Synthesis of chiral C2-symmetric 1,10-phenanthrolines from naturally occurring monoterpenes

Article abstract of DOI:10.1055/s-2003-36260

A convenient procedure for the preparation of chiral C₂-symmetric 1,10-phenanthrolines bearing a chiral framework in the form of a cycloalkeno-condensed substituent in the 2,3- and 8,9-positions of the heterocycle is reported. Starting from the 2-benzyloxycyclohexanone, four 1,10-phenanthrolines derived from (-)-β-pinene, (+)-α-pinene, (-)-isopinocampheol, and (+)-camphor were prepared according to a method based on a double Michael-azaannulation-aromatization sequence.

Full text of DOI:10.1055/s-2003-36260

PAPER
73
Synthesis of Chiral C2-Symmetric 1,10-Phenanthrolines from Naturally
Occurring Monoterpenes
C
hira
l
C
-Symmet
i
ric 1,10
o
-Phenanthro
r
lines gio Chelucci,*a Giovanni Loriga,b Gabriele Murineddu,b Gerard A. Pinnab
2
a
Dipartimento di Chimica, Università di Sassari, via Vienna 2, 07100 Sassari, Italy
Fax +39(79)229559; E-mail: chelucci@ssmain.uniss.it
b
Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via Muroni 23, 07100 Sassari, Italy
Received 19 July 2002; revised 30 September 2002
Abstract: A convenient procedure for the preparation of chiral C2-
symmetric 1,10-phenanthrolines bearing a chiral framework in the
form of a cycloalkeno-condensed substituent in the 2,3- and 8,9-po-
sitions of the heterocycle is reported. Starting from the 2-benzylox-
ycyclohexanone, four 1,10-phenanthrolines derived from (–)- -
pinene, (+)- -pinene, (–)-isopinocampheol, and (+)-camphor were
prepared according to a method based on a double Michael-aza-
annulation-aromatization sequence.
N
N
N
N
1
2
Key words: nitrogen heterocycles, 1,10-phenanthrolines, nitrogen
ligands, bidentate ligands, Michael additions
N
N
N
N
Since the design of chiral ligands plays a key role in the
development of enantioselective reactions, many recent
studies have addressed the development of novel chiral
ligands for metal-catalyzed reactions.1 In the context of
nitrogen based ligands,2 there has been considerable work
involving the synthesis and application of chiral 1,10-
phenanthrolines3 (phens) in asymmetric catalysis. The
studies were, however, limited to C1-symmetric deriva-
tives owing to the difficulties associated with the prepara-
tion of the C2-symmetric counterpart.3i,m,n In fact, only one
example of this kind of phens has been reported3i and used
in asymmetric catalysis.4
3
4
Figure 1 Structures of chiral C2-symmetric phens 1–4
We envisaged that the most direct approach to phens of
type 1–4 could be based on the construction of the 5,6-di-
hydrophen skeleton by a double Michael addition of the
dianion of cyclohexane-1,2-dione to an -methylene ke-
tone, followed by pyridoannulation of the corresponding
1,5-dicarbonyl intermediate, which was not isolated.
Thus, cyclohexane-1,2-dione was treated with lithium di-
isopropylamide (LDA, two equivalents, –40 °C, 2 h) and
then with the Michael acceptor (–)-pinocarvone (8), ob-
tained from (+)- -pinene.6 The crude reaction mixture
was then submitted to azaannulation with concomitant ar-
omatization (NH4OAc, AcOH, reflux, 2 h). However, this
procedure afforded an untractable reaction mixture from
which it was impossible to isolate the desired 5,6-dihydro-
phen.
In a recent communication, we have reported a new ap-
proach to the synthesis of chiral C2-symmetric phens de-
scribing the preparation of the phen 1 in which the chiral
starting material, (–)- -pinene, is present in the form of a
cycloalkeno-condensed substituent in the 2,3- and 8,9-po-
sitions of the heterocycle (Figure 1).5 The preliminary re-
sults obtained with the Cu(I)-complex containing ligand
1, indicate that this kind of phens are good catalysts in
asymmetric catalyzed allylic oxidation of cycloalkenes.5
The outcome of these experiments prompted us to deter-
mine the scope and limitations of the synthetic strategy
used for the preparation of 1 in order to obtain an array of
chiral C2-symmetric phens.
