The synthesis of annulated 4-quinolizinones by two sequential anionic cyclizations

Article abstract of DOI:10.1016/S0040-4020(01)00005-9

Upon base treatment of N-hetaryl substituted heptynone esters of type 9 an efficient ring closure takes place affording cyclohexenone derivatives 11 which undergo a further anionic cyclization to provide tri- and tetracyclic quinolizinone derivatives 12 as final products.

Full text of DOI:10.1016/S0040-4020(01)00005-9

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1771±1777
The synthesis of annulated 4-quinolizinones by two sequential
anionic cyclizations
Thomas Nicola, Diemut Schwarzrock, Manfred Keller and Wolfgang Eberbachp
Institute of Organic Chemistry and Biochemistry, University of Freiburg, Albertstrasse 21, D-79104 Freiburg, Germany
Received 24 November 2000; accepted 27 December 2000
AbstractÐUpon base treatment of N-hetaryl substituted heptynone esters of type 9 an ef®cient ring closure takes place affording cyclo-
hexenone derivatives 11 which undergo a further anionic cyclization to provide tri- and tetracyclic quinolizinone derivatives 12 as ®nal
products. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Recently, we disclosed results on the O-enolate cyclization
of alkynones resulting in the formation of furan and pyran
derivatives, respectively.1 However, if starting compounds
like 2 were used, bearing acidic protons on each side of the
ketone function, both O- and C-enolate cyclization reactions
took place affording the corresponding pyran and cyclo-
hexenone derivatives 1 and 3 (Scheme 1).
In continuation of this work, we investigated the reaction of
the respective pyridyl, quinolinyl and isoquinolinyl pre-
cursors 9a±e which were obtained from the known methyl
6-formyl-hex-2-ynoate (6)2 by
a two-step sequence
(Scheme 2).
Scheme 2. Reagents and conditions: (i) tert-BuLi, Et2O, 2708C; (ii)
MgBr2´OEt2, Et2O, 2788C; (iii) oxalyl chloride, DMSO, NEt3, CH2Cl2,
2708C.
2. Results and discussion
For introduction of the hetaryl groups into 6 Grignard
reagents were used, prepared by initial lithiation of R-CH3
7 with tert-butyllithium followed by transmetallation with
dry magnesium bromide.3 Reaction of RCH2±MgBr with
the aldehyde 6 at 2788C gave the secondary alcohols
8a±e which were transformed by Swern oxidation into the
required heteroaryl substituted carbonyl systems 9a±e.
Scheme 1.
As shown by 1H NMR analysis, the new compounds exist as
keto±enol tautomers in variable amounts, with the enol
double bond being located next to the heteroaryl moiety
(in chloroform solution the ratio of 9/90 at rt is: 7:1 (a),
Keywords: nitrogen heterocycles; annulation; quinolizinones; heterocycli-
zation.
Corresponding author. Fax: 149-0-761-203-6085;
e-mail: eberbach@organik.chemie.uni-freiburg.de
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00005-9

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T. Nicola et al. / Tetrahedron 57 (2001) 1771±1777
Control experiments revealed that the annulated quinolizi-
none 12a is not a primary product of 9a but can be indepen-
dently obtained from 11a under basic conditions. For its
formation two possible mechanisms might be discussed
(see Scheme 4): According to route A ring closure occurs
with elimination of the methoxy group followed by depro-
tonation (11a!13a!12a). Route B involves initial depro-
tonation to 14a and then cyclization with subsequent or
concomitant methoxy elimination. As the transformation
does not take place under neutral conditions or in the
presence of acid we strongly prefer the latter pathway
because step 11a!13a would be expected to be catalyzed
by acids.
A cyclization reaction related to the latter process has been
reported by Mori et al.6 during nitrogen ®xation experi-
ments. On re¯uxing of 15 in THF with Ti(OiPr)4, N2, Li,
TMSCl, CsF the pyrrole 16 was formed as main product,
together with 3% of the bis-annulated indolizinone 17 as a
supposedly secondary product (Scheme 5).
Scheme 3.
4:1 (b and c), and 1:12 (d); for the e-derivative only the enol
isomer 90 was detectable).
On treatment of ca. 0.03 M solutions of ketone 9a in THF
with potassium tert-butoxide at 08C for approximately
30 min (tlc control) a reaction mixture was obtained
which after aqueous work up, diethyl ether extraction and
chromatographic puri®cation afforded two products in 37
and 47% yield, respectively.4 As shown by the MS, only
the minor component was an isomer of 9a, whereas the
latter one has lost 32 mass units (i.e. CH3OH).
1
According to the spectroscopic data, especially the H and
13C NMR spectra, the more polar compound (37% yield)
turned out to be the cyclohexenone derivative 11a, while the
major productÐa yellow, ¯uorescent solidÐwas unam-
biguously identi®ed as the tricyclic benzoquinolizinone
12a (see Scheme 3). Besides the typical NMR signals of
the quinolizinone moiety the missing signal of methoxy
protons clearly supports the loss of methanol.
Scheme 5. Reagents and conditions: (i) Ti(O-iPr)4, N2, Li, TMSCl, CsF,
THF, rfx.
Sequential transformations are likewise achieved with
9b±9e as starting materials.7 Depending on the particular
structure of the ®rst cyclization product 11, the subsequent
annulation to 12 takes place with different ef®ciencies.
Whereas in the b-series the pyridyl methyl group of 11b
obviously impedes the annulation to 12b, the cyclo-
hexenone 11e is too reactive for isolation and reacts spon-
taneously to 12e. On the other hand, the quinolinyl and
isoquinolinyl derivatives 11c/11d can be advantageously
transformed into the tetracyclic compounds 12c,d in a
separate step (see Scheme 6).8
A possible pathway for the rearrangement of 9a into 11a is
sketched in Scheme 3. Deprotonation of 9a leads to the
enolate 10a which undergoes a 6-exo-dig cyclization afford-
ing the cyclohexenone 11a after reprotonation and H-shift.5
The structural identi®cation of the cyclized products 11b±e
and 12b±e is again based on the analytical and spectro-
scopic results. In the case of 12c the structure is additionally
con®rmed by an X-ray analysis. According to these data the
benzoquinolizinone unit of the molecule is almost perfectly
¯at with no unusal deviations of the bond lengths and angles
(Fig. 1).
