Diastereoselective synthesis of linear-fused tricyclic nitrogen heterocycles by a tandem reduction-reductive amination reaction

Article abstract of DOI:10.1002/jhet.5570400113

A two-step diastereoselective synthesis of linear-fused tricyclic nitrogen heterocycles has been developed from cyclic β-ketoesters. The cyclization substrates are readily prepared by alkylation of the methyl 2-oxo-cycloalkanecarboxylates with 2-nitrobenz

Full text of DOI:10.1002/jhet.5570400113

Jan-Feb 2003
Diastereoselective Synthesis of Linear-Fused Tricyclic Nitrogen
Heterocycles by a Tandem Reduction-Reductive Amination Reaction
101
Richard A. Bunce,* Derrick M. Herron [1a], Jason R. Lewis [1a],
Sharadsrikar V. Kotturi and Elizabeth M. Holt [1b]
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071, USA
Received July 12, 2002
A two-step diastereoselective synthesis of linear-fused tricyclic nitrogen heterocycles has been developed
from cyclic β-ketoesters. The cyclization substrates are readily prepared by alkylation of the methyl 2-oxo-
cycloalkanecarboxylates with 2-nitrobenzyl bromide. Hydrogenation of these substrates initiates a reaction
sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the resulting hydroxyl-
amine or aniline nitrogen with the cycloalkanone and (3) reduction of the imine. The products are isolated
in high yield as single diastereomers having the trans-fused ring junction. The observed selectivity is ratio-
nalized in terms of a steric effect imposed by the ester group in the final reductive amination step which
directs the incoming hydrogen to the opposite face of the molecule. By comparison, reductive cyclizations
of substrates lacking the stereodirecting ester group give mixtures of cis and trans products with a preference
for the cis-fused heterocycle.
J. Heterocyclic Chem., 40, 101 (2003).
Introduction.
acetic acid then gave 5a and 5b in 70% and 62% overall
yields, respectively [7].
The search for selective chemical transformations is a
continuing goal. We recently reported [2] a diastereoselec-
tive tandem reduction-reductive amination reaction for the
synthesis of cis-substituted methyl 2-alkyl-1,2,3,4-tetrahy-
droquinoline-4-carboxylates. In this sequence, the selec-
tivity of the reductive ring closures was attributed to steric
hindrance created by a carboxylic ester group β to the final
imine intermediate which controlled the orientation of
hydrogen addition. The current study extends the tandem
reduction-reductive amination reaction to substrates bear-
ing a carboxylic ester group α to the final imine and estab-
lishes the role of the ester in controlling the stereochemical
outcome of the reaction. Finally, since several octahy-
droacridine derivatives are known to express antidepres-
sant activity, structures prepared in this study may possess
useful pharmaceutical properties [3].
Results and Discussion.
The substrates needed for our cyclization studies were
prepared by alkylation of methyl 2-oxocycloalkanecar-
boxylates (1a-c) with 2-nitrobenzyl bromide [4].
Alkylation of the five- and seven-membered cyclic
ketoesters 1a and 1c using anhydrous potassium carbonate
in refluxing acetone gave 2a and 2c in 94% and 82%
yields, respectively [5]; similar treatment of methyl
2-oxocyclohexanecarboxylate (1b), however, resulted in a
complex mixture of products containing predominantly O-
alkylated material. Successful conversion of 1b to 2b was
achieved in 64% yield using potassium fluoride-on-
alumina as the base in dry acetonitrile [6]. Substrates lack-
ing the α ester group were prepared in two steps.
Alkylation of tert-butyl 2-oxocycloalkanecarboxylates 3a
and 3b with 2-nitrobenzyl bromide, as outlined above for
the five- and six-membered cyclic systems, gave 4a and
4b. Ester cleavage and decarboxylation with trifluoro-
Treatment of the 2-nitrobenzyl-substituted ketoesters
2a-c under catalytic hydrogenation conditions (4 atmos-
pheres of hydrogen, 5% palladium-on-carbon, methanol,
30°, 4-6 hours) gave, in each case, a single product in 78-
91% yield. X-ray crystallographic analysis of these prod-
ucts allowed assignment of the structures as 6a-c, respec-
tively. In each product, the ring junction formed in the
final reductive amination step had the trans geometry,
even in the 6-6-5 fused structure where some of the cis
product would be expected [8].

102
R. A. Bunce, D. M. Herron, J. R. Lewis, S. V. Kotturi and E. M. Holt
Vol. 40
To assess the importance of the ester group in direct-
ing an ester group α to the ketone, gave exclusively the
trans-fused heterocycle while 5a-b, lacking the ester, gave
mixtures of cis and trans products with a preference for the
cis-fused system.
ing the stereochemical outcome of the reaction, five- and
six-membered cyclic substrates lacking the ester were
subjected to the same catalytic reduction conditions.
