1-Bromo-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones as α-bromoglycine templates

Article abstract of DOI:10.1016/S0957-4166(01)00067-2

The title compounds behaved as α-bromoglycine templates. Radical substitutions and S_N1-type nucleophilic additions proceeded with retention of stereochemistry, while S_N2-type displacements occurred with net inversion of configuration. A homocoupling product was obtained in attempting a Stille cross-coupling reaction.

Full text of DOI:10.1016/S0957-4166(01)00067-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 411–418
1-Bromo-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones as
a-bromoglycine templates
Mar´ıa Luisa Heredia, Mar´ıa Ferna´ndez, Elena de la Cuesta and Carmen Avendan˜o*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 19 December 2000; accepted 8 February 2001
Abstract—The title compounds behaved as a-bromoglycine templates. Radical substitutions and SN1-type nucleophilic additions
proceeded with retention of stereochemistry, while SN2-type displacements occurred with net inversion of configuration. A
homocoupling product was obtained in attempting a Stille cross-coupling reaction. © 2001 Published by Elsevier Science Ltd.
1. Introduction
haloglycine templates 4 gave trans-3,6-derivatives in
reaction with the radical derived by bromine atom
transfer.14
The use of a-haloglycine derivatives for the elaboration
of glycine residues is extensively documented.1 High
diastereoselectivities, imposed by geometrical con-
straints, have been found for a-haloglycine templates
such as those derived from N-protected (Cbz or BOC)
erythro-5,6-diphenyl-3,4,5,6-tetrahydro-1,4-oxazin-2-
ones 1,2,3 bislactim ethers 24,5 and N,N%-dialkyl- 36–12 or
N,N%-diacylpiperazine-2,5-diones 413,14 (Fig. 1).
The use of 2,4-dialkyl-2,4-dihydro-1H-pyrazino[2,1-
b]quinazoline-3,6-diones such as 5, as nucleophilic16–21
or electrophilic22,23 glycine templates, is being devel-
oped in our group. This system contains rings D–F of
the natural MDR (multi drug resistance) reversal agent
N-acetylardeemin24,25 and retains most of its biological
activity.26 Our interest in this chemotherapeutic prop-
erty moved us to study new synthetic entries to deriva-
tives of this system. Here, we study the a-bromoglycine
templates 7 and 8.
Williams established that compounds 3 cannot directly
be used as glycine templates due to extensive decompo-
sition under a range of Lewis acid conditions, but
found that they could be derived, for a-C-functionalisa-
tion, to their 3,6-bis(2%-thiopyridyl) analogues, which
react with nucleophiles in the presence of thiophilic
metal salts.8,15 The intermediate iminium species thus
formed were attacked in most cases from the same face
of the piperazinedione nucleus as the departing thiopyr-
idyl residue, giving cis-3,6-derivatives. However, a-
2. Results and discussion
Bromination of compounds 516 and 6 under radical
conditions afforded the bromides 7 and 8, respectively,
as single diastereoisomers (Scheme 1). All attempts to
Figure 1. Some a-haloglycine templates.
* Corresponding author. Fax: 34 91 394 18 22; e-mail: avendano@eucmax.sim.ucm.es
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00067-2

412
M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 411–418
Scheme 1. (a) NBS (1 equiv.), AIBN (1%) for 5 or (PhCOO)2 (1%) for 6, CCl4, 2 h, reflux, rt. (b) Isolation of 7 and 8 and
purification attempts by column chromatography. (c) Evaporation of a chloroform (stabilised with ethanol) solution of 7.
enhancement of the H-(1) signal after irradiation of the
C-(4) methyl protons and vice versa), indicating net
inversion of configuration and SN2-type displacement
of the bromine. Although this stereochemistry could be
the result of thermodynamic control (excess nucleo-
phile, room temperature and long reaction time), it has
been clearly established in the more extensively studied
enolate based chemistry of compounds 5 and 616,18,19
that the 1,4-trans-disubstituted derivatives equilibrate
to the more stable cis-isomers. Thus, the trans-isomers
(compounds 16–20, entries 5–9) obtained in these con-
ditions are formed under kinetic control.
study their stereochemistry were unsuccessful because
of partial hydrolysis–oxidation to cis-1-hydroxy and
1-oxo derivatives (9–11). This decomposition occurred
even on standing in carbon tetrachloride solution.
Attempts to purify bromide 7 by evaporation of a
chloroform solution followed by column chromatogra-
phy gave 9 and the cis-1-ethoxy derivative 12 arising
from a substitution reaction with ethanol present as a
chloroform stabiliser. The cis-1,4-stereochemistry of
compound 12 was established by NOE experiments
(signal enhancements of OCH2 and OCH2-CH6 3 protons
6
after irradiation of the C-(4) methyl protons and vice
versa). The stereochemistry of compounds 7 and 8 is
discussed later.
The enantiomeric purity of compound (+)-17, for which
epimerisation of the C-(4)-stereocentre could be
expected given the basicity of the nucleophile, was
confirmed by chiral HPLC analysis, in comparison to a
racemic sample obtained from ( )-7.
The rapid decomposition of bromides 7 and 8 led to
their use as crude products. The results obtained from
some nucleophilic displacement reactions are sum-
marised in Table 1.