In conclusion, we have described an ef®cient anionic ring
closure of the N-hetaryl substituted heptynone esters 9 into
cyclohexene derivatives 11 which undergo a further
cyclization affording tri- and tetracyclic quinolizinone
derivatives of type 12 as ®nal products9 by two sequential
base-induced cyclization reactions. Investigations toward
Scheme 4.

T. Nicola et al. / Tetrahedron 57 (2001) 1771±1777
1773
TMS as internal standard. MS: Finnigan MAT 44 S
(70 eV) with Datasystem MAT SS 200. Elemental analyses:
Perkin±Elmer Elemental Analyzer 240.
3.1.1. X-Ray single crystal analysis of 12c.10 Crystallo-
graphic data for 12c: Mˆ263.28 g mol2 1, monoclinic
system, space group P21/c,aˆ7.4914(2), bˆ8.1850(3),
Ê
Ê 3
cˆ19.8999(8) A, bˆ97.731(2)8, Vˆ1209.11(7) A , Zˆ4,
Dcˆ1.446 g cm23, m(MoKa)ˆ0.095 mm21, crystal dimen-
sions of 0.3£0.2£0.2 mm3. Data were collected at 293 K
with an Enraf-Nonius KappaCCD area-detector diffract-
ometer using w and v scans to ®ll the Ewald sphere. 9583
measured re¯ections, 3315 independent re¯ections, 2297
re¯ections with I.2s(I). The structure was solved with
direct method using sir-92 and the model was re®ned by a
full-matrix least-square technique using shelxl-97 to ®nal
2
Rˆ0.0526 and Rw ˆ0.1466. Hydrogen atoms were located
from a Fourier map and were re®ned isotropically. Data
collection, cell re®nement and data reduction: DENZO
(Otwinowski and Minor, 1997) and COLLECT (Hooft,
1998). Program used to solve structure: sir-92 (Giacovazzo,
1992), program used to re®ne structure: shelxl-97
(Sheldric, 1997).
3.2. General procedure for the 7-hydroxy-2-octynoates 8
Typically, runs were performed with ca. 10 mmol of 6.2 To
the stirred solution of 7 (12 mmol) in 30 ml of diethyl ether
at 2658C was added under nitrogen 1.4N solution of tert-
butyllithium in pentane (15 mmol). Stirring was continued
for 1 h at 2658C and for 45 min at 2208C, then the solution
was treated with freshly prepared MgBr2´Et2O (15 mmol)
and stirred for 45 min at 2208C. The Grignard solution
was cooled to 2788C and added to the solution of 6
(10 mmol) in 70 ml of diethyl ether, precooled to 2788C.
The suspension was stirred for 1 h at 2788C, warmed up to
08C and hydrolyzed with 30 ml of pH 7 buffer. After extrac-
tion with diethyl ether (4£100 ml) the organic phase was
washed with 30 ml of saturated brine, dried (MgSO4) and
concentrated in vacuo. Puri®cation was accomplished by
¯ash chromatography (SiO2, cyclohexane/ethyl acetate).
Scheme 6. Reagents and conditions: (i) KO-tert-Bu, THF, 08C, 30 min; (ii)
NaHCO3, MeOH, rfx, 1.5 h; (iii) KO-tert-Bu, MeOH, rfx, 3 h; (iv) KO-tert-
Bu, THF, 5 min, 2188C.
3.2.1. Methyl 7-hydroxy-8-pyridin-2-yloct-2-ynoate (8a).
45%, yellow oil (35% of 6 were recovered). IR (CCl4):
1
3480, 2950, 2240, 1715, 1595, 1435, 1250, 1075 cm21. H
NMR (250 MHz): dˆ8.49 (m, 1H, 60-H), 7.66 (dt, Jˆ7.6,
1.8 Hz, 1H, 40-H), 7.29±7.15 (m, 2H, 30-H, 50-H), 4.05 (m,
1H, 7-H), 3.76 (s, 3H, OCH3), 2.91 (m, 2H, 8-H), 2.41 (m,
2H, 4-H), 1.90±1.57 (m, 4H, 5-H, 6-H). 13C NMR
(100 MHz): dˆ176.0 (C-20), 159.8 (C-1), 148.3 (C-60),
137.2 (C-40), 124.0 (C-30/50), 121.8 (C-30/50), 89.7 (C-2),
73.2 (C-3), 70.5 (C-7), 52.6 (OCH3), 43.4 (C-8), 36.1 (C-6),
23.8 (C-5), 18.7 (C-4). MS (CI, isobutane): m/z (%)ˆ247 (1)
[M1], 304 (3), 290 (6), 288 (9), 286 (4), 250 (4), 249 (16),
248 (100), 230 (3), 216 (4), 122 (3), 93 (4).
Figure 1. SCHAKAL plot of the crystal structure of compound 12c
(the numbering of the atoms does not correspond with the correct
nomenclature).
the application of this methodology for related systems are
in progress.
3. Experimental
3.1. General
3.2.2. Methyl 7-hydroxy-8-(6-methylpyridin-2-yl)oct-2-
ynoate (8b). 67%, orange oil. 1H NMR (250 MHz):
dˆ7.52 (t, Jˆ7.6 Hz, 1H, 40-H), 7.03 (d, Jˆ7.6 Hz, 1H,
30-H), 6.94 (d, Jˆ7.6 Hz, 1H, 50-H), 5.85 (br, OH), 4.08±
3.97 (m, 1H, 7-H), 3.76 (s, 3H, OCH3), 2.92±2.75 (m, 2H,
8-H), 2.52 (s, 3H, CH3), 2.41 (m, 2H, 4-H), 1.94±1.59 (m,
4H, 6-H, 5-H). 13C NMR (100 MHz): dˆ159.4 (C±Ar),
IR: Perkin±Elmer 257 Infracord. 1H NMR: Bruker AC 250
(250 MHz); 1H/13C NMR AM 400 (400/100 MHz) and
Bruker DRX 500 (500/125 MHz); CDCl3 as solvent and

1774
T. Nicola et al. / Tetrahedron 57 (2001) 1771±1777
157.4 (C±Ar), 154.3 (C-1), 137.1 (C±Ar), 121.1 (C±Ar),
120.5 (C±Ar), 89.7 (C-2), 73.1 (C-3), 70.3 (C-7), 52.5
(OCH3), 42.9 (C-8), 36.1 (C-6), 24.3 (CH3), 23.8 (C-5),
18.6 (C-4).
