Intramolecular friedel-crafts-type reactions involving N-acyliminium ions derived from glycine templates

Article abstract of DOI:10.1021/jo010166y

Enantiomerically pure 4-substituted 2-aralkyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones (1b-m) in which the alkyl chain is (CH₂)_n, n = 1-3, behave as glycine templates giving by treatment with [hydroxy(tosyloxy)iodo]benzene in ethyl acetate cis-1-tosyloxy derivatives. When these compounds contain electron-rich aryl substituents with n = 2, they spontaneously cyclize through intramolecular Friedel-Crafts-type diastereoselective reactions to give penta- or hexacyclic compounds. Otherwise, they give by solvolysis cis-1-alkoxy derivatives, which in a second step, may be cyclized in acid if n = 2, 3. All these reactions must occur through N-acyliminium species in S_N1-like mechanisms. 1-Alkoxy-2-arylmethyl derivatives are reluctant to cyclize, giving trans-1-hydroxy compounds as the only isolated reaction products.

Full text of DOI:10.1021/jo010166y

J . Org. Chem. 2001, 66, 5731-5735
5731
In tr a m olecu la r F r ied el-Cr a fts-Typ e Rea ction s In volvin g
N-Acylim in iu m Ion s Der ived fr om Glycin e Tem p la tes
J uan Domingo Sa´nchez, Mar´ıa Teresa Ramos, and Carmen Avendan˜o*
Departamento de Quı´mica Orga´nica y Farmace´utica, Facultad de Farmacia,
Universidad Complutense, 28040 Madrid, Spain
avendano@eucmax.sim.ucm.es
Received February 12, 2001
Enantiomerically pure 4-substituted 2-aralkyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones
(1b-m ) in which the alkyl chain is (CH2)n, n ) 1-3, behave as glycine templates giving by treatment
with [hydroxy(tosyloxy)iodo]benzene in ethyl acetate cis-1-tosyloxy derivatives. When these
compounds contain electron-rich aryl substituents with n ) 2, they spontaneously cyclize through
intramolecular Friedel-Crafts-type diastereoselective reactions to give penta- or hexacyclic
compounds. Otherwise, they give by solvolysis cis-1-alkoxy derivatives, which in a second step,
may be cyclized in acid if n ) 2, 3. All these reactions must occur through N-acyliminium species
in SN1-like mechanisms. 1-Alkoxy-2-arylmethyl derivatives are reluctant to cyclize, giving trans-
1-hydroxy compounds as the only isolated reaction products.
In tr od u ction
nature as a scaffold for constrained peptidomimetics that
incorporate anthranilic acid as demonstrated by the
isolation of other fungal metabolites such as glyantrypine,9
fumiquinazolines,10 and fiscalins.11 Among other interest-
ing biological properties displayed by these natural
products, N-acetylardeemin reverses the multidrug re-
sistance (MDR) to antitumor agents mediated by glyco-
protein P-170,12 an activity that is much retained in the
above-mentioned tricyclic fragment13 and moved us to
study different synthetic approaches to this system.
In our previous work,7 compound 1a was easily oxi-
dized to tosylate 3a after treatment with the hypervalent
iodine reagent [hydroxy(tosyloxy)iodo]benzene (2), which
is commonly used for R-functionalization of ketones,14 and
the 1-hydroxy (4a ) or 1-methoxy (5a ) derivatives obtained
by acid-catalyzed hydrolysis or methanolysis of 3a re-
acted in acid media with electron-rich arenes to give
1-aryl derivatives 6a as single diastereoisomers (Scheme
1).
N-Acyliminium ion-mediated carbon-carbon bond-
forming reactions have found many applications, espe-
cially in cyclizations with π nucleophiles.1,2 The N-
acyliminium species are generated by acid treatment of
N-(1-hydroxyalkyl)amides, which are frequently obtained
by partial reduction3 or addition of organometallics4 to
cyclic imides and, some times, by addition of amides or
carbamates to aldehydes.5 Access to N-(1-hydroxyalkyl)-
amide precursors by oxidation is a less common meth-
odology6 that we have investigated in the case of 2,4-
dimethyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione (1a ),7 a system that contains three rings of the
hexacyclic fungal metabolite N-acetylardeemin.8 The
pyrazino[2,1-b]quinazoline-3,6-dione structure is used by
(1) (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367-
4416. (b) Hiemstra, H.; Speckamp, W. N. In The Alkaloids; Academic
Press: New York, 1988; Vol. 32, p 271. (c) Hiemstra, H.; Speckamp,
W. N. Additions to N-Acyliminium Ions. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 2, pp 1047-1082. (d) Maryanoff, B. E.; Rebarchak, M. C.
