Regioselectivity of Friedlaender quinoline syntheses

Article abstract of DOI:10.1002/ejoc.200701179

Optically active, bicyclic ketones were submitted to Friedlaender quinoline syntheses with 2-aminobenzaldehyde to yield regioisomeric linear or angular products. When starting from trans-configured ketones, the linear products are the major isomers (ratio

Full text of DOI:10.1002/ejoc.200701179

FULL PAPER
DOI: 10.1002/ejoc.200701179
Regioselectivity of Friedländer Quinoline Syntheses
[a]
[a]
[a]
[a]
Claas Lüder Diedrich, Detlev Haase, Wolfgang Saak, and Jens Christoffers*
Dedicated to Professor Jürgen Martens on the occasion of his 60th birthday
Keywords: Annulation / Quinoline derivatives / Heterocycles / Regioselectivity / Friedländer synthesis
Optically active, bicyclic ketones were submitted to Fried-
länder quinoline syntheses with 2-aminobenzaldehyde to
yield regioisomeric linear or angular products. When starting
from trans-configured ketones, the linear products are the
major isomers (ratios ranging from 76:24 to Ͼ98/2). With cis-
configured ketones the angular products are predominantly
formed, although with lower regioselectivity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
ketones, trans-1 and cis-1, which were separable by column
chromatography. In this work we would like to report on
the regioselectivity of Friedländer quinoline syntheses start-
ing from these optically active bicyclic cyclohexanone deriv-
atives cis-1 and trans-1.
Quinoline derivatives are among the most important
pharmaceuticals and bioactive natural products.[ An im-
portant example are chinchona alkaloids and related anti-
1]
[
2]
malarial drugs. When annulated with one or more rings,
again a vast number of natural and synthetic compounds
with high potential for medicinal applications are known.
The most prominent example in this area is camptothecin
and related inhibitors of DNA topoisomerases.[ The con-
densation of 2-aminobenzaldehyde and an aliphatic ketone
was named after its inventor[ and is still the most efficient
route to quinoline derivatives.[ The acridine skeleton is ac-
cessed, if cyclohexanone is used as the aliphatic ketone in
the Friedländer reaction. With substituted cyclohexanone
derivatives a regioselectivity problem can arise during the
annulation reaction. We have recently reported on Fischer
indole syntheses starting from bicyclic cyclohexanones 1
3]
4]
5]
[
6]
(
Scheme 1). The regioselectivity of this annulation turned
out to be strictly dependent on the relative configuration
of the starting materials 1: trans-annulated ketones 1 gave Scheme 1. Linear or angular indole annulation of bicyclic cyclo-
2 2
hexanones. E = CO Et or CO Me; n = 0, 1, 2.
exclusively linear annulated carbazole derivatives 2, whereas
relative cis configuration of ketones 1 led to angular prod-
ucts 3. Starting materials cis-1 and trans-1 with one five-,
six- or seven-membered ring (n = 0, 1, 2) were readily avail-
able in optically active form by a three-step sequence start-
ing with an asymmetric Michael reaction of methyl vinyl
Results and Discussion
Protocols for Friedländer reaction require either
Brönsted-basic or Brönsted- or Lewis-acidic catalysts. The
main drawback of most protocols is the low stability of
aminobenzaldehyde 7, which tends to self-condensation re-
actions. It has been suggested in the literature, to prepare
[7]
ketone with β-oxo esters, followed by aldol condensation
Robinson annulation)[ and final catalytic C=C double-
8]
(
bond hydrogenation. The latter gave a mixture of both
[
a] Institut für Reine und Angewandte Chemie der Universität this aldehyde 7 by in situ reduction of nitrobenzaldehyde 6
Oldenburg,
with excess SnCl , which seems attractive on the first
2
Carl-von-Ossietzky-Str. 9–11, 26111 Oldenburg, Germany
IV
glance, since Sn species generated under these reaction
conditions are acidic catalysts for the Friedländer reac-
Fax: +49-441-798-3873
E-mail: jens.christoffers@uni-oldenburg.de
Eur. J. Org. Chem. 2008, 1811–1816
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1811

C. L. Diedrich, D. Haase, W. Saak, J. Christoffers
FULL PAPER
Table 1. Starting materials (n, E), products, regioselectivities and yields.
Starting material
n
E
Method
Products
Ratio[a]
Yield
1
2
3
4
5
6
7
8
9
trans-1a
trans-1b
trans-1c
cis-1a
trans-1a
trans-1b
trans-1c
cis-1a
0
1
2
0
0
1
2
0
1
2
CO
CO
2
Et
Et
“Sn”
“Sn”
“Sn”
“Sn”
“Fe”
“Fe”
“Fe”
“Fe”
“Fe”
“Fe”
trans-4a, trans-5a
trans-4b, trans-5b
trans-4c, trans-5c
cis-4a, cis-5a
trans-4a, trans-5a
trans-4b, trans-5b
trans-4c, trans-5c
cis-4a, cis-5a
95:5
74:26
69:31
45:55
Ͼ98:2
80:20
76:24
46:54
44:56
38:62
74%
78%
81%
50%
85%
93%
96%
98%
90%
78%
2
CO
CO
CO
CO
2
Me
2
Et
Et
Et
2
2
CO
CO
CO
2
Me
2
Et
Et
Me
cis-1b
cis-1c
2
cis-4b, cis-5b
cis-4c, cis-5c
10
CO
2
[a] Calcd. from isolated compounds.
tion.[9] We investigated this one-pot protocol for the conver-
sion of starting materials trans-1a–1c and cis-1a (Scheme 2;
Table 1, Entries 1–4, method “Sn”). Yields of products 4
and 5 were in the range of 50–81%. The regioselectivity for
starting materials trans-1a–1c was good to moderate (95:5
to 69:31; Entries 1–3) with linear annulation products trans-
4
a–4c as the major products. For starting material cis-1a
almost no regioselectivity was observed (cis-4a/cis-5a =
5:55), and the yield was low (50%). The most severe prob-
4
lem with this procedure was, however, the separation of the
products from tin-containing materials, which made
workup and extraction very tedious. For this reason, we left Figure 1. ORTEP representation of the structure of compound
the idea of in situ preparation of aminobenzaldehyde 7.
trans-4b in the solid state.
Scheme 2. Friedländer synthesis starting from nitrobenzaldehyde 6
method “Sn”) or from aminobenzaldehyde 7 (method “Fe”); rea-
gents and conditions: (a) method “Sn”, 1 equiv. of aldehyde 6,
Figure 2. ORTEP representation of the structure of compound
trans-4c in the solid state.
(
3
1
1
equiv. of SnCl
.3 equiv. of aldehyde 7, 1 equiv. of pTosOH·H
0 equiv. of Fe powder, cat. HCl, H O/EtOH, 100 °C, 1.5 h, 87%.