The cyclopentanone substrate 5a gave an 86% yield of
the fused-ring product as two isomers, 7a and 8a, in a
ratio of 3.8:1; the six-ring substrate 5b gave an 80%
yield of 7b and 8b in a ratio of 1.7:1. These mixtures
were easily separated by preparative thin layer chro-
matography, and structure elucidation was carried out
using a combination of COSY-45 [9] and NOESY [10]
techniques. Analysis of the spectra for the major prod-
ucts showed a correlation between the signals for the
bridgehead protons indicating a cis ring junction [11].
The minor isomers lacked this correlation and were
assigned as the trans-fused structures.
The mechanism of the reaction involves (1) reduction of
the aromatic nitro group, (2) condensation of the resulting
hydroxylamine or aniline [15] with the cycloalkanone, and
(3) reduction of the imine. The product from cyclization
of the reduced nitrogen intermediate with the ester group
was not detected. The diastereoselectivity in the ring clo-
sures of 2a-c is rationalized in terms of a steric effect
imposed by the ester group which directs the incoming
hydrogen to the opposite face of the molecule giving the
trans ring junction (see Scheme 3). We have noted similar
selectivity in other reductive cyclizations [2,15] when an
ester group was located α or β to a reducing imine or
enamine.
The preference for the cis-fused products from sub-
strates 5a-b is rationalized by analyzing molecular models.
In the final imine reduction, the bridgehead α carbon is
substituted by a sterically small hydrogen. In the expected
conformation, the fused cycloalkane ring tilts away from
this hydrogen creating a molecular cavity that restricts
access to the bottom face of the molecule. Thus, hydrogen
is delivered predominantly from the top side to give the
cis-fused product (see Scheme 3).
Prior to this study, only the octahydroacridine system
had been reported in the literature [3,12]. Analogues vary-
ing the size of the saturated ring have not previously been
described. Cis- and trans-1,2,3,4,4a,9,9a,10-octahy-
droacridine have been prepared by three synthetic routes
[13]. In the first [12c], treatment of 1,2,3,4-tetrahydroacri-
dine under catalytic hydrogenation conditions (1 atmos-
phere of hydrogen, Pd-Pt-C, methanol, 25°) gave the cis
octahydroacridine in 93% yield. In an alternative proce-
dure [3], reduction of 1,2,3,4-tetrahydroacridine with 95%
formic acid at 170-175° followed by boiling with concen-
trated hydrochloric acid [14] gave a 2.7:1 mixture of
trans:cis octahydroacridines in 71% yield. Finally, a 3.2:1
trans:cis mixture of octahydroacridines was formed in
96% yield by ring expansion of 4a-methoxyaminocyclo-
hex[a]indan during reduction with lithium aluminum
hydride [12f]. In the current study, substrates 2a-c, bear-
In summary, we have developed a simple, high-yield
synthesis of linear-fused tricyclic nitrogen heterocycles
based on a tandem reduction-reductive amination reaction.
The current synthesis is more versatile than earlier synthe-
ses in permitting variation of the ring sizes in the final het-
erocyclic targets. The transformation shows a high degree
of trans diastereoselectivity when there is a large ester
group α to the imine intermediate in the final ring closure.
Without this stereodirecting group, the reaction gives mix-
tures of cis and trans products. We are continuing to
explore this process with the goal of preparing enantiomer-
ically pure products.

Jan-Feb 2003
Diastereoselective Synthesis of Linear-Fused Tricyclic Nitrogen Heterocycles
103
EXPERIMENTAL
Anal. Calcd. for C H NO : C, 62.95; H, 6.23. Found: C,
16 19 5
63.18; H, 6.34.
All reactions were run under dry nitrogen in oven-dried glass-
ware. Reactions were monitored by thin layer chromatography
on silica gel GF plates. Preparative separations were performed
using flash column chromatography [16] on silica gel (grade 62,
60-200 mesh) mixed with ultraviolet-active phosphor (Sorbent
Technologies no. 5) or thin layer chromatography on 20-cm x 20-
cm silica gel GF plates; band elution was monitored using a
hand-held ultraviolet lamp. Melting points were uncorrected.
Infrared spectra were run as thin films on sodium chloride disks
tert-Butyl (±)-1-[(2-Nitrophenyl)methyl]-2-oxocyclopentanecar-
boxylate (4a).