Synthesis 1992, 1245-1248 and references therein.
(2) See, for instance: (a) Heaney, H.; Shuhaibar, K. F. Synlett 1995,
47-48. (b) Li, W. H.; Hanau, C. E.; Davignon, A.; Moeller, K. D. J .
Org. Chem. 1995, 60, 8155-8170. (c) Lo¨gers, M.; Overman, L. E.;
Welmaker, G. S. J . Am. Chem. Soc. 1995, 117, 9139-9150. (d) Marson,
C. M.; Pink, J . H.; Smith, C. Tetrahedron Lett. 1995, 36, 8107-8110.
(e) Rigo, B.; El Ghammarti, S.; Couturier, D. Tetrahedron Lett. 1996,
37, 485-486. (f) Yamada, H.; Aoyagi, S.; Kibayashi, C. J . Am. Chem.
Soc. 1996, 118, 1054-1059.
(3) Lee Y. S.; Kang, D. W.; Lee, S. J .; Park, H. J . Org. Chem. 1995,
60, 7149-7152.
(4) Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J .; Lete, E.
J . Org. Chem. 1997, 62, 2080-2092.
(5) Zoller, U.; Ben-Ishai, D. Tetrahedron 1975, 31, 863-866.
(6) (a) Murahashi, S.-I.; Saito, T.; Naota, T.; Kumobayashi, H.;
Akutagawa, S. Tetrahedron Lett. 1991, 32, 5991-5994. (b) Shono, T.
Tetrahedron 1984, 40, 811-850.
(7) Mart´ın-Santamar´ıa, S.; Espada, M.; Avendan˜o, C. Tetrahedron
1999, 55, 1755-1762.
The cis stereochemistry of all these compounds was
supposed to be the result of SN1-like mechanisms in
which either the nucleophile attacks anti respect to the
4-methyl group of the N-acyliminium species A to give
(9) Penn, J .; Mantle, P. G.; Bilton, J . N.; Sheppard, R. N. J . Chem.
Soc., Perkin Trans. 1 1992, 1495-1496.
(10) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto, T.;
Kawai, K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi, H.; Shingu,
T. Tetrahedron Lett. 1992, 33, 1621-1624. (b) Takahashi, C.; Mat-
sushita, T.; Doi, M.; Minoura, K.; Shingu, T.; Kumeda, Y.; Numata, A.
J . Chem. Soc., Perkin Trans. 1 1995, 2345-2353.
(11) (a) Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.; Gillum,
A. M.; Cooper, R. J . Antibiot. 1993, 46, 545-553. (b) Fujimoto, H.;
Negishi, E.; Yamaguchi, K.; Nishi, N.; Yamazaki, M. Chem. Pharm.
Bull. 1996, 44, 1843-1848.
(12) (a) Karwowski, J . P.; J ackson, 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. (b) Chou. T.-C.; Depew, K. M.;
Zheng, Y.-H.; Safer, M. L.; Chan, D.; Helfrich, B.; Zatorska, D.;
Zatorski, A.; Bornmann, W.; Danishefsky, S. J . Proc. Natl., Acad. Sci.
U.S.A. 1998, 95, 8369-8374.
(8) (a) Hochlowski, J . E.; Mullally, M. M.; Spanton, S. G.; Whittern,
D. N.; Hill, P.; McAlpine, J . B. J . Antibiot. 1993, 46, 380-386. (b)
Marsden, S. P.; Depew, K. M.; Danishefsky, S. J . J . Am. Chem. Soc.
1994, 116, 11143-11144. (c) Depew, K. M.; Marsden, S. P.; Zatorska,
D.; Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J . J . Am. Chem.
Soc. 1999, 121, 11953-11963.
(13) Mene´ndez Vidal, C.; Quesada, A. R. Cancer Lett. 1998, 132, 45-
50.
(14) Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.; Wettach,
R. H. J . Org. Chem. 1982, 47, 2487-2489.
10.1021/jo010166y CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/21/2001

5732 J . Org. Chem., Vol. 66, No. 17, 2001
Sa´nchez et al.
