Three-Step Access to the Tricyclic Benzo[a]quinolizine Ring System

Article abstract of DOI:10.1021/jo972035w

Access to the tricyclic benzo[a]quinolizine ring system, which forms the characteristic framework of alkaloids of the berberine and emetine type, is readily obtained by a three-step reaction sequence. This sequence includes the formation of a Schiff base, derived from a 2-bromo-substituted phenylethylamine, and its tandem Mannich/conjugate addition reaction with an electron-rich silyloxy diene forming an intermediate enaminone, which subsequently undergoes a Heck-type cyclization. Highest yields of the tandem Mannich/conjugate addition for aromatic Schiff bases and formaldehyde imines are observed in the presence of ZnCl₂ in THF, whereas aromatic imines give the best results in the presence of EtAlCl₂ in CH₂Cl₂. The best results for the Heck-type cyclizations are obtained either under heterogeneous conditions in the presence of K₂CO₃/NEt₄Cl at 120°C in DMF or in refluxing toluene or under homogeneous conditions at 100°C in DMF in the presence of NEt-(i-Pr)₂. Depending on the substitution pattern of the diene and the steric demand of the base employed in the Heck cyclization, benzo[a]quinolizines carrying a double bond in the 11b,1- or 3,4-position or in an exocyclic position are obtained with fair to good results. A mechanistic rationale for this behavior is proposed. If chiral amines, e.g., derived from an amino acid ester, are employed in the three-step reaction sequence, chiral tricyclic benzo[a]quinolizines become accessible in a straightforward manner.

Full text of DOI:10.1021/jo972035w

4936
J . Org. Chem. 1998, 63, 4936-4946
Th r ee-Step Access to th e Tr icyclic Ben zo[a ]qu in olizin e Rin g
System
Stephan Kirschbaum and Herbert Waldmann*
Institut fu¨r Organische Chemie der Universita¨t Karlsruhe Richard-Willsta¨tter-Allee 2,
D-76128 Karlsruhe, Germany
Received November 5, 1997
Access to the tricyclic benzo[a]quinolizine ring system, which forms the characteristic framework
of alkaloids of the berberine and emetine type, is readily obtained by a three-step reaction sequence.
This sequence includes the formation of a Schiff base, derived from a 2-bromo-substituted phenyl-
ethylamine, and its tandem Mannich/conjugate addition reaction with an electron-rich silyloxy diene
forming an intermediate enaminone, which subsequently undergoes a Heck-type cyclization.
Highest yields of the tandem Mannich/conjugate addition for aromatic Schiff bases and formaldehyde
imines are observed in the presence of ZnCl2 in THF, whereas aromatic imines give the best results
in the presence of EtAlCl2 in CH2Cl2. The best results for the Heck-type cyclizations are obtained
either under heterogeneous conditions in the presence of K2CO3/NEt4Cl at 120 °C in DMF or in
refluxing toluene or under homogeneous conditions at 100 °C in DMF in the presence of NEt-
(i-Pr)2. Depending on the substitution pattern of the diene and the steric demand of the base
employed in the Heck cyclization, benzo[a]quinolizines carrying a double bond in the 11b,1- or
3,4-position or in an exocyclic position are obtained with fair to good results. A mechanistic rationale
for this behavior is proposed. If chiral amines, e.g., derived from an amino acid ester, are employed
in the three-step reaction sequence, chiral tricyclic benzo[a]quinolizines become accessible in a
straightforward manner.
Sch em e 1. Retr osyn th etic An a lysis of th e
In tr od u ction
Ben zo[a ]qu in olizin on e Sk eleton
The tricyclic benzo[a]quinolizine ring system forms the
characteristic framework of numerous heterocyclic physi-
ologically active compounds. For instance, it is found in
alkaloids of the berberine1 and the emetine type2 and in
psychoactive drugs such as tetrabenazine.3 In addition,
benzo[a]quinolizines may bind to the benzodiazepine
receptor and mimic the physiological effects typical for
benzodiazepine drugs.4 Although several methods for the
construction of these polycyclic heterocycles are known,5,6
the development of new efficient and short routes to this
class of compounds would open up new opportunities for
heterocyclic and medicinal chemistry. In an attempt to
devise such a method we have drawn from our previous
* To whom correspondence should be addressed. Fax: Int. code
(+)721-608-4825. E-mail: waldmann@ochhades.chemie.uni-karlsru-
he.de.
(1) J effs, P. W. In The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, London, 1967; Vol. 9, pp 41-115.
experience in the construction of nitrogen heterocycles.7,8
In a retrosynthetic analysis, the underlying heterocycle
1 was dissected between C-11a and C-11b (Scheme 1),
yielding enaminones 2, which should be accessible via
condensation of imines 3 with electron-rich silyloxy
dienes 4.8,9 Heck reaction ring closure10 for the final step
(2) (a) Sza´ntay, C.; To¨ke, L.; Kolonits, P. J . Org. Chem. 1966, 31,
1447-1451. (b) Buzas, A.; Cavier, R.; Cossais, F.; Finet, J .-P.; J acquet,
J .-P.; Lavielle, G.; Platzer, N. Helv. Chim. Acta 1977, 60, 2122-2134.
(3) (a) Schro¨der, E.; Rufer, C.; Schmiechen, R. Pharmazeutische
Chemie; Georg Thieme Verlag: Stuttgart, New York, 1982; pp 295-
298. (b) Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees,
C. W., Eds.; Pergamon Press Ltd.: New York, 1984; p 147.
(4) (a) Spurr, P. R. Tetrahedron Lett. 1995, 36, 2745-2748. (b)
Fischer, U.; Mo¨hler, H.; Schneider, F.; Widmer, U. Helv. Chim. Acta
1990, 73, 763-781.
(5) (a) Popp, F. D.; Watts, R. F. Heterocycles 1977, 6, 1189-1228.
(b) Rubiralta, M.; Diez, A.; Balet, A.; Bosch, J . Tetrahedron 1987, 43,
3021-3030. (c) Rubiralta, M.; Diez, A.; Bosch, J . Heterocycles 1988,
27, 1653-1664. (d) Bosch, J .; Domingo, A.; Linares, A. J . Org. Chem.
1983, 48, 1075-1080. (e) von Strandtmann, M.; Cohen, M. P.; Skavel,
J ., J r. J . Org. Chem. 1966, 31, 797-803. (f) Kametani, T.; Terasawa,
H.; Ihara, M. J . Chem. Soc., Perkin Trans. 1 1976, 2547-2530.
(6) (a) Beckwith, A. L. J .; J oseph, S. P.; Mayadunne, R. T. A. J . Org.
Chem. 1993, 58, 4198-4199. (b) Ku¨ndig, E. P.; Xu, L. H.; Romanens,
P.; Bernardinelli, G. Synlett 1996, 270-272.
(7) (a) Waldmann, H.; Braun, M.; Weymann, M.; Gewehr, M. Synlett
1991, 881-884. (b) Waldmann, H.; Braun, M.; Weymann, M.; Gewehr,
M. Tetrahedron 1993, 49, 397-416. (c) Waldmann, H.; Braun, M.;
Dra¨ger, M. Angew. Chem. 1990, 102, 1445-1447; Angew. Chem., Int.
Ed. Engl. 1990, 29, 1468-1471. (d) Waldmann, H.; Braun, M. J . Org.
Chem. 1992, 57, 4444-4451.
(8) (a) Lock, R.; Waldmann, H. Nat. Prod. Lett. 1993, 2, 49-56. (b)
Lock, R.; Waldmann, H. Liebigs Ann. Chem. 1994, 511-516. (c) Lock,
R.; Waldmann, H. Tetrahedron Lett. 1996, 37, 2753-2756. (d) Lock,
R.; Waldmann, H. Chemistry Eur. J . 1997, 3, 143-151.
(9) (a) Kerwin, J . F., J r.; Danishefsky, S. Tetrahedron Lett. 1982,
23, 3739-3741. (b) Danishefsky, S.; Kitahara, T. J . Am. Chem. Soc.
1974, 96, 7807-7808.
S0022-3263(97)02035-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/26/1998

Tricyclic Benzo[a]quinolizine Ring System
J . Org. Chem., Vol. 63, No. 15, 1998 4937
requires a halogen subustituent.11 A similar approach
to such heterocyclic compounds was recently reported by
Comins et al.12
Sch em e 3. Syn th esis of th e En a m in on es 15 a n d
16
Resu lts a n d Discu ssion
The two amine components, 2-bromohomoveratryl-
amine 513 and the amino acid ester 6, were employed for
the construction of the desired enaminones.
Compound 6 was built up from L-Dopa 7 as shown in
Scheme 2. Subsequent treatment of the amino acid 7
Sch em e 2. Syn th esis of th e Ch ir a l Am in o Acid
Ester 6a
a
Conditions: (a) Br2 (1.05 equiv), AcOH, 1.5 h, rt; (b) SOCl2
(10 equiv), MeOH, 0 °C f rt, 15 h; (c) NEt3 (2.5 equiv), Boc2O
(1.05 equiv), MeOH (degassed), rt, 15 h, 69% (over three steps);
(d) CH2Cl2 at room temperature, CH2N2 (1 M in CH2Cl2 at -78
°C, 6 equiv), 2 h, 74%; (e) CF3COOH, 0 °C, 30 min; (f) H2O/CH2Cl2
3:5, 1 M NaOH to pH 10, 99% (over two steps).
The homoveratrylamine 5 was converted to the re-
quired Schiff bases 12 by treatment with different
aldehydes in CH2Cl2 in the presence of MgSO4 (Scheme
3). These intermediates were not isolated. After ex-
change of the solvent, they were immediately subjected
to the Lewis acid-mediated reaction with the silyloxy
dienes 139b and 14.8d In the ensuing transformation, the
diene first adds to the CdN bond in the sense of a
Mannich reaction to give intermediates of type 17. These
then cyclize to the enaminones 15 and 16 via intramo-
lecular conjugate addition of the amine to the vinylogous
ester group and subsequent elimination of methanol.7,8
For aromatic Schiff bases and the formaldehyde imine,
the highest yields were obtained if ZnCl2 was used as
Lewis acid and THF was employed as solvent (Table 1,
entries 1-6 and 10-13). Whereas a slight excess of the
diene leads to a markedly increased yield (Table 1,
entries 1 and 2), the use of B(OPh)3 in CH2Cl2 as solvent
as recommended by Yamamoto et al.17 was not advanta-
geous (Table 1, entry 3). Aliphatic imines gave the best
results in the presence of EtAlCl2 in CH2Cl2 at -78 °C
with bromine in acetic acid and SOCl2 in methanol14 gave
rise to the methyl ester 8 as a mixture of the hydrobro-
mide and the hydrochloride. After masking of the amino
function as the Boc urethane,15 the phenolic hydrogens
were converted to the methyl ethers by means of diazo-
methane,16 which after removal of the Boc group under
acidic conditions yielded compound 6.