3.3. General procedure for the 7-oxo-2-octynoates 9
Typically, runs were performed with ca. 5 mmol of 8. The
stirred solution of oxalyl chloride (8 mmol) in 30 ml of
dichloromethane was treated at 2608C under nitrogen
with DMSO (17 mmol). After the end of the gas evolution
a solution of 8 (5.0 mmol) in 8 ml of dichloromethane was
added. The mixture was stirred for additional 45 min at
2608C and then treated with triethylamine (25 mmol).
The reaction mixture was warmed up to rt within 30 min,
treated with 40 ml of water and extracted with dichloro-
methane (3£100 ml). The combined organic phase was
washed with 40 ml of water, dried (MgSO4) and concen-
trated in vacuo. Puri®cation was accomplished by ¯ash
chromatography (SiO2, cyclohexane/ethyl acetate).
3.2.3. Methyl 7-hydroxy-8-quinolin-2-yloct-2-ynoate (8c).
72%, orange solid; mp 768C (diethyl ether/pentane). IR
(CCl4): 3395, 3055, 2950, 2240, 1720, 1600, 1505, 1435,
1255, 1080 cm21. 1H NMR (250 MHz): dˆ8.16 (dd, Jˆ8.4,
2.2 Hz, 1H, Ar±H), 8.06 (dd, Jˆ8.5, 2.4 Hz, 1H, Ar±H),
7.84 (m, 1H, Ar±H), 7.74 (ddd, Jˆ8.5, 7.8, 1.4 Hz, 1H, Ar±
H), 7.56 (ddd, Jˆ8.1, 7.8, 2.4 Hz, 1H, Ar±H), 7.30 (m, 1H,
Ar±H), 6.0±5.5 (br, 1H, OH), 4.32±4.18 (m, 1H, 7-H), 3.76
(s, 3H, OCH3), 3.18±3.08 (m, 2H, 8-H), 2.46 (m, 2H, 4-H),
1.96±1.66 (m, 4H, 5-H, 6-H). 13C NMR (100 MHz):
dˆ160.8 (C±Ar), 154.3 (C-1), 137.2 (C±Ar), 130.0
(C±Ar), 128.5 (C±Ar), 127.7 (C±Ar), 126.9 (C±Ar),
126.4 (C±Ar), 122.2 (C±Ar), 89.8 (C-2), 73.2 (C-3), 70.0
(C-7), 52.6 (OCH3), 43.7 (C-8), 36.1 (C-6), 23.9 (C-5), 18.7
(C-4). MS (Cl, isobutane): m/z (%)ˆ340 (7), 338 (7), 299
(20), 298 (100) [M111], 296 (3), 280 (4), 266 (5), 172 (6),
143 (23), 115 (3). HRMS (C18H19NO3): calcd 297.1365;
found 297.1358. C18H19N03 (297.4): calcd C 72.71, H
6.52, N 4.57; found C 72.74, H 6.44, N 4.71.
3.3.1. Methyl 7-oxo-8-pyridin-2-yloct-2-ynoate (9a). 77%
of a 7:1 mixture of 9a/90a (CDCl3/rt), orange oil. The analy-
tical data were obtained from the mixture of the tautomers.
IR (CCl4): 2950, 2240, 1720, 1645, 1595, 1470, 1435, 1250,
1
1075 cm21. H NMR (250 MHz) of 9a: dˆ8.56 (m, 1H,
60-H), 7.67 (dt, Jˆ7.6, 1.8 Hz, 1H, 40-H), 7.21 (m, 2H,
30-H, 50-H), 3.93 (s, 2H, 8-H), 3.76 (s, 3H, OCH3), 2.70
(t, Jˆ7.0 Hz, 2H, 6-H), 2.37 (t, Jˆ7.0 Hz, 2H, 4-H), 1.85
1
(quin, Jˆ7.0 Hz, 2H, 5-H). H NMR (250 MHz) of 90a:
dˆ8.20 (m, 1H, 60-H), 7.56 (dd, Jˆ7.6 Hz, Jˆ1.8 Hz, 1H,
40-H), 6.91 (m, 2H, 30-H, 50-H), 5.34 (s, 1H, 8-H), 3.76 (s,
3H, OCH3), 2.42 (t, Jˆ7.0 Hz, 2H, 6-H), 2.37 (t, Jˆ6.7 Hz,
2H, 4-H), 1.93 (m, 2H, 5-H). MS (70 eV, EI): m/z (%)ˆ245
(14) [M1], 244 (54), 217 (29), 214 (21), 189 (27), 186 (38),
148 (26), 93 (100), 92 (38). HRMS (C14H15NO3): calcd
245.1052; found 245.1052.
3.2.4. Methyl 7-hydroxy-8-isoquinolin-1-yloct-2-ynoate
(8d). 38%, yellow oil. IR (CCl4): 3420, 2950, 2240, 1720,
1565, 1435, 1255, 1080 cm21
.
