Regio- And Diastereoselective Alkylation of 2-Substituted 2,4-Dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones

Full text of DOI:10.1021/jo970037a

6424
J . Org. Chem. 1997, 62, 6424-6428
Here we report the synthesis of 2-methyl and 2-benzyl
derivatives (compounds a and b, respectively) of the 1,4-
dialkyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-di-
one structure through alkylation of the parent 1-unsub-
stituted compounds 1a and 1b. Besides the possible
biological activity as resistance modifier agents (RMAs)
of these compounds, the change of substituents at the
N2-position was expected to permit, after deprotection of
the analogues derived from 3-indolylmethylation at C1-
carbon atom, an alternative total synthesis of N-acetyl-
ardeemin.
Regio- a n d Dia ster eoselective Alk yla tion of
2-Su bstitu ted 2,4-Dih yd r o-1H-
p yr a zin o[2,1-b]qu in a zolin e-3,6-d ion es
Sonsoles Mart´ın-Santamar´ıa, Fe´lix L. Buenadicha,
Modesta Espada, Mo´nica So¨llhuber and
Carmen Avendan˜o*
Departamento de Quı´mica Orga´nica y Farmace´utica,
Facultad de Farmacia, Universidad Complutense,
28040 Madrid, Spain
1
Received J anuary 6, 1997
Conformational studies based on H NMR data showed
that in compound 1a unsubstituted at the C4-position
(incorporating sarcosine, glycine, and anthranilic acid),
the piperazine ring has conformational flexibility, while
the introduction of a 4-methyl group (as in compound 1a ,
incorporating sarcosine, L-alanine, and anthranilic acid)
locks this ring in a boat conformation, in which that
substituent adopts a pseudoaxial disposition.6a This
conformation is a consequence of the extremely severe
steric interaction between the quinazolone carbonyl group
(C6dO) and the alternative pseudoequatorial C4-methyl
substituent.6b The same pseudoaxial disposition has been
shown in the solid state, according to X-ray diffraction
data of 1a .6c
Stereoselective alkylation reactions on anions of bis-
lactim ethers derived from cyclic dipeptides have been
widely used in organic synthesis.7 Examples dealing
with anions of piperazine-2,5-diones have occurred to a
lesser extent and have been mostly exploited in intramo-
lecular enolate C-C bond-forming cyclizations.8 We
considered that alkylation of compounds 1 could take
place regio- and diastereoselectively, with the preferential
formation of the 1,4-anti isomers according to the asym-
metric induction of the chiral C4-center, thus providing
access to interesting products.
Alkylation of N2-protected (4S)-4-alkyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-diones was planned to af-
ford compounds that contain a fragment of the fungal
metabolite 5-N-acetylardeemin, which has been described
as a potent reversal agent of multiple drug resistance
(MDR) in tumor cell lines.1 The MDR phenotype involves
the overexpression of a 170 kDa membrane glycoprotein
(Pgp-170), which is thought to function as a broad-
substrate ATP-dependent pump that exports drugs out
of the cell, thus lowering the intracellular drug concen-
tration below the cytotoxic threshold.2 In spite of the
intrinsic problems derived from the expression of Pgp-
170 in several normal tissues,3 many failures in cancer
chemotherapy could be overcome if this protein could be
effectively inhibited by compounds with less toxicity at
the active concentrations than those which have been
studied so far for this purpose.4
A variety of fungal metabolites, such as auranthine5a
and asperlicin,5b which are biosynthesized from R-amino
acids and anthranilic acid, have fused benzodiazepine
and quinazolinone moieties while other compounds, such
as glyantrypine,5c fumiquinazolines F and G,5d,e or fiscalin
B,5f contain the 2,4-dihydro-1H-pyrazino[2,1-b]quinazo-
line-3,6-dione structure. N-Acetylardeemin can be con-
sidered as a tripeptide derived from tryptophan, alanine,
and anthranilic acid. According to that, its total synthe-
sis has been accomplished starting from L-tryptophan
methyl ester.1c
Resu lts a n d Discu ssion
Our first experiments of alkylation reactions on 1a and
1b (n-BuLi, THF, -78 °C, 1 h, followed by R1X, where
R1 ) methyl, allyl, and benzyl, method A) gave no traces
of C4-alkylation products, thus confirming the expected
regioselectivity, but the observation of an NOE between
the C4-methyl group and the C1-substituent of the
obtained compounds, showed a 1,4-syn relationship,
which was paired with racemization of the C4-stereogenic
center. These disappointing results were attributed to
a thermodynamic control of the reaction, and we became
motivated to study in more detail the influence of the
lithiating agent and the electrophile, as well as time and
temperature variation upon their addition.
(1) (a) Biological activity: Karwowsky, J . P.; J ackson, M.; Rasmus-
sen, R. R.; Humphrey, P. E.; Poddig, J . B.; Kohl, W. L.; Scherr, M. H.;
Kadam, S.; McAlpine, J . B. J . Antibiot. 1993, 46, 374. (b) Isolation
and structure: Hochlowki, J . E.; Mullally, M. M.; Spanton, S. G.;
Whittern, D. N.; Hill, P.; McAlpine, J . B. J . Antibiot. 1993, 46, 380. (c)
Total synthesis: Marsden, S. P.; Depew, K. M.; Danishefsky, S. J . J .