Entries 10 and 11 of Table 1 show the results obtained
through radical mechanisms (intermediates II, Scheme
2), affording compounds 13 and 14. The yields were
better than those obtained in SN1-type reactions (entries
1 and 2). When the benzene used as a solvent in these
radical promoted substitutions was not properly deoxy-
genated, a substantial amount of the 1-phenoxy deriva-
tive 21 was isolated (entry 12). Its structure was
confirmed by mass spectrometry and NMR experiments
(long distance correlations between the H-(1) and C-(1%)
phenyl resonances). This product must be formed in the
Reactions with weak nucleophiles catalysed with strong
Lewis acids (entries 1–4) gave compounds 13–16, which
showed a cis (13–15) or trans (16) 1,4-relationship
(NOE experiments were conclusive in all compounds).
These stereochemical results are in accordance with
SN1-type addition of the nucleophile to N-acyliminium
intermediates I (Scheme 2). In our experience with
experimental protocols starting with C-(1)-oxidation,22
iminium species were diastereoselectively attacked by
nucleophiles with retention of configuration. In this
case, only the bulky trimethylsilylketene acetal of
diethyl malonate (entry 4) gave the inverted product in
order to minimise the 1,4-steric interactions. This also
occurred in the iminium species derived from 4.
reaction of
a
hydroperoxide intermediate with
benzene.27
Since radical mechanisms imply kinetic control, bro-
mides 7 and 8 (also obtained through intermediates II)
must have the same cis-stereochemistry as compounds
13, 14 and 21. Furthermore, assuming that compounds
16–20 have been obtained by SN2-type displacement,
The reactions with good nucleophiles (entries 5–9) gave
compounds 16–20 with a trans-1,4-stereochemistry
(NOE experiments of compounds 17 and 18 showed an

M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 411–418
Table 1. Substitution of a bromine atom in compounds 7 and 8
413
Scheme 2.
the single inversion of stereochemistry at C-(1) supports
the cis-configuration for 7 and 8.
responding to system A (Fig. 2) were similar to those of
compounds so far described, while those of system B,
and especially the H-(4%) proton, were more shielded.
Furthermore, protons H-(1) and H-(1%) resonated as
two nearly superimposed doublets with a coupling con-
stant of 12.6 Hz, which is compatible with either a
nearly eclipsed or staggered conformation around the
C-(1)/C-(1%) bond.
In a first attempt to achieve a cross-coupling reaction,
we investigated the Stille-coupling between 7 and tri-
butylvinyltin with Pd(0) as catalyst, but instead of the
expected 1-vinyl derivative, the homocoupling product
22 (25%) was obtained. This compound must be formed
through a previous transmetallation reaction (Scheme
3).
The H-(4) and H-(4%) chemical shifts (l=5.18 and 4.50
ppm, respectively) are indicative of a cis-1,4-relation-
ship in system A and a trans-relationship in system B,
since in other cis-2,4-dimethyl analogues substituted at
A CDCl3 solution of compound 22 showed two sets of
signals ascribed to non-equivalent moieties. Those cor-

414
M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 411–418
Scheme 3.
3. Experimental
All reagents were of commercial quality (Aldrich,
Fluka, SDS, Probus) and were used as received. Sol-
vents (SDS, Scharlau) were dried and purified using
standard techniques. Reactions were monitored by thin
layer chromatography on aluminium plates coated with
silica gel or aluminium oxide with fluorescent indicator
(Merck 60 F254). Separations by flash chromatography
were performed on silica gel (Merck 60, 230–400 mesh)
or aluminium oxide (Merck 90, 70–230 mesh). Melting
points were measured in open capillary tubes using a
Bu¨chi immersion apparatus or on a Reichert 723 hot
stage microscope, and are uncorrected. Infrared spectra
were recorded on a Perkin–Elmer Paragon 1000 FT-IR
spectrophotometer, with solid compounds compressed
into KBr disks. NMR spectra were obtained at 250 or
Figure 2.
1
300 MHz for H and at 63 or 75 MHz for 13C NMR
(Servicio de Espectroscop´ıa, Universidad Com-
plutense). When necessary, assignments were aided by
DEPT, COSY, CH COLOC and 13C–1H correlation
experiments. Elemental analyses were determined by
the Servicio de Microana´lisis, Universidad Com-
plutense on a Leco 932 microanalyser. Optical rotation
measurements were obtained at 25°C on a 1 mL cell in
CHCl3 or MeOH at 589 nm using a Perkin–Elmer 240
polarimeter; concentrations are given in g/100 mL.
Mass spectra were recorded on a Hewlett–Packard
5993C (EI, 70 eV) (Servicio de Espectroscop´ıa U.C.M.).
HPLC analysis was performed using a Constametric
4100 system equipped with a chiral column (Chiralcel
OD) and UV–vis detector. Mobile phase: hexane/2-
propanol (90:10).