1H NMR (250 MHz):
dˆ8.38 (d, Jˆ5.8 Hz, 1H, Ar±H), 8.14 (m, Jˆ8.4 Hz, 1H,
Ar±H), 7.84 (dd, Jˆ7.6, 1.5 Hz, 1H, Ar±H), 7.71 (ddd,
Jˆ7.9, 6.7, 1.2 Hz, 1H, Ar±H), 7.71±7.54 (m, 3H, Ar±H),
7.62 (ddd, Jˆ8.2, 6.7, 1.5 Hz, 1H, Ar±H), 7.56 (d,
Jˆ5.8 Hz, 1H, Ar±H), 4.39±4.29 (m, 1H, 7-H), 3.76 (s,
3H, OCH3), 3.50 (dd, Jˆ16.5, 2.4 Hz, 1H, 8-H), 3.22 (dd,
Jˆ16.5, 9.8 Hz, 1H, 8-H), 2.49±2.43 (m, 2H, 4-H),
1.98±1.74 (m, 4H, 5-H, 6-H). 13C NMR (100 MHz):
dˆ160.2 (C±Ar), 154.3 (C-1), 140.9 (C±Ar), 136.2
(C±Ar), 130.4 (C±Ar), 127.5 (C±Ar), 127.5 (C±Ar),
127.4 (C±Ar), 124.8 (C±Ar), 119.7 (C±Ar), 89.8(C-2),
73.2 (C-3), 69.2 (C-7), 52.6 (OCH3), 39.8 (C-8), 36.1
(C-6), 23.9 (C-5), 18.7 (C-4). MS (70 eV, El): m/z
(%)ˆ297 (4) [M1], 282 (8), 266 (20), 264 (17), 238 (10).
200 (13), 182 (13), 173 (11), 172 (70), 144 (52), 143 (100),
130 (20), 128 (13), 116 (15), 115 (45). HRMS (C18H19NO3):
calcd 297.1365; found 297.1361.
3.3.2. Methyl 7-oxo-8-(6-methylpyridin-2-yl)oct-2-yno-
ate (9b). 65% of a 4:1 mixture of 9b/90b (CDCl3/rt); yellow
oil. The analytical data were obtained from the mixture of
the tautomers. IR (CCl4): 2950, 2240, 1720, 1650, 1595,
1565, 1455, 1435, 1255, 1155, 1075 cm21 1H NMR
.
(250 MHz) of the 9b: dˆ7.45 (t, Jˆ7.6 Hz, 1H, 40-H),
6.72 (m, 2H, 30-H, 50-H), 3.89 (s, 2H, 8-H), 3.75 (s, 3H,
OCH3), 2.69 (t, Jˆ7.0 Hz, 2H, 6-H), 2.44 (s, 3H, CH3),
2.47±2.34 (m, 2H, 4-H), 1.94 (quin, Jˆ7.0 Hz, 2H, 5-H).
1H NMR (250 MHz) of 90b: dˆ7.55 (t, Jˆ7.6 Hz, 1H,
40-H), 7.03 (m, 2H, 30-H, 50-H), 5.31 (s, 1H, 8-H), 3.76 (s,
3H, OCH3), 2.54 (s, 3H, CH3), 2.47±2.34 (m, 2H, 4-H, 6-H),
1.85 (quin, Jˆ7.0 Hz, 2H, 5-H). MS (70 eV, El): m/z
(%)ˆ259 (3) [M1], 258 (5), 228 (9), 203 (10), 200 (13),
162 (13), 111 (12), 108 (11), 107 (100), 106 (19), 69 (21, 65
(9), 55 (9). HRMS (C15H17NO3): calcd 259.1208; found
259.1210.
3.2.5. Methyl 7-hydroxy-8-(6,7-dimethoxy-3,4-dihydro-
isoquinolin-1-yl)oct-2-ynoate (8e). 41%, yellow oil. H
1
NMR (250 MHz): dˆ6.93 (s, 1H, Ar±H), 6.69 (s, 1H,
Ar±H), 4,90 (br, OH), 4.20±4.07 (m, 1H, 7-H), 3.92 (s,
6H, Ar±OCH3), 3.76 (s, 3H, OCH3), 3.75±3.50 (m, 2H,
30-H). 2.81 (m, 1H, 8-H), 2.76±2.57 (m, 3 H. 8-H, 40-H),
2.44 (m, 2H, 4-H), 1.97±1.61 (m, 4H, 5-H, 6-H). 13C NMR
(100 MHz): dˆ166.6 (C-10), 154.3 (C-1), 151.3 (C±Ar),
147.7 (C±Ar), 131.3 (C±Ar), 122.1 (C±Ar), 110.5
(C±Ar), 108.5 (C±Ar), 89.8 (C-2), 76.1 (C-3), 68.2 (C-7),
56.4/56.0 (Ar±OCH3), 52.5 (OCH3), 46.2 (C-30), 39.9
(C-8), 37.8 (C-6), 25.6 (C-40), 23.8 (C-5), 18.7 (C-4).
MS (70 eV, El): m/z (%)ˆ359 (17) [M1], 341 (35), 340
(29), 326 (19), 310 (20), 298 (25), 282 (100), 266 (19),
244 (43), 242 (35), 205 (80), 190 (40), 178 (41), 150
(15), 77 (13). HRMS (C20H25NO5): calcd 359.1733;
found 359.1733.
3.3.3. Methyl 7-oxo-8-quinolin-2-yloct-2-ynoate (9c).
48% as a 1:4 mixture of 9c/90c (CDCl3/rt), orange solid,
mp 478C (diethyl ether/pentane). The analytical data were
obtained from the mixture of the tautomers. IR (CCl4):
3055, 2950, 2235, 1720, 1635, 1550, 1435, 1415, 1330,
1255, 1135, 1085 cm21 1H NMR (250 MHz) of 9c:
.