2
·2H
2
O, EtOH, 115 °C, 16 h; (b) method “Fe”,
2
O, 110 °C, 1.5 h; (c)
2
For E, n and yields see Table 1.
For further investigations, we prepared aminobenzalde-
hyde 7 freshly by reduction of nitrobenzaldehyde 6 with Fe/
[10]
HCl/H O (method “Fe”).
Product 7 was purified each
2
time by column chromatography (yield ca. 87%) and di-
rectly submitted to an acid-catalyzed Friedländer reaction.
With this approach, yields (78–98%) and regioselectivites
were improved (Entries 5–10). Moreover, the workup was
significantly simplified. For starting materials trans-1a–1c
again the linear annulation products trans-4a–4c are the
major products (yields 85–96%), with decreasing selectivity
when increasing the ring size n (Entries 5–7). For n = 1, no
Figure 3. ORTEP representation of the structure of compound cis-
angular product trans-5a was detectable. For the six- and 4a in the solid state.
1812
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1811–1816

Regioselectivity of Friedländer Quinoline Syntheses
the seven-membered ring annulation, selectivities were
All twelve compounds cis- and trans-4a–4c, cis- and
80:20 (n = 1) and 76:24 (n = 2), respectively. When starting trans-5a–5c are new, and their constitution could be eluci-
with cis-annulated ketones cis-1a–1c (Entries 8–10), the re- dated by 2D NMR spectroscopy (H,H- and C,H-COSY,
gioselectivities were generally lower and increased with in- HMQC, and HMBC). In six cases, single crystals could be
creasing ring size: 45:55 (n = 0), 43:57 (n = 1), and 38:62 grown, which were suitable for X-ray structure analysis.
(
n = 2). In all these cases, the angularly annulated products ORTEP representations of the molecular structures are
[
11]
cis-5a–5c were the major isomer. In all six cases, the regio- given in Figures 1, 2, 3, 4, 5 and 6.
In all six cases the
isomers 4 and 5 could be separated by column chromatog- ester groups E (E = CO Et or CO Me) occupy an axial
2
2
raphy.
position at the C/D ring junction.
Conclusions
Bicyclic ketones 1a–1c are readily available in optically
active form with relative trans or cis configuration. Fried-
länder quinoline synthesis with aminobenzaldehyde 7 yields
regioisomeric linear or angular products. In the cases of
trans-annulated starting materials trans-1, the linear isomers
predominate the product mixtures with selectivities from
76:24 to Ͼ98:2. Ketones cis-1 with relative cis configuration
lead to angular isomers, although the selectivities are lower
in these cases. Mixtures of regioisomers can be separated
by column chromatography and all twelve new tetracyclic
products were fully characterized, in six cases by single-
crystal X-ray structure analysis.
We recommend to use freshly prepared aminobenzalde-
hyde 7 in acid-catalyzed Friedländer reactions. In situ re-
Figure 4. ORTEP representation of the structure of compound cis-
4b in the solid state.
duction of nitroaldehyde 6 with SnCl leads to hardly sepa-
2
rable tin-containing byproducts, and yields and selectivities
are lower.
Experimental Section
General Methods: Preparative column chromatography was carried
out using Merck SiO
2
(0.035–0.070 mm, type 60 A) with hexanes
(
b.p. 40–60 °C) (PE), and ethyl acetate (EA) as eluents. TLC was
1
performed on Merck SiO
2
F254 plates on aluminium sheets. H and
1
3
C NMR spectra were recorded with Bruker Avance DRX 500
and Avance DPX 300 instruments. Multiplicities were determined
with DEPT experiments. EI-MS, CI-MS and HRMS data were ob-
tained with a Finnigan MAT 95 spectrometer. IR spectra were re-
corded with a Bruker Tensor 27 spectrometer equipped with a
“
GoldenGate” diamond-ATR unit. Elemental analyses were mea-
Figure 5. ORTEP representation of the structure of compound
trans-5c in the solid state.
sured with an EA 1108 from Fisons Instruments. Ketones 1 were
prepared according to procedures reported previously.[ All other
starting materials were commercially available.
6]
Preparation of Aminobenzaldehyde 7: Iron powder (5.55 g,
99.3 mmol, 10 equiv.) and concd. hydrochloric acid (ca. 50 mg)
were added to a solution of nitroaldehyde 6 (1.50 g, 9.93 mmol) in
EtOH (30 mL) and water (7.5 mL), and the mixture was heated to
reflux for 90 min. EtOAc (150 mL) was added to the mixture, and
it was dried with MgSO
solvent, the residue was purified by chromatography (SiO
4
. After filtration and evaporation of the
; PE/EA,
= 0.32) to give 1.05 g (8.67 mmol, 87%) of aminoaldehyde
as a yellow solid (m.p. 38–40 °C).
2
7:1; R
f
7
Preparation of Quinolines. General Procedure “Fe”: Freshly pre-
pared aminoaldehyde 7 (1.3 equiv.) was added to 1.0 equiv. of
pTosOH·H
mixture was stirred without solvent at 110 °C for 90 min. After
cooling to 23 °C, CH Cl (20 mL) was added and the solution
washed with aqueous NaHCO solution (2ϫ10 mL) and brine
(1ϫ10 mL). After drying (MgSO ), filtration and evaporation of
2
O and 1.0 equiv. of the corresponding oxo ester 1. The
2
2
Figure 6. ORTEP representation of the structure of compound cis-
3
5c in the solid state.
4
Eur. J. Org. Chem. 2008, 1811–1816
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1813

C. L. Diedrich, D. Haase, W. Saak, J. Christoffers
FULL PAPER
the solvent, the residue was purified by chromatography (SiO
EA).
–
1
2
; PE/
1174 (vs), 1025 (m), 750 (s) cm . MS (EI): m/z (%) = 295 (37)
+
[M ], 221 (100), 193 (18), 180 (20). HR-MS: calcd. for C19
H
21NO
2
2
0
2
C
7
95.1572, found 295.1572. [α]
D
= –113 (c = 2.3 in CDCl
3
).
Conversion of Ketone trans-1a to Quinoline trans-4a According to
General Procedure “Fe”: mixture of trans-1a (480 mg,
.28 mmol), pTosOH·H O (424 mg, 2.23 mmol) and aminoalde-
hyde 7 (350 mg, 2.90 mmol) gave, after purification by chromatog-
raphy on SiO (PE/EA, 2:1; R = 0.56), trans-4a (560 mg,
.90 mmol, 85%) as a colorless solid (mp. 98–99 °C). Isomer trans-
a could only be detected in traces.
19
H
21NO
2
(295.38): calcd. C 77.26, H 7.17, N 4.74; found C
7.25, H 7.18, N 4.78.