C-(1), the H-(4) proton is deshielded because the C-(4)
methyl group adopts a nearly axial disposition in the
boat conformation of the pyrazine ring. Thus H-(4) is
nearly coplanar to the carbonyl group at C-(6). This
deshielding effect is not observed in the trans-1,4-iso-
mers which are more planar.16
A conclusive NOE experiment showed, after irradiation
of the H-(4) signal at 5.18 ppm (system A), enhance-
ment of the 4%-methyl protons (system B), confirming
the stereochemistry. The coupling of C-(1) and C-(1%)
must be produced through a syn-attack in A and an
anti-attack in B to give 22 in a folded conformation,
with stereocentres (S)-C-(1) and (R)-C-(1%) nearly
eclipsed. The cis–trans-stereochemistry in the pyrazine
rings of system A and B, respectively, minimises the
steric repulsion that would exist between methyl groups
at C-(4) and C-(4%) in a syn-attack for both systems that
would give a cis-relationship for 1,4- and 1%,4%-configu-
rations (Fig. 2).
3.1. (+)-(4S)-2-Benzyl-8,9-dimethoxy-4-methyl-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 6
A mixture of 1-benzyl-3-methylpiperazine-2,5-dione16
(0.45 g, 2 mmol), triethyloxonium tetrafluoroborate
(1.14 g, 6 mmol) and anhydrous Na2CO3 (1.06 g, 10
mmol) in dry CH2Cl2 (20 mL) was stirred overnight at
room temperature, poured on ice-water, extracted with
CH2Cl2, dried over anhydrous Na2SO4 and evaporated.
4,5-Dimethoxyanthranilic acid (0.4 g, 2 mmol) was
added to the syrupy residue and the mixture was stirred
vigorously at 110°C for 4 h under argon. The mixture
was dissolved in EtOAc, extracted with diluted ammo-
In conclusion, we have shown that the reactions of
electrophilic glycine templates 7 and 8 are predictive in
their scope and diastereoselectivity under different reac-
tion mechanisms, and that this methodology provides a
new approach to new derivatives of the pyrazinoquina-
zolinedione system.

M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 411–418
415
nium hydroxide, dried (Na2SO4) and concentrated.
Column chromatography of the evaporation residue
(EtOAc, silica gel) afforded 6 as a white solid; yield
95%; mp 175–176°C; [h]2D5=+52 (c 0.15, CHCl3); wmax
(KBr): 1671, 1607 cm−1; lH (CDCl3, 250 MHz) 7.53 (s,
1H), 7.36–7.24 (m, 5H), 6.91 (s, 1H), 5.51 (q, 1H,
J=7.1 Hz), 4.83 (d, 1H, J=14.5 Hz), 4.51 (m, 2H),
4.24 (d, 1H, J=14.5 Hz), 3.94 (s, 3H), 3.92 (s, 3H), 1.58
(d, 3H, J=7.1 Hz); lC (63 MHz, CDCl3) 167.7, 159.3,
155.3, 149.4, 146.6, 143.5, 135.2, 129.2, 128.4, 128.3,
113.9, 107.3, 105.7, 56.5, 56.4, 52.1, 49.7, 49.1, 17.3;
C21H21N3O4 requires: C, 66.47; H, 5.57; N, 11.07.
Found: C, 66.36; H, 5.89; N, 10.95%.
0.05, CHCl3); wmax (KBr): 1736, 1679, 1609 cm−1; lH
(DMSO-d6, 250 MHz) 7.51 (s, 1H), 7.39–7.25 (m, 5H),
7.34 (s, 1H), 5.27 (q, 1H, J=7.0 Hz), 5.03 (s, 2H), 3.94
(s, 3H), 3.93 (s, 3H), 1.65 (d, 3H, J=7.0 Hz); lC (63
MHz, DMSO-d6) 169.3, 158.3, 157.1, 155.3, 150.7,
142.6, 138.4, 136.2, 128.5, 127.6, 127.5, 115.2, 109.3,
105.2, 79.4, 56.5, 56.2, 19.6; C21H19N3O5 requires: C,
64.11; H, 4.87; N, 10.68. Found: C, 63.95; H, 4.63; N,
10.28%.
3.2.4.
(+)-(1S,4S)-1-Ethoxy-2,4-dimethyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 12. 12 was
obtained (EtOAc/hexane 2:3, aluminium oxide) as a
white solid; yield: 20%; mp 115–117°C; [h]2D5=+120 (c
0.26, CHCl3); wmax (KBr): 1684, 1609 cm−1; lH (CDCl3,
250 MHz) 8.28 (dd, 1H, J=7.9 and 1.4 Hz), 7.77 (ddd,
1H, J=8.1, 7.4 and 1.4 Hz), 7.68 (dd, 1H, J=8.1 and
1.4 Hz), 7.51 (ddd, 1H, J=7.9, 7.4 and 1.4 Hz), 5.28 (q,
1H, J=7.0 Hz), 5.27 (s, 1H), 3.78 (q, 2H, J=7.0 Hz),
3.16 (s, 3H), 1.74 (d, 3H, J=7.0 Hz), 1.19 (t, 3H,
J=7.0 Hz); lC (63 MHz, CDCl3) 169.9, 160.2, 147.3,
147.0, 134.8, 127.8, 127.6, 126.9, 121.0, 88.9, 65.3, 52.9,
33.6, 19.2, 15.1; C15H17N3O3 requires: C, 62.71; H, 5.96;
N, 14.62. Found: C, 62.73; H, 6.12; N, 14.93%.