Ta ble 1. Str u ctu r e of Com p ou n d s 1, 8, 15, a n d 16
Sch em e 1a
compd
Ar
n
R
b
c
d
e
f
g
h
i
1-acetyl-3-indolyl
1-acetyl-3-indolyl
C6H5
4-MeOC6H4
3,4-(MeO)2C6H3
2-naphthyl
C6H5
C6H5
3,4-(MeO)2C6H3
C6H5
1
2
1
1
1
1
2
2
2
3
2
2
CH3 (S)
CH3 (S)
CH3 (S)
CH3 (S)
CH3 (S)
CH3 (S)
CH3 (S)
CH3 (R)
CH3 (S)
CH3 (S)
CH(CH3)2 (S)
CH(CH3)2 (S)
j
k
l
C6H5
1-acetyl-3-indolyl
m
Sch em e 3a
a
Reagents and conditions: (a) 2, EtOAc, reflux, 8 h; (b) H2O,
NH4Cl; (c) p-TsOH (cat.), ROH, rt, 20 h; (d) (from 4a ) concd H2SO4,
ArH, rt, 48 h; (e) (from 5a ) BF3‚Et2O (1 equiv), ArH (4 equiv), rt,
24 h.
Sch em e 2a
a
Reagents and conditions: (a) Cbz(Boc)amino acid, EDC,
CH2Cl2, rt, 24 h; (b) H2/Pd-C, MeOH, 20 psi, rt, 3 h; (c) 200 °C,
argon atmosphere; (d) Et3O‚BF4, CH2Cl2, Na2CO3, rt, 24 h; (e)
anthranilic acid, 140 °C, 2 h.
cinates 9 with L-Ala or L-Val to give the corresponding
piperazine-2,5-diones 11 (Scheme 3). The required ethyl
N-aralkylglycinates were prepared by reductive amina-
tion of the corresponding aldehyde with ethyl glycinate18
or, alternatively, by N-alkylation of the corresponding
aralkylamine with ethyl bromoacetate.19 After activation
of the unsubstituted amide function of compounds 11 to
lactim ethers 12, condensation with anthranilic acid
afforded compounds 1b-m .
Compounds 1j and 1m that, as well as 1c have an
electron-rich arene tethered by a ethylene chain, gave
the cyclic compounds 13 (62%) and 14 (71%) as single
diastereomers (NMR of the crude reaction product) after
treatment with 2.
a
Reagents and conditions: (a) 2, EtOAc, reflux, 8 h.
the trans isomers, which equilibrate to the most stable
cis isomers through enamine tautomers, or is the result
of a kinetically preferred syn attack.
When this strategy was applied to intramolecular
cyclizations looking for new synthetic entries to N-
acetylardeemin analogues, and 1c was used as the
starting material,15 compound 7 (Scheme 2) was directly
obtained after treatment with 2. However, 1b gave in
the same treatment compound 8b.16 No traces of the
alternative isomers were observed in the reaction crudes.
Here we investigate in more detail these reactions and
study their scope and stereochemistry by using repre-
sentative N-aralkyl derivatives.
All the remaining compounds 1, which have less
nucleophilic arenes and/or n * 2, gave the corresponding
cis-1-ethoxy derivatives 8 in moderate to good yields
when the crude products of the reaction with 2 were
purified by column chromatography. Since compounds 8
were obtained in the same yields after exclusion of the
Resu lts a n d Discu ssion
Synthesis of compounds 1b-m (Table 1) was ac-
complished following a straightforward methodology17
that starts with the condensation of ethyl N-aralkylgly-
(17) Sa´nchez, J . D.; Ramos, M. T.; Avendan˜o, C. Tetrahedron 1998,
54, 969-980.
(15) Sa´nchez, J . D.; Ramos M. T.; Avendan˜o, C. Tetrahedron Lett.
2000, 41, 2745-2748.
(16) This compound was erroneously reported in ref 15 as the
1-hydroxy derivative.
(18) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
1971, 93, 2897-2904.
(19) Kruijtzer, J . A. W.; Liskamp, R. M. J . Tetrahedron Lett. 1995,
36, 6969-6972.

Intramolecular Friedel-Crafts-Type Reactions
J . Org. Chem., Vol. 66, No. 17, 2001 5733
Sch em e 4
Sch em e 6a
Sch em e 5a
a
Reagents and conditions: (a) (1) concd H2SO4, rt, 2 h; (2) ice-
water.
Sch em e 7
a
Reagents and conditions: (a) (1) 2, MeCN, 100 °C, 18 h; (2)
NH4Cl, H2O/Cl2CH2, rt, 6 h.
possible traces of ethanol present in the solvent,20 the
ethoxy group of 8 must come from ethyl acetate itself
(Scheme 4).