Am. Chem. Soc. 1994, 116, 11143.
(2) (a) Gottesman, M. M.; Pastan, I. J . Biol. Chem. 1988, 263, 12163.
(b) Endicott, J . A.; Ling, V. Annu. Rev. Biochem. 1989, 58, 137. (c) Ford,
J . M.; Hait, W. N. Pharmacol. Rev. 1990, 42, 155. (d) Gottesman, M.
M.; Pastan, I. Annu. Rev. Biochem. 1993, 62, 385. (e) Patel, N. H.;
Rothenberg, M. L. Invest. New Drug 1994, 12, 1. (f) Simon, S. M.;
Schindler, M. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3497.
The reaction of 1a with LHMDS as base at -78 °C,
followed by fast addition of benzyl bromide as electro-
(3) Tsuruo, T.; Tomida, A. Anti-Cancer Drugs 1995, 6, 213.
(4) (a) Tsuruo, T.; Iida, H.; Tsukagoshi, S.; Sakurai, J . Cancer Res.
1981, 41, 1967. (b) Twentyman, P. R.; Bleehen, N. M. Eur. J . Cancer
1991, 27, 1639. (c) Loor, F.; Boesch, D.; Gaveriaux, C.; J achez, B.;
Pourtier-Manzanedo, A.; Emmer, G. Br. J . Cancer 1992, 65, 11. (d)
Kellen, J . A. Anticancer Res. 1993, 13, 959. (e) Stratmann, K.;
Burgoyne, D. L.; Moore, R. E.; Patterson, G. M. L. J . Org. Chem. 1994,
59, 7219. (f) Garrido, C.; Chauffert, B.; Pinard, D.; Tibaut, F.; Genne,
P.; Assem, M.; Dimanche-Boitrel, M. T. Int J . Cancer 1995, 61, 873.
(5) (a) Yeulet, S. E.; Mantle, P. G. FEMS Microbiol. Lett. 1987, 41,
207. (b) Liesch, J . M.; Hensens, O. D.; Springer, J . P.; Chang, R. S. L.;
Lotti, V. J . J . Antibiot. 1985, 38, 1638. (c) Penn, J .; Mantle, P. G.;
Bilton, J . N.; Sheppard, R. N. J . Chem. Soc., Perkin Trans. 1 1992,
1495. (d) Takahashi, Ch.; Matsushita, T.; Doi, M.; Minoura, K.; Shingu,
T.; Kumeda, Y.; Numata, A. J . Chem. Soc., Perkin Trans 1 1995, 2345.
(e) Numata, A.; Takahashi, Ch.; Matsushita, T.; Miyamoto, T.; Kawai,
K.; Usami, Y.; Matsumura, E.; Inone, M.; Ohishi, H.; Shingu, T.
Tetrahedron Lett. 1992, 33, 1621. (f) Wong, S.; Musza, L. L.; Kydd, G.
C.; Kullnig, R.; Gillum, A. M.; Cooper, R. J . Antibiot. 1993, 46, 545.
(6) (a) Rajappa, S.; Advani, B. G. Tetrahedron 1973, 29, 1299. (b)
Rajappa, S.; Advani, B. G. J . Chem. Soc., Perkin Trans. 1 1974, 2122.
(c) Suguna, K.; Ramakumar, S.; Rajappa, S. Acta Crystallogr. B 1982,
B38, 1654.
(7) For summaries of the alkylation of bis-lactim ethers, see: (a)
Scho¨llkopf, U. Tetrahedron 1983, 39, 2085. (b) Scho¨llkopf, U. Pure Appl.
Chem. 1983, 55, 1799. (c) Scho¨llkopf, U. Top. Curr. Chem. 1983, 109,
65. (d) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Pergamon Press, 1989; Chapter 1.
(8) See: (a) Williams, R. M.; Glinka, T.; Kwast, E. J . Am. Chem.
Soc. 1988, 110, 5927. (b) Williams, R. M.; Glinka, T.; Kwast, E.;
Coffman, H.; Stille, J . K. J . Am. Chem. Soc. 1990, 112, 808. (c)
Williams, R. M.; Kwast, E. J . Org. Chem. 1988, 53, 5785. (d) Williams,
R. M.; Durham, C. A. Chem. Rev. 1988, 88, 511. (e) D’Arrigo, M. C.;
Porzi, G.; Sandri, S. J . Chem. Res. Synop. 1995, 430 and references
cited therein.