3.2. General procedure for the preparation of bromides 7
and 8
To a stirred solution of 516 or 6 (1.0 equiv.) in CCl4 (0.1
M) under nitrogen was added N-bromosuccinimide (1.1
equiv.) and a catalytic amount (1 mol%) of azobis-
isobutylnitrile for 5 or benzoyl peroxide for 6. The
mixture was refluxed for 2 h, cooled to room tempera-
ture, filtered and concentrated. The crude product was
used without purification; otherwise, oxidation prod-
ucts 9–11 formed and were isolated by column
chromatography.
3.3. General procedure for SN1-type nucleophilic addi-
tion to bromides 7 and 8
Compound 12 was obtained with 9 from evaporation of
a chloroform solution of 7 followed by column
chromatography.
To a stirred solution of unpurified 7 or 8 (1 equiv., 0.82
mmol) in dry THF (10 mL) at room temperature under
argon was added the corresponding nucleophile
(allyltrimethyl silane, 2-methylfuran or the trimethyl-
silylketene acetal of diethyl malonate2) (4 equiv.), fol-
lowed by addition of a solution of ZnCl2 in THF (0.5
M, 2 equiv., 1.64 mmol). After 12 h the mixture was
poured into saturated aqueous sodium bicarbonate and
extracted with ethyl acetate. The combined organic
extract was dried over anhydrous sodium sulfate,
filtered and concentrated. The residue was purified by
flash chromatography to afford compounds 13–16.
3.2.1. (+)-(1S,4S)-2,4-Dimethyl-1-hydroxy-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 9.
9
was
obtained (EtOAc, silica gel) as a white solid; yield: 20%;
mp 200–202°C; [h]D25=+55 (c 0.35, CHCl3); wmax (KBr):
3520, 1685, 1660 cm−1; lH (CDCl3, 250 MHz) 8.32 (d,
1H, J=7.8 Hz), 7.81 (t, 1H, J=8.3 Hz), 7.67 (d, 1H,
J=7.4 Hz), 7.53 (t, 1H, J=8.2 Hz), 5.80 (s, 1H), 5.37
(q, 1H, J=7.0 Hz), 4.97 (s, 1H), 3.22 (s, 3H), 1.80 (d,
3H, J=7.0 Hz); lC (63 MHz, CDCl3) 169.5, 159.9,
149.3, 146.8, 135.0, 128.0, 127.1, 127.0, 121.0, 114.2,
82.8, 52.7, 32.9, 19.5; C13H13N3O3 requires: C, 60.22; H,
5.05; N, 16.20. Found: C, 60.38; H, 5.28; N, 16.42%.
3.3.1. (+)-(1S,4S)-1-Allyl-2,4-dimethyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 13. 13 was obtained
(EtOAc/hexane 2:1, aluminium oxide) as a white solid;
yield: 41%; mp 193–194°C; [h]2D5=+49 (c 0.12, CHCl3);
wmax (KBr): 1671, 1598 cm−1; lH (CDCl3, 250 MHz)
8.25 (dd, 1H, J=7.9 and 1.5 Hz), 7.75 (ddd, 1H,
J=8.2, 7.5 and 1.5 Hz), 7.61 (dd, 1H, J=8.2 and 1.2
Hz), 7.47 (ddd, 1H, J=7.9, 7.5 and 1.2 Hz), 5.87 (m,
1H), 5.28 (q, 1H, J=7.2 Hz), 5.2 (m, 2H), 4.56 (t, 1H,
J=6.8 Hz), 3.11 (s, 3H), 2.82 (t, 2H, J=6.8 Hz), 1.73
(d, 3H, J=7.2 Hz); lC (63 MHz, CDCl3) 167.1, 160.3,
150.1, 146.9, 134.9, 132.2, 127.2, 127.1, 126.8, 120.1,
119.9, 63.4, 52.4, 40.6, 34.3, 19.3; C16H17N3O2 requires:
C, 67.83; H, 6.05; N, 14.83. Found: C, 67.78; H, 6.01;
N, 14.9%.
3.2.2. (+)-(1S,4S)-2-Benzyl-1-hydroxy-8,9-dimethoxy-4-
methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-di-
one 10. 10 was obtained (EtOAc/hexane 2:1, silica gel)
as a white solid; yield: 15%; mp 119–120°C; [h]2D5=
+56 (c 0.17, CHCl3); wmax (KBr): 3274, 1675, 1610 cm−1;
lH (CDCl3, 250 MHz) 7.54 (s, 1H), 7.34–7.23 (m, 5H),
6.98 (s, 1H), 5.64 (d, 1H, J=3.3 Hz), 5.44 (q, 1H,
J=7.0 Hz), 5.15 (d, 1H, J=14.8 Hz), 5.04 (d, 1H,
J=3.3 Hz), 4.45 (d, 1H, J=14.8 Hz), 3.95 (s, 3H), 3.91
(s, 3H), 1.81 (d, 3H, J=7.0 Hz); lC (63 MHz, CDCl3)
169.5, 159.2, 155.4, 149.8, 148.1, 142.9, 135.7, 129.2,
128.6, 128.4, 114.2, 107.2, 105.7, 79.8, 56.5, 52.7, 47.9,
19.6; C21H21N3O5 requires: C, 63.78; H, 5.35; N, 10.66.
Found: C, 63.45; H, 5.28; N, 10.36%.
3.3.2.
(+)-(1S,4S)-1-Allyl-2-benzyl-8,9-dimethoxy-4-
3.2.3.