(10) (a) Heck, R. F. Org. React. 1982, 27, 345-390. (b) For a review
on application in heterocyclic chemistry, see: Hegedus, L. S. Angew.
Chem. 1988, 100, 1147-1161; Angew. Chem., Int. Ed. Engl. 1988, 27,
1113-1126. (c) Heck, R. F. Palladium Reagents in Organic Synthesis;
Academic Press: London, 1985. (d) Hegedus, L. S. Palladium in
Organic Synthesis. In Organometallics in SynthesissA Manual; Schlo-
sser, M., Ed.; Wiley: New York, 1994; pp 383-459.
(11) For
a preliminary publication of part of the results see:
Kirschbaum, S.; Waldmann, H. Tetrahedron Lett. 1997, 38, 2829-2831.
(12) (a) Comins, D. L.; J oseph, S. P.; Zhang, Y. Tetrahedron Lett.
1996, 37, 793-796. (b) Friestad, G. K.; Branchaud, B. P. Tetrahedron
Lett. 1995, 36, 7047-7050.
(13) (a) Harley-Mason, J. J . Chem. Soc. 1953, 200-203. (b) Tolknach-
er, O. N.; Voronin, V. G.; Pheobrazhenskii, N. A. J . Gen. Chem. USSR.
(Engl. Trans.) 1958, 28, 3345-3348.
(16) (a) Hudlicky, M. J . Org. Chem. 1980, 45, 5377-5378. (b) de
Boer, T. J ., Baker, H. J . Organic Synthesis; Wiley: New York, 1963;
Collect. Vol. IV, pp 250-253. (c) Black, T. H. Aldrichim. Acta 1983,
16, 3-11.
(14) Barnerjee, S. N.; Ressler, C. J . Org. Chem. 1976, 41, 3056-
3058.
(15) Ponnusmy, E.; Fotadar, U.; Spinsini, A.; Fiat, D. Synthesis 1986,
48-49.
(17) Hattori, K.; Yamamoto, H. Tetrahedron 1993, 49, 1749-1760.

4938 J . Org. Chem., Vol. 63, No. 15, 1998
Kirschbaum and Waldmann
Ta ble 1. Resu lts of th e Ta n d em Ma n n ich /Con ju ga te Ad d ition Cycliza tion betw een th e Im in es 12 a n d th e Dien es
13 a n d 14
entry
no.
R1
Lewis acid/equiv/solvent
diene/equiv
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15a
15a
15a
15b
15c
15d
15e
15f
15g
16a
16b
16c
16d
16e
Ph
Ph
Ph
p-OMePh
o-NO2Ph
H
n-Pr
i-Pr
t-Bu
Ph
ZnCl2/2/THF
ZnCl2/2/THF
B(OPh)3/1/CH2Cl2
ZnCl2/2/THF
ZnCl2/2/THF
ZnCl2/2/THF
EtAlCl2/1/CH2Cl2
EtAlCl2/1/CH2Cl2
ZnCl2/2/THF
ZnCl2/2/THF
ZnCl2/2/THF
ZnCl2/2/THF
ZnCl2/2/THF
ZnCl2/2/THF
13/1.0
13/1.2
13/1.25
13/1.2
13/1.2
13/1.2
13/1.2
13/1.25
13/1.2
14/1.3
14/1.2
14/1.2
14/1.2
14/1.2
rt
rt
40
18
5
18
20
24
20
3
18
20
72
24
72
96
47
58
14
66
33
47
43
65
-78 to rt
rt
rt
rt
-78 to rt
-78 to rt
rt
rt
rt
rt
rt
rt
45
77
54
67
22
p-NO2Ph
p-OMePh
H
Hep
Sch em e 4. Syn th esis of th e Ch ir a l En a m in on e
19a
Sch em e 5. Syn th esis of th e Ch ir a l En a m in on e
22a
a
Conditions: (a) THF, ZnCl2 (2 equiv), diene 14 (1.4 equiv), rt,
20 h, yielded 22 (48%), 23 (9%); (b) THF, ZnCl2 (3 equiv), diene
14 (1.2 equiv), rt, 18 h, yielded 22 (34%), 23 (21%).
a
Conditions: (a) B(OPh)3 (1 equiv), diene 13 (1.7 equiv), CH2Cl2,
-78 °C f rt, 20 h, yielded 19 (28%), 20 (13%).
(Table 1, entries 7 and 8); however, the tert-butyl-
substituted imine did not react at all (Table 1, entry 9).
If the more stable ethyl-substituted diene 14 is used
instead of 13, for aliphatic imines ZnCl2/THF can be used
advantageously (Table 1, entry 14).
were isolated (Scheme 5). The side product 23 must have
been formed via two successive Mannich-type additions,
e.g., to iminium intermediates such as 24 and 25, which
may be formed from the cyclic hexahydrotriazine trimer
21 in the presence of the Lewis acid.
The reaction of the chiral imine 18 with the diene 13
in the presence of B(OPh)3 as activating Lewis acid
yielded the desired enaminone 19 albeit in moderate yield
(Scheme 4). However, in addition to 19, the side product
20 was isolated in a substantial amount. The occurrence
of this compound sheds light on the mechanism of the
condensation detailed above, since 20 represents the
initial adduct resulting from the Mannich reaction prior
to ring closure via conjugate addition.7,18 Similarly, from
the condensation of the formaldehyde imine (which is
formed in situ from the cyclic trimer 21) with the diene
14 to give the ethyl-substituted enaminone 22, substan-
tial amounts of the bis-N-alkylated amino acid ester 23
Having the desired bromo-substituted enaminones 15,
16, and 22 in hand, their cyclization to benzo[a]quino-
lizines under the conditions of the Heck reaction10 was
investigated. To find advantageous conditions for the
attempted cyclization, an initial study was carried out.
In this study the enaminone 15a was employed and
several reaction parameters were varied (Scheme 6,
19
Table 2). As catalyst system, the Pd2(dba)3‚CHCl3
complex together with varying amounts of PPh3 was
used. When the reaction mixture was heated to 45 °C,
the color changed from deep red to light yellow (exchange
of the ligands on Pd), and upon prolonged heating it
turned brown accompanied by precipitation of palladium.
(18) Kunz, H.; Pfrengle, W. Angew. Chem. 1989, 101, 1041-1042;
Angew. Chem., Int. Ed. Engl. 1989, 28, 1067-1068.
(19) Ukai, T.; Kawazawa, H.; Ishii, Y.; Bonnett, J . J .; J bers, J . A. J .
Organomet. Chem. 1974, 65, 253-266.

Tricyclic Benzo[a]quinolizine Ring System
J . Org. Chem., Vol. 63, No. 15, 1998 4939
Ta ble 2. Op tim iza tion of th e Heck -Typ e Cycliza tion of th e P h en yl-Su bstitu ted En a m in on e 15a
entry
Pda (mol %)
PPh3 (mol %)
base/equiv
solvent
additive/equiv
Tb (°C)
time (h)
26a (%)
1
2
3
4
5
6
7
8
9
16
10
11
10
10
10
24
10
10
42
20
48
20
20
20
48
20
20
NEt(i-Pr)2/1.8
NEt(i-Pr)2/1.8
NEt(i-Pr)2/2.5
K2CO3/1.5
K2CO3/1.5
K2CO3/1.5
NaOH/2
CH3CN
DMF
DMF
CH3CN
DMF
DMF
toluene
toluene
toluene
80
150
100
80
100
120
120
120
120
120
5
6
24
3.5
3
20
22
20
20
67
22c
45
87
30
36
25
NEt4Cl/1
NEt4Cl/1
NEt4Cl/1
NEt4Cl/1.2
NEt4Cl/1.2
NEt4Cl/1.2
NaOH/2
DBU/2
a
b
Pd2(dba)3‚CHCl3. Oil bath temperature. c 66% of 15a reisolated.
Ta ble 3. Resu lts of th e Heck -Typ e Cycliza tion s of
6-Su bstitu ted En a m in on es 15
Sch em e 6. Heck -Typ e Cycliza tion of
6-Su bstitu ted En a m in on es 15 To Give
Ben zo[a ]qu in olizin on es 26 a n d 27
entry
R
15 methoda time (h) 26 (%) 27 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
p-OMePh
p-OMePh
o-NO2Ph
H
H
n-Pr
n-Pr
n-Pr
a
a
b
b
c
d
d
e
e
e
f
A
B
A
B
A
A
B
A
B
C
A
B
C
6
3
20
3
25
15
6
12
8
17
6
20
16
67
87
51
76
65
12
17
9
26
16
12
20
30
9
35
42
30
i-Pr
i-Pr
i-Pr
f
f
38
60
a
Conditions: (Method A) Pd2(dba)3‚CHCl3 (5 mol %), PPh3 (40
mol %), DMF, NEt(i-Pr)2 (2 equiv), 100 °C; (Method B) Pd2(dba)3‚
CHCl3 (5 mol %), PPh3 (20 mol %), DMF, K2CO3 (1.5 equiv), NEt4Cl
(1-1.2 equiv), 120 °C; (Method C) Pd2(dba)3‚CHCl3 (5 mol %),
PPh3 (20 mol %), toluene, K2CO3 (10 equiv), NEt4Cl (1.1 eqiuv),
120 °C.
of the enaminones 15 derived from aliphatic and aromatic
aldehydes, as well as formaldehyde in the presence of
Pd(0) under the conditions of method A or B, yielded the
benzo[a]quinolizinones 26 in moderate to high yields
(Scheme 6, Table 3). In general, under heterogeneous
conditions (method B), the yields were higher than under
homogeneous conditions (method A).
Unexpectedly, under the heterogeneous conditions the
enaminones derived from aliphatic aldehydes and form-
aldehyde did not only give the expected products 26, but
instead, enaminones 27 carrying the double bond in the
3,4-position were formed (Table 3, entries 4, 7, 9, 10, 12,
and 13). This was also observed if toluene was employed
as solvent instead of DMF (Table 3, entries 10 and 13).
With the exception of the p-methoxyphenyl-substituted
enaminone (Table 3, entry 4), in the presence of aromatic
substituents the formation of these isomers was not
observed.
The tricyclic benzo[a]quinolizinones 26 and 27 are
readily separated by means of flash chromatography and
can be identified by characteristic signals in their 1H
NMR spectra. Thus, in the 3,4-unsaturated compounds
27, H-3 and H-11 are shifted by ca. 0.5 ppm toward
higher field as compared to the signals for the analogous
H-1 and H-11 of the isomers 26 (Table 4). In 26, H-1
and H-11 deshield each other, whereas in 27 this is no
longer the case. In addition, 27e was subjected to
analysis by means of NOE measurements (Figure 1).21
Upon irradiation at H-11, a signal enhancement for
The use of NEt(i-Pr)2 in CH3CN was not advantageous;
however, changing the solvent to DMF led to formation
of the tricyclic enaminone 26a . At 100 °C and in the
presence of 4 equiv of PPh3 (with respect to Pd), the yield
reached 67%, whereas at higher temperatures it was
substantially lower (Table 2, entries 1-3). If K2CO3 and
NEt4Cl were used in DMF in accord with the heteroge-
neous system as recommended by J effery et al.,20 the
yield could be further increased to 87%, whereas CH3-
CN once more gave an inferior result (Table 2, entries
4-6). In this case, 2 equiv of the phosphine ligand are
sufficient, presumably because chloride may serve as
ligand for Pd(0), as well, thereby stabilizing it. Finally,
the use of toluene as solvent was investigated; however,
neither in the presence of NaOH/NEt4Cl or DBU/NEt4Cl
was a satisfactory yield obtained (Table 2, entries 7-9).