S0022-3263(97)00037-6 CCC: $14.00 © 1997 American Chemical Society

Notes
Ta ble 1. 1-Alk yla ted Der iva tives of 1a a n d 1b u n d er
J . Org. Chem., Vol. 62, No. 18, 1997 6425
Sch em e 1
Sta n d a r d Rea ction Con d ition s (Meth od B)
%
anti/syn
entry compound
R1
R2 yielda
ratiob
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
2a , 3a
2b, 3b
4a , 5a
4b, 5b
6a , 7a
6b, 7b
8a , 9a
8b, 9b
10a , 11a
10b, 11b
12a , 13a
12b, 13b
14a , 15a
14b, 15b
16a , 17a
16b, 17b
18a , 19a
18b, 19b
20a , 21a
20b, 21b
Bn
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Bn
Me
Bn
75
72
58
90
68
35
70
68
70
52
90
54d
20
60d
20e
56
50
57
98
64
87:13
74:26
86:14
66:33
74:26
60:40
71:29c
74:26
86:14
58:42
100:0
54:46
100:0
60:40
e
p-MeC6H4CH2
p-MeC6H4CH2
p-F3CC6H4CH2
p-F3CC6H4CH2
p-FC6H4CH2
p-FC6H4CH2
o-FC6H4CH2
o-FC6H4CH2
m-ClC6H4CH2
m-ClC6H4CH2
2-naphthylmethyl Me
2-naphthylmethyl Bn
allyl
allyl
p-O2NC6H4CH2
Me
Bn
Me
Bn
Me
Bn
63:37
10:90
f
p-O2NC6H4CH2
Me
Me
30:70
0:100
0:100
tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphor-
ate] [(+)-Eu(HFC)3] as chiral shift reagent. It was
gratifying to observe that all compounds so far mentioned
showed enantiomeric excess >95%. Racemized syn iso-
mers were only obtained at much longer reaction times.
The diastereoselection found in the synthesis of com-
pounds 2-17 in favor of the anti isomers supported that
the electrophilic substitution in compounds 1 is governed
by the asymmetric induction imposed by the pseudoaxial
methyl group at the C4-position.
The apparent diastereoselection puzzle reflected in
Table 1 can be interpreted through the scrambling of
anions that can be present in the reaction. According to
the mechanism outlined in Scheme 1, the kinetically
favored anti isomers derived from anion A epimerize to
the syn isomers through their transformation to anion
B. This assumption was corroborated by treatment of
compound 8a and 8b with LHMDS under standard
reaction conditions, affording a mixture of compounds 8a :
9a and 8b:9b, respectively, in a 1:3 and 1:9 ratios. The
same experiment on compounds 9a and 9b left them
unchanged.
a
b
Yields are given for isolated, purified compounds. ee >95%
for all compounds was showed. c Syn and anti isomers could not
be separated. The reaction time was longer. e Only the syn isomer
d
17a was isolated. f Both isomers could not be obtained analytically
pure.
phile, gave (method B) a diastereomeric excess of 74%
in favor of the enantiopure anti diastereoisomer 2a over
the syn diastereoisomer 3a after 20 min (Table 1). The
same reaction on compound 1b gave compounds 2b (anti
isomer) and 3b (syn isomer) in lower diastereomeric
excess (48%). Other benzyl halides gave similar results
(see Table 1, entries 3-10), the most favorable diaste-
reoselection (de >95%) being the one observed in the
reactions of 1a with m-chlorobenzyl bromide and 2-naph-
thylmethyl bromide (see Table 1, entries 11 and 13,
respectively). The reaction of 1b with allyl bromide gave
lower diastereomeric excess (24%), while in analogous
reactions with 1a , only the syn isomer 17a could be
isolated. With p-nitrobenzyl bromide the observed dias-
tereoselectivity was in favor of the syn isomers for both
1a and 1b, under the same reaction conditions (see Table
1, entries 17 and 18) while, in the case of methyl iodide
as electrophile (see Table 1, entries 19 and 20), a
diastereoisomeric excess >95% of the syn isomers was
obtained.
Racemization of syn isomers at prolonged reaction
times must involve the dianion C derived from anion B
instead of anion A, since the same treatment of com-
pounds 1 in base did not produce traces of racemized 1.
The alternative equilibration of syn-(1S,4S) or anti-
(1R,4S) isomers to syn-(1R,4R) isomers through the C4-
anion was ruled out by alkylation experiments on (1S)-
1,2-dialkylated compounds 4a , 4b, 7a , and 8b.
Small amounts of 1,1-dialkylated compounds were also
produced as secondary products, and in some reactions
on compound 1b, the dialkylation took also place in the
1,4-positions.
Whether or not racemization or epimerization had
taken place in the alanine moiety was studied through
1H-NMR spectroscopy in the presence of europium(III)
The diastereoselectivity is apparently controlled by the
relative availability of anions B, that is, by the equilib-
rium between anti isomers and their B anions. The 1,4-

6426 J . Org. Chem., Vol. 62, No. 18, 1997
Notes
Ta ble 2. Ca lcu la ted En er gies (MM2, k ca l/m ol) for Som e
Rep r esen ta tive Com p ou n d s
anti isomers
calcd energies
calcd energies
syn isomers
2a
2b
16a
16b
20a
20b
3.15
3.12
6.27
5.14
3.78
2.27
1.35
0.92
2.18
2.98
1.12
0.80
3a
3b
17a
17b
21a
21b
syn diastereoselectivity observed for p-nitrobenzylation
and methylation indicates that SN2-like conditions tend
to favor the formation of the thermodynamic product by
a slower reaction, resulting in equilibration. Moreover,
equilibration may occur faster when R1 is methyl or allyl
than when R1 is benzyl (see later).