This compound (2.81 g, 8.81 mmole, 88%) was isolated as a
-1
1
light yellow oil; ir: 1750, 1727, 1530, 1355 cm ; H nmr: δ 7.89
(d, 1H, J = 8.0), 7.55-7.35 (complex, 3H), 3.68 (ABd, 1H, J =
14.2), 3.39 (ABd, 1H, J = 14.2), 2.41 (m, 2H), 2.09 (dd, 1H, J =
13
18.8, 8.5), 2.04-1.70 (complex, 3H), 1.41 (s, 9H);
C nmr: δ
214.5, 170.1, 150.8, 133.0, 132.7, 132.3, 127.8, 124.7, 82.4, 61.8,
38.0, 34.2, 33.5, 27.8, 19.6; hrms: m/z Calcd. for C H NO :
1
13
17 21
5
and were referenced to polystyrene. H and C nuclear mag-
netic resonance spectra were measured in deuteriochloroform at
300 MHz and 75 MHz, respectively, and were referenced to inter-
nal tetramethylsilane; coupling constants (J) have been given in
Hz. COSY-45 and NOESY experiments were performed on a
400 MHz instrument. High resolution mass spectra (electron
impact/direct probe) were obtained at 70 electron volts.
Commercial reagents and solvents were used as received.
Potassium carbonate was ground to a fine powder, dried under
vacuum at 120° for 24 hours and stored in an oven at 120°.
Potassium fluoride-on-alumina was prepared according to the
procedure of Yadav and co-workers [6] using neutral alumina
(60-325 mesh) obtained from Fisher Scientific. Compounds 3a
and 3b were prepared according to the method of Taylor and co-
workers [7].
319.1419; Found: 319.1419.
Anal. Calcd. for C H NO : C, 63.95; H, 6.58. Found: C,
17 21
5
63.76; H, 6.49.
Representative Procedure for the Alkylation of Alkyl (±)-2-
Oxocyclohexanecarboxylates: Methyl (±)-1-[(2-Nitrophenyl)-
methyl]-2-oxocyclohexanecarboxylate (2b).
Attempts to prepare this compound from 1b as described
above resulted predominantly in O-alkylation. The synthesis was
accomplished using the general procedure of Yadav and co-work-
ers [6]. To a solution of 1.56 g (10.0 mmole) of 1b and 2.59 g
(12.0 mmole) of 2-nitrobenzyl bromide in 30 mL of dry acetoni-
trile was added 4.80 g of potassium fluoride-on-alumina (30.0
mmole of potassium fluoride) and the mixture was stirred at
room temperature for 24 hours. At this time, a second charge of
1.20 g of potassium fluoride-on-alumina (7.5 mmole of potas-
sium fluoride) was added and the reaction was stirred for an addi-
tional 24 hours. The suspension was filtered, concentrated under
vacuum and flash chromatographed on a 40 cm x 2.5 cm silica
gel column eluted with increasing concentrations of ether in
hexane. Band 3 gave 1.86 g (6.39 mmole, 64%) of 2b as a light
Representative Procedure for the Alkylation of Alkyl (±)-2-
Oxocycloalkanecarboxylates: Methyl (±)-1-[(2-Nitrophenyl)-
methyl]-2-oxocyclopentanecarboxylate (2a).
The procedure of Barco and co-workers [5] was adapted. To a
solution of 1.42 g (10.0 mmole) of 1a and 2.59 g (12.0 mmole) of
2-nitrobenzyl bromide [4] in 50 mL of dry acetone was added
5.52 g (40.0 mmole) of anhydrous potassium carbonate. The sus-
pension was stirred and heated under reflux for 3 hours, then
cooled, filtered and concentrated. The resulting light yellow oil
was flash chromatographed on a 30 cm x 2.5 cm silica gel col-
umn eluted with increasing concentrations of ether in hexane.
The major band gave 2.60 g (9.39 mmole, 94%) of 2a as a light
yellow oil that crystallized upon standing at 0°, mp 30-31°; ir:
-1
1
yellow solid, mp 89-90°; ir: 1738, 1716, 1530, 1354 cm ;
nmr: δ 7.86 (d, 1H, J = 8.0), 7.47 (t, 1H, J = 7.6), 7.37 (t, 1H, J =
7.6), 7.25 (d, 1H, J = 7.7), 3.80 (ABd, 1H, J = 14.3), 3.64 (s, 3H),
3.33 (ABd, 1H, J = 14.3), 2.47 (m, 2H), 2.32 (dq, 1H, J = 13.0,
H
13
2.8), 2.00 (m, 1H), 1.72 (m, 1H), 1.70-1.40 (complex 3H);
C
nmr: δ 206.5, 171.2, 150.7, 133.4, 132.1, 131.5, 127.8, 124.8,
61.6, 52.5, 41.1, 36.0, 35.4, 27.3, 22.5; hrms: m/z Calcd. for
C H NO : 291.1106; Found: 291.1104.
-1
1
1756, 1728, 1530, 1355 cm ; H nmr: δ 7.90 (d, 1H, J = 8.1),
15 17
5
7.50 (t, 1H, J = 7.6), 7.40 (m, 2H), 3.74 (ABd, 1H, J = 14.3), 3.71
Anal. Calcd. for C H NO : C, 61.86; H, 5.84. Found: C,
15 17 5
(s, 3H), 3.43 (ABd, 1H, J = 14.3), 2.50-2.37 (complex, 2H), 2.19
61.97; H, 5.91.