The best yields were obtained either by running the
cyclization in DMF either at 100 °C and in the presence
of NEt(i-Pr)2 (method A) or at 120 °C in the presence of
K2CO3/NEt4Cl (method B), and all further cyclizations
were studied using these reaction conditions. Treatment
(20) (a) J effery, T. J . Chem. Soc., Chem. Commun. 1984, 1287-1289.
(b) J effery, T. Tetrahedron Lett. 1985, 26, 2667-2670. (c) J effery, T.
Synthesis 1987, 70-71. (d) J effery, T. Tetrahedron Lett. 1994, 35,
3051-3054. (e) J effery, T.; Galland, J .-C. Tetrahedron Lett. 1994, 35,
4103-4106. (f) J effery, T. Tetrahedron 1996, 52, 10113-10130. (g)
J effery, T. Adv. Met.-Org. Chem. 1996, 5, 152-260.
(21) Derome, A. E. Modern NMR Techniques for Chemistry Research;
Pergamon Press: Oxford, New York, 1987.

4940 J . Org. Chem., Vol. 63, No. 15, 1998
Kirschbaum and Waldmann
Ta ble 4. Ch a r a cter istic 1H NMR Ch em ica l Sh ifts of H-1,
The catalytic cycle starts with the oxidative addition of
the aryl bromide 15 to the Pd(0) catalyst to give the
intermediate σ-Pd complex 28, which then undergoes a
syn addition to the double bond of the enaminone ring.
For steric reasons, C-2 of the aryl ring attacks exclusively
C-2 of the enaminone and anti to the substituent R at
the 6-position of the enaminone. Consequently, in ring
C of 29 the substituents are in a trans orientation, and
for the Pd no syn hydrogen is available for subsequent
elimination.22 Intermediate 29 now may undergo two
different reactions leading either to 26 or 27. On the one
hand (pathway A), 29 can rearrange to the σ-Pd-enolate
31 via π-oxoallyl complex 30.23,24 From 31, the Pd now
can reach the other side of the ring (f 32) where a
hydrogen is accessible for syn elimination and closure of
the catalytic cycle. On the other hand (pathway B), the
ketone in 29 can be converted to the enol 33. This
reaction pathway should be accessible in particular if the
substituent R is sterically less demanding and if a small
base is present. The η1-σ-allylpalladium intermediate 33
can then isomerize to the η1-compound 35 by a σ-π-σ
1,3 shift via the η3-π-complex 34.25 In 35, the Pd now
must be syn to the hydrogen at C-4 so that a syn elim-
ination to close the catalytic cycle is possible. Tautomer-
ization of the enol to the carbonyl group finally gives 27.
H-3, a n d H-11 in 26 a n d 27 (δ in p p m )
26
27
R
H-1
H-11
H-3
H-11
p-OMePh
H
n-Pr
b
d
e
f
5.72
5.69
5.56
5.52
7.22
7.16
7.16
7.17
5.23
5.06
5.11
5.22
6.65
6.61
6.62
6.67
i-Pr
F igu r e 1. NOE signal enhancements observed for 27e. Signal
amplification: bold ) strong, plain ) weak.
H-11b and H-1eq was recorded, and similarly it was
proven that H-8 is in the vicinity of H-7eq. Most
significantly, irradiation at H-3 yielded an enhancement
of the signal for the first methylene group of the propyl
side chain. In turn, irradiation into the signal charac-
teristic for this CH2 group proved that it is in the vicinity
of H-3 and H-6eq. Thus, the double bond and the propyl
side chain lie close to each other; i.e., the double bond
must be in the 3,4-position.
If the base employed in the Pd-mediated reaction and
the substituent R are sterically demanding, i.e., if EtN-
(i-Pr)2 is used and R is aromatic, pathway B is not or
only hardly accessible to the system and the isomers 26
are formed. If the steric demand of R and the base are
lower, i.e., if R is aliphatic or hydrogen and K2CO3 is
To explain the formation of the isomers 26 and 27, we
propose the mechanistic rationale depicted in Scheme 7.
Sch em e 7. Mech a n istic P r op osa l To Ra tion a lize th e F or m a tion of th e Ben zo[a ]qu in olizin on es 26 a n d 27

Tricyclic Benzo[a]quinolizine Ring System
J . Org. Chem., Vol. 63, No. 15, 1998 4941
Ta ble 5. Resu lts of th e Heck -Typ e Cycliza tion s of
3-Eth yl-Su bstitu ted En a m in on es 16a
Sch em e 8. Heck -Typ e Cycliza tion of
3-Eth yl-Su bstitu ted En a m in on es 16 To Give th e
Ben zo[a ]qu in olizin on es (E)-36 a n d (Z)-37
time yield
38
entry 16
R
ligand/mol % (h)
(%)
36:37 (%)
1
2
3
4
5
6
7
8
9
a
a
a
b
c
c
d
d
e
Ph
Ph
Ph
PPh3/25
4
4
9
5
3
53
60
36
41
37c
4:1
3:1
2.5:1 29
3:1
3:1
3:1
30
18
P(o-tol)3/25b
(R)-BINAP/11
p-NO2Ph P(o-tol)3/25
p-OMePh P(o-tol)3/20
p-OMePh (R)-BINAP/11
H
H
35
24
6.5 53
6
7
PPh3/25
P(o-tol)3/25
(R)-BINAP/11 48
24
>20:1
30
5
Hep
40
1:1
a
Conditions: Pd2(dba)3‚CHCl3 (5 mol %), NEt4Cl (1.1-1.2
b
equiv), toluene, argon atmosphere, 120 °C oil bath. When 20 mol
% ligand is used 39 (15%) can be isolated. c 25% of 39 can be
isolated.
ditional ethyl substituent, in the intermediate analogous
to 29, hydrogen atoms are now accessible for elimination
of a hydridopalladium species, thus forming an exocyclic
double bond. In accord with this process, the benzo[a]-
quinolizinones 36 and 37 are obtained in moderate yields
with the E-isomer of the double bond being formed in
excess (Table 5). For the phenyl-substituted compound
16a , the influence of different phosphines on this process
was investigated (Table 5, entries 1-3). The best result
was obtained if P(o-tol)3 was employed; PPh3 was less
advantageous. The use of a sterically more demanding
phosphine like BINAP led to a decreased yield and a
lower E/Z ratio. In all cases, compound 38 (R ) Ph),
which must arise from reduction of the initial σ-Pd
complex, was isolated as an undesired side product. In
addition, in two cases 39 was isolated as a byproduct.
This compound embodies an additional 3,4 double bond
(Table 5, entries 2 and 5). The occurrence of the
reduction product 38 is in line with observations by
Comins et al.12a and Branchaud et al.12b for related
reactions.
Enaminones with substituted aromatic groups can be
cyclized in yields of ca. 40% (Table 5, entries 4 and 5),
using the o-tolylphosphine ligand. However, the use of
BINAP may be advantageous (Table 5, entry 6). In
particular for aliphatic groups “R”, this phosphine gives
the best result (Table 5, entry 9). If R ) H, the use of
o-tolylphosphine leads only to the formation of the
reduction product 38 (R ) H); however, in this case, the
application of PPh3 yielded the cyclization product formed
as a single regioisomer (Table 5, entries 7 and 8).
employed, both pathways can be followed and mixtures
of 26 and 27 result. These assumptions are supported
by force field calculations,26 which indicate that in 32 the
protons at C-3 are not accessible if R is aromatic.
The carbon atoms C-11b, C-1, C-2, and C-3 of the
benzo[a]quinolizinones built up via the route described
above originate from the diene employed. Therefore, the
use of dienes carrying additional substituents would give
access to further substituted tricyclic compounds in a
straightforward manner and without the need to carry
out additional transformations after generation of the
ring system. Therefore, the Heck-type cyclizations were
studied for the ethyl-substituted enaminones 16 (Scheme
8, Table 5). In these cases, the use of K2CO3/NEt4Cl in
refluxing toluene in the presence of additional phosphines
turned out to be most advantageous. Following the
mechanism proposed above (Scheme 7), the initially
formed arylpalladium intermediate in these cases also
undergoes a syn addition to the double bond of the
enaminone. However, due to the presence of the ad-
(22) For examples of trans- or anti-elimination, see: (a) Zhang, Y.;
O’Conner, B.; Negishi, E. J . Org. Chem. 1988, 53, 5590-5592. (b) Amos,
P. C.; Whiting, D. A. J . Chem. Soc., Chem. Commun. 1987, 510-511.
(c) Chida, N.; Ohtsuka, M.; Ogawa, S. Tetrahedron Lett. 1991, 35,
4525-4228. (d) Martin, S. F.; Tso, H.-H. Heterocycles 1993, 35, 85-
88. (e) Ahmad-J unan, S. A.; Amos, P. C.; Whiting, D. A. J . Chem. Soc.,
Perkin Trans. 1 1992, 539-545. (f) Chida, N.; Ohtsuka, M.; Ogawa, S.
J . Org. Chem. 1993, 58, 4441-4447. (g) Hudlicky, T.; Olivo, H. F. J .
Am. Chem. Soc. 1992, 114, 9694-9696. (h) McIntosh, M. C.; Weinreb,
S. M. J . Org. Chem. 1993, 58, 4823-4832 and references therein.
(23) (a) Grigg, R.; Loganathan, V.; Sukirthalingam, S.; Sridharan,
V. Tetrahedron Lett. 1990, 31, 6573-6576. (b) Ishibashi, H.; Ito, K.;
Hirano, T.; Tabuchi, M.; Ikeda, M. Tetrahedron 1993, 49, 4173-4182.
(c) Ogoshi, S.; Morimoto, T.; Nishio, K.; Ohe, S.; Murai, K. J . Org.
Chem. 1993, 58, 9-10. (d) Friestad, G. K.; Branchaud, B. P. Tetrahe-
dron Lett. 1995, 36, 7047-7050.
In both compounds 36 and 37, a new stereocenter is
built up; in the presence of the chiral (R)-BINAP ligand,
asymmetric induction might occur. But unfortunately,
in all cases examined the heterocycles 36 and 37 did not
display any specific rotation.
The relative stereochemistry of the tricyclic targets 36
1
and 37 was ascertained by examination of their H NMR
spectra and additional NOE studies. Thus, due to the
influence of the CdO group, the hydrogen substituent of
the exocyclic double bond displays a chemical shift of ca.
7 ppm for the E isomers 36, whereas for the Z isomers
(24) (a) Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa, T.