Thus, when some compounds (1h ,k ,l) were treated
with 2 using acetonitrile as solvent, 1-oxo (compounds
15) and trans-1-hydroxy (16) derivatives were the only
reaction products after the reaction workup (Scheme 5).
Similar oxidation compounds have been formed in other
reactions with this system.21 It is possible that com-
pounds 15 are formed by dehydrogenation of the 1-oxo-
11,11a-dihydro tautomers of compounds 16.
The above results prompted us to use 1-ethoxy com-
pounds 8 as equivalents of glycine cations instead of the
nonisolated tosyloxy intermediates. The reactivity of
representative compounds in SN1-type reactions was
confirmed with 8d ,g-i,l; by using methanol as solvent
in the presence of catalytic amounts of p-toluenesulfonic
acid, the corresponding cis-1-methoxy derivatives 5 were
obtained as single isomers in nearly quantitative yields
(see Scheme 4). In the treatment of homologous series of
compounds 8d , 8h , and 8k (where Ar ) Ph and n ) 1, 2,
and 3, respectively) with concentrate sulfuric acid at room
temperature, compounds 16d (a single isomer from 8d )
and 19 (a single isomer from 8k ) were obtained after
workup with a large excess of water, while 8h gave 17
and 18 as a 4:1 unseparable mixture. Lower amounts of
water in the case of 8h afforded the bisulfate of the
isomer 17 as the only isolable compound (Scheme 6).
In solution, the mixture of isomers 17 and 18 must be
in equilibrium through an easily oxidizable enamine
form. In fact, when the evolution of a CDCl3 solution of
1
this mixture was followed by H NMR, the 16b-hydroxy
derivative 20 (Scheme 7) was isolated as the major
product after 1 week. The same mixture generated an
anion with lithium hexamethyldisilazide that was al-
kylated to give compounds 21 and 22 as single dia-
stereomers. Their stereochemistry was unequivocally
assigned by NOE experiments. Thus, a significant en-
hancement of the H-2′(6′) doublet (δ ) 7.12 ppm) was
observed in compound 22 after irradiation of the methyl
protons (δ ) 1.90 ppm). The syn attack of the anion
derived from 17 and 18 contrasts to the kinetically
favored anti attack previously observed in the anions
derived from 1a , 1d , and other related tricyclic com-
pounds, which is controlled by the 1,4-asymmetric induc-
tion of the pseudoaxial 4-methyl substituent.22 These
results are ascribable to a different conformation of the
piperazine ring in the pentacyclic intermediate that must
(20) Ethyl acetate was refluxed for 4 h with acetic anhydride and
some drops of concd H2SO4, distilled, dried with anhydrous K2CO3,
filtered, and redistilled from CaH2.
(21) Compounds 15 have been also formed in the attempted reduc-
tive (95% formic acid-C/Pd) or oxidative (DDQ) N(2)-debenzylation of
the corresponding compounds 1: Buenadicha, F. L.; Bartolome´, M. T.;
Aguirre, M. J .; Avendan˜o, C.; So¨llhuber, M. M. Tetrahedron: Asymmetry
1998, 9, 483-501.

5734 J . Org. Chem., Vol. 66, No. 17, 2001
Sa´nchez et al.
1 and 2 in EtOAc (25 mL) was refluxed for 18 h and then was
allowed to reach rt. Solvent was removed under vacuum to
leave a residue that was chromatographed on silica gel using
EtOAc as eluent.
place the methyl group pseudoequatorial being the R-face
(anti attack) here prevented by the ethylene chain.
Several other attempts to cyclize compounds 8 in which
n) 1 also failed. For instance, treatment of 8e and 8f
with catalytic amounts of p-toluenesulfonic acid in re-
fluxing benzene gave the 1-hydroxy derivatives 16e (54%)
and 16f (61%) as the only reaction products.
(7S,16bR)-16-Acetyl-7-m eth yl-10,11,16,16b-tetr a h yd r o-
7H -q u in a zolin o[2′,3′:3,4]p yr a zin o[2,1-a ]â-ca r b olin e-5,8-
d ion e (7): 65% yield from 1c (0.48 mmol); viscous oil; [R]25
D
1
) +84.0 (c ) 0.10, CH2Cl2); H NMR δ 8.24 (d, 1H, J ) 8.0
The cis or trans stereochemistry of all compounds,
when indicated, was determined by conclusive NOE
experiments, while their enantiomeric purity was con-
firmed by the absence of splitting of any signal in the H
NMR spectra after addition of Eu(hfc)3 and by chiral
HPLC for the starting materials.