The steric interaction between R1 and R2 substituents
will be rather high in anion B because of its planarity.
Thus, the higher de of anti isomers corresponds to the
bulkier substituents (2-naphthylmethyl and m-chloroben-
zyl) in a series. The lower anti diastereoselectivity
observed for the N-benzyl derivatives b as compared to
the N-methyl compounds a suggests that in 1b the
asymmetric induction of the chiral C4-center is in part
counterbalanced with that of the phenyl moiety of the
N2-substituent at the opposite face.
A high-temperature molecular dynamics study of rep-
resentative compounds was carried out by using Hyper-
Chem 3 program in order to explore their putative
minimum energy conformations. To avoid the risks
inherent to this methodology, additional molecular dy-
namics was used and, finally, the minimum energy
conformers were minimized using MM calculations and
Fletcher-Reeves algorithm (RMS gradient 0.01 kcal/Å
mol) (Table 2). As expected, the calculated energies for
the more favorable conformers were lower in the syn
isomers.
F igu r e 1. Proposed conformations of the piperazine ring
according to NMR data and molecular mechanics calculations.
epimerization of the anti-benzyl conformation might take
place only through a higher energy conformation, result-
ing in a slower rate of equilibration.
1
It has been previously mentioned that H NMR spec-
troscopy was of great value in the assignment of syn and
anti configurations through NOE experiments, and in
determining the enantiomeric purity by using chiral
reagents. In addition, 1H NMR data of 1-benzylated
compounds with an anti-1,4-relationship showed signifi-
cant changes in the C4-H resonances respect to the
corresponding syn isomers, which corroborates the con-
formation proposed by MD studies. The changes were
less significant in the C4-Me resonances. For instance,
δ values for these protons in 2a /2b are 4/4.04 (C4-H) and
1.5/1.54 (C4-Me) ppm, while in 3a /3b they are 5.2/5.27
and 1.1/1.2 ppm, respectively. These data clearly show
that the C4-H proton is coplanar with the C6dO group
in the syn isomers (pseudoequatorial) but not in the anti
isomers. A twist boat conformation with the H4-proton
in a pseudoequatorial arrangement is also inferred from
the chemical shift values of C4-H protons in the syn
isomers of allyl and methyl derivatives. All of them
showed analogous low-field resonances, which are due
to the fact that this proton is strongly deshielded by the
anisotropic effect of the quasi-coplanar C6dO carbonyl
group. The same conformation has been observed in the
The minimum energy calculated conformations for the
syn isomers were in agreement with NMR data (see
later). They showed a boat conformation for piperazine
ring, in which the R2-substituent adopts a pseudoequa-
torial disposition and both C1- and C4-substituents are
in a pseudoaxial disposition (Figure 1). For the anti
isomers, the conformations of minimum energy showed
this ring in a more planar conformation, and the same
disposition for the R2-substituent. In allyl and methyl
derivatives (16 and 20), molecular dynamics calculations
of anti isomers show a pseudoaxial disposition for the
C4-methyl group and a pseudoequatorial one for the C1-
substituent, the chemical shift for C4-H of 16b being very
similar to the value of the syn isomer (δ ) 5.34 and 5.4
ppm, respectively). On the other hand, in anti-C1-benzyl
derivatives, the C1-substituent is pseudoaxial and the C4-
substituent is pseudoequatorial. These conformations
imply that the steric interactions between the substitu-
ents at C1- and N2-positions in the anti-benzylated
compounds are greater than that of the C4-methyl and
the C6dO groups. Furthermore, while in compounds 2
and 3, and their analogues, the aryl group adopts an exo
configuration, in 1,1-dibenzylated compounds, the syn-
aryl group is in an endo configuration (see Figure 1),
oxopiperazine ring of fumiquinazolines.5d The general 13
C
NMR spectral features of syn compounds closely resemble
those of anti isomers, except for the signals of C1- and
C4-carbon atoms, which appear at higher δ values in the
syn isomers, especially the C1 carbon atom.
We can conclude that alkylation of the title compounds
may be useful from a synthetic point of view. Further
studies with derivatives of 1 carrying bulkier substitu-
ents at C4 are in progress. The preliminary biological
activity studies have shown that several of the com-
pounds here described are moderately active as resis-
tance modifier agents.
1
which also agrees with H NMR data.