J . Am. Chem. Soc. 1979, 101, 494-496. (b) Ito, Y.; Aoyama, H.;
Saegusa, T. J . Am. Chem. Soc. 1980, 102, 4519-4521.
(25) Trost, B. M. J . Organomet. Chem. 1986, 300, 263-280.
(26) CHEM-3D, release 3.0, CambridgeSoft Corp., Cambridge, MA.

4942 J . Org. Chem., Vol. 63, No. 15, 1998
Kirschbaum and Waldmann
Ta ble 6. Ch a r a cter istic 1H NMR Ch em ica l Sh ifts of
H-exo,exo-CH3 a n d H-11b in (E)-36 a n d (Z)-37 (δ in p p m )
of an imine, a tandem Mannich/conjugate addition reac-
tion, and a subsequent cyclization by means of a Heck
reaction. The desired tricyclic heterocycles are accessible
via this very short sequence with fair to good results. This
method should be readily amenable to the construction
of natural products and analogues thereof and thereby
open up new alternatives to the already existing methods.
(E)-37
(Z)-37
R
H-exo exo-CH3 H-11b H-exo exo-CH3 H-11b
Ph
a
b
c
d
e
7.02
7.04
7.01
6.99
6.99
1.94
1.95
1.94
1.90
1.88
5.39
5.41
5.41
5.19
5.26
5.81
5.80
5.80
2.06
2.08
2.05
4.98
4.98
4.95
p-NO2Ph
p-OMePh
H
Hep
5.39
1.90
4.81
Exp er im en ta l Section
Gen er a l P r oced u r es. The analytical instruments and
general experimental techniques used have already been
described.27 The solutions of ZnCl2 and B(OPh)3 were prepared
by dissolving the neat Lewis acids in anhydrous THF and
CH2Cl2. K2CO3 was heated for several hours and then stored
under argon atmosphere. NEt4Cl was heated at 120 °C for
24 h at reduced pressure prior to use and stored under argon
atmosphere. Methanol and triethylamine (Et3N) were care-
fully degassed prior to use by freezing three times under argon
atmosphere and warming under reduced pressure.
(S)-(2-Br om o-4,5-d ih yd r oxy)p h en yla la n in e Meth yl Es-
ter Hyd r och lor id e/Hyd r obr om id e (8).13 To a solution of
L-Dopa 7 (9.86 g, 50 mmol) in acetic acid (250 mL) was added
a solution of Br2 (2.67 mL, 8.39 g, 52.5 mmol) in 50 mL of acetic
acid during 1.5 h. The solvent was evaporated in vacuo, and
the crude solid was treated with an ice-cold mixture of SOCl2
(20 mL) and methanol (150 mL). The reaction mixture then
was allowed to warm to room temperature during 15 h, and
the solvent was evaporated in vacuo to give the product as a
light yellow amorphous solid (19.12 g, quant) (hydrochloride
and hydrobromide), which was used without further purifica-
tion: 1H NMR (DMSO-d6, 250 MHz) δ 9.71 (br s, 1H), 9.45 (br
s, 1H), 8.77 (br s, 3H), 7.12 (s, 1H), 6.91 (s, 1H), 4.22 (br t, J
) 7.2 Hz, 1H), 3.83 (s, 3H), 3.22 (br d, J ) 7.2 Hz).
F igu r e 2. NOE signal enhancements observed for (E)-36 and
(Z)-37. Signal amplification: bold ) strong, plain ) weak.
Sch em e 9. Heck -Typ e Cycliza tion of En a m in on e
22 To Give th e Ben zo[a ]qu in olizin on e 40a
a
Conditions: Pd2(dba)3CHCl3 (5 mol %), P(o-tol)3 (20 mol %),
K2CO3 (10 equiv), NEt4Cl (1.1 equiv), toluene, 120 °C oil bath, 3
(S)-N-(ter t-Bu tyloxyca r bon yl)-2-br om o-4,5-d ih yd r oxy-
p h en yla la n in e Meth yl Ester (9). To a solution of methyl
ester 8 (19.12 g, 50 mmol) in degassed methanol (200 mL) was
added at room temperature Et3N (17.4 mL, 125 mmol) followed
by a solution of Boc2O (11.5 g, 52.5 mmol) in methanol (50
mL). The orange red solution was stirred for 12 h, and the
solvent was evaporated in vacuo. The residue was purified
by flash chromatography on silica gel, employing hexane-
acetone (1:1) as eluent to afford 13.6 g (70%) of urethane 9 as
a colorless amorphous solid: mp 93-95 °C; silica gel TLC Rf
h, 32%; ratio of isomers at H-11b, 3:4; E:Z, 85:15.
37 it appears at 5.4-5.8 ppm (Table 6). For the methyl
substituents of the double bond, the effect is opposite but
it is less pronounced. In addition, in the E isomers 36,
H-11b appears above 5 ppm, whereas in the Z isomers
the signal is found below 5 ppm. Furthermore, in both
isomers an NOE signal enhancement between H-11b and
the substituents of the double bond as well as between
H-11b and H-11 were detected (Figure 2). H-4 and
H-11b, however, do not show an NOE effect. H-4 only
displays signal enhancements with H-3 and the side-
chain substituents. Consequently, H-11b and H-4 lie on
different faces of the tricyclic nitrogen heterocycles, which
can be explained by means of the proposed mechanism
detailed in Scheme 7.
The reaction sequence described above has the poten-
tial to provide access to enantiomerically enriched benzo-
[a]quinolizinones. To this end, the enaminone 22 was
subjected to the cyclization reaction. In this case, the
heterogeneous reaction conditions employing Pd2(dba)3‚
CHCl3, P(o-tol)3, and K2CO3/NEt4Cl in refluxing toluene
as solvent proved to be best. Under these conditions, the
desired tricyclic compound 40 was obtained as a mixture
of isomers (Scheme 9). This mixture consisted mainly
(ca. 85%) of the two isomers with an E-configured
exocyclic double bond but a different configuration at
C-11b (isomer ratio 2:1). In addition, two minor isomers
(ca. 15%) with Z-double bonds were formed.
0.23 (1:1 hexane-acetone); [R]25 ) -13.4 (c 1, MeOH); 1H
D
NMR (CDCl3, 250 MHz) δ 7.02 (s, 1H), 6.85 (br s, 1H), 6.75 (s,
1H), 6.68 (br s, 1H), 5.35 (d, J ) 8.6 Hz, 1H), 4.55 (ddd, J )
8.6, 5.5, 8.7 Hz, 1H), 3.74 (s, 3H), 3.14 (dd, J ) 5.5, 14.1 Hz,
1H), 2.95 (dd, J ) 8.7, 14.1 Hz, 1H), 1.39 (s, 9H). Anal. Calcd
for C15H20BrNO6 (390.23): C, 46.17; H, 5.17; N, 3.58. Found:
C, 46.51; H, 5.32; N, 3.21.
(S)-N-(ter t-Bu tyloxyca r bon yl)-2-br om o-4,5-d im eth oxy-
p h en yla la n in e Meth yl Ester (10). To a solution of catechol
9 (2.7 g, 6.92 mmol) in CH2Cl2 (60 mL) in an open Erlenmeyer
flask was added a 1 M solution of diazomethane in CH2Cl2
(40 mL) precooled to -78 °C. After the mixture was stirred
for 2 h, acetic acid was added until the yellow color disap-
peared. The solvent was evaporated in vacuo, the residue was
dissolved in toluene (50 mL), and the solvent was evaporated.
Purification of the crude residue by flash chromatography
(silica gel, 4:1-3:1 hexane-acetone) afforded 10 as colorless
viscous oil, which solidified over days upon standing under
reduced pressure to give a colorless amorphous solid (2.15 g,
74%): mp 119-121 °C; silica gel TLC Rf 0.12 (4:1 hexane-
1
acetone); [R]25 ) +16.1 (c 1, CH2Cl2); H NMR (CDCl3, 400
D
MHz) δ 7.00 (s, 1H), 6.70 (s, 1H), 5.09 (d, J ) 8.3 Hz, 1H),
4.60 (m, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 3.22 (dd, J ) 5.9, 14.0
Hz, 1H), 3.05 (dd, J ) 7.9, 14.0 Hz, 1H), 1.39 (s, 9H); 13C NMR
(CDCl3, 100.5 MHz) δ 172.4, 154.9, 148.5, 148.3, 127.8, 115.4
(CH), 114.9, 113.5 (CH), 79.9, 56.1 (CH3), 56.0 (CH3), 53.6 (CH),
52.4 (CH3), 38.1 (CH2), 28.3 (3C, CH3); IR (drift) 1733, 1686,
Con clu sion
The results presented in this paper demonstrate that
functionalized benzo[a]quinolizidinones can be built up
in a three-step reaction, which consists of the formation
(27) Pohl, T.; Waldmann, H. J . Am. Chem. Soc. 1997, 119, 6702-
6710.

Tricyclic Benzo[a]quinolizine Ring System
J . Org. Chem., Vol. 63, No. 15, 1998 4943
1524 cm-1; UV (λmax (ꢀ), MeOH) 204 (48 400), 232 (11 250), 284
(4150) nm; MS (85 °C) m/e 419 (8), 417 (8), 363, 361 (8), 300,
-78 °C 1.1 equiv of a 1 M solution of EtAlCl2 in hexane (5.5
mL) followed by 1.25 equiv of the diene 13 (1.25 mL, 6.3 mmol).
The reaction mixture was stirred for 3 h and allowed to warm
to room temperature. After addition of a NaHCO3 solution
(30 mL) (half-saturated), the aqueous phase was extracted
with CH2Cl2 (30 mL). The combined organic phases were
extracted with saturated NaHCO3 (50 mL), H2O (50 mL), and
brine (50 mL) and dried with MgSO4, and the solvent was
evaporated in vacuo. The residue was purified by flash
chromatography with hexane-acetone mixtures as eluents.
302 (8), 231 (98), 229 (100), 57 (37). Anal. Calcd for C17H24
-
BrNO6 (418.28): C, 48.82; H, 5.78; N, 3.35. Found: C, 49.10;
H, 5.75; N, 3.25.