Therefore, we decided to build the two pyridines rings in
succession starting from a cyclohexanone derivative bear-
ing a functional group in the -position that could be eas-
ily converted into a carbonyl group after the construction
of the first pyridine ring. To this purpose, the 1,4-dithia-
spiro[4.5]decan-6-one (5)7 was initially identified as a
suitable substrate (Scheme 1). Thus, following the same
method outlined above (Michael-azaannulation-aromati-
zation sequence) the pyridine 6 was obtained in moderate
yield (38%). However, the conversion of the dithiolane
function into carbonyl group was proven to be very prob-
lematic. In fact, although many procedures were
explored8 in no case the yield of the desired ketone was
>19% (NBS, acetone).9
Herein, we wish to report full experimental details for the
synthesis 1 and the results obtained using this protocol for
the synthesis of the C2-symmetric phens 2–4 and their 5,6-
dihydro derivatives from other monoterpenes, namely
(+)- -pinene, (–)-isopinocampheol and (+)-camphor.
Synthesis 2003, No. 1, 30 12 2002. Article Identifier:
1437-210X,E;2003,0,01,0073,0078,ftx,en;T08002SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

74
G. Chelucci et al.
PAPER
benzyloxy derivatives gave the corresponding mixture of
the carbinol 11 (92%) that was oxidized under Swern con-
ditions to ketone 7 (89%). Starting from this key interme-
diate, the 5,6-dihydrophen 12 was prepared by building up
the second pyridine ring in a similar manner to that used
to prepare 10 from 9 (38% overall yield). Dehydrogena-
tion by using a catalytic amount of palladium on charcoal
in refluxing decalin completes the synthesis of 2 (91%).
1) LDA, THF, -40 °C, 2 h;
then 8 from -40 °C
slowly to r.t.
2) AcOH, NH4OAc, THF,
reflux, 3 h
O
N
S
S
S
S
38%
6
5
NBS, acetone
19%
Having obtained the desired phen 2, in order to determine
the scope and limitations of this protocol, more sterically
hindered -methylene ketones were submitted to this re-
action sequence (Schemes 3–5). Thus, the ketones 17, 22
and 27 obtained from (–)- -pinene,11 (–)-isopino-
campheol12 and (+)-camphor,11 respectively, yielded the
benzyloxypyridines 13, 18 and 23 (35%, 28% and 14%
yields, respectively).
N
O
7
O2, TPP, Ac2O, Py,
DMPA, CH2Cl2
O
97%
(+)-α-pinene
8
Cleavage of these benzyl ethers afforded the alcohols 14,
19 and 24 (95%, 95% and 52% yields, respectively) that
were transformed into the ketones 15, 20 and 25 (93%,
91% and 72% yields, respectively). These ketones gave
the corresponding dihydrophens 16, 21 and 26 (35%, 37%
Scheme 1
Then, we devoted our attention to racemic 2-benzyloxy-
cyclohexanone (9) that is easily prepared from 2-hydroxy-
cyclohexanone dimer10 (Scheme 2). The lithium enolate
of this ketone (LDA, one equivalent, THF, –40 °C, 2 h)
was treated with (–)-pinocarvone (8) to give a 1,5-dicar-
bonyl intermediate by conjugate addition, which was not
isolated. This intermediate underwent azaanulation-arom-
atization in the usual way to afford the pyridine 10 as a
52:48 mixture of epimers at C5 (36% overall yield). Cat-
alytic hydrogenolysis (Pd/C at 3 atm) of this mixture of
1) LDA, THF, -40 °C, 2 h;
then 17 from -40 °C
slowly to r.t.
2) AcOH, NH4OAc, THF,
reflux, 3 h
O
N
O
O
Bn
9
35%
13
Bn
H2, 10% Pd/C, MeOH,
Swern
3 atm, 40 °C
oxidation
93%
N
95%
1) LDA, THF, -40 °C, 2 h;
then 8 from -40 °C
slowly to r.t.
OH
14
1) LDA, THF, -40 °C, 2 h; then 17 from
-40 °C slowly to r.t.
2) AcOH, NH4OAc, THF, reflux, 3 h
2) AcOH, NH4OAc, THF,
reflux, 3 h
O
N
O
O
N
36%
Bn
9
10
Bn
O
35%
15
H2, 10% Pd/C, MeOH,
3 atm, 40 °C
Swern
oxidation
N
N
N
92%
89%
OH
11
10% Pd/C,
decalin,
reflux, 3 h
N
N
16
1
1) LDA, THF, -40 °C, 2 h; then 8 from
-40 °C slowly to r.t.