Hz), 7.74 (d, 1H, J ) 8.4 Hz), 7.65-7.33 (m, 6H), 6.83 (s, 1H),
5.64 (q, 1H, J ) 7.4 Hz), 4.87 (m, 1H), 3.10 (m, 1H), 2.90 (m,
1H), 2.85 (s, 3H), 2.70 (m, 1H), 1.77 (d, 3H, J ) 7.4 Hz) ppm;
13C NMR δ 169.1, 160.3, 149.1, 147.0, 137.6, 134.5, 130.3,
128.7, 128.2, 127.6, 127.4, 126.9, 125.2, 123.1, 119.6, 119.3,
113.9, 54.5, 52.9, 39.0, 27.0, 20.4, 16.0 ppm; IR 2934, 1680,
744 cm-1; MS 412 (M+), 369 (100), 355, 311, 185, 143, 130.
Anal. Calcd for C24H20N4O3: C, 69.89; H, 4.89; N, 13.58.
Found: C, 66.69; H, 4.56; N, 13.25.
1
In conclusion, acyliminium species directly formed from
nonisolated 1-tosyloxy derivatives of compounds 1b-m
or by acid treatment of the corresponding 1-ethoxy
derivatives 8 give intramolecular Friedel-Crafts-type
reactions if the arene and the pyrazinoquinazoline por-
tions are linked through di- or trimethylene chains.
Otherwise, alkoxy or hydroxy derivatives are formed by
nucleophilic attack of the solvents.
The frontal overlap of the orbitals involved in the SN1-
type reactions described here takes place preferentially
by the upper (â) face of the cation, syn with respect to
the C-4 substituent (see all compounds 8 and 5 as well
as the cyclic compounds 13, 17, and 19). Only in the case
of important steric interactions, such as those imposed
by the N-acetyl substituent in compounds 7 and 14, does
the aromatic ring interact with the lower (R) face of the
cation, anti with respect to the C-4 substituent. The trans
stereochemistry found in the 1-hydroxy derivatives 16
points to SN2-type mechanisms.
(1S,4S)-1-E t h oxy-4-m et h yl-2-p h en et 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 (8h ): 80% yield
from 1h (0,60 mmol); viscous oil; [R]25 ) +70 (c ) 0.12,
D
1
CH2Cl2); H NMR δ 8.28 (d, 1H, J ) 8.0 Hz) 7.80 (t, 1H, J )
8.0 Hz), 7.61 (d, 1H, J ) 8.0 Hz), 7.51 (t, 1H, J ) 8.0 Hz),
7.25-7.05 (m, 5H), 5.33 (q, 1H, J ) 7.1 Hz), 5.13 (s, 1H), 4.15-
4.05 (m, 1H), 3.68 (q, 2H, J ) 7.0 Hz), 3.52-3.42 (m, 1H), 2.95
(t, 2H, J ) 7.5 Hz), 1.77 (d, 3H, J ) 7.1 Hz), 1.18 (t, 3H, J )
7.0 Hz) ppm; 13C NMR δ 169.4, 160.2, 147.2, 147.0, 138.2,
134.8, 128.8, 128.7, 127.8, 127.6, 126.9, 126.8, 121.0, 87.9, 64.9,
53.1, 48.6, 34.7, 19.2, 15.1 ppm; IR 1684, 1609 cm-1. Anal.
Calcd for C22H23N3O3: C, 70.01; H, 6.14; N, 11.13. Found: C,
69.87; H, 6.30; N, 10.83.
(1S,4S)-1-E t h oxy-4-m et h yl-2-(3-p h en ylp r op yl)-2,4-d i-
h yd r o-1H-p yr a zin o[2,1-b]qu in a zolin e-3,6-d ion e (8k ): 48%
yield from 1k (0,17 mmol); viscous oil; [R]25D ) +47.5 (c ) 0.18,
CH2Cl2); 1H NMR δ 8.27 (d, 1H, J ) 8.0 Hz), 7.80 (m, 2H),
7.53 (t, 1H, J ) 7.0 Hz), 7.23-7.00 (m, 5H), 5.20 (q, 1H, J )
7.2 Hz), 5.19 (s, 1H), 3.95-3.85 (m, 1H), 3.69 (q, 2H, J ) 7.0
Hz), 3.40-3.30 (m, 1H), 2.66-2.56 (m, 2H), 2.05-1.96 (m, 2H),
1.76 (d, 3H, J ) 7.2 Hz), 1.18 (t, 3H, J ) 7.0 Hz) ppm; 13C
NMR δ 167.4, 167.1, 147.2, 147.0, 140.9, 134.9, 128.5, 128.3,
127.4, 127.0, 126.2, 120.7, 87.0, 64.8, 52.9, 45.7, 33.1, 29.3, 19.0,
14.9 ppm; IR 1685, 1608 cm-1. Anal. Calcd for C23H25N3O3:
C, 70.57; H, 6.44; N, 10.73. Found: C, 70.77; H, 5.94; N, 11.19.