13
(m, 1H), 2.02-1.77 (complex, 3H);
C nmr: δ 213.9, 171.3,
tert-Butyl (±)-1-[(2-Nitrophenyl)methyl]-2-oxocyclohexanecar-
boxylate (4b).
150.4, 132.9, 132.8, 131.9, 128.0, 124.8, 61.2, 52.8, 38.1, 34.7,
33.4, 19.5; hrms: m/z Calcd. for C H NO : 277.0950; Found:
14 15
5
This compound (2.63 g, 7.90 mmole, 79%) was isolated as a
light yellow oil; ir: 1716, 1530, 1355 cm ; H nmr: δ 7.81 (d,
277.0949.
Anal. Calcd. for C H NO : C, 60.65; H, 5.42. Found: C,
-1
1
14 15
5
1H, J = 8.0), 7.50-7.30 (complex, 3H), 3.61 (ABd, 1H, J = 14.3),
60.82; H, 5.49.
3.42 (ABd, 1H, J = 14.3), 2.52 (m, 2H), 2.31 (dq, 1H, J = 13.2,
Methyl (±)-1-[(2-Nitrophenyl)methyl]-2-oxocycloheptanecar-
boxylate (2c).
13
2.9), 2.05 (m, 1H), 1.77-1.56 (complex, 4H), 1.35 (s, 9H);
C
nmr: δ 207.1, 170.0, 150.9, 136.0, 133.6, 132.0, 127.5, 124.5,
This compound (2.49 g, 8.17 mmole, 82%) was isolated as a
light yellow solid, mp 72-73°; ir: 1739, 1716, 1530, 1353 cm ;
H nmr: δ 7.86 (d, 1H, J = 8.0), 7.48 (t, 1H, J = 7.6), 7.37 (t, 1H,
82.6, 62.6, 41.1, 36.6, 34.8, 27.7, 27.3, 22.6; hrms: m/z Calcd.
-1
for C H NO : 333.1576; Found: 333.1574.
18 23
5
1
Anal. Calcd. for C H NO : C, 64.86; H, 6.91. Found: C,
18 23
5
J = 7.6), 7.24 (d, 1H, J = 7.6), 3.84 (ABd, 1H, J = 14.3), 3.67 (s,
64.63; H, 6.86.
3H), 3.36 (ABd, 1H, J = 14.3), 2.62 (m, 1H), 2.48 (m, 1H), 1.80-
Representative Ester Cleavage-Decarboxylation: (±)-2-[(2-
Nitrophenyl)methyl]cyclopentanone (5a).
13
1.57 (complex, 7H), 1.38 (m, 1H);
C nmr: δ 208.2, 172.1,
150.8, 133.1, 132.2, 131.9, 127.8, 124.8, 63.7, 52.4, 41.8, 35.1,
31.9, 29.7, 25.8, 24.2; hrms: m/z Calcd for C
305.1263; Found: 305.1260.
H NO :
A solution of 2.75 g (8.62 mmole) of 4a in 25 mL of trifluo-
roacetic acid was stirred at room temperature for 48 hours, then
16 19 5

104
R. A. Bunce, D. M. Herron, J. R. Lewis, S. V. Kotturi and E. M. Holt
Vol. 40
concentrated under vacuum. The residue was diluted with ether
and washed with water (two times), sodium bicarbonate (four
times) and sodium chloride, dried (magnesium sulfate), and con-
centrated under vacuum. The brown oil was chromatographed on
a 30 cm x 2.5 cm silica gel column with increasing concentrations
of ether in hexane. The major band gave 1.51 g (6.90 mmole,
58.1, 51.4, 43.7, 40.3, 35.8, 28.1, 24.9, 22.7; hrms: m/z Calcd.
for C H NO : 245.1416; Found: 245.1416.
15 19
2
Anal. Calcd. for C H NO : C, 73.47; H, 7.76; N, 5.71.
15 19
2
Found: C, 73.66; H, 7.78; N, 5.68.
Methyl (±)-(5aS*,10aS*)-5,5a,6,7,8,9,10,10a,11-Octahydro-6H-
cyclohepta[b]quinoline-10a-carboxylate (6c).
-1
1
80%) of 5a as a yellow oil; ir: 1740, 1530, 1355 cm ; H nmr: δ
7.91 (d, 1H, J = 8.2), 7.53 (t, 1H, J = 7.6), 7.38 (d, 1H, J = 7.5), 7.37
(t, 1H, J = 7.6), 3.46 (dd, 1H, J = 13.8, 5.3), 2.82 (dd, 1H, J = 13.8,
8.5), 2.50 (m, 1H), 2.41 (dd, 1H, J = 18.4, 8.8), 2.22-1.95 (com-
This compound (0.66 g, 2.56 mmole, 78%) was isolated as a
-1
1
white solid, mp 130-131°; ir: 3400, 1728 cm ; H nmr: δ 6.97
(m, 2H), 6.63 (t, 1H, J = 7.5), 6.53 (d, 1H, J = 8.2), 3.60 (br s,
1H), 3.55 (s, 3H), 3.10 (dd, 1H, J = 10.5, 2.2), 3.06 (ABd, 1H, J =
15.5), 2.81 (ABd, 1H, J = 15.5), 2.39 (qm, 1H, J = 10.5), 2.05 (m,
13
plex, 3H), 1.77 (m, 1H), 1.56 (m, 1H); C nmr: δ 219.0, 149.7,
135.1, 132.9, 132.5, 127.4, 124.7, 50.2, 37.6, 32.3, 29.4, 20.4;
hrms: m/z Calcd. for C H NO : 219.0895; Found: 219.0894.