(−)-(4S)-2-Benzyl-8,9-dimethoxy-4-methyl-2,4-
methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-di-
one 14. 14 was obtained (EtOAc/hexane 1:2, aluminium
oxide) as a white solid; yield: 40%; mp 150–151°C;
[h]2D5=+16 (c 0.15, CHCl3); wmax (KBr): 3274, 1675,
dihydro-1H-pyrazino[2,1-b]quinazoline-1,3,6-trione 11.
11 was obtained (EtOAc/hexane 2:1, silica gel) as a
white solid; yield: 20%; mp 210–211°C; [h]2D5=−24 (c

416
M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 411–418
1610 cm−1; lH (CDCl3, 250 MHz) 7.55 (s, 1H), 7.30–
7.23 (m, 5H), 6.97 (s, 1H), 5.44 (d, 1H, J=14.9 Hz),
5.40 (q, 1H, J=7.1 Hz), 5.14 (m, 2H), 4.54 (t, 1H,
J=6.6 Hz), 4.13 (d, 1H, J=14.9 Hz), 3.99 (s, 3H), 3.96
(s, 3H), 2.97 (t, 1H, J=6.9 Hz), 1.79 (d, 3H, J=7.1
Hz); lC (63 MHz, CDCl3) 167.6, 159.8, 155.4, 149.4,
148.9, 143.5, 135.4, 132.6, 129.1, 128.5, 128.3, 119.9,
113.8, 107.3, 105.5, 59.8, 56.5, 56.4, 52.4, 48.2, 40.7,
19.7; C24H25N3O4 requires: C, 68.72; H, 6.01; N, 10.02.
Found: C, 68.69; H, 6.07; N, 9.98%.
3.4.1. (+)-(1R,4S)-2,4-Dimethyl-1-phenylthio-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 17. 17 was
obtained (EtOAc/hexane 2:3, aluminium oxide) as a
yellow solid; yield: 60%; mp 159–161°C; [h]2D5=+227 (c
0.22, CHCl3); wmax (KBr): 1677, 1601 cm−1; lH (CDCl3,
250 MHz) 8.25 (dd, 1H, J=7.8 and 1.5 Hz), 7.71 (ddd,
1H, J=8.4, 7.6 and 1.5 Hz), 7.59 (m, 2H), 7.49–7.43
(m, 2H), 7.38–7.30 (m, 3H), 5.58 (s, 1H), 5.33 (q, 1H,
J=7.2 Hz), 3.10 (s, 3H), 1.84 (d, 3H, J=7.2 Hz); lC (63
MHz, CDCl3) 168.0, 160.3, 148.5, 147.2, 135.0, 134.8,
132.2, 129.6, 129.5, 127.5, 127.4, 126.9, 120.5, 71.5,
52.7, 33.2, 19.1; C19H17N3O2S requires: C, 64.94; H,
4.88; N, 11.96. Found: C, 64.92; H, 5.22; N, 11.62%.
3.3.3. (+)-(1R,4S)-2,4-Dimethyl-1(5-methyl-2-furyl)-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 15. 15
was obtained (EtOAc/hexane 2:1, aluminium oxide)
as a white solid; yield: 68%; mp 180–181°C; [h]2D5=
+31 (c 0.17, CHCl3); wmax (KBr): 1690, 1589 cm−1; lH
(CDCl3, 250 MHz) 8.27 (dd, 1H, J=8.0 and 1.5 Hz),
7.75 (ddd, 1H, J=8.2, 7.0 and 1.5 Hz), 7.66 (dd, 1H,
J=8.2 and 1.3 Hz), 7.48 (ddd, 1H, J=8.0, 7.0 and 1.3
Hz), 6.27 (d, 1H, J=3.1 Hz), 5.94 (d, 1H, J=3.1 Hz),
5.57 (s, 1H), 5.36 (q, 1H, J=7.1 Hz), 3.14 (s, 3H), 2.2
(s, 3H), 1.69 (d, 3H, J=7.1 Hz); lC (63 MHz, CDCl3)
167.8, 160.4, 153.8, 147.7, 147.3, 146.4, 134.8, 127.4,
127.2, 126.9, 120.5, 110.8, 106.9, 61.1, 52.7, 33.4, 18.2,
13.7; C18H17N3O3 requires: C, 66.86; H, 5.29; N, 12.99.
Found: C, 66.80; H, 5.32; N, 13.02%.
3.4.2. (+)-(1R,4S)-2-Benzyl-8,9-dimethoxy-4-methyl-1-
phenylthio-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-
3,6-dione 18. 18 was obtained (EtOAc/CH2Cl2 4:3, silica
gel) as a white solid; yield: 80%; mp 92–93°C; [h]2D5=
+179 (c 0.23, CHCl3); wmax (KBr): 1674, 1610, 1594
cm−1; lH (CDCl3, 250 MHz) 7.47 (s, 1H), 7.44–7.07 (m,
5H), 7.26–7.20 (m, 3H), 7.06 (d, 2H, J=8.0 Hz), 7.04
(s, 1H), 5.74 (d, 1H, J=14.4 Hz), 5.54 (s, 1H), 4.41 (d,
1H, J=14.4 Hz), 3.97 (s, 3H), 3.96 (s, 3H), 3.83 (q, 1H,
J=6.6 Hz), 1.49 (d, 3H, J=6.6 Hz); lC (63 MHz,
CDCl3) 167.5, 159.0, 155.4, 149.4, 146.7, 143.0, 137.4,
134.6, 131.1, 129.3, 129.2, 128.9, 128.6, 126.8, 113.6,
107.1, 105.4, 66.6, 56.3, 56.2, 52.1, 46.3, 21.2;
C27H25N3O4S requires: C, 66.51; H, 5.17; N, 8.62.
