-(1S,4S)-4-Benzyl-2-methyl-1-{2-[(40S)-40-benzyl-
20-methyl-3060-dioxo-20,30,40,60-tetrahydro-10H-pyrazino-
[2,1-b]quinazolinyliden]ethyl}-2,4-dihydro-1H-pyrazino-
Financial support from CICYT (SAF-97-0143 and SAF-
2000-0130) and a MEC fellowship to M. L. Heredia are
gratefully acknowledged.
[2,1-b]quinazoline-3,6-dione (7). Compound
7
was
obtained from 6 (EtOAc/hexane, 1:1) as a white solid,
(109 mg, 40%) [found: C, 72.61; H, 4.99; N, 12.75.
C40H34N6O4 requires: C, 72.49; H, 5.17; N, 12.68]; mp
References
25
114±1158C; [a]D ˆ1182 (c 0.12, CHCl3); nmax (KBr)
1676 cm21; dH (250 MHz, CDCl3) 8.33 (dd, 1H, Jˆ8.0
and 1.4 Hz), 8.32 (dd, 1H, Jˆ8.3 and 1.3 Hz), 7.79 (dt,
1H, Jˆ6.9 and 1.5 Hz), 7.76 (dt, 1H, Jˆ6.8 and 1.5 Hz),
7.6 (d, 1H, Jˆ8.1 Hz), 7.58 (d, 1H, Jˆ7.5 Hz), 7.51 (t, 2H,
Jˆ7.5 Hz), 7.25±7.23 (m, 3H), 7.11±7.08 (m, 2H), 7.04±
6.98 (m, 3H), 6.81±6.77 (m, 2H), 5.75 (t, 1H, Jˆ5.0 Hz),
5.54 (t, 1H, Jˆ5.5 Hz), 4.92 (dd, 1H, Jˆ10.8 and 5.2 Hz),
4.81 (dd, 1H, Jˆ9.8 and 7.3 Hz), 3.47 (d, 2H, Jˆ5.5 Hz),
3.28 (d, 2H, Jˆ5.0 Hz), 3.24 (s, 3H), 3.17(m, 1H), 3.10 (s,
3H), 0.94 (m, 1H); dC (63 MHz, CDCl3) 165.1, 164.9,
160.6, 159.9, 149.4, 146.9, 146.7, 145.1, 135.9, 135.1,
134.9, 134.6, 130.6, 129.9, 129.5, 128.6, 128.4, 127.7,
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M. L. Heredia et al. / Tetrahedron 58 (2002) 6163±6170
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Â
È
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 Â
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È
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Ä
6428.
22. 1H NMR (250 MHz, CDCl3) d 8.64 (ws, 1H), 8.34 (dd, 1H,
Jˆ7.9 and 1.4 Hz), 7.81 (ddd, 1H, Jˆ8.2, 7.6 and 1.4 Hz),
7.68 (dd, 1H, Jˆ8.2 and 1.3 Hz), 7.54 (ddd, 1H, Jˆ7.9, 7.6
and 1.3 Hz), 7.22 (m, 1H), 7.16±7.10 (m, 2H), 6.84 (d, 2H,
Jˆ7.6 Hz), 5.76 (dd, 1H, Jˆ5.0 and 3.8 Hz), 5.54 (d, 1H,
Jˆ1.2 Hz), 4.55 (d, 1H, Jˆ1.2 Hz), 3.43 (d, 1H, Jˆ5.0 Hz),
3.42 (d, 1H, Jˆ3.8 Hz). 13C NMR (63 MHz, CDCl3) d 166.1,
160.8, 147.4, 143.8, 135.3, 134.1, 133.0, 130.2, 129.0, 128.2,
127.8, 127.3, 120.6, 101.4, 57.3, 38.2. [found: C, 71.76; H,
4.68; N, 13.28. C19H15N3O2 requires: C, 71.91; H, 4.76; N,
13.24].
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Â
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