Some representative compounds were studied as MDR
reversal agents and as Ca2+ channel blockers and showed
a moderate activity.23
Exp er im en ta l Section
(9S,16b S)-2,3-Dim et h oxy-9-m et h yl-5,6,9,16b -t et r a h y-
d r oisoqu in o[1′,2′:3,4]p yr a zin o[2,1-b]qu in a zolin e-8,11-d i-
All reagents were of commercial quality and were used as
received. Solvents were dried and purified using standard
techniques. Reactions were monitored by TLC, on aluminum
plates coated with silica gel with fluorescent indicator (Merck
60 F254). Separations by flash chromatography were performed
on silica gel (Merck 60, 230-400 mesh). Melting points were
measured in open capillary tubes using a Reichert 723 hot-
stage microscope and are uncorrected. IR spectra were ob-
tained from films deposited on NaCl plates or from compressed
KBr pellets for solid compounds. Unless otherwise noted, NMR
on e (13): 62% yield from 1j (0.16 mmol); viscous oil; [R]25
)
D
-11.6 (c ) 0.40, CH2Cl2); 1H NMR δ 8.31 (d, 1H, J ) 7.7 Hz),
7.85-7.74 (m, 2H), 7.53 (t, 1H, J ) 7.6 Hz), 6.96 (s, 1H), 6.64
(s, 1H), 5.81 (s, 1H), 5.33 (q, 1H, J ) 7.1 Hz), 4.74 (m, 1H),
3.83 (s, 3H), 3.66 (s, 3H), 3.37-3.14 (m, 2H), 2.74 (m, 1H), 1.16
(d, 3H, J ) 7.1 Hz) ppm; 13C NMR δ 168.8, 160.3, 149.1, 148.4,
147.5, 147.0, 1135.1, 127.6, 127.2, 127.1, 125.9, 125.1, 120.6,
112.5, 107.6, 60.9, 56.0, 56.0, 51.7, 42.6, 26.3, 19.0 ppm; IR
2931, 1678 cm-1. MS m/e 391 (M+, 100), 376, 348, 304, 262,
234, 190, 176, 130, 84, 77. Anal. Calcd for C22H21N3O4: C,
67.51; H, 5.41; N, 10.74. Found: C, 67.22; H, 5.43; N, 11.25.
1
spectra were recorded in CDCl3 at 250 or 300 MHz for H and
at 63 or 75 MHz for 13C (Servicio de Espectroscop´ıa, Univer-
sidad Complutense). When necessary, assignments were aided
by DEPT, COSY, and 13C-1H correlation experiments. Ele-
mental analyses were determined by the Servicio de Micro-
ana´lisis, Universidad Complutense. Optical rotations were
measured at 25 °C on a 1 mL cell in CHCl3 or MeOH at 589
nm, concentrations expressed in g/100 mL. Mass spectra (m/
e) were obtained in the EI (70 eV) mode in Servicio de
Espectroscop´ıa U.C.M. HPLC analyses were performed using
a Constametric 4100 system equipped with a chiral column
(Chiracel OD) and UV-vis detector. Mobile phase: hexane/
2-propanol (90:10).