dˆ8.17 (dd, Jˆ8.4, 3.2 Hz, 1H, Ar±H), 8.05 (dd, 1H,
Jˆ8.5, 2.4 Hz, Ar±H), 7.82 (ddd, Jˆ8.3, 7.9 Hz,
Jˆ1.4 Hz, 1H, Ar±H), 7.76±7.66 (m, 1H, Ar±H), 7.47
(m, 1H, Ar±H), 7.33 (m, 1H, Ar±H), 4.15 (s, 2H, 8-H),
3.73 (s, 3H, OCH3), 3.70±3.40 (m, 2H, 8-H), 2.77 (t,
Jˆ7.0 Hz, 2H, 6-H), 2.36 (t, Jˆ7.0 Hz, 2H, 4-H), 1.87

T. Nicola et al. / Tetrahedron 57 (2001) 1771±1777
1775
1
(quin, Jˆ7.0 Hz, 2H, 5-H). H NMR (250 MHz) of 90c:
with diethyl ether. The combined organic phase was washed
with brine, dried (MgSO4) and concentrated in vacuo. Puri-
®cation was accomplished by ¯ash chromatography of the
residue (SiO2, cyclohexane/ethyl acetate), and in some cases
by crystallization.
dˆ15.0 (br, OH), 7.55 (d, Jˆ9.2 Hz, 1H, Ar±H), 7.47 (m,
2H, 80-H, Ar±H), 7.33 (m, 1H, Ar±H), 7.21 (m, Jˆ7.02,
1.2 Hz, 1H, Ar±H), 6.66 (d, Jˆ9.2 Hz, 1H, Ar±H), 5.36 (s,
1H, 8-H), 3.75 (s, 3H, OCH3), 2.53±2.41 (m, 4H, 6-H, 4-H),
1.97 (quin, Jˆ7.0 Hz, 2H, 5-H). MS (El): m/z (%)ˆ295 (43)
[M1], 296 (10), 294 (47), 264 (27), 239 (39), 238 (19), 236
(100), 218 (5), 208 (30), 206 (12), 198 (20), 180 (31), 170
(16), 143 (89), 128 (14), 115 (19). MS (Cl, isobutane): m/z
(%)ˆ295 (12) [M1], 338 (4), 312 (6). 310 (18), 297 (22),
296 (100), 264 (5), 208 (2), 143 (4). C18H17NO3 (295.4):
calcd C 73.20, H 5.80, N 4.74; found. C 72.85, H 5.82, N
4.56.
3.5. Base treatment of 9a
3.5.1. Methyl 2-(3-oxo-2-pyridin-2-ylcyclohex-1-en-1-
yl)acetate (11a). 37%, brown oil. IR (CCl4): 2950, 1740,
1715, 1680, 1640, 1470, 1435, 1430, 1365, 1330, 1260,
1
1180, 1005 cm21. H NMR (250 MHz): dˆ8.63 (m, 1H,
600-H), 7.74 (dt, Jˆ7.6, 1.8 Hz, 1H, 400-H), 7.30±7.20 (m,
2H, 300 -H, 500 -H), 3.65 (s, 3H, OCH3), 3.19 (s, 2H, 2-H),
2.60 (m, 4H, 40-H, 60-H), 2.15 (quin, Jˆ6.5 Hz, 2H, 50-H).
13C NMR (100 MHz): dˆ197.6 (C-30), 175.7 (C-10), 170.1
(C-1), 154.4 (C-20/200), 154.1 (C-20/200), 149.0 (C-600), 136.5
(C-400), 125.9 (C-300 /500), 122.7 (C-300 /500), 52.2 (OCH3),
40.7 (C-2/40), 37.8 (C-2/40), 31.1 (C-60), 22.1 (C-50). MS
(70 eV, EI): m/z (%)ˆ245 (28) [M1], 244 (8), 214 (16), 187
(15), 186 (100), 185 (8), 157 (5), 131 (5), 130 (11). HRMS
(C14H15NO3): calcd for 245.1052; found 245.1059.
3.3.4. Methyl 8-isoquinolin-1-yl-7-oxo-oct-2-ynoate (9d).
84%, as a 1:12 mixture of 9d/90d (CDCl3/rt), yellow solid,
mp 105±1068C (diethyl ether/pentane). The analytical data
were obtained from the mixture of the tautomers. IR (CCl4):
2950, 2240, 1720, 1595, 1495, 1435, 1250, 1135,
1075 cm21. H NMR (250 MHz) of the 9d: dˆ8.47 (d,
1
Jˆ5.8 Hz, 1H, Ar±H), 8.03 (m, 1H, Ar±H), 7.85 (dd,
Jˆ7.5, 1.2 Hz, 1H, Ar±H), 7.72 (m, 1H, Ar±H), 7.75±
7.45 (m, 2H, Ar±H), 4.43 (s, 2H, 8-H), 3.75 (s, 3H,
OCH3), 2.72 (t, Jˆ7.0 Hz, 6-H), 2.34 (t, Jˆ7.0 Hz, 2H,
4-H), 1.85 (quin, Jˆ7.0 Hz, 2H, 5-H). 1H NMR
(250 MHz) of the 90d: dˆ8.07 (d, Jˆ7.9 Hz, 1H, Ar±H),
7.64 (ddd, Jˆ8.2, 6.7, 1.2 Hz, 1H, Ar±H), 7.57±7.45 (m,
2H, 70-H, Ar±H), 7.31±7.25 (m, 1H, Ar±H), 6.73 (d,
Jˆ6.7 Hz, 1H, Ar±H), 6.05 (s, 1H, 8-H), 3.76 (s, 3H,
OCH3), 2.58 (t, Jˆ7.3 Hz, 2H, 6-H), 2.46 (t, Jˆ7,0 Hz,
2H, 4-H), 2.00 (quin, Jˆ7.0/7.3 Hz, 2H, 5-H). MS (70 eV,
El): m/z (%)ˆ295 (12) [M1], 294 (16), 267 (15), 264 (13),
239 (23), 236 (29), 235 (35), 208 (16), 198 (13), 180 (16),
170 (11), 144 (16), 143 (100), 142 (16), 128 (13). 115 (32).
3.5.2. 8,9,10,11-Tetrahydro-benzo[a]chinolizine-6,11-
dione (12a). 47%, yellow crystals; mp 1468C (diethyl
ether/dichloromethane). IR (CCl4): 2940, 1685, 1630,
1565, 1465, 1365, 1175 cm21
.