A
2
2
Conversion of Ketone trans-1b to Quinolines trans-4b/trans-5b Ac-
cording to General Procedure “Fe”: A mixture of trans-1b (500 mg,
2
f
1
5
2.23 mmol), pTosOH·H
hyde 7 (360 mg, 2.97 mmol) gave after chromatography (SiO
EA, 3:1) compound trans-4b (510 mg, 1.65 mmol, 74%) in the first
fraction (R = 0.70) as a colorless solid (m.p. 106–107 °C). The
second fraction (R = 0.53) contained compound trans-5b (130 mg,
.42 mmol, 19%, light yellow solid, m.p. 76–77 °C).
2
O (424 mg, 2.23 mmol) and aminoalde-
2
; PE/
Conversion of Ketone trans-1a to Quinolines trans-4a/trans-5a. Pro-
cedure “Sn”: A mixture of ketone trans-1a (500 mg, 2.38 mmol),
f
f
nitroaldehyde
.14 mmol, 3 equiv.) and EtOH (0.5 mL) was heated in a tightly
closed reaction flask to 115 °C for 16 h. The resulting black mixture
was poured into aqueous NaHCO solution (30 mL) and extracted
with EtOAc (2ϫ30 mL). After drying with MgSO , filtration and
evaporation of the solvent, the residue was purified by chromatog-
raphy on SiO (PE/EA, 2:1) to give trans-4a (490 mg, 1.66 mmol,
0%) in the first fraction (R = 0.56) as a colorless solid (m.p. 98–
9 °C). The second fraction (R = 0.46) contained trans-5a (30 mg,
.10 mmol, 4%, light yellow resin).
6
(359 mg, 2.38 mmol), SnCl
2
·2H
2
O
(1.61 g,
0
7
(
+)-Ethyl (6aS,10aR)-6,6a,7,8,9,10,10a,11-Octahydrobenzo[b]acrid-
1
ine-10a-carboxylate (trans-4b): H NMR (CDCl
3
, 500 MHz): δ =
3
1
1
1
1
.03 (t, J = 7.1 Hz, 3 H), 1.28–1.52 (m, 3 H), 1.63–1.78 (m, 2 H),
4
.82–2.02 (m, 3 H), 2.32 (d, J = 13.1 Hz, 1 H), 2.78 (d, J = 16.0 Hz,
H), 3.15 (dd, J = 6.1, J = 18.4 Hz, 1 H), 3.31 (dd, J = 12.0, J =
8.4 Hz, 1 H), 3.35 (d, J = 16.0 Hz, 1 H), 3.97 (q, J = 7.0 Hz, 2
H), 7.43 (t, J = 7.5 Hz, 1 H), 7.61 (t, J = 7.5 Hz, 1 H), 7.69 (d, J
8.1 Hz, 1 H), 7.78 (s, 1 H), 7.97 (d, J = 8.5 Hz, 1 H) ppm.
2
7
9
0
f
f
=
1
3
1
C{ H} NMR (CDCl
5.77 (CH ), 28.86 (CH
2.19 (CH ), 45.73 (C), 59.72 (CH
3
, 125 MHz): δ = 13.84 (CH
), 37.35 (CH ), 37.66 (CH
), 125.24 (CH), 126.68 (C),
3
), 22.89 (CH
2
),
(+)-Ethyl (3aS,11aR)-2,3,3a,4,11,11a-Hexahydro-1H-cyclopenta[b]-
2
4
1
1
2
(
[
3
1
2
2
2
2
), 40.80 (CH),
1
acridine-11a-carboxylate (trans-4a): H NMR (CDCl
δ = 1.03 (t, J = 7.1 Hz, 3 H, OCH CH ), 1.61 (ddd, J = 8.7, J =
.9, J = 12.9 Hz, 1 H, 1-H), 1.82–1.95 (m, 2 H, 2-H, 3-H), 1.96–
3
, 500 MHz):
2
2
2
3
26.70 (CH), 128.10 (CH), 128.33 (CH), 128.66 (C), 134.32 (CH),
46.65 (C), 158.51 (C), 174.18 (C) ppm. IR (ATR): ν˜ = 2992 (w),
9
2
1
.07 (m, 2 H, 2-H, 3-H), 2.16–2.25 (m, 1 H, 3a-H), 2.27–2.34 (m,
H, 1-H), 2.81 (d, J = 15.9 Hz, 1 H, 11-H), 3.08 (dd, J = 13.4, J
937 (m), 2858 (w), 2360 (w), 2340 (w), 1704 (vs), 1490 (w), 1441
–1
w), 1416 (m), 1210 (s), 1188 (s) cm . MS (EI): m/z (%) = 309 (28)
=
17.5 Hz, 1 H, 4-H), 3.35 (dd, J = 5.3, J = 17.5 Hz, 1 H, 4-H),
.64 (d, J = 15.9 Hz, 1 H, 11-H), 3.97 (q, J = 7.1 Hz, 2 H,
OCH CH ), 7.41–7.46 (m, 1 H, 7-H or 8-H), 7.58–7.63 (m, 1 H, 8-
H or 7-H), 7.70 (d, J = 7.9 Hz, 1 H, 9-H), 7.84 (s, 1 H, 10-H), 7.97
+
M ], 236 (42), 235 (100), 193 (25). HR-MS: calcd. for C20H23NO
2
3
20
09.1729, found 309.1728. [α]
D 3
= +95 (c = 5.02 in CDCl ). M.p.
2
3
06–107 °C. C20 (309.40): calcd. C 77.64, H 7.49, N 4.53;
H23NO
2
found C 77.98, H 77.47, N 4.52.
d, J = 8.5 Hz, 1 H, 6-H) ppm. 13C{ H} NMR (CDCl
δ = 13.99 (CH , OCH CH ), 22.75 (CH , C-2), 28.79 (CH
6.22 (CH , C-4), 36.67 (CH , C-1), 40.20 (CH , C-11), 46.64 (CH,
C-3a), 52.11 (C, C-11a), 60.16 (CH , OCH CH ), 125.61 (CH, C-
or C-7), 126.89 (C, C-9a), 126.90 (CH, C-9), 128.32 (CH, C-6),
28.51 (CH, C-7 or C-8), 130.27 (C, C-10a), 135.13 (CH, C-10),
46.44 (C, C-5a), 158.69 (C, C-4a), 175.08 (C, CO Et) ppm. IR
1
, 125 MHz):
, C-3),
(
3
(
4
(
(
(
–)-Ethyl (4aR,12bS)-1,2,3,4,4a,5,6,12b-Octahydrobenzo[a]acridine-
3
2
3
2
2
1
3
a-carboxylate (trans-5b): H NMR (CDCl , 500 MHz): δ = 1.04
3
2
2
2
t, J = 7.1 Hz, 3 H), 1.28–1.42 (m, 2 H), 1.42–1.54 (m, 1 H), 1.74
d, J = 13.0 Hz, 1 H), 1.89–2.06 (m, 3 H), 2.30–2.49 (m, 3 H), 2.74
d, J = 11.3 Hz, 1 H), 3.02 (ddd, J = 6.5, J = 13.0, J = 18.5 Hz, 1
2
2
3
8
1
1
H), 3.26 (dd, J = 5.9, J = 18.5 Hz, 1 H), 3.92 (q, J = 7.1 Hz, 2 H),
.43 (t, J = 7.5 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 7.71 (d, J =
2
7
(
(
(
ATR): ν˜ = 2966 (m), 2873 (w), 1710 (vs), 1415 (m), 1179 (s), 1140
1
3
1
–1
+
3
8.1 Hz, 1 H), 7.92–7.95 (m, 2 H) ppm. C{ H} NMR (CDCl ,
s) 756 (s) cm . MS (EI): m/z (%) = 295 (32) [M ], 221 (100), 193
21). HR-MS: calcd. for C19 295.1572, found 295.1572.