(S)-2-Br om o-4,5-d im eth oxyp h en yla la n in e Meth yl Es-
ter Hyd r otr iflu or oa ceta te (11). A solution of methyl ester
10 (225 mg, 0.54 mmol) in trifluoroacetic acid (5 mL) was
stirred at 0 °C for 30 min. The solvent was removed at room
temperature under reduced pressure, and the residue was
dried in vacuo for 2 d to yield the hydrotrifluoroacetate 11 as
According to the procedures described above, the following
2,3-didehydro-4-oxopiperidines were prepared.
a colorless solid (233 mg, 99%): mp 122 °C; [R]25 ) +10.6 (c
D
1
1.18, MeOH); H NMR (CDCl3, 400 MHz) δ 6.99 (s, 1H), 6.95
N-[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-2,3-d id eh y-
d r o-4-oxo-6-p h en ylp ip er id in e (15a ). Procedure 1: yield
58%; yellowish amorphous solid; mp 102-103 °C; silica gel
TLC Rf 0.25 (1:1 hexane-acetone); 1H NMR (CDCl3, 250 MHz)
δ 7.43-7.29 (m, 5H), 7.07 (d, J ) 8.0 Hz, 1H), 6.97 (s, 1H),
6.49 (s, 1H), 5.02 (d, J ) 8.0 Hz, 1H), 4.63 (dd, J ) 6.9, 8.5
Hz, 1H), 3.85 (s, 3H), 3.70 (s, 3H), 3.38-3.26 (m, 2H), 2.92-
2.83 (m, 2H), 2.83 (dd, J ) 6.9, 16.6 Hz, 1H), 2.70 (dd, J )
8.5, 16.5 Hz, 1H); 13C NMR (CDCl3, 100.6 MHz) δ 190.2, 153.9
(CH), 148.5, 148.4, 138.6, 129.0 (2C, CH), 128.9, 128.3 (CH),
127.1 (2C, CH), 115.6 (CH), 114.1, 113.3 (CH), 98.6 (CH), 61.5
(CH), 56.1 (CH3), 56.0 (CH3), 53.2 (CH2), 43.8 (CH2), 35.5 (CH2);
IR (drift) 1637, 1593, 1511 cm-1; UV (λmax (ꢀ), MeOH) 202
(50 400), 228.3 (sch, 11 550), 293 (5810), 327 (15 440) nm; MS
(130 °C) m/e 417 (23), 415 (22), 231, 229 (4), 186 (100), 117
(11), 82 (73); HRMS (130 °C) m/e calcd for (M+) 415.0783, found
415.0798.
N-[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-2,3-d id eh y-
d r o-4-oxop ip er id in e (15d ). Procedure 1: yield 47%; yellow
oil; silica gel TLC Rf 0.11 (1:1 hexane-acetone); 1H NMR
(CDCl3, 250 MHz) δ 7.03 (s, 1H), 6.88 (d, J ) 7.4 Hz, 1H),
6.67 (s, 1H), 4.90 (d, J ) 7.4 Hz, 1H), 3.87 (s, 3H), 3.85 (s,
3H), 3.51 (t, J ) 7.8 Hz, 2H), 3.45 (t, J ) 7.1 Hz, 2H), 2.95 (t,
J ) 7.1 Hz, 2H), 2.47 (t, J ) 7.8 Hz, 2H); 13C NMR (CDCl3,
100.6 MHz) δ 191.3, 154.0 (CH), 148.6, 148.5, 128.7, 115.7
(CH), 114.1, 113.4 (CH), 98.0 (CH), 56.2 (2C, CH3), 55.8 (CH2),
47.3 (CH2), 35.6 (CH2), 35.5 (CH2); MS (140 °C) m/e 341 (14),
339 (14), 260 (4), 231, 229 (5), 110 (100), 82 (11); HRMS (105
°C) m/e calcd for C15H18BrNO3 (M+, 340.22) 339.0470, found
339.0456.
N-[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-2,3-d id eh y-
d r o-4-oxo-6-p r op ylp ip er id in e (15e). Procedure 3: yield
43%; brown viscous oil; silica gel TLC Rf 0.22 (1:1 hexane-
acetone); major conformational isomer at C-6 (equatorial); 1H
NMR (CDCl3, 400 MHz) δ 7.03 (s, 1H), 6.82 (d, J ) 7.3 Hz,
1H), 6.69 (s, 1H), 4.85 (d, J ) 7.3 Hz, 1H), 3.87 (s, 3H), 3.84
(s, 3H), 3.49-3.39 (m, 3H), 3.07-2.88 (m, 2H), 2.69 (dd, J )
6.9, 16.4 Hz, 1H), 2.29 (dd, J ) 2.6, 16.4 Hz, 1H), 1.75-1.20
(4m, 4H), 0.91 (t, J ) 7.3 Hz, 3H); 13C NMR (CDCl3, 62.9 MHz)
δ 190.4, 152.2 (CH), 148.7, 148.5, 128.8, 115.7 (CH), 114.2,
113.6 (CH), 96.8 (CH), 56.6 (CH), 56.2 (CH3), 56.1 (CH3), 53.8
(CH2), 39.5 (CH2), 36.8 (CH2), 31.2 (CH2), 18.8 (CH2), 14.0
(CH3); MS (120 °C) m/e 383 (13), 381 (13), 340 (2), 338 (2), 302
(4), 244, 242 (10), 231, 229 (15), 164 (42), 152 (100), 151 (32),
110 (45), 86 (23), 84 (37), 82 (27); HRMS (120 °C) m/e calcd
for C18H24BrNO3 (M+, 382.29) 381.0939, found 381.0924.
(s, 1H), 4.30 (br s, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.42 (m, 1H),
3.21 (m, 1H); 13C NMR (CDCl3, 100.5 MHz) δ 169.5, 162.0 (q,
2J CF ) 35 Hz, CF3C), 149.1, 148.5, 125.1, 116.4 (q, J CF ) 291
1
Hz, CF3), 115.7 (CH), 114.7 (CH), 114.5, 56.2 (CH3), 56.1 (CH3),
53.4 (CH3), 52.6 (CH), 36.4 (CH2); MS (75 °C) m/e 319 (0.7),
317 (0.8), 258, 260, 237, 239 (10), 238 (82), 230, 232 (21), 229,
231 (100), 151 (18), 88 (23), 69 (28). Anal. Calcd for C14H17
-
BrF3NO6‚3/2H2O (432.19): C, 36.62; H, 4.39; N, 3.05. Found:
C, 36.94; H, 4.37; N, 2.58.
(S)-2-Br om o-4,5-d im eth oxyp h en yla la n in e Meth yl Es-
ter (6). Hydrotrifluoroacetate 11 (233 mg, 0.54 mmol) was
dissolved in a mixture of H2O (30 mL) and CH2Cl2 (50 mL),
and the pH was adjusted to 10 with 1 M NaOH at room
temperature. After separation of the phases, the aqueous
phase was extracted with CH2Cl2 (30 mL), the combined
organic phases were dried with MgSO4, and the solvent was
evaporated in vacuo. The yellowish oil (171 mg, 99%) was
immediately used in subsequent reactions without further
purification: 1H NMR (CDCl3, 500 MHz) δ 7.02 (s, 1H), 6.75
(s, 1H), 3.85 (s, 3H), 3.83 (dd, J ) 5.7, 8.6 Hz, 1H), 3.72 (s,
3H), 3.18 (dd, J ) 5.7, 13.7 Hz, 1H), 2.90 (dd, J ) 8.6, 13.7
Hz, 1H), 1.65 (br s, 2H); 13C NMR (CDCl3, 125.7 MHz) δ 175.3,
148.6, 148.4, 128.8, 115.7 (CH), 114.8, 113.9 (CH), 56.2 (CH3),
56.1 (CH3), 54.7 (CH), 52.2 (CH3), 40.9 (CH2); MS (75 °C) m/e
319 (0.7), 317 (0.8), 258, 260, 237, 239 (10), 238 (82), 230, 232
(21), 229, 231 (100), 151 (18), 88 (23); HRMS m/e calcd for
C
12H16BrNO4 (318.17) 317.0263, found 317.0280.
Gen er a l P r otocol for th e P r ep a r a tion of th e Im in es
12. To a solution of 1 mmol of the respective amine in of
CH2Cl2 (20 mL) was added 1 mmol of the corresponding
aldehyde and 1 g of MgSO4. The solution was stirred for 12-
15 h and filtered through a G4 glass frit, and the solvent was
evaporated in vacuo. The resulting imines were directly used
in subsequent reactions without further purification.
Gen er a l P r otocol for th e Syn th esis of th e 2,3-Did eh y-
d r op ip er id in on es. (1) Usin g Zn Cl2 a s Lew is Acid . To a
solution of 10 mmol of the respective imine 12 in THF (100
mL) was added under argon a 1 M solution of ZnCl2 in THF
(20 mL) followed by 1.3 equiv of the diene 13 (2.4 mL, 13
mmol). The solution was stirred for 20 h at room temperature.
After addition of 1 N HCl (20 mL), the organic phase was
extracted with saturated NaHCO3 (50 mL), H2O (50 mL), and
brine (50 mL) and was dried with MgSO4. The solvent was
removed in vacuo, and the residue was purified by flash
chromatography on silica gel with hexane-acetone mixtures
as eluents.
(2) Usin g B(OP h )3 a s Lew is Acid . To an ice-cold solution
of 5 mmol of the respective imine 12 in CH2Cl2 (100 mL) was
added 5 g of molecular sieves (4 Å) and 1 equiv of a 1 M
solution of B(OPh)3 in CH2Cl2 (5 mL). The solution was stirred
for 20 min under argon atmosphere, cooled to -78 °C, and 1.25
equiv of diene 13 (1.25 mL, 6.3 mmol) was added. The mixture
was stirred for additional 15 h and allowed to warm to room
temperature during that time. After filtration over a G3-glass
frit, the residue was washed with CH2Cl2 (20 mL) and the
organic phase extracted with 1 N HCl (50 mL), saturated
NaHCO3 (50 mL), H2O (50 mL), and brine (50 mL). The
organic layer was dried with MgSO4, the solvent was evapo-
rated in vacuo, and the residue was purified by flash chroma-
tography with hexane-acetone mixtures as eluents.
N-[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-2,3-d id eh y-
d r o-3-eth yl-4-oxo-6-p h en ylp ip er id in e (16a ). Procedure
1: yield 45%; red orange viscous oil; silica gel TLC Rf 0.18
(2:1 hexane-acetone); 1H NMR (CDCl3, 250 MHz) δ 7.37-7.26
(m, 5H), 6.96 (s, 1H), 6.89 (s, 1H), 6.47 (s, 1H), 4.57 (dd, J )
6.8, 9.8 Hz, 1H), 3.83 (s, 3H), 3.85 (s, 3H), 3.31-3.16 (m, 2H),
2.88-2.76 (m, 2H), 2.75-2.65 (m, 2H), 2.13 (q, J ) 7.4 Hz,
2H), 0.97 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz) δ
189.6, 151.7 (CH), 148.5, 148.4, 139.0, 129.3, 128.9 (2C, CH),
128.2 (CH), 127.3 (2C, CH), 115.6 (CH), 114.1, 113.4 (CH),
112.4, 62.1 (CH), 56.2 (CH3), 56.0 (CH3), 52.9 (CH2), 44.4 (CH2),
35.3 (CH2), 20.3 (CH2), 14.5 (CH3); IR (drift) 1640, 1609, 1508
cm-1; UV (λmax (ꢀ), MeOH) 192 (46 960), 202 (53 550), 229 (sch,
12 720), 291 (4250), 341 (17 480) nm; MS (115 °C) m/e 445 (21),
443 (21), 365 (4), 229 (2), 214 (100), 117 (9), 110 (40); HRMS
(115 °C) calcd for (M+) 443.1096, found 443.1084. Anal. Calcd
(3) Usin g EtAlCl2 a s Lew is Acid . To a solution of 5 mmol
of the respective imine 12 in CH2Cl2 (60 mL) was added at

4944 J . Org. Chem., Vol. 63, No. 15, 1998
Kirschbaum and Waldmann
for C23H26BrNO3 (444.37): C, 62.17; H, 5.89; N, 3.15. Found:
C, 62.14; H, 5.72; N, 2.63.