13
1H), 1.90-1.49 (complex, 6H), 1.46 (m, 2H); C nmr: δ 175.1,
12 13
3
Anal. Calcd. for C H NO : C, 65.75; H, 5.94. Found: C,
144.4, 129.0, 126.7, 121.1, 117.8, 114.8, 61.7, 51.4, 46.6, 40.4,
12 13
3
65.85; H, 6.02.
36.1, 32.6, 27.6, 25.7, 22.6; hrms: m/z Calcd. for C H NO :
16 21 2
259.1572; Found: 259.1570.
Anal. Calcd for C H NO : C, 74.13; H, 8.11; N, 5.41.
Found: C, 74.25; H, 8.18; N, 5.29.
(±)-2-[(2-Nitrophenyl)methyl]cyclohexanone (5b).
16 21
2
This compound (1.42 g, 6.09 mmole, 78%) was isolated as a
light yellow solid, mp 54-55°; ir: 1711, 1530, 1355 cm ;
nmr: δ 7.91 (d, 1H, J = 8.2), 7.49 (m, 2H), 7.35 (m, 1H), 3.48 (dd,
-1
1
H
Cyclization of 5a.
1H, J = 16.1, 8.8), 2.72 (m, 2H), 2.52-2.22 (complex, 2H), 2.10
(m, 2H), 1.88 (m, 1H), 1.65 (m, 2H), 1.44 (m, 1H); C nmr: δ
The reductive ring closure of 5a was carried out as described
for the synthesis of 6a above. Preparative thin layer chromatog-
raphy using 5-10% ether in hexanes gave two bands. Band 1
(fastest moving) contained product 7a; band 2 contained 8a.
13
211.7, 149.7, 135.6, 133.4, 132.7, 127.2, 124.7, 51.5, 42.3, 34.4,
32.7, 28.1, 25.3; hrms: m/z Calcd. for C H NO : 233.1052;
13 15
3
Found: 233.1053.
Anal. Calcd. for C H NO : C, 66.95; H, 6.44. Found: C,
66.65; H, 6.38.
(±)-(3aR*,9aR*)-2,3,3a,4,9,9a-Hexahydro-1H-cyclopenta[b]-
quinoline (7a).
13 15
3
This compound (268 mg, 1.55 mmole, 68%) was isolated as a
Representative Procedure for the Tandem Reduction-Reductive
Amination: Methyl (±)-(3aS*,9aS*)-2,3,3a,4,9,9a-Hexahydro-
1H-cyclopenta[b]quinoline-9a-carboxylate (6a).
-1
1
light yellow oil; ir: 3400 cm ; H nmr: δ 6.97 (m, 2H), 6.60 (t,
1H, J = 7.2), 6.47 (d, 1H, J = 8.2), 3.65 (td, 1H, J = 5.6, 4.3), 3.60
(br s, 1H), 2.85 (dd, 1H, J = 15.8, 5.9), 2.45 (dd, 1H, J = 15.8,
To a solution of 1.00 g (3.61 mmole) of 2a in 150 mL of
methanol was added 200 mg of 5% palladium-on-carbon, and the
mixture was shaken under 4 atmospheres of hydrogen at 30° for 4
hours. The solvent was removed, the residue was diluted with
ether, and the suspension was filtered through a pad of Celite
topped with a layer of magnesium sulfate to separate the catalyst.
Concentration under vacuum gave a yellow oil that was flash
chromatographed on a 25 cm x 2 cm silica gel column eluted with
5% ether in hexane. The major band afforded 0.73 g (3.14
mmole, 87%) of 6a as a white solid, mp 117-118°; ir: 3366, 1722
6.0), 2.25 (m, 1H), 1.95-1.72 (complex, 3H), 1.58 (m, 2H), 1.42
13
(m, 1H);
C nmr: δ 144.6, 129.1, 126.7, 121.2, 116.7, 113.2,
55.5, 37.3, 34.8, 29.8, 29.7, 22.1; hrms: m/z Calcd. for C H N:
12 15
173.1205; Found: 173.1203.
Anal. Calcd. for C H N: C, 83.24; H, 8.67; N, 8.09. Found:
12 15
C, 82.98; H, 8.60; N, 8.13.