). M.p. 98–99 °C. C19
295.38): calcd. C 77.26, H 7.17, N 4.74; found C 77.43, H 7.20, N
.74.
1
3 2 2
25 MHz): δ = 13.84 (CH ), 22.80 (CH ), 24.97 (CH ), 25.77
H
21NO
2
2
0
(CH ), 30.79 (CH ), 34.97 (CH ), 37.28 (CH ), 44.56 (CH), 46.98
[α]
D
= +157 (c = 7.75 in CDCl
3
H
21NO
2
2
2
2
2
(
(
(
1
[
2
C), 59.81 (CH ), 125.20 (CH), 127.06 (C), 127.13 (CH), 127.79
CH), 128.14 (CH), 130.17 (CH), 134.11 (C), 145.71 (C), 157.35
(
4
C), 174.15 (C) ppm. IR (ATR): ν˜ = 2925 (s), 2855 (m), 1720 (vs),
(–)-Ethyl (3aR,11bS)-2,3,3a,4,5,11b-Hexahydro-1H-cyclopenta[a]-
–1
454 (w), 1376 (w), 1191 (m) cm . MS (EI): m/z (%) = 309 (31)
1
acridine-3a-carboxylate (trans-5a): H NMR (CDCl
0.94 (t, J = 7.2 Hz, 3 H, OCH CH ), 1.62–1.70 (m, 1 H, 1-H),
.91–2.03 (m, 3 H, 4-H, 2 2-H), 2.21 (dq, J = 6.8, J = 11.5 Hz, 1
3
, 500 MHz): δ
+
M ], 236 (50), 235 (100), 193 (19). HR-MS: calcd. for C20H23NO
2
=
1
2
3
20
3
7
09.1729, found 309.1728. [α]
D 3
= –109 (c = 4.75 in CDCl ). M.p.
6–77 °C. C20 (309.40): calcd. C 77.64, H 7.49, N 4.53;
H
23NO
2
H, 3-H), 2.26–2.34 (m, 2 H, 1-H, 3-H), 2.69 (ddd, J = 1.8, J = 8.0,
J = 13.1 Hz, 1 H, 4-H), 3.04 (dd, J = 8.8, J = 10.4 Hz, 1 H, 11b-
H), 3.21 (ddd, J = 8.0, J = 10.6, J = 18.7 Hz, 1 H, 5-H), 3.32 (ddd,
J = 1.8, J = 8.2, J = 18.7 Hz, 1 H, 5-H), 3.85–3.92 (m, 2 H,
found C 77.25, H 7.49, N 4.46.
Conversion of Ketone trans-1c to Quinolines trans-4c/trans-5c Ac-
cording to General Procedure “Fe”: A mixture of trans-1c (500 mg,
2
.23 mmol), pTosOH·H
hyde 7 (360 mg, 2.97 mmol) gave after chromatography (SiO
EA, 5:1) compound trans-4c (500 mg, 1.62 mmol, 73%) in the first
fraction (R = 0.42) as a colorless solid (m.p. 144–145 °C). The
second fraction (R = 0.25) contained compound trans-5c (160 mg,
.52 mmol, 23%, light yellow solid, m.p. 117–118 °C).
2
O (424 mg, 2.23 mmol) and aminoalde-
2 3
OCH CH ), 7.43 (t, J = 7.1 Hz, 1 H, 8-H), 7.57–7.62 (m, 1 H, 9-
2
; PE/
H), 7.72 (d, J = 8.0 Hz, 1 H, 7-H), 7.75 (s, 1 H, 11-H), 7.95 (d, J
13
1
=
8.4 Hz, 1 H, 10-H) ppm. C{ H} NMR (CDCl
13.86 (CH , OCH CH ), 22.62 (CH , C-2), 25.21 (CH
, C-5), 32.19 (CH , C-4), 36.58 (CH , C-1), 50.18 (CH,
C-11b), 53.78 (C, C-3a), 60.06 (CH , OCH CH ), 125.48 (CH, C-
), 127.08 (CH, C-7), 127.13 (C, C-10a), 128.25 (CH, C-10), 128.26
CH, C-9), 130.62 (CH, C-11), 133.97 (C, C-11a), 146.26 (C, C-6a),
58.82 (C, C-5a), 174.79 (C, CO Et) ppm. IR (ATR): ν˜ = 3054
vw), 2955 (m), 2872 (w), 1715 (vs), 1491 (w), 1456 (w), 1225 (w),
3
, 125 MHz): δ
f
=
3
2
3
2
2
, C-3),
f
3
1.48 (CH
2
2
2
0
2
2
3
8
(
1
(
(+)-Methyl (6aS,11aR)-6a,7,8,9,10,11,11a,12-Octahydro-6H-cyclo-
1
hepta[b]acridine-11a-carboxylate (trans-4c):
3
H NMR (CDCl ,
2
500 MHz): δ = 1.38–1.52 (m, 2 H), 1.53–1.76 (m, 3 H), 1.80–1.98
(m, 3 H), 1.98–2.06 (m, 1 H), 2.06–2.24 (m, 2 H), 3.12–3.20 (m, 2
1814
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1811–1816

Regioselectivity of Friedländer Quinoline Syntheses
H), 2.95 (d, J = 16.1 Hz, 1 H), 3.32 (d, J = 16.1 Hz, 1 H), 3.53 (s,
3 2
+69 (c = 3.65 in CDCl ). M.p. 80–81 °C. C19H21NO (295.38):
3
H), 7.42 (t, J = 7.3 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.69 (d,
calcd. C 77.26, H 7.17, N 4.74; found C 77.04, H 7.19, N 4.69.
J = 8.0 Hz, 1 H), 7.82 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H) ppm.