The difference in conformations for the anti isomers
when R1 is methyl or allyl versus anti-benzyl derivatives
is consistent with a higher rate for the equilibration in
methyl and allyl compounds, where the anti conformation
is favorably aligned for deprotonation. In contrast, the
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. IR spectra were
recorded with all solid compounds compressed into KBr pellets
and liquid compounds placed between NaCl plates. NMR

Notes
J . Org. Chem., Vol. 62, No. 18, 1997 6427
spectra were recorded at 250 MHz for 1H and 62.5 MHz for 13C
in CDCl3, with TMS as the internal reference (Servicio RMN,
UCM). Mass spectra were recorded at 70 eV, quadrupole
detector, EI (Servicio de Espectroscop´ıa UCM). Elemental
analyses were obtained from the Servicio de Microana´lisis, UCM
Optical rotations were determined at 25 °C in CHCl3 or EtOH
at 589 nm. Separations by chromatography were performed on
silica gel (35-70 µm) for compounds b or alumina (63-200 µm)
for compounds a . Tetrahydrofuran was freshly distilled from
sodium benzophenone. All reagents were of commercial quality
and were used as received. The expression “petroleum ether”
refers to the fraction boiling at 40-60 °C. Starting material 1a
was obtained according to the literature.6b
(1R ,4S )-1,2-Dib e n zyl-4-m e t h yl-2,4-d ih yd r o-1H -p yr a -
zin o[2,1-b]qu in a zolin e-3,6-d ion e (2b) was obtained as a white
solid: mp 161-163 °C; yield 53%; [R]25 +99.6 (c 0.25, CHCl3);
D
IR (KBr) 1704, 1694 cm-1; H NMR (CDCl3) δ 1.54 (d, 3H, J )
1
6.7 Hz), 3.26 (dd, 1H, J ) 13.9 and 3.4 Hz), 3.46 (dd, 1H, J )
13.9 and 3.9 Hz), 4.04 (q, 1H, J ) 6.7 Hz), 4.07 (d, 1H, J ) 14.9
Hz), 4.82 (“t”, 1H, J ) 3.6 Hz), 5.79 (d, 1H, J ) 14.9 Hz), 6.7 (m,
2H), 7.09-7.37 (m, 8H), 7.46 (td, 1H, J ) 8 and 1.1 Hz), 7.6 (dd,
1H, J ) 8 and 1.1 Hz), 7.73 (td, 1H, J ) 8 and 1.5 Hz), 8.17 (dd,
1H, J ) 8 and 1.1 Hz); 13C NMR (CDCl3) δ 167.8, 160.2, 149.9,
146.8, 135.4, 134.9, 133.6, 129.6, 129.3, 128.8, 128.5, 128.3, 128.1,
127.1, 127.0, 126.7, 120.6, 59.2, 52.1, 46.6, 39.9, 20.8. Anal.
Calcd for C26H23N3O2: C, 76.28; H, 5.62; N, 10.26. Found: C,
75.90; H, 5.62; N, 10.33.
(4S )-2-Be n zyl-4-m e t h yl-2,4-d ih yd r o-1H -p ir a zin o[2,1-
b]qu in a zolin e-3,6-d ion e (1b). A mixture of 4.36 g (20 mmol)
of (3S)-1-benzyl-3-methylpiperazine-2,5-dione,9 triethyloxonium
tetrafluoroborate (11.4 g, 60 mmol), and anhydrous Na2CO3 (10.6
g, 100 mmol) in 200 mL of dry CH2Cl2 was stirred overnight at
room temperature, poured on ice water, extracted with CH2Cl2,
dried over anhydrous Na2SO4, and evaporated. Anthranilic acid
was added to the syrupous residue, and the mixture was stirred
vigorously at 130-140 °C for 2.5 h under argon, dissolved in
CH2Cl2, extracted with diluted ammonium hydroxide, dried
(Na2SO4), and concentrated. Flash chromatography (EtOAc/
MeOH, 95:5) afforded 3.76 g (59%) of 1b as a white solid: mp
(1S,4S)-1-Ben zyl-2,4-d im et h yl-2,4-d ih yd r o-1H -p yr a zi-
n o[2,1-b]qu in a zolin e-3,6-d ion e (3a ) was obtained (EtOAc/
hexane, 7:3) as a white solid: mp 151-152 °C; yield 10%; [R]25
D
-6.5 (c 2, EtOH); IR (KBr) 1684, 1596 cm-1; 1H NMR (CDCl3) δ
1.19 (d, 3H, J ) 7.1 Hz), 2.92 (s, 3H), 3.41 (m, 2H), 4.79 (m,
1H), 5.15 (q, 1H, J ) 7.1 Hz), 7.09 (dd, 2H, J ) 6.5 and 1.9 Hz),
7.25 (m, 3H), 7.50 (t, 1H, J ) 7.5 Hz), 7.69 (dd, 1H, J ) 7.4 and
1.4 Hz), 7.81 (m, 1H), 8.26 (dd, 1H, J ) 7.9 and 1.4 Hz); 13C
NMR (CDCl3) δ 167.2, 160.4, 150.3, 147.3, 135.5, 134.9, 129.9,
127.9, 127.2, 127.0, 126.9, 120.3, 65.2, 52.4, 41.6, 34.1, 18.4. Anal.
Calcd for C20H19N3O2: C, 72.07; H, 5.70; N, 12.61. Found: C,
71.87; H, 5.68; N, 12.52.