(±)-(3aS*,9aR*)-2,3,3a,4,9,9a-Hexahydro-1H-cyclopenta[b]-
quinoline (8a).
This compound (72 mg, 0.42 mmole, 18%) was isolated as a
-1
1
-1
1
cm ; H nmr: δ 7.03 (d, 1H, J = 7.7), 7.00 (t, 1H, J = 7.7), 6.74
(t, 1H, J = 7.5), 6.63 (d, 1H, J = 7.8), 4.02 (br s, 1H), 3.56 (s, 3H),
3.36 (ABd, 1H, J = 15.7), 3.25 (t, 1H, J = 9.1), 2.78 (ABd, 1H, J =
15.7), 2.23 (m, 1H), 2.02 (m, 3H), 1.88 (m, 1H), 1.52 (m, 1H);
light yellow oil; ir: 3366 cm ; H nmr: δ 6.99 (d, 1H, J = 7.2),
6.98 (t, 1H, J = 7.4), 6.66 (t, 1H, J = 7.4), 6.55 (d, 1H, J = 7.8),
3.89 (br s, 1H), 2.94 (td, 1H, J = 10.5, 6.8), 2.90 (dd, 1H, J = 15.8,
5.1), 2.62 (dd, 1H, J = 15.8, 12.1), 1.99 (m, 2H), 1.91-1.71 (com-
13
13
C nmr: δ 175.0, 145.1, 129.8, 126.5, 123.3, 119.1, 116.8, 62.4,
plex, 3H), 1.46 (ddd, 1H, J = 22.1, 10.8, 8.4), 1.27 (m, 1H);
C
51.6, 50.4, 39.1, 34.6, 27.6, 21.2; hrms: m/z Calcd. for
nmr: δ 145.7, 130.1, 126.6, 122.7, 118.0, 115.4, 58.9, 41.7, 34.0,
C H NO : 231.1259; Found: 231.1258.
30.8, 29.0, 21.2; hrms: m/z Calcd. for C
Found: 173.1204.
H N: 173.1205;
14 17
2
12 15
Anal. Calcd. for C H NO : C, 72.73; H, 7.36; N, 6.06.
14 17
2
Found: C, 72.86; H, 7.33; N, 5.99.
Anal. Calcd. for C H N: C, 83.24; H, 8.67; N, 8.09. Found:
12 15
C, 83.06; H, 8.64; N, 8.18.
Methyl (±)-(8aS*,10aS*)-5,6,7,8,8a,9,10,10a-Octahydro-
acridine-8a-carboxylate (6b).
Cyclization of 5b.
This compound (0.77 g, 3.13 mmole, 91%) was isolated as a
The reductive ring closure of 5b was carried out as described
for the synthesis of 6a above. Preparative thin layer chromatog-
raphy using 5-10% ether in hexanes gave two bands. Band 1
(fastest moving) contained product 7b; band 2 contained 8b.
-1
1
white solid, mp 133-134°; ir: 3389, 1728 cm ; H nmr: δ 6.98
(t, 1H, J = 7.6), 6.91 (d, 1H, J = 7.5), 6.63 (t, 1H, J = 7.5), 6.55 (d,
1H, J = 7.9), 3.66 (br s, 1H), 3.54 (s, 3H), 3.10 (ABd, 1H, J =
15.6), 3.07 (dd, 1H, J = 11.9, 4.3), 2.68 (ABd, 1H, J = 15.6), 2.26
(dq, 1H, J = 13.3, 1.9), 2.10 (qd, 1H, J = 12.4, 4.3), 1.85 (m, 1H),
1.78 (m, 1H), 1.64 (m, 1H), 1.50-1.31 (complex, 2H), 1.22 (m,
(±)-(4aR*,9aR*)-1,2,3,4,4a,9a,10-Octahydroacridine (7b).
This compound (280 mg, 1.50 mmole, 50%) was isolated as a
13
-1
1H); C nmr: δ 174.1, 144.0, 129.1, 126.9, 120.5, 117.8, 115.5,
white solid, mp 68-69° (lit [3,12c] mp 67-68°); ir: 3400 cm ;

Jan-Feb 2003
Diastereoselective Synthesis of Linear-Fused Tricyclic Nitrogen Heterocycles
105
1
REFERENCES AND NOTES
H nmr: δ 6.94 (m, 2H), 6.56, (t, 1H, J = 7.4), 6.44 (d, 1H, J =
8.0), 3.50 (m, 1H), 3.48 (br s, 1H), 2.90 (dd, 1H, J = 16.3, 5.7),
2.53 (dd, 1H, J = 16.3, 4.1), 1.96 (m, 1H), 1.79-1.56 (complex,
4H), 1.50-1.28 (complex, 4H); C nmr: δ 143.9, 129.7, 126.5,
[*] Corresponding author. E-mail: rab@okstate.edu
13
[1a] Undergraduate Research Participants: D. M. H., 1999-pre-
sent; J. R. L., 2001-2002. [b] Author to whom questions regarding
the X-ray crystal structures should be addressed. E-mail:
betsy@biochem.okstate.edu.