(
+)-Ethyl (3aR,11bR)-2,3,3a,4,5,11b-Hexahydro-1H-cyclopenta[a]-
13
1
C{ H} NMR (CDCl
8.92 (CH ), 31.59 (CH
4.00 (CH), 49.29 (C), 51.44 (CH
3
, 125 MHz): δ = 22.73 (CH
2
), 28.64 (CH
), 41.41 (CH
2
),
),
1
acridine-3a-carboxylate (cis-5a): H NMR (CDCl
3
, 500 MHz): δ =
2
4
1
1
2
2
2
), 38.36 (CH ), 39.74 (CH
2
2
2
1
1
2
.22 (t, J = 7.1 Hz, 3 H, OCH CH ), 1.62–1.70 (m, 1 H, 1-H),
2 3
3
), 125.54 (CH), 126.91 (CH),
.73–1.91 (m, 3 H, 2-H, 3-H), 1.98 (ddd, J = 4.7, J = 10.7, J =
4.3 Hz, 1 H, 4-H), 2.24–2.85 (m, 3 H, 3-H, 4-H, 1-H), 3.01 (ddd,
27.02 (C), 128.28 (CH), 128.59 (CH), 129.51 (C), 134.79 (CH),
46.69 (C), 158.70 (C), 176.14 (C) ppm. IR (ATR): ν˜ = 2922 (m),
860 (w), 2359 (w), 2340 (w), 1723 (vs), 1492 (m), 1446 (m), 1431
J = 4.7, J = 10.7, J = 17.2 Hz, 1 H, 5-H), 3.10 (dt, J = 17.2, J =
5
4
1
7
1
.2 Hz, 1 H, 5-H), 3.85 (dd, J = 9.2, J = 9.6 Hz, 1 H, 11b-H), 4.08–
.20 (m, 2 H, OCH CH ), 7.41–7.47 (m, 1 H, 9-H), 7.59–7.64 (m,
H, 8-H), 7.72 (d, J = 4.9 Hz, 1 H, 10-H), 7.91 (s, 1 H, 11-H),
–1
+
(
m), 1416 (m), 1188 (s) cm . MS (EI): m/z (%) = 309 (30) [M ],
2
3
2
3
1
50 (50), 249 (100), 193 (28). HR-MS: calcd. for C20H23NO
2
09.1729, found 309.1729. [α]2
0
D
3
= +108 (c = 2.76 in CDCl ). M.p.
1
3
1
.97 (d, J = 8.5 Hz, 1 H, 7-H) ppm. C{ H} NMR (CDCl
25 MHz): δ = 14.12 (OCH CH ), 23.96 (CH , C-2), 29.93 (CH
, C-5), 36.57 (CH , C-1), 38.07 (CH
CH, C-11b), 51.23 (C, C-3a), 60.70 (OCH CH ), 125.55 (CH, C-
9), 126.94 (CH, C-10), 127.37 (C, C-10a), 128.25 (CH, C-8), 128.61
CH, C-7), 132.90 (C, C-11a), 135.24 (CH, C-11), 146.33 (C, C-6a),
3
,
44–145 °C. C20 (309.40): calcd. C 77.64, H 7.49, N 4.53;
H23NO
2
2
3
2
2
,
found C 77.85, H 7.45, N 4.54.
C-4), 30.99 (CH
2
2
2
, C-3), 45.27
(
2
3
(
–)-Methyl (5aR,13bS)-2,3,4,5,5a,6,7,13b-Octahydro-1H-cyclo-
1
hepta[a]acridine-5a-carboxylate (trans-5c):
H
NMR (CDCl
3
,
(
500 MHz): δ = 1.62–1.79 (m, 7 H), 2.00 (ddd, J = 6.3, J = 11.8, J
1
2
1
2
2
2
58.02 (C, C-5a), 176.97 (C, CO Et) ppm. IR (ATR): ν˜ = 3057 (w),
=
13.4 Hz, 1 H), 2.54–2.62 (m, 1 H), 2.08–2.18 (m, 1 H), 2.22–2.28
952 (m), 2870 (w), 1715 (s), 1491 (m), 1419 (m), 1250 (s), 1172 (s),
(m, 2 H), 2.93 (dd, J = 4.4, J = 9.5 Hz, 1 H), 3.04 (ddd, J = 6.2, J
–
1
+
161 (s), 751 (s) cm . MS (EI): m/z (%) = 295 (20) [M ], 266 (14),
=
1
11.7, J = 17.7 Hz, 1 H), 3.15 (ddd, J = 3.5, J = 6.3, J = 17.7 Hz,
H), 3.52 (s, 3 H), 7.40–7.45 (m, 1 H), 7.57–7.62 (m, 1 H), 7.72
21 (100), 180 (18), 167 (8). HR-MS: calcd. for C19
H
21NO
2
2
0
95.1572, found 295.1572. [α]
D
= +26 (c = 7.5 in CDCl
3
).
(
d, J = 8.1 Hz, 1 H), 7.95 (d, J = 8.4 Hz, 1 H), 8.04 (s, 1 H) ppm.
13
1
19 21 2
C H NO (295.38): calcd. C 77.26, H 7.17, N 4.74; found C
7
C{ H} NMR (CDCl
6.94 (CH ), 30.47 (CH
5.91 (CH), 49.40 (C), 51.27 (CH
3
, 125 MHz): δ = 25.10 (CH
2
), 26.59 (CH
), 40.14 (CH
2
),
),
7.52, H 7.12, N 4.78.
2
4
1
1
2
2
2
), 31.18 (CH ), 36.46 (CH
2
2
2
3
), 125.38 (CH), 127.29 (C),
Conversion of Ketone cis-1b to Quinolines cis-4b/cis-5b According to
General Procedure “Fe”: A mixture of cis-1b (500 mg, 2.23 mmol),
27.31 (CH), 127.90 (CH), 128.49 (CH), 132.15 (CH), 135.19 (C),
45.75 (C), 158.00 (C), 175.70 (C) ppm. IR (ATR): ν˜ = 2927 (m),
860 (w), 2360 (w), 2342 (w), 1724 (vs), 1455 (m), 1415 (m), 1259
pTosOH·H
.40 mmol) gave after chromatography (SiO
pound cis-4b (271 mg, 0.88 mmol, 40%) in the first fraction (R
2
O (424 mg, 2.23 mmol) and aminoaldehyde 7 (410 mg,
3
2
; PE/EA, 3:1) com-
–1
+
(m) 1015 (s) cm . MS (EI): m/z (%) = 309 (67) [M ], 249 (100),
f
=
1
3
80 (23), 168 (45). HR-MS: calcd. for C20
H
23NO
2
309.1729, found
). M.p. 117–118 °C.
(309.40): calcd. C 77.64, H 7.49, N 4.53; found C
7.81, H 7.46, N 4.54.
0
=
.39) as a colorless solid (m.p. 87–88 °C). The second fraction (R
f
0.30) contained cis-5b (349 mg, 1.13 mmol, 51%, m.p. 59–60 °C).