Found: C, 66.69; H, 5.20; N, 8.31%.
3.3.4.
(+)-(1R,4S)-1-Bis(ethoxycarbonyl)methyl-2,4-
dimethyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 16. 16 was obtained (EtOAc/hexane 2:1, silica gel)
as a white solid; yield: 85%; mp 46–48°C; [h]2D5=+49 (c
0.21, CHCl3); wmax (KBr): 1734, 1676 cm−1; lH (CDCl3,
250 MHz) 8.24 (dd, 1H, J=8.2 and 1.5 Hz), 7.70 (dt,
1H, J=7.7 and 1.3 Hz), 7.45 (m, 2H), 5.36 (d, 1H,
J=3.8 Hz), 5.27 (q, 1H, J=6.9 Hz), 4.36 (d, 1H, J=3.8
Hz), 4.3 (m, 2H), 4.15 (m, 2H), 3.0 (s, 3H), 1.63 (d, 3H,
J=6.9 Hz), 1.23 (t, 3H, J=7.1 Hz), 1.14 (t, 3H, J=7.1
Hz); lC (63 MHz, CDCl3) 167.8, 166.1, 166.0, 160.1,
147.6, 146.2, 134.5, 127.0, 126.7, 126.6, 120.5, 62.0,
59.9, 53.9, 51.9, 31.9, 19.6, 13.9, 13.8; C20H23N3O6
requires: C, 59.84; H, 5.77; N, 10.47. Found: C, 60.16;
H, 5.52; N, 10.71%.
3.4.3.
(+)-(1R,4S)-2,4-Dimethyl-1(2%-pyridylthio)-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 19. 19
was obtained (EtOAc/hexane 1:1, aluminium oxide)
as a yellow solid; yield: 95%; mp 62–64°C; [h]2D5=
+405 (c 0.27, CHCl3); wmax (KBr): 1680, 1602 cm−1; lH
(CDCl3, 250 MHz) 8.55 (ddd, 1H, J=4.5, 1.6 and 0.8
Hz), 8.20 (dd, 1H, J=8.0 and 1.5 Hz), 7.65 (ddd, 1H,
J=8.1, 7.5 and 1.5 Hz), 7.54–7.51 (m, 2H), 7.41 (ddd,
1H, J=8.0, 7.5 and 1.2 Hz), 7.29 (s, 1H), 7.14 (m, 2H),
5.39 (q, 1H, J=7.2 Hz), 3.09 (s, 3H), 1.76 (d, 3H,
J=7.2 Hz); lC (63 MHz, CDCl3) 168.4, 159.9, 154.4,
149.5, 148.9, 147.3, 137.0, 134.5, 127.4, 127.2, 126.6,
122.8, 121.3, 120.2, 64.1, 52.2, 31.8, 19.0. C18H16N4O2S
requires: C, 61.35; H, 4.58; N, 15.89. Found: C, 61.47;
H, 4.46; N, 15.89%.
3.4. General procedure for direct SN2-type displacement
of bromides 7 and 8
3.4.4.
(+)-(1R,4S)-2-Benzyl-8,9-dimethoxy-4-methyl-
1-(2%-pyridylthio)-2,4-dihydro-1H-pyrazino[2,1-b]quin-
azoline-3,6-dione 20. It was obtained (EtOAc/CH2Cl2
4:3, silica gel) as a white solid; yield: 65%; mp 170–
171°C; [h]2D5=+520 (c 0.06, CHCl3); wmax (KBr): 1670,
1610 cm−1; lH (CDCl3, 250 MHz) 8.57 (dd, 1H, J=4.0
and 0.9 Hz), 7.60 (dt, 1H, J=7.9 and 1.8 Hz), 7.58 (s,
1H), 7.33–7.15 (m, 7H), 7.26 (s, 1H), 6.94 (s, 1H), 5.55
(q, 1H, J=7.2 Hz), 5.37 (d, 1H, J=14.7 Hz), 4.18 (d,
1H, J=14.7 Hz), 3.99 (s, 3H), 3.89 (s, 3H), 1.86 (d, 3H,
J=7.2 Hz); lC (63 MHz, CDCl3) 168.3, 159.3, 154.9,
154.7, 149.5, 149.4, 147.8, 143.7, 137.0, 135.7, 128.6,
127.8, 122.7, 121.2, 119.9, 113.7, 107.8, 105.3, 62.3,
56.3, 56.2, 52.2, 46.7, 19.3. C26H24N4O4S requires: C,
63.92; H, 4.95; N, 11.47. Found: C, 63.96; H, 4.92; N,
11.30%.