[2] R. A., Bunce, D. M. Herron, L. B. Johnson and S. V. Kotturi,
J. Org. Chem., 66, 2822 (2001).
119.2, 116.3, 113.2, 49.9, 32.9, 32.5, 31.7, 27.2, 24.7, 20.7;
hrms: m/z Calcd. for C H N: 187.1361; Found: 187.1362.
13 17
Anal. Calcd. for C H N: C, 87.42; H, 9.09; N, 7.49. Found:
13 17
C, 87.13; H, 9.01; N, 7.61.
(±)-(4aS*,9aR*)-1,2,3,4,4a,9,9a,10-Octahydroacridine (8b).
This compound (168 mg, 0.90 mmole, 30%) was isolated as a
[3] V. G. Ermolaeva, V. G. Yashunskii, A. I. Polezhaeva and M.
D. Mashkovskii, Khim.-Farm. Zh., 2, 20 (1968); Chem. Abstr., 69,
106517 (1968).
[4] D. J. Collins, P. F. Drygala and J. M. Swan, Aust. J. Chem., 36,
2095 (1983).
[5] A. Barco, S. Benetti and G. P. Pollini, Synthesis, 316 (1973).
[6] D. A. Jeyaraj, K. K. Kapoor, V. K. Yadav, H. M. Grauniyal
and M. Parvez, J. Org. Chem., 63, 287 (1998). For the preparation of
potassium fluoride-on-alumina see, V. K. Yadav and K. K. Kapoor,
Tetrahedron, 52, 3659 (1996).
-1
1
white solid, mp 80-81° (lit [3,12f] mp 80-82°); ir: 3400 cm ;
H
nmr: δ 6.93 (m, 2H), 6.59 (t, 1H, J = 7.4), 6.46 (d, 1H, J = 8.0),
3.59 (br s, 1H), 2.84 (td, 1H, J = 10.3, 3.8), 2.66 (dd, 1H, J = 16.1,
5.0), 2.47 (dd, 1H, J = 16.1, 11.8), 1.87 (m, 2H), 1.75 (m, 2H),
13
1.52 (m, 1H), 1.42-1.24 (complex, 3H), 1.02 (m, 1H); C nmr: δ
144.5, 129.2, 126.6, 121.5, 116.9, 113.6, 56.0, 37.6, 34.6, 33.5,
31.9, 25.9, 24.6; hrms: m/z Calcd. for C
Found: 187.1359.
H N: 187.1361;
13 17
[7] D. Henderson, K. A. Richardson, R. J. K. Taylor and J.
Saunders, Synthesis, 996 (1983).
Anal. Calcd. for C H N: C, 87.42; H, 9.09; N, 7.49. Found:
13 17
C, 87.19; H, 9.05; N, 7.56.
[8a] E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of
Organic Compounds, Wiley-Interscience, New York, NY, 1994, pp 774-
777; [b] T. A. Crabb, in Cyclic Organonitrogen Stereodynamics, J. B.
Lambert and Y. Takeuchi, Eds., VCH, New York, NY, 1992, pp 253-287.
[9a] A. E. Derome, Modern NMR Techniques for Chemistry
Research, Elsevier Science, New York, NY, 1987, pp 227-230; [b] T. D.
W. Claridge, High-Resolution NMR Techniques in Organic Chemistry;
Elsevier Science, New York, NY, 1999, pp 158, 188, 197-199.
[10] D. Neuhaus and M. P. Williamson, The Nuclear Overhauser
Effect in Structural and Conformational Analysis, VCH, New York, NY,
1989, pp 253-306.
Experimental X-ray Data for 6a, 6b and 6c.
Intensity data were measured on a Brucker P4 diffractometer
with MoK radiation (λ = 0.71073Å) at room temperature [17].
α
All non-hydrogen positions were determined using the SHELXS
[18] structure solution program and refined by full matrix least
squares methods on the basis of F using the SHELXL97 [19]
refinement program. Hydrogen atoms were placed in calculated
positions using idealized geometry and constrained to those posi-
tions during final refinements. For 6a: C
2
H NO , formula
14 17 2
[11] An X-ray structure of the benzamide derivative of 7a gave the
weight 231.29, a = 6.896(8), b = 22.333(10), c = 7.914(3) Å, β =
104.37(4)°, V = 1190.5(15) Å , Z = 4, monoclinic space group
following crystallographic data: C
H NO, formula weight 277.35, a =
3
19 19
7.681(3), b = 15.657(7), c = 12.422(6) Å, β = 101.45(1)°, V = 1464.2(11)
3
P2 /c, density(calculated) = 1.290 Mg/m , 2081 unique reflec-
1
3
Å , Z = 4, monoclinic space group P2 /c, density(calculated) = 1.258
1
tions, R = 0.0676. For 6b: C H NO , formula weight 245.31, a
15 19
2
3
Mg/m , 2021 observed reflections (F˚ > 2.0(σF)). This crystal, and sev-
= 9.354(1), b = 8.954(1), c = 15.796(2) Å, β = 93.33(1)°, V =
eral others of this compound, diffracted poorly. Refinement of non-
hydrogen positional and anisotropic thermal parameters along with posi-
tional parameters for hydrogen atoms (using idealized geometry) refined
to only 12.9%, but clearly showed the cis ring junction.