09.1729. [α]2
0
D 3
= –272 (c = 0.90 in CDCl
20 2
C H23NO
7
(
+)-Ethyl (6aR,10aR)-6,6a,7,8,9,10,10a,11-Octahydrobenzo[b]acrid-
1
ine-10a-carboxylate (cis-4b): H NMR (CDCl
(
1
(
2
1
1
1
1
2
3
1
1
3
, 500 MHz): δ = 1.16
Conversion of Ketone cis-1a to Quinolines cis-4a/cis-5a According to
General Procedure “Fe”: A mixture of cis-1a (500 mg, 2.38 mmol),
t, J = 7.1 Hz, 3 H), 1.33 (dq, J = 3.4, J = 15.6 Hz, 1 H), 1.41–
.52 (m, 1 H), 1.52–1.62 (m, 1 H), 1.64–1.73 (m, 2 H), 1.73–1.80
m, 2 H), 1.88 (ddd, J = 4.4, J = 12.0, J = 13.2 Hz, 1 H), 2.53–
pTosOH·H
.89 mmol) gave after chromatography (SiO
pound cis-4a (317 mg, 1.07 mmol, 45%) in the first fraction (R
.57) as a light yellow solid (m.p. 80–81 °C). The second fraction
= 0.50) contained compound cis-5a (373 mg, 1.26 mmol, 53%,
colorless oil).
2
O (452 mg, 2.38 mmol) and aminoaldehyde 7 (350 mg,
2
2
; PE/EA, 2:1) com-
.60 (m, 1 H), 2.96 (dd, J = 2.9, J = 18.3 Hz, 1 H), 3.24 (d, J =
7.1 Hz, 1 H), 3.25 (dd, J = 6.5, J = 18.2 Hz, 1 H), 3.32 (d, J =
7.1 Hz, 1 H), 4.05–4.16 (m, 2 H), 7.41–7.46 (m, 1 H), 7.58–63 (m,
H), 7.72 (d, J = 8.0 Hz, 1 H), 7.87 (s, 1 H), 7.95 (d, J = 8.5 Hz,
f
=
0
(R
f
13
1
H) ppm. C{ H} NMR (CDCl
1.10 (CH ), 24.62 (CH ), 28.02 (CH
5.63 (CH), 37.18 (CH ), 45.57 (C), 60.46 (CH
3
, 125 MHz): δ = 13.95 (CH
3
),
),
2
2
2
), 30.64 (CH ), 33.15 (CH
2
2
(
+)-Ethyl (3aR,11aR)-2,3,3a,4,11,11a-Hexahydro-1H-cyclopenta-
2
2
), 125.36 (CH),
1
[b]acridine-11a-carboxylate (cis-4a): H NMR (CDCl
3
, 500 MHz):
CH ),
.40 (ddd, J = 6.4, J = 10.0, J = 12.7 Hz, 1 H, 1-H), 1.46–1.54 (m,
26.74 (CH), 127.06 (C), 128.03 (CH), 128.08 (C), 128.36 (CH),
34.87 (CH), 146.74 (C), 156.76 (C), 176.65 (C) ppm. IR (ATR): ν˜
δ = 1.08–1.17 (m, 1 H, 3-H), 1.23 (t, J = 7.2 Hz, 3 H, OCH
2
3
1
1
2
=
(
3
2977 (w), 2928 (m), 2856 (w), 1720 (vs), 1493 (m), 1450 (m), 1424
H, 2-H), 1.54–1.62 (m, 1 H, 2-H), 1.97–2.04 (m, 1 H, 3-H), 2.18–
.25 (m, 1 H, 1-H), 2.84 (d, J = 14.6 Hz, 1 H, 11-H), 2.93 (dd, J
–
1
m), 1288 (m), 1215 (s), 1185 (s), 750 (s) cm . MS (EI): m/z (%) =
+
09 (24) [M ], 235 (100), 193 (19), 180 (15), 168 (13). HR-MS:
=
1
(
5.3, J = 14.4 Hz, 1 H, 4-H), 2.99 (ddd, J = 5.6, J = 8.0, J =
3.9 Hz, 1 H, 3a-H), 3.18 (dd, J = 5.9, J = 14.4 Hz, 1 H, 4-H), 3.30
d, J = 14.6 Hz, 1 H, 11-H), 4.10–4.16 (m, 2 H, OCH CH ), 7.46–
2
0
calcd. for C20
7
H 7.49, N 4.53; found C 77.82, H 7.46, N 4.56.
H23NO
2
309.1729, found 309.1728. [α]
D
= +95 (c =
.5 in CDCl ). M.p. 87–88 °C. C20H23NO (309.40): calcd. C 77.64,
3 2
2
3
7.50 (m, 1 H, 8-H), 7.62–7.67 (m, 1 H, 7-H), 7.75 (d, J = 7.5 Hz,
1
H, 9-H), 7.83 (s, 1 H, 10-H), 8.03 (d, J = 8.4 Hz, 1 H, 6-H) ppm.
(–)-Ethyl (4aR,12bR)-1,2,3,4,4a,5,6,12b-Octahydrobenzo[a]acridine-
13
1
1
C{ H} NMR (CDCl
3
, 125 MHz): δ = 14.15 (OCH
, C-3), 36.94 (CH , C-11 or C-4), 37.26
, C-4 or C-11), 38.42 (CH , C-1), 42.30 (CH, C-3a), 52.70 (C, 1.80 (m, 2 H), 1.81–1.89 (m, 1 H), 1.90–1.96 (m, 1 H), 2.12–2.19
CH ), 125.69 (CH, C-8), 127.12 (CH, C-9), (m, 1 H), 2.40 (ddd, J = 6.7, J = 11.5, J = 13.4 Hz, 1 H), 3.12 (ddd,
27.72 (C, C-9a), 128.58 (CH, C-6), 128.59 (CH, C-7), 130.16 (C, J = 7.0, J = 11.5, J = 18.5 Hz, 1 H), 3.23 (ddd, J = 2.7, J = 6.7, J
C-10a), 133.94 (CH, C-10), 146.99 (C, C-5a), 160.63 (C, C-4a), = 18.5 Hz, 1 H), 3.45 (dd, J = 4.6, J = 11.6 Hz, 1 H), 4.05 (dq, J
77.76 (C, CO Et) ppm. IR (ATR): ν˜ = 3058 (w), 2954 (m), 2867 = 2.1, J = 7.1 Hz, 2 H), 7.43 (t, J = 7.2 Hz, 1 H), 7.58–7.62 (m, 1
w), 1715 (vs), 1420 (m), 1277 (s), 1184 (vs), 1145 (s), 755 (vs) cm .