(7S,16bR)- 16-Acetyl-7-isop r op yl-10,11,16,16b-tetr a h y-
d r o-7H-qu in a zolin o[2′,3′:3,4]p yr a zin o[2,1-a ]â-ca r bolin e-
5,8-d ion e (14): 71% yield from 1m (0.22 mmol); viscous oil;
1H NMR δ 8.24 (d, 1H, J ) 8.0 Hz), 7.75 (d, 1H, J ) 8.3 Hz),
7.65-7.33 (m, 6H), 6.90 (s, 1H), 5.41 (d, 1H, J ) 9.9 Hz), 4.87
(m, 1H), 3.15-3.02 (m, 1H), 2.93 (m, 1H), 2.86 (s, 3H), 2.70
(m, 1H), 2.45 (m, 1H), 1.30 (d, 3H, J ) 6.6 Hz), 1,10 (d, 3H, J
) 6.6 Hz) ppm; 13C NMR δ 167.5, 160.3, 149.6, 146.7, 135.4,
134.0, 128.5, 128.2, 127.4, 127.0, 126.9, 124.8, 122.8, 120.3,
119.3, 118.8, 113.6, 61.6, 54.5, 38.4, 30.3, 29.5, 26.7, 20.1, 19.8
ppm; IR 1682 cm-1. Anal. Calcd for C26H24N4O3: C, 70.89; H,
5.49; N, 12.72. Found: C, 70.56; H, 5.38; N, 13.03.
R ea ct ion s of 8 w it h Con cen t r a t ed H2SO4. Gen er a l
P r oced u r e. A solution of compounds 8 in concd H2SO4 (3 mL)
was stirred at room temperature for 2 h. A mixture of ice-
water was added, and then it was extracted with EtOAc. The
combined organic layers were dried and concentrated, and the
residue was chromatographed in silica gel with EtOAc/CH2Cl2
(1:1) as eluent.
Rea ction s of Com p ou n d s 1 w ith 2. Gen er a l P r oced u r e
in EtOAc. A suspension of equimolar amounts of compounds
(22) (a) Mart´ın-Santamar´ıa, S.; Buenadicha, F. L.; Espada, M.;
So¨llhuber, M. M.; Avendan˜o, C. J . Org. Chem. 1997, 62, 6424-6428.
(b) Mart´ın-Santamar´ıa, S.; Espada, M.; Avendan˜o, C. Tetrahedron
1997, 53, 16795-16802. (c) Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber,
M. M.; Tetrahedron: Asymmetry 1998, 9, 4275-4284.
(23) Unpublished results.

Intramolecular Friedel-Crafts-Type Reactions
J . Org. Chem., Vol. 66, No. 17, 2001 5735
(9S,16b S)-9-Met h yl-5,6,9,16b -t et r a h yd r oisoq u in o[1,2:
3,4]p yr a zin o[2,1-b]qu in a zolin e-8,11-d ion e bisu lfa te (17‚
H2SO4): 65% yield from 8h (0.53 mmol); yellow solid; mp 194-
trated to leave a residue that was chromatographed in silica
gel using petroleum ether/EtOAc (1:1) as eluent.
(9S,16bR)-16b-Ben zyl-9-m eth yl-5,6,9,16b-tetr ah ydr oiso-
qu in o[1′,2′:3,4]pyr azin o[2,1-b]qu in azolin e-8,11-dion e (21):
44% yield; oil; 1H NMR δ 8.24 (d, 1H, J ) 8.3 Hz), 8,00 (t, 1H,
J ) 7.9 Hz), 7.66 (m, 2H), 7.50-7.00 (m, 9H), 5.20 (q, 1H, J )
7.0 Hz), 4.96 (dd, 1H, J ) 13.5 Hz, 6.5 Hz), 4.32 (d, 1H, J )
15.2 Hz), 4.21 (d,1H, J ) 15.2 Hz), 3.75 (td, 1H, J ) 13.5 Hz,
5.2 Hz), 3.30 (m, 1H), 2.90 (m, 1H), 1.12 (d, 3H, J ) 7.0 Hz)
ppm; 13C NMR δ 169.1, 160.4, 151.4, 149.5, 146.4, 138.3, 135.8,
134.9, 133.2, 130.5, 129.8, 128.8, 128.4, 127.8, 127.6, 127.1,
126.9, 126.7, 125.8, 120.3, 67.3, 50.8, 47.5, 37.9, 27.2, 1.8 ppm;
IR 1680, 1600, 1514 cm-1. Anal. Calcd for C27H23N3O2: C,
76.94; H, 5.50; N, 9.97. Found: C, 77.22; H, 5.83; N, 9.59.