2) AcOH, NH4OAc, THF, reflux, 3 h
93%
N
38%
O
7
1) NaNH2, benzene,
reflux, 15h
2) isopentyl formate,
r.t. 4h,
TMO, OsO4, Py,
10% Pd/C, decalin,
reflux, 3 h
t-BuOH/H2O
1) NaIO4, r.t.,
2) reflux, 2h,
N
N
91%
3) HCl
12
66%
71%
O
(-)-β-pinene
N
Na2CO3, HCHO,
r.t., 40 min
HO
O
N
2
O
92%
17
Scheme 2
Scheme 3
Synthesis 2003, No. 1, 73–78 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Chiral C2-Symmetric 1,10-Phenanthrolines
75
1) LDA, THF, -40 °C, 2 h;
then 22 from -40 °C
slowly to r.t.
2) AcOH, NH4OAc, THF,
reflux, 3 h
O
N
O
O
9
Bn
28%
18
Bn
Swern
H2, 10% Pd/C, MeOH,
oxidation
3 atm, 40 °C
N
91%
95%
OH
19
1) LDA, THF, -40 °C, 2 h; then 22 from
-40 °C slowly to r.t.
2) AcOH, NH4OAc, THF, reflux, 3 h
N
O
20
37%
10% Pd/C, decalin,
reflux, 3 h
N
91%
N
21
N
N
3
1) HCO2Et,
Na, Et2O,
CrO3, H2SO4,
acetone
EtOH, 15h
2) HCl
58%
HO
O
82%
(-)-isopinocampheol
K2CO3, HCHO,
r.t., 50 min
HO
O
Scheme 5
O
83%
All reagents and solvents were purchased from Aldrich and used as
received. Low boiling petroleum ether was the fraction collected
between 40 °C and 60 °C. THF was distilled from sodium-ben-
zophenone ketyl and degassed thoroughly with dry N2 directly be-
fore use.
22
Scheme 4
Melting points were determined on a Büchi 510 capillary apparatus
and are uncorrected. The NMR spectra were recorded on a Varian
VXR-300 spectrometer at 300 for 1H and 75.4 MHz for 13C. Chem-
ical shifts are reported in ppm downfield from internal Me4Si in
CDCl3. Optical rotations were measured with a Perkin-Elmer 241
polarimeter in a 1 dm tube. Elemental analyses were performed on
a Perkin-Elmer 240 B analyser.
and 26% yields, respectively) that were finally converted
into the phens 1, 3 and 4 (93%, 91% and 67% yields, re-
spectively).
The overall yield of the process was comparable for all
phens (10%) with the exception of phen 4, derived from
camphor. This ketone afforded a much lower overall yield
(2%) which principally differs from that obtained with the
(–)-Pinocarvone (8) was obtained by oxidation of (+)- -pinene
(98% pure, 91% ee by GC, Aldrich).6 (1R,5R)-6,6-Dimethyl-3-me-
other phens by the two Michael-azaannulation-aromatiza- thylenebicyclo[3.1.1]heptan-2-one (17), (1R,4S,5R)-4,6,6-trimeth-
yl-2-methylenebicyclo[3.1.1] heptan-3-one (22) and (1R,4S)-1,7,7-
tion steps in that the overall yield of the other three steps,
conversion of the protected hydroxy group to ketone and
final aromatization, is fairly good. This great difference
can be attributed to the steric hindrance of camphor carbo-
nyl group that reduces the ability of this ketone to undergo
the azaannulation step.3a,13
trimethyl-3-methylenebicyclo[2.2.1] heptan-2-one (27) were pre-
pared from (–)- -pinene (99% pure, Aldrich),11 (–)-isopinocam-
pheol (98% pure, 95% ee by GC, Aldrich),12 and (+)-camphor (98%
pure, Aldrich),11 respectively. 1,4-Dithiaspiro[4.5]decan-6-one (5)7
and 2-benzyloxycyclohexanone (9)10 were prepared according to
reported procedures.
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G. Chelucci et al.