1H NMR (400 MHz):
dˆ9.74 (td, Jˆ9.4, 1.2 Hz, 1H, 4-H), 9.35 (ddd, Jˆ7.0,
1.6, 1.2 Hz, 1H, 1-H), 7.78 (ddd, Jˆ9.4, 7.0, 1.6 Hz, 1H,
3-H), 7.26 (dt, Jˆ7.0, 1.2 Hz, 1H, 2-H), 6.36 (s, 1H, 7-H),
2.96 (t, Jˆ6.4 Hz, 2H, 10-H), 2.69 (t, Jˆ6.4 Hz, 2H, 8-H),
2.08 (quin, Jˆ6.4 Hz, 2H, 9-H). 13C NMR (100 MHz):
dˆ195.7 (C-11), 157.4 (C-11b), 156.5 (C-6), 145.2
(C-7a), 135.8 (C-4), 128.7 (C-7), 125.1 (C-1), 117.1 (C-3),
107.4 (C-11a), 105.7 (C-2), 40.7 (C-10), 32.0 (C-8), 22.0
(C-9). MS (70 eV, EI): m/z (%)ˆ213 (100) [M1], 214
[M111] (15), 185 (34), 157 (58), 129 (21), 128 (10).
HRMS (C13H11NO2): calcd 213.0790; found 213.0789.
C13H11NO2 (213.1): calcd C 73.23, H 5.20, N 6.55; found
C 72.78, H 5.20, N 6.57.
3.3.5. Methyl 8-(6,7-dimethoxy-3,4-dihydroisoquinolin-
1-yl)-7-hydroxy-oct-2-en-2-ynoate (90e). 41%, light
brown oil. IR (CCl4): 2950, 2240, 1720, 1605, 1500,
1465, 1435, 1340, 1255, 1215, 1110, 1075, 910 cm21. H
1
NMR (250 MHz): dˆ11.3 (br, 1H, O±H), 7.14 (s, 1H,
80-H), 6.69 (s, 1H, 50-H), 5.53 (s, 1H, 8-H), 3.96 (s, 3H,
Ar±OCH3). 3.93 (s, 3H, Ar±OCH3), 3.76 (s. 3H, OCH3),
3.46 (dt, Jˆ6.7, 3.4 Hz, 2H, 30-H), 2.85 (t. Jˆ6.7 Hz, 2H,
40-H), 2.52 (t, Jˆ7.3 Hz, 2H, 6-H), 2.44 (t, Jˆ7.0 Hz, 2H,
4-H), 1.95 (m, 2H, 5-H). 13C NMR (125 MHz): dˆ196.3
(C-7). 157.5 (C-10), 154.3 (C-1), 151.7 (C±Ar), 148.1
(C±Ar), 130.7 (C±Ar), 121.1 (C±Ar), 110.8 (C±Ar),
108.5 (C±Ar), 89.7 (C-2), 89.0 (C-8), 73.3 (C-3), 56.3/
56.1 (Ar±OCH3), 52.6 (OCH3), 40.8 (C-30), 38.7 (C-6),
28.1 (C-40), 24.0 (C-5), 18.5 (C-4). MS (70 eV, El): m/z
(%)ˆ357 (47) [M1], 356 (61), 340 (13), 326 (100), 301
(31), 298 (77), 282 (33), 270 (27), 254 (13), 245 (45), 232
(90), 216 (27), 205 (70), 190 (23), 159 (9), 116 (10). HRMS
(C20H23NO5): calcd 357.1576; found 357.1574.
3.6. Base treatment of 9b
3.6.1. Methyl [-2-(6-methylpyridin-3-oxo-2-yl)cyclohex-
1-en-1-yl]acetate (11b). 68%, yellow oil. 1H NMR
(250 MHz): dˆ7.61 (t, Jˆ7.6 Hz, 1H, 400-H), 7.10 (d,
Jˆ7.6 Hz, 1H, 300-H), 7.01 (d, Jˆ7.6 Hz, 1H, 500-H), 3.66
(s, 3H, OCH3), 3.18 (s, 2H, 2-H), 2.63±2.56 (m, 4H, 40-H,
60-H), 2.55 (s, 3H, CH3), 2.41 (m, 2H, 50-H). 13C NMR
(100 MHz): dˆ197.7 (C-30), 170.3 (C-1), 158.0 (C-10),
154.0 (C-2 or C-200), 153.7 (C-200 or C-2), 139.5 (C±Ar),
136.4 (C±Ar), 122.7 (C±Ar), 122.1 (C±Ar), 52.2 (OCH3),
40.9 (C-2), 38.0 (C-40), 31.3 (C-60), 24.5 (CH3), 22.1 (C-50).
MS (70 eV, El): m/z (%)ˆ259 (26) [M1], 228 (11), 201
(15), 200 (100), 144 (11), 131 (6), 119 (6) 69 (27). HRMS
(C15H17NO3): calcd 259.1208; found. 259.1210.
3.4. General procedure for the base catalyzed
transformation of 9a±e
3.6.2. 4-Methyl-9,10-dihydro-6H-pyrido[2,1-a]isoquino-
line-6,11(8H)-dione (12b). ,5%. 1H NMR (400 MHz):
dˆ9.57 (m, 1H, 1-H), 7.50 (m, 1H, 2-H), 6.83 (d, 1H,
3-H), 6.19 (s, 1H, 7-H), 2.99 (s, 3H, CH3), 2.88 (t,
Jˆ7 Hz, 2H, 10-H), 2.64 (t, Jˆ7 Hz, 2H, 8-H), 2.01 (m,
2H, 9-H).
Typically, runs were performed with 0.5 mmol of 9. To a
solution of 1.5 equiv. of potassium tert-butoxide in 12 ml of
dry THF were added at 08C the solution of 9 in 3 ml of THF.
After stirring for additional 30 min at 08C the reaction
mixture was poured into 30 ml of water and then extracted

1776
T. Nicola et al. / Tetrahedron 57 (2001) 1771±1777
3.7. Base treatment of 9c
40.6 (C-2), 37.9 (C-40), 31.0 (C-60), 22.4 (C-50). MS (70 eV,
El): m/z (%)ˆ295 (14) [M1], 294 (10), 267 (15), 237 (9),
236 (59), 235 (100), 208 (12), 180 (28), 167 (8), 128 (8).