Gen er a l P r oced u r e for th e Heck -Typ e Cycliza tion .
(A) Un d er Hom ogen eou s Con d ition s. A mixture of 1 mmol
of the respective enaminone 15, 5 mol % of Pd2(dba)3‚CHCl3,
and 40 mol % of PPh3 was dried under reduced pressure by
carefully heating. After addition of DMF (25 mL) and 2.5
mmol of NEt-i-Pr2 under argon, the resulting solution was
stirred at room temperature until the color turned to yellow.
After the solution was heated to 100 °C for several hours (see
Table 3), the solvent was removed in vacuo and the crude
benzo[a]quinolizinone was purified by flash chromatography
using hexane-acetone mixtures as eluents.
N-[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-2,3-d id eh y-
d r o-3-eth yl-4-oxop ip er id in e (16d ). Procedure 1: yield 64%;
yellow viscous oil; silica gel TLC Rf 0.19 (3:2 hexane-acetone);
1H NMR (CDCl3 , 400 MHz) δ 7.03 (s, 1H), 6.72 (s, 1H), 6.68
(s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.46-3.39 (m, 4H), 2.94 (t, J
) 7.1 Hz, 2H), 2.45 (t, J ) 7.8 Hz, 2H), 2.08 (q, J ) 7.5 Hz,
2H), 0.93 (t J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 100.6 MHz) δ
190.4, 151.8 (CH), 148.6, 148.5, 129.1, 115.7 (CH), 114.2, 113.5
(CH), 111.6, 56.2 (CH3), 56.1 (CH3), 55.8 (CH2), 47.5 (CH), 36.1
(CH2), 35.4 (CH2), 20.3 (CH2), 14.5 (CH3); IR (drift) 1664, 1591,
1510 cm-1; UV (λmax (ꢀ), MeOH) 203 (44 550), 230 (sch, 11 000),
291 (4400), 337 (14 550) nm; MS (90 °C) m/e 369 (13), 367 (13),
288 (1), 229 (2), 138 (100), 110 (3); HRMS (100 °C) m/e calcd
for (M+) 367.0783, found 367.0769.
(B) Un d er Heter ogen eou s Con d ition s. A mixture of 1
mmol of the respective enaminone 15, 5 mol % of Pd2(dba)3‚
CHCl3, 20 mol % of PPh3, 1-10 mmol of K2CO3, and 1-1.2
mmol NEt4Cl was dried under reduced pressure by carefully
heating. After addition of DMF (25 mL), the resultion solution
was stirred at room temperature or at 40 °C until the color
turned to yellow and then was heated at 120 °C for several
hours (see Table 3). The solvent was removed in vacuo, and
the residue was purified by flash chromatography using
hexane-acetone mixtures as eluents.
N-[2-(2-Br om o-4,5-d im eth oxyp h en yl)eth yl]-2,3-d id eh y-
d r o-3-eth yl-6-h ep tyl-4-oxop ip er id in e (16e). Procedure 1:
yield 22%; amber viscous oil; silica gel TLC Rf silica gel TLC
1
Rf 0.15 (4:1 hexane-acetone); H NMR (CDCl3, 400 MHz) δ
7.03 (s, 1H), 6.70 (s, 1H), 6.67 (s, 1H), 3.86 (s, 3H), 3.82 (s,
3H), 3.45-3.35 (m, 3H), 3.02-2.87 (m, 2H), 2.65 (dd, J ) 6.7,
16.3 Hz, 1H), 2.30 (dd, J ) 3.9, 16.3 Hz, 1H), 2.07 (q, J ) 7.4
Hz, 2H), 1.67-1.56 (m, 2H), 1.26 (br s, 10H), 0.93 (t, J ) 7.4
Hz, 3H), 0.87 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3, 100.5 MHz)
δ 189.3, 150.1 (CH), 148.5, 148.4, 129.1, 115.7 (CH), 114.1,
113.7 (CH), 110.0, 56.8 (CH), 56.1 (CH3), 56.0 (CH3), 53.6 (CH2),
39.8 (CH2), 36.7 (CH2), 31.7 (CH2), 29.5 (CH2), 29.1 (CH2), 29.0
(CH2), 25.5 (CH2), 22.5 (CH2), 20.1 (CH2), 14.6 (UH3), 14.0
(CH3); IR (drift) 1636, 1601, 1510 cm-1; UV (λmax (ꢀ), MeOH)
203 (39 700), 229 (9900), 288 (3600), 343 (11 850) nm; MS (110
°C) m/e 467 (16), 465 (16), 387 (4), 368, 366 (4), 244, 242 (14),
236 (100), 231, 229 (9), 164 (6), 138 (39), 126 (16); HRMS (115
°C) m/e calcd for C24H36BrNO3 (M+, 466.46) 465.1879, found
465.1866.
According to the procedures described above, the following
4-substituted benzo[a]quinolizinones were prepared.
9,10-Dim eth oxy-4-(4-m eth oxyp h en yl)-2-oxo-3,4,6,7-tet-
r a h yd r oben zo[a ]qu in olizin e (26b). Procedure A: 6 h; yield
51%. Procedure B: 3 h; yield 76%; yellowish amorphous solid;
mp 167-170 °C; silica gel TLC Rf 0.17 (1:2 hexane-acetone);
1H NMR (CDCl3, 400 MHz) δ 7.26 (d, J ) 8.7 Hz, 2H), 7.22 (s,
1H), 6.87 (d, J ) 8.7 Hz, 2H), 6.67 (s, 1H), 5.72 (s, 1H), 4.69 (t,
J ) 6.9 Hz, 1H), 3.92, 3.90 and 3.79 (3s, 9H), 3.35-3.22 (m,
2H), 3.02 (dd, J ) 7.0, 16.4 Hz, 1H), 2.85 (t, J ) 6.8 Hz, 2H),
2.71 (dd, J ) 6.8, 16.4 Hz, 1H); 13C NMR (CDCl3, 100.5 MHz)
δ 190.2, 159.3, 157.0, 151.6, 147.9, 131.7, 129.5, 128.0 (2C, CH),
121.1, 114.3 (2C, CH), 110.2 (CH), 108.7 (CH), 94.8 (CH), 64.2
(CH), 56.0 and 55.3 (3C, CH3), 46.3 (CH2), 43.4 (CH2), 28.6
(CH2); MS (150 °C) m/e 366 (21), 365 (100), 350 (8), 338 (8),
337 (29), 336 (21), 322 (24), 277 (10), 263 (10), 262 (64), 258
(7), 230 (9), 207 (9), 200 (5), 191 (14), 183 (29), 178 (23), 176
(9), 175 (9), 135 (20), 134 (13); HRMS (150 °C) m/e calcd for
(M+) 365.1627, found 365.1613. Anal. Calcd for C22H23NO4‚
1/3H2O (365.43): C, 71.14; H, 6.42; N, 3.76. Found: C, 71.22;
H, 6.41; N, 3.32.
9,10-Dim eth oxy-4-(4-m eth oxyp h en yl)-2-oxo-1,6,7,11b-
tetr a h yd r oben zo[a ]qu in olizin e (27b). Procedure B: yield
9%; brown oil; silica gel TLC Rf 0.33 (1:2 hexane-acetone);
1H NMR (CDCl3, 250 MHz) δ 7.34 (d, J ) 8.7 Hz, 2H), 6.96 (d,
J ) 8.7 Hz, 2H), 6.68 (s, 1H), 6.65 (s, 1H), 5.23 (s, 1H), 4.96
(dd, J ) 12.7, 7.0 Hz, 1H), 3.88, 3.87 and 3.86 (3s, 9H), 3.73
(td, J ) 4.0, 12.4 Hz, 1H), 3.26 (td, J ) 12.3, 3.1 Hz, 1H), 2.90-
2.84 (m, 1H), 2.74-2.63 (m, 3H); 13C NMR (CDCl3, 100.5 MHz)
δ ) 192.6, 165.3, 160.9, 148.2, 147.9, 129.6 (2C, CH), 128.1,
127.3, 126.2, 114.0 (2C, CH), 111.1 (CH), 108.7 (CH), 102.7
(CH), 57.9 (CH), 56.0 (CH3), 55.9 (CH3), 55.4 (CH3), 46.2 (CH2),
44.9 (CH2), 30.2 (CH2); MS (150 °C) m/e 366 (22), 365 (100),
350 (8), 338 (7), 337 (30), 336 (21), 322 (26), 258 (7), 230 (9),
N-[(1S)-(Ca r b oxym et h yl)-2-(2-b r om o-4,5-d im et h oxy-
p h en yl)eth yl]-2,3-d id eh yd r o-6-(4-n itr op h en yl)-4-oxop ip -
er id in e (19). Procedure 2: yield 28%; brownish amorphous
solid; mp 61-63 °C; silica gel TLC Rf 0.31 (2:1 hexane-
acetone); [R]25 ) -28.8 (c 1, CH2Cl2); dr 89:11; major isomer;
D
1H NMR (CDCl3, 400 MHz) δ 8.04 (d, J ) 8.8 Hz, 2H), 7.42 (d,
J ) 8.1 Hz, 1H), 7.07 (d, J ) 8.8 Hz, 2H), 6.93 (s, 1H), 6.58 (s,
1H), 5.29 (d, J ) 8.1 Hz, 1H), 4.78 (dd, J ) 6.0, 10.9 Hz, 1H),
3.93 (dd, J ) 5.5, 10.1 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 3.71
(s, 3H), 3.30 (dd, J ) 5.5, 14.3 Hz, 1H), 3.07 (dd, J ) 10.1,
14.3 Hz, 1H), 2.71 (dd, J ) 5.9, 16.4 Hz, 1H), 2.57 (dd, J )
10.9, 16.4 Hz, 1H); 13C NMR (CDCl3, 100.5 MHz) δ 189.9,
170.5, 150.5 (CH), 149.2, 148.4, 147.8, 145.4, 128.3 (2C, CH),
126.7, 124.2 (2C, CH), 115.5 (CH), 114.8, 114.4 (CH), 101.9
(CH), 63.0 (CH), 61.8 (CH), 56.3 (CH3), 56.2 (CH3), 52.8 (CH3),
43.8 (CH2), 36.4 (CH2); MS (150 °C) m/e 520 (9), 518 (9), 461,
459 (3), 289 (6), 238 (11), 231 (98), 229 (100), 221 (7), 151 (10),
140 (15), 88 (4); HRMS (150 °C) m/e calcd for (M+) 518.0688,
found 518.0668.
As a side reaction product the Mannich adduct 20 was
isolated (see the Supporting Information).