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(6S,8S)-(+)-6,8-Methano-7,7-dimethyl-4-(1,4-dithiaspiro-
cyclopentane)-2,3,5,6,7,8-hexahydro-1H-acridine (6)
1H NMR: = 7.44–7.36 (m, 2 H), 7.36–7.18 (m, 3 H), 6.94 (s, 1 H,
major isomer), 6.92 (s, 1 H, minor isomer), 4.82 (AB, JAB = 12.0
Hz, 2 H), 4.59–4.55 (m, 1 H), 3.10 (d, 2 H, J = 2.4 Hz), 2.84–2.58
(m, 4 H), 2.38–2.22 (m, 2 H), 2.18–2.02 (m, 1 H), 1.86–1.66 (m, 2
H), 1.38 (s, 3 H), 1.24 (d, 1 H, J = 9.3 Hz), 0.65 (s, 3 H, minor iso-
mer), 0.63 (s, 3 H, major isomer),
A solution of 1,4-dithiaspiro[4.5]decan-6-one (5; 1.13 g, 6.0 mmol)
in anhyd THF (5 mL) was added dropwise to a cooled (–78 °C) so-
lution of LDA (6.0 mmol) in anhyd THF (30 mL). The resulting so-
lution was stirred at –40 °C for 2 h and then a solution of (–)-
pinocarvone (8; 901 mg, 6.00 mmol) in THF (5 mL) was added
dropwise at –40 °C. After 15 min at –40 °C, the solution was al-
lowed to reach slowly r.t. (overnight) and then poured into a mixture
of NH4OAc (9.24 g, 0.12 mol) and AcOH (30 mL). The flask was
connected with a distillation head and the THF was distilled off over
a 3 h period. Most part of the AcOH was removed under reduced
pressure and the residue was taken up with H2O (0.5 L) and extract-
ed with Et2O (3 100 mL). The combined organic phases were
washed with a 5% NaOH solution (2 100 mL) and then dried
(Na2SO4). The solvent was evaporated and the residue was purified
by flash chromatography (petroleum ether–EtOAc, 8:2); yield: 725
mg (38%); mp 125 °C; [ ]D25 +40.0 (c = 3.12, CHCl3).
Anal. Calcd for C23H27NO: C, 82.84; H, 8.16; N, 4.20. Found: C,
82.66; H, 8.15; N, 4.18.
(4R,5R,7R)- and (4S,5R,7R)-4-Benzyloxy-5,7-methano-6,6-
dimethyl-1,2,3,4,5,6,7,8-octahydroacridine (13)
Compound 13 was obtained as a 55:45 mixture of epimers at C4;
yield: 1.12 g (35%); oil.
1H NMR: = 7.43–7.34 (m, 2 H), 7.32–7.20 (m, 3 H), 7.16 (s, 1 H,
minor isomer), 7.14 (s, 1 H, major isomer), 4.80 (AB, JAB = 12.0
Hz, 2 H), 4.55–4.53 (m, 1 H), 3.03–2.99 (m, 1 H), 2.89 (d, 2 H,
J = 3.0 Hz), 2.79–2.62 (m, 3 H), 2.30–2.22 (m, 2 H), 2.15–2.02 (m,
1 H), 1.85–1.73 (m, 2 H), 1.42 (s, 3 H, minor isomer), 1.40 (s, 3 H,
major isomer), 1.28–1.24 (m, 1 H), 0.66 (s, 3 H, major isomer), 0.65
(s, 3 H, minor isomer).
1H NMR: = 6.78 (s, 1 H), 3.90–3.78 (m, 2 H), 3.52–3.40 (m, 2 H),
3.06 (d, 2 H, J = 2.7 Hz), 2.76–2.65 (m, 4 H), 2.54–2.44 (m, 2 H),
2.38–2.28 (m, 1 H), 2.04–1.94 (m, 2 H), 1.37 (s, 3 H), 1.25 (d, 1 H,
J = 9.3 Hz), 0.64 (s, 3 H).
Anal. Calcd for C23H27NO: C, 82.84; H, 8.16; N, 4.20. Found: C,
82.93; H, 8.15; N, 4.19.
Anal. Calcd for C18H23NS2: C, 68.09; H, 7.30; N, 4.41. Found: C,
68.23; H, 7.33; N, 4.43.
(4R,5S,6R,8R)- and (4S,5S,6R,8R)-4-Benzyloxy-6,8-methano-
5,7,7-trimethyl-1,2,3,4,5,6,7,8-octahydroacridine (18)
Compound 18 was obtained as a 55:45 mixture of epimers at C4;
yield: 0.96 g (28%); oil.
(6S,8S)-(+)-6,8-Methano-7,7-dimethyl-2,3,5,6,7,8-hexahydro-
1H-acridin-4-one (7)
A solution of 6 (2.68 g, 8.45 mmol) in acetone (30 mL) was added
dropwise to a cooled (0 °C) solution of NBS (12.00 g, 67.42 mmol)
in 90% aq acetone (100 mL). After stirring at r.t. for 20 min, the
mixture was basified with a 4 N aq solution of NaOH (100 mL) and
then treated with a sat. solution of Na2SO3 (100 mL). The mixture
was extracted with Et2O (3 100 mL) and the organic phase was
washed with H2O (2 100 mL) and then dried (Na2SO4). The sol-
vent was evaporated and the residue was purified by flash chroma-
tography (petroleum ether–EtOAc, 1:1); yield: 0.39 g (19%); mp
112–114 °C; [ ]D25 +63.8 (c = 1.24, CHCl3).