HRMS (C18H17NO3): calcd 295.1208; found 295.1209
3.7.1. Methyl 2-(3-oxo-2-quinolin-2-ylcyclohex-1-en-1-
yl)acetate (11c). 71%, red oil. IR (CCl4): 3055, 2950,
1740, 1705, 1680, 1625, 1600, 1560, 1505, 1435, 1150,
1020, 910 cm21
.
1H NMR (250 MHz): dˆ8.16 (dd,
3.8.2. 3,4-Dihydro-1H-isoquino[1,2-a]isoquinoline-1,6(2H)-
dione (12d). 53%, yellow crystals, mp 167±1688C (metha-
nol). IR (CCl4): 2950, 2875, 1695, 1655, 1570, 1545, 1470,
Jˆ8.5, 0.9 Hz, 1H, Ar±H), 8.05 (m, Jˆ8.5 Hz, 1H, Ar±
H), 7.83 (dd, Jˆ8.2, 1.2 Hz, 1H, Ar±H), 7.70 (ddd,
Jˆ8.5, 7.0, 1.2 Hz, 1H, Ar±H), 7.54 (ddd, Jˆ8.2, 7.0,
1.2 Hz, 1H, Ar±H), 7.34 (d, Jˆ8.5 Hz, 1H, Ar±H), 3.63
(s, 3H, OCH3), 3.29 (s, 2H, 2-H), 2.70±2.61 (m, 4H, 60-H,
40-H), 2.20 (quin, Jˆ6.1 Hz, 2H, 50-H). 13C NMR
(125 MHz): dˆ197.8 (C-30), 170.1 (C-1), 155.3 (C-20 or
C±Ar), 155.1 (C-20 or C±Ar), 147.7 (C±Ar), 139.5
(C±Ar), 135.7 (C-400), 129.4/129.3 (C±Ar), 127.6 (C±Ar),
127.2 (C±Ar), 126.7 (C±Ar), 123.4 (C±Ar), 52.1 (OCH3),
40.7 (C-2), 37.9 (C-40), 31.5 (C-60), 22.0 (C-50). MS (70 eV,
EI): m/z (%)ˆ295 (68) [M1], 294 (40), 264 (22), 237 (35),
(236 (100), 208 (17), 181 (20), 180 (54), 178 (18), 167 (21),
128 (22), 77 (12). HRMS (C18H17NO3): calcd 295.1208;
found 295.1206.
1
1430, 1395, 1300, 1215, 1000 cm21. H NMR (250 MHz):
dˆ8.98 (d, Jˆ7.6 Hz, 1H, 8-H), 8.20 (m, 1H, Ar±H), 7.74±
7.70 (m, 2H, 9-H, Ar±H), 7.54±7.44 (m, 1H, Ar±H), 7.35
(dd, Jˆ7.6, 0.6 Hz, 1H, 9-H), 6.41 (t, Jˆ1.1 Hz, 2H, 5-H),
2.92 (t, Jˆ6.1 Hz, 2H, 2-H), 2.80 (t, Jˆ6.6 Hz, 2H, 4-H),
2.19 (m, 2H, 3-H). 13C NMR (100 MHz): dˆ196.7 (C-1),
158.0 (C-6), 155.8, 146.6, 133.7, 132.6, 131.9, 126.9, 124.8,
122.7, 116.7, 112.2, 107.7, 40.1 (C-2), 31.2 (C-4), 21.7
(C-3). MS (70 eV, El): m/z (%)ˆ263 (55) [M1], 262
(100), 235 (6), 234 (7), 207 (18), 179 (19), 178 (19), 150
(5), 102 (4), 88 (4), 76 (4). HRMS (C17H13NO2) calcd
263.0946; found 263.0941. C17H13NO2 (263.3): calcd C
77.55, H 4.98, N 5.32 N; found C 76.97, H 4.90, N 5.24.
For the transformation of 11c into 9,10-dihydro-6H-
isoquino[2,1-a]quinoline-6,11(8H)-dione (12c), the follow-
ing conditions were applied: A solution of 11c (70 mg,
0.24 mmol) and NaHCO3 (101 mg, 1.20 mmol) in 20 ml
of methanol was re¯uxed for 1.5 h until completion of the
reaction (tlc control). The reaction mixture was diluted with
20 ml of water and then extracted with CH2Cl2. The organic
layers were dried (MgSO4) and concentrated in vacuo. Flash
chromatography (SiO2, cyclohexane/ethyl acetate 5:1) gave
12c (67%) as yellow needles, mp 152±1538C (ethanol). IR
(CCl4): 294, 2870, 1690, 1650, 1585, 1515, 1455, 1375,
3.9. Base treatment of 9e
3.9.1. 11,12-Dimethoxy-3,4,8,9-tetrahydro-1H-isoquino-
[1,2-a]isoquinoline-1,6(2H)-dione (12e). 71%, light beige
crystals, mp 245±246 (methanol). IR (CCl4): 2950, 1690,
1650, 1480, 1465, 1385, 1290, 1260, 1220, 1165, 1085,
1
1010 cm21. H NMR (250 MHz): dˆ6.91 (s, 1H, 13-H),
6.74 (s, 1H, 10-H), 6.30 (t, Jˆ1.2 Hz, 1H, 5-H), 4.12 (m,
Jˆ6.4 Hz, 2H, 8-H), 3.95 (s, 3H, Ar±OCH3), 3.81 (s, 3H,
Ar±OCH3), 2.87 (m, Jˆ6.4 Hz, 2H, 9-H), 2.78 (t, Jˆ6.1 Hz,
2H, 2-H), 2.66 (t, Jˆ6.4 Hz, 2H, 4-H), 2.10 (m, 2H, 3-H).