133-135 °C (EtOAc-hexane); [R]25 +36.2 (c 0.25, CHCl3); IR
D
(KBr) 1670, 1608 cm-1; 1H NMR (CDCl3) δ 1.61 (d, 3H, J ) 7.2
Hz), 4.30 (d, 1H, J ) 16.9 Hz), 4.50 (d, 1H, J ) 16.9 Hz), 4.53
(d, 1H, J ) 14.6 Hz), 4.9 (d, 1H, J ) 14.6 Hz), 5.55 (q, 1H, J )
7.2 Hz), 7.32 (m, 5H), 7.47 (ddd, 1H, J ) 8, 7, and 1.2 Hz), 7.56
(dd, 1H, J ) 8.2 and 1.6 Hz), 7.74 (ddd, 1H, J ) 8.2, 7, and 1.6
Hz), 8.27 (dd, 1H, J ) 8 and 1.2 Hz); 13C NMR (CDCl3) δ 167.6,
160.0, 148.0, 147.3, 135.2, 134.9, 129.2, 128.4, 127.4, 127.0, 120.6,
52.2, 49.8, 49.3, 17.2. Anal. Calcd for C19H17O2N3: C, 71.45;
H, 5.36; N, 13.15. Found: C, 71.28; H, 5.56; N, 13.06.
(1S,4S)-1,2-Dib en zyl-4-m et h yl-2,4-d ih yd r o-1H -p yr a zi-
n o[2,1-b]qu in a zolin e-3,6-d ion e (3b) was obtained as a white
solid: mp 188-189 °C (ethyl ether); yield 19%; [R]25D -11 (c 0.25,
CHCl3); IR (KBr) 1680, 1668 cm-1 1H NMR (CDCl3) δ 1.2 (d,
;
3H, J ) 7.1 Hz), 3.33 (dd, 1H, J ) 13.8 and 7.1 Hz), 3.45 (dd,
1H, J ) 13.8 and 4.8 Hz), 3.5 (d, 1H, J ) 14.9 Hz), 4.75 (dd, 1H,
J ) 7.1 and 4.9 Hz), 5.27 (q, 1H, J ) 7.1 Hz), 5.48 (d, 1H, J )
14.9 Hz), 7.11 (m, 2H), 7.28 (m, 3H), 7.47 (ddd, 1H, J ) 8, 8 and
1.2 Hz), 7.55 (dd, 1H, J ) 8 and 1.2 Hz), 7.74 (ddd, 1H, J ) 8,
8 and 1.5 Hz), 8.25 (dd, 1H, J ) 8 and 1.5 Hz); 13C NMR (CDCl3)
δ 167.4, 160.4, 150.4, 147.2, 135.7, 135.3, 134.8, 129.9, 129.3,
129.1, 128.5, 127.9, 127.6, 127.1, 127.0, 126.9, 120.4, 61.1, 52.4,
47.8, 41.6, 18.5. Anal. Calcd for C26H23N3O2: C, 76.28; H, 5.62;
N, 10.26. Found: C, 75.95; H, 5.30; N, 10.04.
Gen er a l P r oced u r es for th e Alk yla tion of Com p ou n d s
1a a n d 1b. Meth od A. To a cold (-78 °C), magnetically stirred
solution of 1a or 1b (1 mmol) in dry THF (15 mL) was added,
under argon, dropwise via syringe 1.3 mmol of n-butyllithium
(2.5 M in hexane), followed by the adequate halide (1 mmol in
5 mL of THF) 1 h later. The reaction mixture was maintained
at -78 °C overnight, allowed to warm up to rt, quenched with
a cold saturated solution of ammonium chloride, diluted with
CH2Cl2 or ethyl acetate, and worked up as described in method
B.
Gen er a l P r oced u r es for th e Alk yla tion of Com p ou n d s
1a a n d 1b. Meth od B. To a cold (-78 °C), magnetically stirred
solution of compounds 1a or 1b (1 mmol) in dry THF (15 mL)
was added, under argon, dropwise via syringe a 1 M solution of
lithium hexamethyl disilazide in THF (1 mL), followed by the
adequate halide (1.1 mmol dissolved in 5 mL of THF if solid, or
without solvent if liquid) 5-10 min later. The reaction mixture
was maintained at -78 °C during 10-20 min, allowed to warm
to rt until decoloration (or up to 1 h), quenched with a cold
saturated ammonium chloride solution, and diluted with ethyl
acetate (for 1a derivatives) or CH2Cl2 (for 1b derivatives). The
separated aqueous layer was extracted with ethyl acetate or
CH2Cl2 (3 × 20 mL), respectively, and the combined organic
layers were washed with water, dried, and evaporated. Chro-
matography of the residue on silica gel (CH2Cl2/EtAcO, 9:1, for
most 1b derivatives) or alumina, provided first the 1,4-dialky-
lated, 1,1-dialkylated, if any, followed by the anti-1-alkylated
and syn-1-alkylated compounds.