1H NMR: = 7.55–7.40 (m, 2 H), 7.40–7.20 (m, 3 H), 6.91 (s, 1 H,
minor isomer), 6.88 (s, 1 H, major isomer), 4.87 (s, 2 H, major iso-
mer), 4.86 (s, 2 H, minor isomer), 4.54–4.48 (m, 1 H), 3.30–3.10 (m,
1 H), 2.81–2.57 (m, 3 H), 2.55–2.48 (m, 1 H), 2.29–1.98 (m, 3 H),
1.95–1.54 (m, 2 H), 1.48–1.35 (m, 6 H), 1.29 (d, 1 H, J = 10.5 Hz),
0.66 (s, 3 H, minor isomer), 0.65 (s, 3 H, major isomer).
Anal. Calcd for C24H29NO: C, 82.95; H, 8.41; N, 4.03. Found: C,
82.83; H, 8.46; N, 4.05.
1H NMR: = 7.14 (s, 1 H), 3.21 (d, 2 H, J = 2.4 Hz), 2.95 (t, 2 H,
J = 5.7 Hz), 2.86–2.64 (m, 4 H), 2.43–2.34 (m, 1 H), 2.20–2.10 (m,
2 H), 1.42 (s, 3 H), 1.26 (d, 1 H, J = 9.6 Hz), 0.65 (s, 3 H).
(4R,5R,8S)- and (4S,5R,8S)-4-Benzyloxy-5,8-methano-5,9,9-
trimethyl-1,2,3,4,5,6,7,8-octahydroacridine (23)
This compound was purified by flash chromatography using petro-
leum ether–EtOAc, 97:3. Yield: 0.48 g (14%); oil.
1H NMR: = 7.43 (d, 2 H, J = 9.0 Hz), 7.33–7.23 (m, 3 H), 7.20 (s,
1 H), 4.84 (AB, JAB = 13.8 Hz, 2 H), 4.60–4.52(m, 1 H), 2.80–2.62
(m, 3 H), 2.30–2.22 (m, 2 H), 2.12–2.05 (m, 1 H), 1.85–1.60 (m, 3
H), 1.42 (s, 3 H), 1.26–1.05 (m, 2 H), 0.97 (s, 3 H), 0.67 (s, 3 H).
Anal. Calcd for C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C,
79.88; H, 7.97; N, 5.83.
4-Benzyloxy-1,2,3,4,5,6,7,8-octahydroacridines 10, 13, 18, 23;
General Procedure
A solution of 2-benzyloxycyclohexanone (9) (2.04 g, 10.00 mmol)
in anhyd THF (5 mL) was added dropwise to a cooled (–78 °C) so-
lution of lithium diisopropylamide (10.00 mmol) in anhyd THF (50
mL). The resulting solution was stirred at –40 °C for 2 h and then a
solution of the -methylene ketone 8 (or 17, 22, 27) (10.00 mmol)
in THF (5 mL) was added dropwise at –40 °C. After 15 min at –
40 °C, the solution was allowed to reach slowly r.t. (overnight) and
then poured into a mixture of NH4OAc (7.71 g, 0.10 mol) and
AcOH (50 mL). The flask was connected with a distillation head
and the THF was distilled off over a 3 h period. Most of the AcOH
was removed under reduced pressure and the residue was taken up
with H2O (500 mL) and extracted with Et2O (3 150 mL). The or-
ganic phase was separated, washed with a 5% aq NaOH solution
(3 50 mL) and then dried (Na2SO4). The solvent was evaporated
and the residue was purified by flash chromatography (petroleum
ether–EtOAc, 9:1) to give 4-benzyloxyoctahydroacridines as a mix-
ture of diastereomers.
Anal. Calcd for C24H29NO: C, 82.95; H, 8.41; N, 4.03. Found: C,
82.77; H, 8.45; N, 4.05.
1,2,3,4,5,6,7,8-Octahydroacridin-4-ols 11, 14, 19, 24; General
Procedure
A mixture of benzyloxyoctahydroacridine 10 (or 13, 18, 23) (10.00
mmol) and 10% Pd/C (0.80 g) in 95% EtOH (50 mL) was hydroge-
nated at 40 °C and 3 atm in a Parr apparatus. H2 absorption ceased
after the uptake of one equivalent. The mixture was filtered, the fil-
trate was evaporated at reduced pressure and the residue was puri-
fied by flash chromatography (petroleum ether–EtOAc, 9:1) to give
4-hydrooxyoctahydroacridines as a mixture of diastereomers.
(4R,6S,8S)- and (4S,6S,8S)-6,8-Methano-7,7-dimethyl-
1,2,3,4,5,6,7,8-octahydroacridin-4-ol (11)
Compound 11 was obtained as a 53:47 mixture of epimers at C4;
yield: 2.23 g (92%); oil.