13C NMR (125 MHz): dˆ196.3 (C-1), 161.2 (C-6), 154.5,
152.3, 150.2, 147.0, 131.9, 120.5, 115.5, 113.2, 113.0,
109.4, 56.3/56.1 (Ar±OCH3), 40.4 (C-2), 39.8 (C-8), 30.8
(C-4), 27.7 (C-9), 21.7 (C-3). MS (70 eV, EI): m/z (%)ˆ325
(100) [M1], 326 (20), 324 (59), 310 (46), 294 (11), 280 (9),
269 (9), 241 (6), 226 (5), 147 (7), 146 (19), 86 (5), 84 (7).
HRMS (C19H19NO4): calcd 325.1314; found 325.1315.
1
1325, 1270, 1230, 1135, 985 cm21. H NMR (400 MHz):
dˆ9.54 (d, br, Jˆ8.9 Hz, 1H, 4-H), 9.28 (d, Jˆ9.6 Hz, 1H,
12-H), 7.74 (d, Jˆ9.6 Hz, 1H, 13-H), 7.67 (dd, Jˆ7.50,
1.9 Hz, 1H, 1-H), 7.60 (ddd, Jˆ8.9, 7.2, 1.9 Hz, 1H, 3-H),
7.52 (m, 1 H. 2-H), 6.48 (t, Jˆ1.1 Hz, 1H, 7-H), 2.90 (t,
Jˆ6.2 Hz, 2H, 10-H), 2.70 (t, Jˆ6.4 Hz, 2H, 8-H), 2.07 (m,
2H, 9-H). 13C NMR (125 MHz): dˆ196.5 (C-11), 163.0
(C-6), 153.6, 146.3, 135.2, 129.0, 127.5, 127.0, 126.0,
122.6, 121.5, 112.6, 109.6, 41.1 (C-10), 31.1 (C-8), 21.6
(C-9). MS (70 eV, El) m/z (%)ˆ263 (89) [M1], 264 (17),
235 (63), 208 (15), 207 (95), 206 (14), 180 (13), 179 (42),
178 (100), 129 (12), 128 (21), 102 (14), 101 (11), 89 (30), 76
(9). C17H13NO2 (263.3): calcd C 77.54, H 4.98, N 5.32;
found C 77.47, H 4.98, N 5.22.
Acknowledgements
Thanks are due to the Fonds der Chemischen Industrie for
®nancial support of this work.
3.8. Base treatment of 9d
References
3.8.1. Methyl 2-(2-isoquinolin-1-yl-3-oxocyclohex-1-en-
1-yl)acetate (11d). 36%, orange oil. IR (CCl4): 3055,
2950, 1740, 1680, 1630, 1560, 1500, 1435, 1390, 1330,
1. (a) Nicola, T.; Vieser, R.; Eberbach, W. Eur. J. Org. Chem.
2000, 527±538. (b) Vieser, R.; Eberbach, W. Tetrahedron
Lett. 1995, 36, 4405±4408.
1
1250, 1200, 1170 cm21. H NMR (250 MHz): dˆ8.55 (d,
2. Trost, B. M.; Shi, Y. J. Am. Chem. Soc. 1993, 115, 12491±
12509.
Jˆ5.5 Hz, 1H, Ar±H), 7.84 (d, br, Jˆ8.2 Hz, 1H, Ar±H),
7.73 (m, Jˆ8.5 Hz, 1H, Ar±H), 7.70±7.63 (m, 2H, Ar±H),
7.52 (ddd, Jˆ8.2, 7.0, 1.3 Hz, 1H, Ar±H), 3.46 (s, 3H,
OCH3), 3.06 (dd, Jˆ15.9, 1.0 Hz, 2H, 2-H), 2.88±2.58
(m, 4H, 40-H, 60-H), 2.29 (quin, Jˆ6.1 Hz, 2H, 50-H). 13C
NMR (125 MHz): dˆ197.6 (C-30), 169.6 (C-1), 156.4 (C-10
or C-100), 155.3 (C-100 or C-10), 142.2 (C±Ar), 138.4 (C-20),
136.2 (C±Ar), 130.4 (C±Ar), 128.1 (C±Ar), 127.3 (C±Ar),
127.0 (C±Ar), 126.6 (C±Ar), 120.7 (C±Ar), 51.9 (OCH3),
3. Eberbach, W. Methoden Org. Chem. (Houben-Weyl), Vol. E
6a, 4 ed.; Thieme: Stuttgart, 1994; part 1, 141pp.
4. Nicola, T. Part of the forthcoming dissertation, University of
Freiburg.
5. For a related cyclization reaction, see: Arcadi, A.; Cacchi, S.;
Fabrizi, G.; Manna, F.; Pace, P. Synlett 1998, 446±448.
6. Akashi, M.; Nishida, M.; Mori, M. Chem. Lett. 1999, 465±
466.

T. Nicola et al. / Tetrahedron 57 (2001) 1771±1777
1777
7. Schwarzrock, D. Part of the Staatsexamensarbeit, University
of Freiburg, 1999.
9. For pertinent recent work on the synthesis and biological
activity of 4-quinolizinones, see: Ma, Z.; Chu, D. T. W.;
Cooper, C. S.; Li, Q.; Fung, A. K. L.; Wang, S.; Shen, L. L.;
Flamm, R. K.; Nilius, A. M.; Alder, J. D.; Meulbroek, J. A.;
Or, Y. S. J. Med. Chem. 1999, 42, 4202±4213 and references.
10. Crystallographic data have been deposited at the CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, and copies can be
obtained on request free of charge, by quoting the publication
citation and the deposition number CCDC 154899.
8. An alternative access to simple and annulated 4-quinolizi-
nones has been accomplished by a route involving a 1,7-dipo-
lar electrocyclization as key step: (a) Bussenius, J.; Laber, N.;
MuÈller, T.; Eberbach, W. Chem. Ber. 1994, 127, 247±259.
È
(b) Lopez-Calle, E.; Ho¯er, J.; Eberbach, W. Liebigs Ann.
Chem. 1996, 1855±1866 and references. See also: (c) Birch-
ler, A. G.; Liu, F.; Liebeskind, L. S. J. Org. Chem. 1994, 59,
7737±7745.