(1R,4S)-1-Allyl-2-ben zyl-4-m eth yl-2,4-d ih yd r o-1H-p yr a zi-
n o[2,1-b]qu in a zolin e-3,6-d ion e (16b) was obtained as a white
solid: mp 107-109 °C; yield 35%; [R]25D +77 (c 0.25, CHCl3); IR
(KBr) 1684, 1652 cm-1; 1H NMR (CDCl3) δ 1.68 (d, 3H, J ) 6.9
Hz), 2.9 (ddd, 1H, J ) 14.9, 7.6, and 4.6 Hz), 3.08 (dddd, 1H, J
) 14.9, 6.4, 3.1, and 1.6 Hz), 4.04 (d, 1H, J ) 14.9 Hz), 4.6 (dd,
1H, J ) 4.6 and 3.1 Hz), 5.05 (dd, 1H, J ) 17.4 and 1.5 Hz),
5.07 (dd, 1H, J ) 10.5 and 1.5 Hz), 5.34 (q, 1H, J ) 6.9 Hz),
5.57 (dddd, 1H, J ) 17.4, 10.5, 7.6, and 6.4 Hz), 5.71 (d, 1H, J
) 14.9 Hz), 7.3 (m, 5H), 7.45 (ddd, 1H, J ) 8, 8 and 1.2 Hz),
7.56 (dd, 1H, J ) 8 and 1.2 Hz), 7.72 (ddd, 1H, J ) 8, 8, and 1.5
Hz), 8.23 (dd, 1H, J ) 8 and 1.5 Hz); 13C NMR (CDCl3) δ 167.9,
160.2, 149.5, 146.9, 135.4, 134.6, 130.7, 129.0, 128.0, 127.9, 127.0,
126.9, 126.7, 120.7, 120.2, 56.9, 51.9, 45.6, 35.9, 20.0. Anal.
Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69. Found: C,
73.14; H, 5.67; N, 11.60.
(1S,4S)-1-Allyl-2,4-dim eth yl-2,4-dih ydr o-1H-pyr azin o[2,1-
b]qu in a zolin e-3,6-d ion e (17a ) was obtained (EtOAc/hexane,
7:3) as a white solid: mp 191-192 °C; yield 20%; [R]25 +1.6 (c
D
0.81, EtOH); IR (film) 1666, 1601 cm-1; 1H NMR (CDCl3) δ 1.77
(d, 3H, J ) 7.0 Hz), 2.82 (“t”, 2H, J ) 6.7 Hz), 3.12 (s, 3H), 4.58
(t, 1H, J ) 6.7 Hz), 5.19 (dd, 1H, J ) 11.1 and 1.3 Hz), 5.21 (dd,
1H, J ) 15.8 and 1.3 Hz), 5.32 (q, 1H, J ) 7.1 Hz), 5.91 (m, 1H),
7.49 (m, 1H), 7.65 (dd, 1H, J ) 7.5 and 1.2 Hz), 7.79 (m, 1H),
8.38 (dd, 1H, J ) 7.9 and 1.3 Hz); 13C NMR (CDCl3) δ 167.3,
160.5, 150.2, 147.3, 134.8, 132.4, 127.2, 127.1, 126.8, 120.4, 120.1,
63.6, 52.4, 40.8, 34.3, 19.5. Anal. Calcd for C16H17N3O2: C,
67.84; H, 6.01; N, 14.84. Found: C, 67.61; H, 5.93; N, 14.66.
(1S,4S)-1-Allyl-2-ben zyl-4-m eth yl-2,4-d ih yd r o-1H-p yr a zi-
n o[2,1-b]qu in a zolin e-3,6-d ion e (17b) was obtained as a white
(1R,4S)-1-Be n zyl-2,4-d im e t h yl-2,4-d ih yd r o-1H -p ir a zi-
n o[2,1-b]qu in a zolin e-3,6-d ion e (2a ) was obtained (EtOAc/
hexane 7:3) as a white solid: mp 140-141 °C; yield 65%; [R]25
D
+180 (c ) 1, EtOH); IR (KBr) 1684, 1654 cm-1; 1H NMR (CDCl3)
δ 1.50 (d, 3H, J ) 6.6 Hz), 3.25 (s, 3H), 3.33 (dd, 1H, J ) 13.8
and 3.6 Hz), 3.43 (dd, 1H, J ) 13.8 and 3.7 Hz), 4.0 (q, 1H, J )
6.6 Hz), 4.95 (m, 1H), 6.65 (m, 2H), 7.08-7.23 (m, 3H), 7.50 (m,
1H), 7.69 (dd, 1H, J ) 7.3 and 1.3 Hz), 7.83 (m, 1H), 8.20 (dd,
1H, J ) 8.0 and 1.4 Hz); 13C NMR (CDCl3) δ 167.5, 160.1, 152.0,
146.7, 134.7, 133.4, 129.3, 128.7, 127.9, 126.9, 126.8, 126.7, 120.5,
62.8, 51.9, 40.1, 33.1, 20.2. Anal. Calcd for C20H19N3O2: C,
72.07; H, 5.70; N, 12.61. Found: C, 71.96; H, 5.75; N, 12.53.