[12a] W. H. Perkins Jr. and W. G. Sedgwick, J. Chem. Soc., 125,
2437 (1924); [b] H. Adkins and H. L. Coonradt, J. Am. Chem. Soc., 63,
1563 (1941); [c] E. Hayashi and T. Nagao, Yakugaku Zasshi, 84, 198
(1964); Chem Abstr., 63, 3071 (1964); [d] I. Mochida, M. Ohira, K.
Sakanishi, H. Fujitsu and H. Okazaki, Nippon Kagaku Kaishi, 1033
(1987); Chem Abstr., 108, 112189y (1988); [e] K. Sakanishi, M. Ohira,
I. Mochida, H. Okazaki and M. Soeda, J. Chem. Soc., Perkin Trans. 2,
1769 (1988); [f] S. E. Booth, P. R. Jenkins and C. J. Swain, J. Chem.
Soc., Chem. Commun., 147 (1993).
3
1320.8(3) Å , Z = 4, monoclinic space group P2 /c, density(cal-
1
3
culated) = 1.234 Mg/m , 2694 unique reflections, R = 0.0580.
For 6c: C H NO , formula weight 259.34, a = 11.026(2), b =
16 21
2
11.989(2), c = 12.188(3) Å, α = 85.49(2), β = 68.02(1), γ =
69.30(2)°, V = 1394.9(5) Å , Z = 4, triclinic space group P1 bar,
density(calculated) = 1.235 Mg/m , 6150 unique reflections, R =
0.0671.
Structural and atomic parameters have been deposited with the
Cambridge Crystallographic Data Center as deposition nos.
176509 (6a), 176510 (6b) and 176511 (6c). Copies may be
obtained from the Director, CCDC, 12 Union Road, Cambridge
CB2 1EZ.
3
3
[13] These compounds were also synthesized in ref 12a by reduc-
tion of 1,2,3,4-tetrahydroacridine with tin and hydrochloric acid, but no
product ratio was given. In a latter paper, the cis and trans assignments
were unclear, see W. H. Perkin Jr. and W. G. Sedgwick, J. Chem. Soc.,
438 (1926). Compare melting points with J. Buckingham, Ed.,
Dictionary of Organic Compounds, Vol 4, 5th Ed., Chapman and Hall,
New York, NY, 1982, p 4368, entry O-00284.
[14] These conditions are more commonly used for the reduction
of pyridines and involve reduction of the N-formylated heterocycle with
formic acid followed by deformylation with concentrated hydrochloric
acid. See [a] R. Lukes and J. Pliml, Collect. Czech. Chem. Commun., 15,
463 (1950); [b] M. Hudlicky, Reductions in Organic Chemistry, 2nd Ed.,
ACS, Washington, DC, 1996, pp 47 and 71.
Acknowledgment.
We wish to thank the Oklahoma Center for the Advancement
of Science and Technology (HR01-015) for support of this
research. D. M. H. wishes to thank Oklahoma State University
for a Wentz Project Scholarship and the Department of Chemistry
for a Skinner Scholarship. Funds for the 300 and 400 MHz NMR
spectrometers of the Oklahoma Statewide Shared NMR Facility
were provided by the NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education, the W. M. Keck Foundation, and
Conoco, Inc. Partial support for our mass spectrometers by the
NSF and the Oklahoma Center for the Advancement of Science
and Technology is also appreciated.
[15] R. A. Bunce, D. M. Herron, J. R. Lewis and S. V. Kotturi, J.

106
R. A. Bunce, D. M. Herron, J. R. Lewis, S. V. Kotturi and E. M. Holt
Vol. 40
Heterocyclic Chem., 40, 113 (2003).. In this study, control experiments
indicated that either the hydroxylamine or the aniline could be intermedi-
ates in the reaction.
[17] XSCANS Users Manual; Siemens Analytical X-ray
Instruments, Inc., Madison, WI, USA (1991).
[18] G. M. Sheldrick, Acta Cryst., A46, 467 (1990).
[16] W. C. Stille, M. Kahn and A. Mitra, J. Org. Chem., 43, 2923
(1978).
[19] G. M. Sheldrick, SHELXL97 Program for the Refinement of
Crystal Structures, University of Gottingen, Germany (1997).