(9S,16b R)-16b -(4-Met h oxyb en zyl)-9-m et h yl-5,6,9,16b -
tetr a h yd r oisoqu in o[1′,2′:3,4]p yr a zin o[2,1-b]qu in a zolin e-
1
196 °C; H NMR (DMSO-d6) δ 8.20 (d, 1H, J ) 7.9 Hz), 7.92
(m, 1H), 7.80 (d, 1H, J ) 8.0 Hz), 7.61 (m, 1H), 7.25-7.12 (m,
4H), 6.11 (s, 1H), 5.04 (q, 1H, J ) 7.0 Hz), 4.42 (m, 1H), 3.50
(m, 1H), 3.14 (m, 1H), 2.93 (m, 1H), 0.94 (d, 3H, J ) 7.0 Hz)
ppm; 13C NMR (DMSO-d6) δ 167.6, 160.0, 147.9, 148.2, 135.0,
134.9, 134.0, 129.9, 128.1, 126.2, 123.5, 120.0, 59.4, 51.1, 40.7,
25.8, 18.1 ppm; IR 1670, 1608, 1600, 1589 cm-1; MS 331 (100,
M+), 316, 288, 275, 201, 173, 130, 77. Anal. Calcd for
C20H17N3O2. H2SO4: C, 55.94; H, 4.46; N, 9.78. Found: C,
55.51; H, 4.66; N, 9.64.
(10S,17bS)-10-Meth yl-6,7,10,17b-tetr a h yd r o-5H-ben zo-
[3′,4′]a zep in o[2′,1′:3,4]p yr a zin o[2,1-b]qu in a zolin e-9,12-d i-
on e (19): 53% yield from 8k (0.15 mmol); oil; [R]25 ) +53.6
D
1
1
(c ) 0.27, CH2Cl2); H NMR δ 8.34 (d, 1H, J ) 7.8 Hz), 7.80
8,11-d ion e (22): 57% yield; oil; H NMR δ 8,22 (d, 1H, J )
(m, 1H), 7.67 (d, 1H, J ) 7.4 Hz), 7.54 (m, 1H), 7.25-6.60 (m,
4H), 5.91 (s, 1H), 5.35 (q, 1H, J ) 7.1 Hz), 4.85 (m, 1H), 3.15-
3.05 (m, 3H), 2.05-1.95 (m, 2H), 1.35 (d, 3H, J ) 7.1 Hz) ppm;
13C NMR δ 167.3, 160.0, 149.6, 147.1, 141.7, 138.1, 135.0,
131.2, 129.0, 137.6, 127.4, 127.1, 126.5, 126.4, 120.0, 64.4, 52.9,
7.5 Hz), 8.00 (m, 1H), 7.66 (m, 1H), 7.50-7.15 (m, 5H), 7.12
(d, 2H, J ) 8,6 Hz), 6.85 (d, 2H, J ) 8.6 Hz), 5.51 (q, 1H, J )
7.1 Hz), 4.96 (m, 1H), 4.32 (d, 1H, J ) 9.5 Hz), 4.21 (d, 1H, J
) 9.5 Hz), 3.77 (s, 3H), 3.20-3.80 (m, 2H), 2.89 (m, 1H), 1.90
(d, 3H, J ) 7.1 Hz) ppm; 13C NMR δ 171.3, 161.0, 158.0, 151.0,
146.4, 137.2, 134.3, 132.8, 130.2, 129.5, 129.3, 128.8, 128.3,
128.0, 127.7, 114.1, 66.0, 55.3, 54.2, 52.4, 40.3, 29.3, 17.9 ppm;
IR 1680, 1513 cm-1. Anal. Calcd for C28H25N3O3: C, 74.48; H,
5.58; N, 9.31. Found: C, 73.95; H, 5.43; N, 9.25.
49.0, 35.6, 27.0, 17.1 ppm; IR 1668, 1607, 1600, 1589 cm-1
.
MS: 345 (100, M+), 330, 316, 302, 288, 247, 201, 173, 144,
117, 91, 77. Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54; N,
12.17. Found: C, 73.20; H, 5.56; N, 12.58.
Alk yla tion Rea ction s of th e Mixtu r e 17 a n d 18. Gen -
er a l P r oced u r e. To a stirred solution of the mixture of 17
and 18 in anhyd THF (10 mL) at -78 °C under argon
atmosphere was added LHMDS (1 equiv), and after 20 min, a
solution of the corresponding benzyl halide in anhyd THF (5
mL) was also added. These conditions were kept for an
additional 30 min, after which time the mixture was allowed
to reach rt. After 4 h, the colorless solution was treated with
saturated NH4Cl solution and extracted with EtOAc. The
organic layers were washed with water, dried, and concen-
Ack n ow led gm en t. Financial support from CICYT
(SAF 97-0143) is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Complete spectro-
scopic and analytical data of compounds 8b,d -g,i,l, 15, 16,
and 20. A description of compounds 1 and their precursors is
available upon request. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O010166Y