200 (5), 175 (9), 134 (11); HRMS (150 °C) m/e calcd for C22H23
-
NO4 (365.43) 365.1627, found 365.1614.
N-[(1S)-(Ca r b oxym et h yl)-2-(2-b r om o-4,5-d im et h oxy-
ph en yl)eth yl]-2,3-dideh ydr o-3-eth yl-4-oxopiper idin e (22).
Procedure 1: yield 48%; yellow viscous oil; silica gel TLC Rf
9,10-Dim eth oxy-2-oxo-3,4,6,7-tetr a h yd r oben zo[a ]qu in -
olizin e (26d ). Procedure A: 15 h; yield 13%. Procedure B:
6 h; 17%; brownish amorphous solid; silica gel TLC Rf 0.10
(1:4 hexane-acetone); not fully separable from PPh3O; 1H
NMR (CDCl3, 250 MHz) δ 7.16 (s, 1H), 6.67 (s, 1H), 5.69 (s,
1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.63 (t, J ) 8.0 Hz, 2H), 3.39 (t,
J ) 7.1 Hz, 2H), 2.95 (t, J ) 7.1 Hz, 2H), 2.59 (t, J ) 8.0 Hz,
2H); 13C NMR (CDCl3, 125 MHz) δ 192.1, 157.8, 151.6, 148.1,
128.8, 120.8, 110.3 (CH), 108.3 (CH), 95.0 (CH), 56.0 (2C, CH3),
51.5 (CH2), 48.9 (CH2), 35.6 (CH2), 28.5 (CH2); MS (125 °C)
m/e 278 (21), 277 (36), 259 (100), 258 (54), 231 (23), 230 (53),
228 (11), 216 (12), 201 (6), 189 (10), 177 (8), 129 (5); HRMS
(125 °C) m/e calcd for C15H17NO3 (259.31) 259.1208, found
259.1196.
0.12 (2:1 hexane-acetone); [R]25 ) -104.9 (c 0.92, CH2Cl2);
D
1H NMR (CDCl3, 400 MHz) δ 7.01 (s, 1H), 6.84 (s, 1H), 6.66
(s, 1H), 4.18 (dd, J ) 6.5, 8.9 Hz, 1H), 3.85 (s, 3H), 3.79 (s,
3H), 3.75 (s, 3H), 3.51-3.44 (m, 1H), 3.36-3.29 (m 1H), 3.33
(dd, J ) 6.5, 14.1 Hz, 1H), 3.07 (dd, J ) 8.9, 14.1 Hz, 1H),
2.41-2.37 (m, 2H), 2.09 (q, J ) 7.5 Hz, 2H), 0.94 (t, J ) 7.5
Hz, 3H); 13C NMR (CDCl3, 100.5 MHz) δ 191.2, 170.5, 149.9
(CH), 148.9, 148.5, 127.4, 115.7 (CH), 114.4, 114.1 (CH), 113.7,
66.1 (CH), 56.2 (CH3), 56.1 (CH3), 52.6 (CH3), 46.7 (CH2), 36.5
(CH2), 36.3 (CH2), 20.5 (CH2), 14.5 (CH3); MS (100 °C) m/e 427
(13), 425 (13), 368, 366 (6), 246 (23), 245 (10), 244 (22), 243
(8), 231, 229 (17), 196 (100), 86 (44), 84 (71), 51 (25), 49 (79);
HRMS (100 °C) m/e calcd for (M+) 425.0838, found 425.0826.
Anal. Calcd for C19H24BrNO5‚H2O (426.31): C, 51.36; H, 5.89;
N, 3.15. Found: C, 51.55; H, 5.65; N, 2.75.
9,10-Dim et h oxy-2-oxo-1,6,7,11b -t et r a h yd r ob en zo[a ]-
qu in olizin e (27d ). Procedure B: 11 h; yield 35%; yellowish
solid; mp 169-170 °C; silica gel TLC Rf 0.31 (1:4 hexane-
acetone); 1H NMR (CDCl3, 250 MHz) δ 7.19 (d, J ) 7.2 Hz,

Tricyclic Benzo[a]quinolizine Ring System
J . Org. Chem., Vol. 63, No. 15, 1998 4945
1H), 6.67 (s, 1H), 6.61 (s, 1H), 5.06 (d, J ) 7.2 Hz, 1H), 4.68
(dd, J ) 4.3, 14.5 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.63 (m,
1H), 3.44 (td, J ) 12.5, 3.5 Hz, 1H), 3.10 (ddd, J ) 5.0, 12.5,
16.5 Hz, 1H), 2.82 (m, 1H), 2.75 (dd, J ) 4.3, 14 Hz, 1H), 2.51
(dd, J ) 11.5, 14 Hz, 1H); 13C NMR (CDCl3, 62.9 MHz) δ 192.9,
151.2 (CH), 148.3, 148.0, 126.7, 125.4, 110.5 (CH), 108.1 (CH),
98.4 (CH), 56.4 (CH), 56.1 (CH3), 56.0 (CH3), 49.8 (CH2), 44.9
(CH2), 29.8 (CH2); MS (120 °C) m/e 260 (15), 259 (100), 258
(5), 244 (6), 231 (20), 230 (61), 216 (15), 200 (7), 175 (12), 115
(6), 43 (3); HRMS (120 °C) m/e calcd for C15H17NO3 (259.31)
259.1208, found 259.1218.
(dd, J ) 4.2, 15.6 Hz, 1H), 2.06 (d, J ) 7.1 Hz, 3H); 13C NMR
(CDCl3, 100.6 MHz ) δ 201.3, 148.0, 147.2, 142.1, 137.0, 136.6
(CH), 128.6 (2C, CH), 127.6 (CH), 127.4 (2C, CH), 126.8, 125.5,
111.6 (CH), 111.2 (CH), 63.5 (CH), 60.1 (CH), 56.0 (CH3), 55.9
(CH3), 48.7 (CH2), 46.2 (CH2), 25.5 (CH2), 15.1 (CH3); MS (105
°C) m/e 363 (100), 362 (49), 348 (13), 320 (4), 294 (50), 231
(10), 218 (47), 192 (36), 191 (22), 190 (37), 176 (12), 131 (8),
104 (9), 103 (11), 91 (10), 77 (7); HRMS (110 °C) m/e calcd for
C
23H25NO3 (363.46) 363.1834, found 363.1825.
9,10-Dim eth oxy-1(E)-eth ylen yl-2-oxo-1,3,4,6,7,11b-h exa-
h yd r oben zo[a ]qu in olizin e (36d ): 6 h; yield 24%; brownish
amorphous solid; mp 146-150 °C; silica gel TLC Rf 0.12 (1:1
9,10-Dim eth oxy-2-oxo-4-p r op yl-3,4,6,7-tetr a h yd r oben -
zo[a ]qu in olizin e (26e). Procedure B: 5 h; yield 26%; brown
viscous oil; silica gel TLC Rf 0.17 (1:4 hexane-acetone); 1H
NMR (CDCl3, 250 MHz) δ 7.16 (s, 1H), 6.67 (s, 1H), 5.56 (s,
1H), 3.92 (s, 3H), 3.88 (s, 3H), 3.77-3.55 (m, 1H, 4-H), 3.47 (t,
J ) 6.4 Hz, 2H), 2.94-2.86 (m, 3H), 2.41 (br d, J ) 16.6 Hz,
1H), 1.25-1.94 (m, 4H), 0.94 (t, J ) 6.5 Hz, 3H); 13C NMR
(CDCl3, 125.7 MHz) δ 191.0, 155.5, 151.9, 148.5, 129.4, 121.9,
110.6 (CH), 109.2 (CH), 93.7 (CH), 61.5 (CH), 56.4 (2C, CH3),
47.6 (CH2), 39.4 (CH2), 31.6 (CH2), 29.3 (CH2), 19.6 (CH2), 14.4
(CH3); MS (120 °C) m/e 302 (17), 301 (100), 300 (30), 259 (98),
258 (58), 242 (11), 232 (15), 231 (74), 230 (38), 216 (17), 214
(11), 207 (17), 205 (12), 150 (8), 129 (11), 43 (8); HRMS (120
°C) m/e calcd for C18H23NO3 (301.39) 301.1677, found 301.1667.
9,10-Dim eth oxy-2-oxo-4-pr opyl-1,6,7,11b-tetr ah ydr oben -
zo[a ]qu in olizin e (27e). Procedure B: 8 h; yield 42%; brown
1
hexane-acetone); H NMR (CDCl3, 400 MHz) δ 6.99 (q, J )
7.4, 1H), 6.63 (s, 1H), 6.38 (s, 1H), 5.19 (s, 1H), 3.86 (s, 3H),
3.76 (s, 3H), 3.50 (ddd, J ) 6.1, 12.5, 13.7 Hz, 1H), 3.35 (dd, J
) 6.8, 13.8 Hz, 1H), 3.17-3.03 (m, 2H), 2.92-2.87 (m, 1H),
2.69-2.59 (m, 2H), 2.43 (ddd, J ) 2.1, 3.6, 17 Hz, 1H), 1.90
(d, J ) 7.3, 2H); 13C NMR (CDCl3, 100.6 MHz) δ 198.4, 148.0,
147.5, 136.8, 136.1 (CH), 125.8, 124.9, 112.2 (CH), 110.4 (CH),
58.5 (CH), 55.9 (2C, CH3), 51.2 (CH2), 43.2 (CH), 39.82 (CH2),
22.84 (CH2), 14.2 (CH3); IR (drift) 1691, 1606, 1513 cm-1; UV
(λmax (ꢀ), MeOH) 202 (26 700), 225 (12 600), 257 (sch, 6250),
278 (sch, 5100), 308 (3900), 350 (2200) nm; MS (115 °C) m/e
287 (42), 286 (25), 272 (100), 256, 228 (3), 207 (8), 178 (4), 150
(4), 123 (3), 84 (5); C17H21NO3 (287.36); HRMS (115 °C) m/e
calcd for C17H21NO3 (M+, 287.36) 287.1512, found 287.1533.