2
CH
3
), 25.11
4a-carboxylate (cis-5b): H NMR (CDCl
3
, 500 MHz): δ = 1.14 (t,
(
(
CH
CH
2
, C-2), 33.95 (CH
2
2
J = 7.1 Hz, 3 H), 1.41–1.61 (m, 3 H), 1.61–1.70 (m, 1 H), 1.71–
2
2
C-11a), 60.75 (OCH
1
2
3
1
(
2
–
1
H), 7.72 (d, J = 7.9 Hz, 1 H), 7.89 (s, 1 H), 7.95 (d, J = 8.5 Hz, 1
+
13
1
MS (EI): m/z (%) = 295 (25) [M ], 221 (100), 180 (18), 167 (10).
HR-MS: calcd. for C19
H) ppm. C{ H} NMR (CDCl
3
, 125 MHz): δ = 13.94 (CH
), 30.31 (CH ), 32.78 (CH
3
),
),
2
0
H21NO
2
295.1572, found 295.1572. [α]
D
=
20.95 (CH ), 24.61 (CH ), 25.18 (CH
2
2
2
2
2
Eur. J. Org. Chem. 2008, 1811–1816
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1815

C. L. Diedrich, D. Haase, W. Saak, J. Christoffers
FULL PAPER
3
1
1
4.29 (CH
2
), 41.02 (CH), 45.27 (C), 60.30 (CH
2
), 125.29 (CH),
[2] a) H. Suzuki, N. S. Aly, Y. Wataya, H.-S. Kim, I. Tamai, M.
Kita, D. Uemura, Chem. Pharm. Bull. 2007, 55, 821–824; b) A.
Savarino, M. B. Lucia, R. ter Heine, E. Rastrelli, S. Rutella, G.
Majori, A. Huitema, J. R. Boelaert, R. Cauda, Drug Dev. Res.
2006, 67, 806–817; c) S. Hostyn, B. U. W. Maes, G. van Baelen,
A. Gulevskaya, C. Meyers, K. Smits, Tetrahedron 2006, 62,
26.92 (CH), 127.14 (C), 127.98 (CH), 128.44 (CH), 134.85 (C),
34.86 (CH), 146.56 (C), 156.91 (C), 176.53 (C) ppm. IR (ATR): ν˜
2931 (m), 2856 (m), 1721 (s), 1491 (w), 1418 (w), 1239 (s), 1226
=
–1
+
(
(
3
s), 909 (s), 727 (vs) cm . MS (EI): m/z (%) = 309 (27) [M ], 280
12), 235 (100), 193 (12), 180 (13). HR-MS: calcd. for C20
H23NO
2
4
676–4684; d) C. Biot, J. Dessolin, I. Ricard, D. Dive, J. Or-
09.1729, found 309.1727. [α]2
(309.40): calcd. C 77.64, H 7.49, N 4.53; found C
7.70, H 7.48, N 4.51.
0
D 3
= –67 (c = 7.0 in CDCl ).
ganomet. Chem. 2004, 689, 4678–4682. Reviews: e) P. L. Olli-
aro, W. R. J. Taylor, J. Exp. Biol. 2003, 206, 3753–3759; f) M.
Foley, L. Tilley, Pharmacol. Ther. 1998, 79, 55–87.
20 2
C H23NO
7
Conversion of Ketone cis-1c to Quinolines cis-4c/cis-5c According to
General Procedure “Fe”: A mixture of cis-1c (500 mg, 2.23 mmol),
[3] a) S. P. Chavan, A. B. Pathak, U. R. Kalkote, Synlett 2007,
2635–2638; b) C.-T. Tang, M. Babjak, R. J. Anderson, A. E.
Greene, A. Kanazawa, Org. Biomol. Chem. 2006, 4, 3757–3759;
c) R. J. Anderson, G. B. Raolji, A. Kanazawa, A. E. Greene,
Org. Lett. 2005, 7, 2989–2991; d) T. Brunin, J.-P. Henichart,
B. Rigo, Tetrahedron 2005, 61, 7916–7923. e) Review: W. Du,
Tetrahedron 2003, 59, 8649–8687.
pTosOH·H
.40 mmol) gave after chromatography (SiO
pound cis-4c (210 mg, 0.68 mmol, 30%) in the first fraction (R
.45) as a light yellow solid (m.p. 64–64 °C). The second fraction
= 0.34) contained cis-5c (330 mg, 1.07 mmol, 48%, m.p. 101–
02 °C).
2
O (424 mg, 2.23 mmol) and aminoaldehyde 7 (410 mg,
3
2
; PE/EA, 3:1) com-
f
=
0
(R
f
[
4] a) P. Friedländer, Ber. Dtsch. Chem. Ges. 1882, 15, 2572–2575.
Reviews: b) C.-C. Cheng, S.-J. Yan, Org. React. 1982, 28, 37–
201; c) R. P. Thummel, Synlett 1992, 1–12.
1
(
+)-Methyl (6aR,11aR)-6a,7,8,9,10,11,11a,12-Octahydro-6H-cyclo-
1
hepta[b]acridine-11a-carboxylate (cis-4c):
00 MHz): δ = 1.30–1.39 (m, 1 H), 1.42–1.53 (m, 3 H), 1.62–1.74
m, 3 H), 1.76–1.84 (m, 2 H), 2.12–2.20 (m, 1 H), 2.85–2.87 (m, 1
H), 2.87–2.91 (m, 2 H), 3.09–3.17 (m, 1 H), 3.25 (d, J = 15.3 Hz,
H), 3.59 (s, 3 H), 7.42–7.45 (m, 1 H), 7.60–7.64 (m, 1 H), 7.72
d, J = 8.1 Hz, 1 H), 7.80 (s, 1 H), 8.00 (d, J = 8.5 Hz, 1 H) ppm.
H
NMR (CDCl
3
,
[5]
a) R. Martinez, D. J. Ramon, M. Yus, Eur. J. Org. Chem. 2007,
1599–1605; b) S. V. Ryabukhin, D. M. Volochnyuk, A. S. Plas-
kon, V. S. Naumchik, A. A. Tolmachev, Synthesis 2007, 1214–
1224; c) A. Shaabani, E. Soleimani, Z. Badri, Synth. Commun.
5
(
2007, 37, 629–635; d) C.-S. Jia, Y.-W. Dong, S.-J. Tu, G.-W.
1
Wang, Tetrahedron 2007, 63, 892–897; e) S. Atechian, N. Nock,
R. D. Norcross, H. Ratni, A. W. Thomas, J. Verron, R. Mascia-
dri, Tetrahedron 2007, 63, 2811–2823; f) D. Yang, K. Jiang, J.
Li, F. Xu, Tetrahedron 2007, 63, 7654–7658; g) C.-S. Jia, Z.