solid: mp 138-140 °C (ethyl ether); yield 21%; [R]25 +19.9 (c
D
0.25, CHCl3); IR (KBr) 1686, 1649 cm-1; 1H NMR (CDCl3) δ 1.79
(d, 3H, J ) 7.1 Hz), 2.80 (t, 2H, J ) 7.0 Hz), 4.14 (d, 1H, J )
14.9 Hz), 4.54 (t, 1H, J ) 6.6 Hz), 5.13 (ddd, 1H, J ) 16.8, 2.7,
1.5 Hz), 5.17 (dd, 1H, J ) 10, 1.5 Hz), 5.40 (q, 1H, J ) 7.1 Hz),
5.45 (d, 1H, J ) 14.9 Hz), 5.85 (ddt, 1H, J ) 16.8, 10.1, and 7.3
Hz), 7.24 (m, 5H), 7.45 (ddd, 1H, J ) 7.9, 7.0, and 1.2 Hz), 7.55
(dd, 1H, J ) 8.2 and 0.6 Hz), 7.71 (ddd, 1H, J ) 8.2, 7.0, and 1.5
(9) Kiely, J . S.; Priebe, S. R. Org. Prep. Proced. Int. 1990, 22, 761.

6428 J . Org. Chem., Vol. 62, No. 18, 1997
Notes
Hz), 8.25 (dd, 1H, J ) 7.9 and 1.2 Hz); 13C NMR (CDCl3) δ 167.2,
160.3, 150.0, 147.0, 135.2, 134.6, 132.3, 128.9, 128.3, 128.1, 127.0,
126.9, 126.6, 120.2, 119.7, 59.9, 52.4, 48.3, 40.6, 19.6. Anal.
Calcd for C22H21N3O2: C, 73.52; H, 5.89; N, 11.69. Found: C,
73.25; H, 5.80; N, 11.42.
5.39 (q, 1H, J ) 7.0 Hz), 7.26 (m, 5H), 7.42 (ddd, 1H, J ) 8.2,
7.3, 1.2 Hz), 7.52 (ddd, 1H, J ) 8.0, 1.5, 0.6 Hz), 7.69 (ddd, 1H,
J ) 8.2, 7.0, 1.5 Hz), 8.22 (dd, 1H, J ) 8.0 and 1.2 Hz); 13C NMR
(CDCl3) δ 167.2, 160.4, 151.7, 147.4, 135.6, 134.8, 128.9, 128.3,
128.1, 126.9, 126.7, 126.6, 120.1, 55.8, 52.2, 47.6, 21.4, 19.2. Anal.
Calcd for C20H19N3O2: C, 72.07; H, 5.70; N, 12.61. Found: C,
71.85; H, 5.86; N, 12.70.
(1S ,4S )-1,2,4-Tr im e t h yl-2,4-d ih yd r o-1H -p yr a zin o[2,1-
b]qu in a zolin e-3,6-d ion e (21a ) was obtained (EtOAc/hexane,
7:3) as a white solid: mp 181-182 °C; yield 98%; [R]25 +101.8
D
(c 1, EtOH); IR (KBr) 1654, 1600 cm-1; 1H NMR (CDCl3) δ 1.70
(d, 3H, J ) 7.1 Hz), 1.75 (d, 3H, J ) 7.1 Hz), 3.10 (s, 3H), 4.60
(q, 1H, J ) 7.1 Hz), 5.30 (q, 1H, J ) 7.1 Hz), 7.45 (m, 1H), 7.61
(dd, 1H, J ) 8.1 and 1.2 Hz), 7.82 (m, 1H), 8.30 (dd, 1H, J ) 8.0
and 1.2 Hz); 13C NMR (CDCl3) δ 167.1, 160.3, 151.5, 147.3, 134.8,
127.1, 126.9, 126.8, 120.2, 59.1, 52.1, 32.5, 21.1, 19.2. Anal.
Calcd for C14H15N3O2: C, 65.37; H, 5.84; N, 16.34. Found: C,
65.03; H, 5.61; N, 16.08.
Ack n ow led gm en t. We thank CICYT for financial
support (Project SAF94-0517) and Universidad Com-
plutense de Madrid for a research studentship to S.M.-
S.
Su p p or tin g In for m a tion Ava ila ble: Complete spectro-
scopic and analytical data of compounds 4-15, 18, and 19 (11
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(1S,4S)-2-Ben zyl-1,4-d im et h yl-2,4-d ih yd r o-1H -p yr a zi-
n o[2,1-b]qu in a zolin e-3,6-d ion e (21b) was obtained (EtOAc/
petroleum ether, 7:3) as a light yellow oil; yield 64%; [R]25 +11
D
(c 0.25, CHCl3); IR (film) 1684, 1659 cm-1; H NMR (CDCl3) δ
1
1.63 (d, 3H, J ) 7.0 Hz), 1.73 (d, 3H, J ) 7.0 Hz), 4.13 (d, 1H,
J ) 15 Hz), 4.53 (q, 1H, J ) 7.0 Hz), 5.30 (d, 1H, J ) 15.0 Hz),
J O970037A