To a stirred suspension of NaH (1.2 equiv., 0.98 mmol)
in dry THF (5 mL) at 0°C under argon, the nucleophile
(1.2 equiv., 0.98 mmol) dissolved in dry THF was
added. To the resultant mixture was added after 10 min
a solution of compounds 7 or 8 (1 equiv., 0.82 mmol) in
dry THF (10 mL). This solution was allowed to stir for
2 h at 0°C and at room temperature overnight. The
mixture was quenched with a saturated ammonium
chloride solution, and extracted with ethyl acetate, the
combined organic layers were washed with sodium
bicarbonate solution and brine, dried over anhydrous
sodium sulfate, filtered and concentrated. Chromatog-
raphy of the residue on silica gel or aluminium oxide
provided compounds 16 (72% yield) and 17–20.

M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 411–418
417
3.5. General procedure for radical substitution of
bromides 7 and 8
Acknowledgements
Financial support from CICYT (SAF-97-0143 and
SAF-94-0517) and an MEC fellowship (M.L.H.) are
gratefully acknowledged.
A solution of bromide 7 or 8 (0.82 mmol) in dry
deoxygenated benzene (5 mL) under argon was treated
with allyltributyltin (1.1 equiv., 0.9 mmol) at reflux for
1.5 h, with azobisisobutylnitrile to initiate the reaction.
After removal of the solvent, the residue was dissolved
in CH2Cl2, washed with brine and the organic solution
was dried over anhydrous sodium sulfate, filtered and
concentrated. The residue was purified by flash chro-
matography giving compounds 13 (85% yield) or 14
(60% yield).
References
1. For a review, see: Williams, R. M. In Synthesis of Opti-
cally Active h-Amino Acids, Organic Chemistry Series;
Baldwin, J. E.; Magnus, P. D., Eds.; Pergamon Press,
1989; Vol. 7.
2. Williams, R. M.; Sinclair, P. J.; Zhai, W. J. Am. Chem.
Soc. 1988, 110, 482–483.
The first experiments with compound 7 using dry ben-
zene as solvent gave compound 21.
3. Williams, R. M.; Sinclair, P. J.; Zhai, D.; Chen, D. J.
3.5.1. (+)-(1S,4S)-2,4-Dimethyl-1-phenoxy-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 21. It was
obtained (EtOAc/hexane 1:1, aluminium oxide) as a
white solid; yield: 68%; mp 98–100°C; [h]2D5=+164 (c
0.29, CHCl3); wmax (KBr): 1732, 1690 cm−1; lH (CDCl3,
250 MHz) 8.26 (dd, 1H, J=8.0 and 1.4 Hz), 7.95 (dd,
2H, J=7.9 and 1.3 Hz), 7.74 (ddd, 1H, J=8.2, 7.4 and
1.4 Hz), 7.66 (dd, 1H, J=8.2 and 1.4 Hz), 7.55 (dd, 1H,
J=7.0 and 1.3 Hz), 7.47 (ddd, 1H, J=8.0, 7.4 and 1.4
Hz), 7.40 (dd, 2H, J=7.9 and 7.0 Hz), 7.19 (s, 1H),
5.44 (q, 1H, J=7.1 Hz), 3.23 (s, 3H), 1.88 (d, 3H,
J=7.1 Hz); lC (63 MHz, CDCl3) 169.8, 165.2, 159.9,
147.1, 145.6, 134.9, 134.2, 130.0, 128.8, 128.2, 127.9,
126.9, 121.0, 82.0, 52.7, 33.8, 19.6. C19H17N3O3
requires: C, 68.05; H, 5.11; N, 12.53. Found: C, 68.41;
H, 4.75; N, 12.70%.
Am. Chem. Soc. 1988, 110, 1547–1557.
4. Sho¨llkopf, U.; Neubauer, H. J.; Hauptreif, M. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1066–1067.
5. Sho¨llkopf, U.; Gru¨ttner, S.; Anderskewitz, R.; Egert, E.;
Dyrbusch, M. Angew. Chem., Int. Ed. Engl. 1987, 26,
683–684.
6. Yoshimura, J.; Nakamura, H.; Matsunari, K. Bull. Chem.
Soc. Jpn. 1975, 48, 605–609.
7. Yoshimura, J.; Sugiyama, Y.; Nakamura, H. Bull. Chem.
Soc. Jpn. 1973, 46, 2850–2853.
8. Williams, R. M.; Armstrong, R. W.; Maruyama, L. K.;
Dung, J.-S.; Anderson, O. P. J. Am. Chem. Soc. 1985,
107, 3246–3253.
9. Williams, R. M.; Kwast, A. J. Org. Chem. 1988, 53,
5785–5789.
10. Badran, T. W.; Easton, Ch. J. Aust. J. Chem. 1990, 43,
1455–1459.