1H NMR: = 6.93 (s, 1 H), 4.77–4.68 (m, 1 H), 4.43 (br s, 1 H, ex-
changeable with H2O), 3.03 (s, 2 H), 2.78–2.58 (m, 4 H), 2.38–2.28
(m, 1 H), 2.24–2.14 (m, 1 H), 2.04–1.92 (m, 1 H), 1.92–1.70 (m, 2
(4R,6S,8S)- and (4S,6S,8S)-4-Benzyloxy-6,8-methano-7,7-
dimethyl-1,2,3,4,5,6,7,8-octahydroacridine (10)
Compound 10 was obtained as a 52:48 mixture of epimers at C4;
yield: 1.20 g (36%); oil.
Synthesis 2003, No. 1, 73–78 ISSN 0039-7881 © Thieme Stuttgart · New York

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Chiral C2-Symmetric 1,10-Phenanthrolines
77
H), 1.38 (s, 3 H), 1.24 (d, 1 H, J = 9.3 Hz), 0.64 (s, 3 H, major iso-
mer), 0.62 (s, 3 H, minor isomer).
(5R,7R)-(–)- 5,7-Methano-6,6-dimethyl-2,3,5,6,7,8-hexahydro-
1H-acridin-4-one (15)
Yield: 2.32 g (93%); mp 113–116 °C; [ ]D –11.3 (c = 1.65,
25
Anal. Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C,
78.88; H, 8.72; N, 5.75.
CHCl3).
1H NMR: = 7.39 (s, 1 H), 3.24 (t, 1 H, J = 5.4 Hz), 3.02–2.94 (m,
4 H), 2.80–2.70 (m, 3 H), 2.36–2.28 (m, 1 H), 2.22–2.12 (m, 2 H),
1.41 (s, 3 H), 1.25 (d, 1 H, J = 10.2 Hz), 0.65 (s, 3 H).
(4R,5R,7R)- and (4S,5R,7R)-5,7-Methano-6,6-dimethyl-
1,2,3,4,5,6,7,8-octahydroacridine-4-ol (14)
Compound 14 was obtained as a 60:40 mixture of epimers at C4;
yield: 2.28 g (95%); oil.
1H NMR: = 7.14 (s, 1 H), 4.72–4.63 (m, 1 H), 3.95 (br s, 1 H, ex-
changeable with H2O), 2.94 (t, 1 H, J = 5.7 Hz), 2.89 (d, 2 H, J = 1.8
Hz), 2.74–2.65 (m, 3 H), 2.33–2.20 (m, 2 H), 2.03–1.92 (m, 1 H),
1.84–1.75 (m, 2 H), 1.41 (m, 3 H), 1.25 (d, 1 H, J = 10.5 Hz), 0.66
(s, 3 H, major isomer), 0.64 (s, 3 H, minor isomer).
Anal. Calcd for C16H19NO: C, 79.63; H, 7.94; N, 5.80. Found: C,
79.55; H, 7.93; N, 5.82.
(5S,6R,8R)-(–)-6,8-Methano- 5,7,7-trimethyl-2,3,5,6,7,8-hexa-
hydro-1H-acridin-4-one (20)
25
Yield: 2.42 g (91%); mp 162–164 °C; [ ]D –0.6 (c = 1.08,
CHCl3).
Anal. Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C,
78.77; H, 8.69; N, 5.74.
1H NMR: = 7.10 (s, 1 H), 3.35–3.28 (m, 1 H), 2.96–2.91 (m, 2 H),
2.82–2.73 (m, 3 H), 2.61–2.54 (m, 1 H), 2.19–2.11 (m, 3 H), 1.42
(s, 6 H), 1.30 (d, 1 H, J = 9.9 Hz), 0.64 (s, 3 H).
(4R,5S,6R,8R)- and (4S,5S,6R,8R)-6,8-Methano-5,7,7-trime-
thyl-1,2,3,4,5,6,7,8-octahydroacridin-4-ol (19)
Compound 19 was obtained as a 1:1 mixture of epimers at C4; yield:
2.57 g (95%); mp 78–80 °C.
1H NMR: = 7.12 (s, 1 H), 4.90–4.86 (m, 1 H), 4.88 (br s, 1 H, ex-
changeable with H2O), 3.31–3.25 (m, 1 H), 2.79–2.45 (m, 4 H),
2.40–2.07 (m, 2 H), 2.07–1.60 (m, 3 H), 1.48 (d, 3 H, J = 1.8 Hz,
one isomer), 1.46 (d, 3 H, J = 2.1 Hz, one isomer), 1.42 (m, 3 H),
1.29 (d, 1 H, J = 10.5 Hz), 0.64 (s, 3 H, one isomer), 0.63 (s, 3 H,
one isomer).