Zhang, S.-J. Tu, G.-W. Wang, Org. Biomol. Chem. 2006, 4, 104–
(
1
3
1
C{ H} NMR (CDCl
9.66 (CH ), 32.81 (CH
9.90 (CH ), 50.59 (C), 52.04 (CH
3
, 125 MHz): δ = 24.84 (CH
), 37.23 (CH ), 38.65 (CH
), 125.55 (CH), 127.07 (CH),
2
), 27.85 (CH
2
),
2
3
1
1
2
2
2
2
2
), 38.69 (CH),
2
3
27.49 (C), 128.45 (CH), 128.54 (CH), 129.35 (C), 133.46 (CH),
46.94 (C), 159.75 (C), 177.77 (C) ppm. IR (ATR): ν˜ = 2924 (m),
855 (w), 1726 (vs), 1495 (w), 1459 (w), 1427 (m), 1194 (m), 751
110; h) J. Wu, H.-G. Xia, K. Gao, Org. Biomol. Chem. 2006,
4, 126–129; i) G.-W. Wang, C.-S. Jia, Y.-W. Dong, Tetrahedron
Lett. 2006, 47, 1059–1063; j) C. S. Cho, W. X. Ren, S. C. Shim,
Tetrahedron Lett. 2006, 47, 6781–6785; k) G. C. Muscia, M.
Bollini, J. P. Carnevale, A. M. Bruno, S. E. Asis, Tetrahedron
Lett. 2006, 47, 8811–8815.
–1
+
(m) cm . MS (EI): m/z (%) = 309 (38) [M ], 266 (9), 250 (100),
2
3
6
06 (22), 193 (26), 180 (23). HR-MS: calcd. for C20H23NO
2
09.1729, found 309.1729. [α]2
0
D
3
= +23 (c = 8.0 in CDCl ). M.p. 64–
[
[
6] a) J. Christoffers, Synlett 2006, 318–320; b) C. L. Diedrich, W.
Frey, J. Christoffers, Eur. J. Org. Chem. 2007, 4731–4737.
7] a) B. Kreidler, A. Baro, J. Christoffers, Eur. J. Org. Chem. 2005,
5 °C.
(
–)-Methyl (5aR,13bR)-2,3,4,5,5a,6,7,13b-Octahydro-1H-cyclohep-
1
ta[a]acridine-5a-carboxylate (cis-5c): H NMR (CDCl
3
, 500 MHz):
5339–5348; b) B. Kreidler, A. Baro, W. Frey, J. Christoffers,
δ = 1.20–1.31 (m, 1 H), 1.45–1.57 (m, 2 H), 1.64–1.78 (m, 3 H),
Chem. Eur. J. 2005, 11, 2660–2667; c) B. Kreidler, A. Baro, J.
Christoffers, Synlett 2005, 465–468; d) J. Christoffers, H.
Scharl, W. Frey, A. Baro, Eur. J. Org. Chem. 2004, 2701–2706;
e) J. Christoffers, H. Scharl, W. Frey, A. Baro, Org. Lett. 2004,
6, 1171–1173; f) J. Christoffers, H. Scharl, Eur. J. Org. Chem.
1
2
.78–1.86 (m, 1 H), 1.86–1.94 (m, 2 H), 1.94–2.02 (m, 1 H), 2.23–
.33 (m, 2 H), 2.94 (ddd, J = 5.9, J = 13.0, J = 18.6 Hz, 1 H), 3.21
(ddd, J = 2.1, J = 5.6, J = 18.3 Hz, 1 H), 3.59 (s, 3 H), 3.78 (d, J
=
=
9.6 Hz, 1 H), 7.37–7.43 (m, 1 H), 7.56–7.61 (m, 1 H), 7.71 (d, J
2
002, 1505–1508. g) Review: J. Christoffers, Chem. Eur. J. 2003,
8.1 Hz, 1 H), 7.93 (d, J = 8.5 Hz, 1 H), 7.97 (s, 1 H) ppm.
13
1
9, 4862–4867.
C{ H} NMR (CDCl
3
, 125 MHz): δ = 23.15 (CH
), 31.35 (CH ), 31.52 (CH ), 36.71 (CH
5.23 (CH), 49.23 (C), 52.49 (CH
28.02 (C), 128.58 (CH), 129.19 (CH), 136.69 (C), 137.11 (CH),
47.12 (C), 157.35 (C), 177.63 (C) ppm. IR (ATR): ν˜ = 2925 (m),
2
), 30.19 (CH
), 39.79 (CH
2
),
),
[
8] a) J. Christoffers, K. Schuster, Chirality 2003, 15, 777–782; b)
J. Christoffers, A. Mann, Chem. Eur. J. 2001, 7, 1014–1027; c)
J. Christoffers, A. Mann, Angew. Chem. 2000, 112, 2871–2874;
Angew. Chem. Int. Ed. 2000, 39, 2752–2754; d) J. Christoffers,
U. Rößler, T. Werner, Eur. J. Org. Chem. 2000, 701–705.
3
4
1
1
2
1.19 (CH
2
2
2
2
2
3
), 125.92 (CH), 127.52 (CH),
855 (w), 1722 (vs), 1490 (m), 1420 (m), 1244 (s), 1195 (s), 1166 [9] a) B. R. McNaughton, B. L. Miller, Org. Lett. 2003, 5, 4257–
–1
+
(vs), 749 (s), 731 (s) cm . MS (EI): m/z (%) = 309 (20) [M ], 249
4259; b) M. K. Chaudhuri, S. Hussain, J. Chem. Sci. 2006, 118,
199–202.
(
C
100), 220 (9), 206 (17), 194 (18), 180 (24). HR-MS: calcd. for
309.1729, found 309.1728. [α]2
0
[10] a) C. A. Merlic, S. Motamed, B. Quinn, J. Org. Chem. 1995,
20
H23NO
2
D
= –101 (c = 17.5 in
60, 3365–3369; b) A.-H. Li, E. Ahmed, X. Chen, M. Cox, A. P.
CDCl
3 2
). M.p. 101–102 °C. C20H23NO (309.40): calcd. C 77.64, H
Crew, H.-Q. Dong, M. Jin, L. Ma, B. Panicker, K. W. Siu,
A. G. Steinig, K. M. Stolz, P. A. R. Tavares, B. Volk, Q. Weng,
D. Werner, M. J. Mulvihill, Org. Biomol. Chem. 2007, 5, 61–64.
11] CCDC-647822 (trans-4b), -647823 (trans-4c), -647824 (cis-4a),
7.49, N 4.53; found C 77.63, H 7.45, N 4.56.
[
Acknowledgments
This work was generously supported by the Fonds der Chemischen
Industrie.
-
647826 (cis-4b), -647825 (trans-5c), and -647821 (cis-5c) con-
tain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[
1] a) M. Hesse, Alkaloids – Nature’s Curse or Blessing?, Wiley-
VCH, Weinheim, 2002; b) E. Breitmaier, Alkaloide, Teubner,
Stuttgart, 1997.
Received: December 12, 2007
Published Online: February 13, 2008
1816
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1811–1816