3.5.2. (+)-1,1%-Bi[(4S)-2,4-dimethyl-3,6-dioxo-2,3,4,6-tet-
rahydro-1H-pyrazino[2,1-b]quinazolinyl] 22. Pd2(dba)3·
CHCl3 (0.04 equiv., 0.025 mmol, 26 mg) and AsPh3 (0.3
equiv., 0.19 mmol, 61 mg) were stirred in dry THF at
room temperature for 10 min. The crude bromo deriva-
tive 7 (1 equiv., 0.62 mmol) and the tributylvinyltin (1.1
equiv., 0.22 mmol, 0.19 mL) were dissolved in THF and
added to the solution of the catalyst. The reaction
mixture was stirred under reflux for 5 h, cooled to room
temperature, washed with brine and extracted with
ethyl acetate. The combined organic extracts were dried
over anhydrous sodium sulfate, filtered and concen-
trated. Silica gel chromatography of the residue with
EtOAc gave a white solid (25% yield); mp 96–98°C;
[h]2D5=+41 (c 0.19, CHCl3); wmax (KBr): 1669, 1597,
1567 cm−1; lH (CDCl3, 250 MHz) 8.34 (dd, 1H, J=8.0
and 1.2 Hz), 8.17 (dd, 1H, J=7.9 and 1.3 Hz), 7.79
(ddd, 1H, J=8.2, 7.5 and 1.5 Hz), 7.67 (ddd, 1H,
J=7.9, 7.8 and 1.5 Hz), 7.62 (d, 1H, J=8.2 Hz), 7.54
(ddd, 1H, J=8.0, 7.5 and 1.1 Hz), 7.44 (ddd, 1H,
J=7.9, 7.7 and 1.0 Hz), 7.04 (d, 1H, J=7.9 Hz), 5.31
(d, 1H, J=12.6 Hz), 5.30 (d, 1H, J=12.6 Hz), 5.18 (q,
1H, J=7.1 Hz), 4.50 (q, 1H, J=6.6 Hz), 3.31 (s, 3H),
3.19 (s, 3H), 1.64 (d, 3H, J=6.6 Hz), 1.63 (d, 3H,
J=7.1 Hz); lC (63 MHz, CDCl3) 167.8, 166.9, 161.2,
160.0, 147.5, 146.8, 145.8, 145.2, 135.3, 134.9, 128.0,
127.5, 127.1, 127.0, 126.9, 126.8, 124.3, 121.2, 70.0,
64.1, 52.7, 51.9, 36.1, 33.5, 20.4, 18.6. C26H24N6O4
requires: C, 64.45; H, 4.99; N, 17.35. Found: C, 64.19;
11. Badran, T. W.; Chai, C. L. L.; Easton, Ch. J.; Harper, J.
B.; Page, D. M. Aust. J. Chem. 1995, 48, 1379–1384.
12. Whitlock, C. R.; Cava, M. P. Tetrahedron Lett. 1994, 35,
371–374.
13. Chai, C. L. L.; Page, D. M. Tetrahedron Lett. 1993, 34,
4373–4376.
14. Badran, T. W.; Easton, Ch. J.; Horn, E.; Kociuba, K.;
May, B. L.; Schliebs, D. M.; Tiekink, E. R. T. Tetra-
hedron: Asymmetry 1993, 4, 197–200.
15. Williams, R. M.; Armstrong, R. W.; Dung, J.-S. J. Am.
Chem. Soc. 1984, 106, 5748–5750.
16. Martin-Santamar´ıa, S.; Buenadicha, F.; Espada, M.; So¨ll-
huber, M.; Avendan˜o, C. J. Org. Chem. 1997, 62, 6424–
6428.
17. Mart´ın-Santamar´ıa, S.; Espada, M.; Avendan˜o, C. Tetra-
hedron 1997, 53, 16795–16802.
18. Bartolome´, M. T.; Buenadicha, F. L.; Avendan˜o, C.;
So¨llhuber, M. Tetrahedron: Asymmetry 1998, 9, 249–258.
19. Buenadicha, F.; Bartolome´, M. T.; Aguirre, M. J.; Aven-
dan˜o, C.; So¨llhuber, M. Tetrahedron: Asymmetry 1998, 9,
483.
20. Ferna´ndez, M.; Heredia, M. L.; de la Cuesta, E.; Aven-
dan˜o, C. Tetrahedron 1998, 54, 2777–2784.
21. Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber, M. Tetra-
hedron: Asymmetry 1998, 9, 4275–4284.
22. Mart´ın-Santamar´ıa, S.; Espada, M.; Avendan˜o, C. Tetra-
hedron 1999, 55, 1755–1762.
23. Sa´nchez, J. D.; Ramos, M. T.; Avendan˜o, C. Tetrahedron
Lett. 2000, 41, 2745–2748.
H, 5.16; N, 17.41%.
.

418
M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 411–418
24. Karwoski, J. P.; Jackson, M.; Rasmussen, R. R.;
Humphrey, P. E.; Poddig, J. B.; Kohl, W. L.; Scherr, M.
H.; Kadam, S.; McAlpine, J. B. J. Antibiot. 1993, 46,
374–379.
25. Chou, T.-C.; Depew, K. M.; Zheng, Y.-H.; Safer, M. L.;
Chan, D.; Helfrich, B.; Zatorska, D.; Zatorski, A.; Born-
mann, W.; Danishefsky, S. J. Proc. Natl. Acad. Sci. USA
1998, 95, 8369–8374.
26. Mendez-Vidal, C.; Quesada, A. R. Cancer Lett. 1998,
132, 45–50.
27. Evacuation of oxygen is advisable in radical reactions
since nearly all radicals add to triplet oxygen, but given
the low reactivity of benzene against radicals [see: Com-
prehensive Organic Synthesis; Trost, B. M.; Fleming, I.,
Eds.; Pergamon Press, 1991; Vol. 4, p. 720], this unprece-
dented result was not expected.
.