Anal. Calcd for C17H21NO: C, 79.96; H, 8.29; N, 5.49. Found: C,
79.85; H, 8.34; N, 5.47.
(5R,8S)-(–)-5,8-Methano-5,11,11-trimethyl-2,3,5,6,7,8-hexa-
hydro-1H-acridin-4-one (25)
25
Yield: 1.89 g (72%); mp 176–177 °C; [ ]D –1.4 (c = 1.12,
CHCl3).
1H NMR: = 7.26 (s, 1 H), 2.96 (t, 2 H, J = 6.3 Hz), 2.88 (d, 1 H,
J = 4.2 Hz), 2.77–2.72 (m, 2 H), 2.19–2.11 (m, 3 H), 1.93–1.84 (m,
1 H), 1.41 (s, 3 H), 1.33–1.24 (m, 1 H), 1.17–1.09 (m, 1 H), 1.00 (s,
3 H), 0.54 (s, 3 H).
Anal. Calcd for C17H23NO: C, 79.33; H, 9.01; N, 5.44. Found: C,
79.15; H, 9.03; N, 5.47.
Anal. Calcd for C17H21NO: C, 79.96; H, 8.29; N, 5.49. Found: C,
79.79; H, 8.27; N, 5.51.
(4R,5S,8R)- and (4S,5S,8R)-5,8-Methano-5,9,9-trimethyl-
1,2,3,4,5,6,7,8-octahydroacridin-4-ol (24)
Compound 24 was obtained as a 52:48 mixture of epimers at C4;
yield: 1.32 (52%); oil.
1H NMR: = 7.06 (s, 1 H), 4.74–4.67 (m, 1 H), 4.41 (br s, 1 H, ex-
changeable with H2O), 2.79–2.64 (m, 3 H), 2.28–2.17 (m, 1 H),
2.12–2.05 (m, 1 H), 2.02–1.92 (m, 1 H), 1.88–1.70 (m, 3 H), 1.28
(s, 3 H, major isomer), 1.27 (s, 3 H, minor isomer), 1.23–1.04 (m, 2
H), 0.97 (s, 3 H), 0.54 (s, 3 H, major isomer), 0.53 (s, 3 H, minor
isomer).
Dihydrophenanthrolines 12, 16, 21, 26; General Procedure
Starting from the 4-oxooctahydroacridine 7 (or 15, 20, 25) (5.00
mmol), the procedure used for the preparation of 4-benzyloxyoc-
tahydroacridines was followed. The crude mixture was purified by
flash chromatography (petroleum ether–EtOAc, 8:2).
(2S,4S, 9S,11S)-(+)-2,4,9,11-Dimethano-3,3,10,10-tetramethyl-
1,2,3,4,6,7,9,10,11,12-decahydrodibenzo[b,j][1,10]phenan-
throline (12)
25
Yield: 0.70 g (38%); mp 62–64 °C; [ ]D +153.6 (c = 1.25,
Anal. Calcd for C17H23NO: C, 79.33; H, 9.01; N, 5.44. Found: C,
79.23; H, 9.02; N, 5.46.
CHCl3).
1H NMR: = 7.05 (s, 2 H), 3.30 (m, 4 H), 2.92–2.84 (m, 4 H), 2.75
(t, 2 H, J = 5.7 Hz), 2.70–2.62 (m, 2 H), 2.42–2.33 (m, 2 H), 1.40 (s,
6 H), 1.27 (d, 2 H, J = 9.3 Hz), 0.69 (s, 6 H).
2,3,5,6,7,8-Hexahydro-1H-acridin-4-ones 7, 15, 20, 25; General
Procedure
A solution of DMSO (820 mg, 10.50 mmol) in anhyd CH2Cl2 (3
mL) was added dropwise to a cooled (–60 °C) solution of oxalyl
chloride (672 mg, 5.30 mmol) in CH2Cl2 (13 mL). After stirring for
5 min, a solution of 4-hydroxyoctahydroacridine 11 (or 14, 19, 24)
(4.00 mmol) in CH2Cl2 (5 mL) was added. The cloudy mixture was
stirred at –60 °C for 50 min and Et3N (2.02 g, 20.00 mmol) was add-
ed dropwise. The resulting mixture was warmed to r.t. and stirred
for 1 h. The mixture was poured into H2O (50 mL) and extracted
with CH2Cl2 (2 100 mL). The organic phase was dried (Na2SO4),
the solvent was evaporated and the residue was purified by flash
chromatography (petroleum ether–EtOAc, 1:1).