9,10-Dim et h oxy-1-et h ylen yl-4-h ep t yl-2-oxo-1,3,4,6,7,-
11b-h exa h yd r oben zo[a ]qu in olizin e (36e/37e): 48 h. (1E)-
Isom er 36e: yield 20%; dark yellow glassy solid; silica gel
TLC Rf 0.23 (3:1 hexane-acetone); 1H NMR (CDCl3, 250 MHz)
δ 6.99 (q, J ) 7.4 Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 5.26 (s,
1H), 3.86 (s, 3H) 3.75 (s, 3H), 3.59 (dd, J ) 6.3, 14.2 Hz, 1H),
3.35 (ddd, J ) 5.5, 12.6, 14.2 Hz, 1H), 3.09-2.99 (m, 2H), 2.57
(dd, J ) 5.3, 17.0 Hz, 1H), 2.47 (dd, J ) 4.3, 16.5 Hz, 1H),
2.29 (dd, J ) 9.2, 16.5 Hz, 1H), 1.88 (d, J ) 7.4 Hz, 3H), 1.40-
1.27 (br. m, 12 H), 0.88 (t, J ) 6.9 Hz, 3H); 13C NMR (CDCl3,
100.6 MHz) δ 198.9, 147.9, 147.5, 136.9, 135.3 (CH), 126.7,
126.1, 112.2 (CH), 109.9 (CH), 59.2 (CH), 55.9 (2C, CH3), 50.8
(CH), 47.1 (CH2), 44.3 (CH2), 34.5 (CH2), 31.8 (CH2), 29.9 (CH2),
29.2 (CH2), 24.7 (CH2), 22.8 (CH2), 22.6 (CH2), 14.1 (CH3), 14.0
(CH3); IR (film) 1693, 1622, 1518 cm-1; UV (λmax (ꢀ), MeOH)
202 (42 850), 225 (sch, 16 200), 286 (7400), 31 (sch, 4950) nm;
MS (80 °C) m/e 386 (7), 286 (50), 254 (15), 253 (13), 252 (12),
236 (47), 234 (30), 218 (21), 189 (41), 165 (18), 152 (16), 131
(100), 103 (47), 91 (25), 77 (35); HRMS (80 °C) m/e calcd for
1
glassy solid; silica gel TLC Rf 0.25 (1:2 hexane-acetone); H
NMR (CDCl3, 400 MHz) δ 6.65 (s, 1H), 6.62 (s, 1H), 5.11 (s,
1H), 4.69 (dd, J ) 16.0, 3.8 Hz, 1H), 3.98 (ddd, J ) 12.3, 4.0,
2.6 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.15 (td, J ) 12.1, 2.7
Hz, 1H), 3.00 (ddd, J ) 15.5, 11.7, 4.0 Hz, 1H), 2.76 (dd, J )
15.5, 2.4, 1H), 2.69 (dd, J ) 4.0, 16.3 Hz, 1H), 2.45 (dd, J )
16.0, 16.2 Hz, 1H), 2.37 (m, 2H), 1.62 (sext, J ) 7.5 Hz, 2H),
1.03 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 100.5 MHz) δ 192.2,
166.2, 148.2, 147.9, 127.3, 125.7, 111.0 (CH), 108.4 (CH), 100.7
(CH), 58.0 (CH), 55.9 (2C, CH3), 45.0 (CH2), 43.6 (CH2), 35.9
(CH2), 29.9 (CH2), 21.2 (CH2), 13.9 (CH3); MS (110 °C) m/e 302
(16), 301 (89), 300 (26), 286 (8), 273 (28), 272 (100), 258 (24),
245 (13), 244 (63), 207 (14), 190 (14), 150 (9), 124 (8), 82 (10);
HRMS (110 °C) m/e calcd for C18H23NO3 (301.39) 301.1677,
found 301.1671.
Gen er a l P r oced u r e for th e Heck -Typ e Cycliza tion of
3-Eth yl-Su bstitu ted En a m in on es u n d er Heter ogen eou s
Con d ition s. A mixture of 1 mmol of the respective enaminone
16, 5 mol % of Pd2(dba)3‚CHCl3, 20 mol % of the used
phosphine, 8-10 mmol of K2CO3, and 1.1-1.2 mmol NEt4Cl
was dried under reduced pressure by carefully heating. After
addition of toluene (40 mL), the resulting solution was stirred
at 40 °C until the color turned to yellow and then was refluxed
for several hours (see Table 5). The solvent was evaporated
in vacuo, and the residue was purified by flash chromatogra-
phy using hexane-acetone mixtures as eluents.
According to the procedure described above, the following
1-ethenyl-substituted benzo[a]quinolizinones were prepared.
9,10-Dim et h oxy-1-et h ylen yl-2-oxo-4-p h en yl-1,3,4,6,7,-
11b-h exa h yd r oben zo[a ]qu in olizin e (36a /37a ): brownish
amorphous solid; mp 79-81 °C; silica gel TLC Rf 0.35 (4:3
hexane-acetone). (1E)-Isom er 36a : 1H NMR (CDCl3, 400
MHz) δ 7.42-7.29 (m, 5H), 7.02 (q, J ) 7.3 Hz, 1H), 6.64 (s,
1H), 6.44 (s, 1H), 5.39 (br. s, 1H), 4.09 (dd, J ) 4.1, 10.7 Hz,
1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.18 (dd, J ) 5.6, 12.6 Hz, 1H),
3.10 (dd, J ) 6.4, 14.1 Hz, 1H), 2.86-2.77 (m, 1H), 2.61 (dd, J
) 10.7, 16.9 Hz, 1H), 2.53 (dd, J ) 4.1, 16.9 Hz, 1H), 2.36 (dd,
J ) 5.4, 17.2 Hz, 1H), 1.94 (d, J ) 7.3, 3H); 13C NMR (CDCl3,
100.6 MHz ) δ 198.3, 148.1, 147.6, 141.8, 136.9, 135.5 (CH),
128.8 (2C, CH), 127.8 (CH), 127.6 (2C, CH), 126.6, 124.9, 112.3
(CH), 110.4 (CH), 59.4 (CH), 56.6 (CH), 55.9 (2C, CH3), 48.8
(CH2), 46.9 (CH2), 22.6 (CH2), 14.2 (CH3); MS (110 °C) m/e 363
(100), 362 (51), 348 (14), 294 (41), 231 (8), 218 (39), 192 (22),
191 (12), 190 (20), 176 (5), 91 (5). (1Z)-Isom er 37a : 1H NMR
(CDCl3, 250 MHz ) δ 7.6-7.1 (m, 5H), 6.63 (s, 1H), 6.51 (s,
1H), 5.81 (q, J ) 7.1 Hz, 1H), 4.98 (s, 1H), 4.00 (dd, J ) 4.2,
10.3 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.02 (t, J ) 6.2 Hz,
2H), 2.86 (dd, J ) 10.4, 15.6 Hz, 1H), 2.80-2.66 (m, 2H), 2.60
C
24H35NO3 (385.55) 385.2617, found 385.2607. (1Z)-Isom er
37e: yield 20%; dark yellow glassy solid; silica gel TLC Rf 0.33
1
(3:1 hexane-acetone); H NMR (CDCl3, 400 MHz) δ 6.63 (s,
1H), 6.45 (s, 1H), 5.39 (q, J ) 7.2 Hz, 1H), 4.81 (s, 1H), 3.86
(s, 3H), 3.80 (s, 3H), 3.15-3.09 (m, 1H), 2.99-2.88 (m, 2H),
2.84 (ddd, J ) 3.1, 6.2, 11.2 Hz, 1H), 2.71 (td, J ) 3.5, 15.7
Hz, 1H), 2.69 (dd, J ) 5.5, 15.5 Hz, 1H), 2.47 (dd, J ) 6.3,
15.2 Hz, 1H), 1.90 (d, J ) 7.2 Hz, 3H), 1.71-1.61 (m, 1H),
1.55-1.44 (m, 1H), 1.36-1.26 (br m, 10H), 0.87 (t, J ) 6.9 Hz);
13C NMR (CDCl3, 100.6 MHz) δ 203.1, 148.1, 146.9, 138.9,
135.3 (CH), 127.3, 125.5, 111.7 (CH), 111.7 (CH), 60.2 (CH),
59.4 (CH), 56.0 (CH3), 55.9 (CH3), 46.2 (CH2), 44.5 (CH2), 35.2
(CH2), 31.9 (CH2), 29.7 (CH2), 29.3 (CH2), 28.4 (CH2), 26.2
(CH2), 22.7 (CH2), 15.0 (CH3), 14.2 (CH3); IR (Film) 1693, 1624,
1607 cm-1; UV (λmax (ꢀ), MeOH) 202 (43 550), 227 (17 000), 285
(7500), 328 (sch, 2750) nm; MS (85 °C) m/e 385 (11), 286 (100),
234 (12), 218 (37), 210 (15), 191 (13), 189 (23), 165 (36), 131
(21), 113 (13), 103 (13), 77 (15), 60 (15); HRMS (85 °C) m/e
calcd for C24H25NO3 (385.55) 385.2617, found 385.2605.
(6S,11b RS)-6-(Ca r b oxym et h yl)-9,10-d im et h oxy-1(E)-
et h ylid en -2-oxo-1,3,4,6,7,11b-h exa h yd r ob en zo[a ]q u in o-
lizin e (40): 3 h; yield 32%; dr 2:1; reddish glassy solid; major
1
stereoisomer at C-11b; H NMR (CDCl3, 500 MHz) δ 7.10 (q,
J ) 7.3 Hz, 1H), 6.74 (s, 1H), 6.42 (s, 1H), 5.12 (br s, 1H), 3.88
(s, 3H), 3.80 (s, 3H), 3.55 (t, J ) 7.1 Hz, 1H), 3.14-3.03 (m,
2H), 2.97-2.93 (m, 1H), 2.85-2.61 (m, 2H), 2.44-2.37 (m, 1H),
1.78 (d, 3H); 13C NMR (CDCl3, 125.8 MHz) δ 197.8, 173.4,
148.3, 147.7, 137.7 (CH), 134.9, 126.5, 125.5, 111.7 (CH), 109.9
(CH), 62.5 (CH), 56.1 (CH3), 56.0 (CH3), 54.5 (CH), 52.4 (CH3),
47.5 (CH2), 40.0 (CH2), 26.8 (CH2), 14.1 (CH3); minor stereo-

4946 J . Org. Chem., Vol. 63, No. 15, 1998
Kirschbaum and Waldmann
isomer at C-11b; 1H NMR (CDCl3, 500 MHz) δ 7.02 (q, 7.3 Hz,
1H), 6.68 (s, 1H), 6.39 (s, 1H), 5.30 (br s, 1H), 4.22 (dd, J )
5.7, 12.6 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.21 (dd, J ) 12.6,
14.5 Hz, 1H), 2.97-2.93 (m, 1H), 2.85-2.61 (m, 3H), 2.44-
2.37 (m, 1H), 1.90 (d, J ) 7.3 Hz, 3H); 13C NMR (CDCl3, 125.8
MHz) δ 197.8, 171.8, 148.3, 147.9, 136.7 (CH), 136.5, 125.0,
124.1, 112.2 (CH), 110.5 (CH), 61.8 (CH), 60.4 (CH), 56.0 (CH3),
55.9 (CH3), 52.5 (CH3), 39.5 (CH2), 39.2 (CH2), 24.8 (CH2), 14.3
(CH3); MS (120 °C) m/e 345 (11), 344 (5), 330 (12), 305 (22),
286 (100), 284 (16), 259 (7), 258 (7), 257 (5), 190 (6), 165 (5),
88 (7), 86 (94), 84 (76), 49 (8), 74 (25), 45 (6), 43 (55); HRMS
(120 °C) m/e calcd for C19H22NO5 (345.39) 345.1576, found
345.1594.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support by the Fonds der Chemischen Industrie
and the Land Baden-Wuerttemberg.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and NMR spectra of selected new compounds (60 pages).
This material is contained in libraries on microfiche, im-
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