Anal. Calcd for C26H30N2: C, 84.28; H, 8.16; N, 7.59. Found: C,
84.38; H, 8.15; N, 7.61.
(1R,3R,10R,12R)-(+)-1,3,10,12-Dimethano-2,2,11,11-
tetramethyl-1,2,3,4,6,7,9,10,11,12-decahydrodibenzo-
[b,j][1,10]phenanthroline (16)
25
Yield: 0.64 g (35%); mp 118–120 °C; [ ]D +111.5 (c = 1.04,
CHCl3).
1H NMR: = 7.26 (s, 2 H), 3.29 (t, 2 H, J = 5.7 Hz), 3.00–279 (m,
8 H), 2.69 (m, 2 H), 2.29 (m, 2 H), 1.40 (s, 6 H), 1.30 (d, 2 H, J = 9.6
Hz), 0.69 (s, 6 H).
(6S,8S)-(+)-6,8-Methano-7,7-dimethyl-2,3,5,6,7,8-hexahydro-
1H-acridin-4-one (7)
This compound was purified by flash chromatography using petro-
Anal. Calcd for C26H30N2: C, 84.28; H, 8.16; N, 7.59. Found: C;
84.15; H, 8.14; N, 7.61.
25
leum ether–EtOAc, 8:2, yield: 2.23 g (89%); mp 113–114 °C; [ ]D
+64.4 (c = 1.32, CHCl3). For spectral data, vide supra.
Synthesis 2003, No. 1, 73–78 ISSN 0039-7881 © Thieme Stuttgart · New York

78
G. Chelucci et al.
PAPER
(1S,2S,4S,9S,11S,12S)-(+)-2,4,9,11-Dimethano-1,3,3,10,10,12-
hexamethyl-1,2,3,4,6,7,9,10,11,12-decahydrodibenzo-
[b,j][1,10]phenanthroline (21)
Yield: 0.94 g (37%); mp 238–240 °C; [ ]D +111.3 (c = 1.12,
CHCl3).
13C NMR: = 162.2, 144.3, 141.2, 130.9, 126.6, 125.4, 47.6, 47.0,
41.4, 39.8, 29.3, 26.5, 21.3, 18.5.
Anal. Calcd for C28H32N2: C, 84.80; H, 8.13; N, 7.06. Found: C,
84.89; H, 8.11; N, 7.05.
25
1H NMR: = 7.02 (s, 2 H), 3.32–3.25 (m, 2 H), 2.93–2.73 (m, 6 H),
2.58–2.51 (m, 2 H), 2.18–2.13 (m, 2 H), 1.57 (d, 6 H, J = 6.9 Hz),
1.41 (s, 6 H), 1.31 (d, 2 H, J = 9.6 Hz), 0.67 (s, 6 H).
(1R,4S, 9S,12R)-(–)-1,4,9,12-Dimethano-1,12,13,13,14,14-
hexamethyl-1,2,3,4,9,10,11,12-octahydrodibenzo[b,j][1,10]-
phenanthroline (4)
Yield: 266 mg (67%); mp 253–255 °C; [ ]D –72.8 (c = 0.85,
CHCl3).
1H NMR: = 7.80 (s, 2 H), 7.66 (s, 2 H), 3.02 (d, 2 H, J = 3.9 Hz),
2.58–2.15 (m, 2 H), 1.95 (dt, 2 H, J = 12.6, 3.9 Hz), 1.62 (s, 6 H),
1.62–1.53 (m, 2 H), 1.25–1.17 (m, 2 H), 1.08 (s, 6 H), 0.59 (s, 6 H).
13C NMR: = 171.2, 144.1, 140.9, 127.4, 126.7, 125.3, 56.2, 54.8,
51.3, 31.8, 26.3, 20.6, 19.2, 10.7.
25
Anal. Calcd for C28H34N2: C, 84.37; H, 8.60; N, 7.03. Found: C,
84.25; H, 8.63; N, 7.04.
(1R,4S, 9S,12R)-(–)-1,4,9,12-Dimethano-1,12,13,13,14,14-
hexamethyl-1,2,3,4,6,7,9,10,11,12-decahydrodibenzo-
[b,j][1,10]phenanthroline (26)
Yield: 0.51 g (26%); mp 229–231; [ ]D25 –54.4 (c = 0.86, CHCl3).
1H NMR: = 7.21 (s, 2 H), 2.92–2.80 (m, 6 H), 2.17–2.07 (m, 2 H),
1.93 (dt, 2 H, J = 12.8, 3.8 Hz), 1.47 (s, 6 H), 1.47–1.40 (m, 2 H),
1.14–1.06 (m, 2 H), 1.00 (s, 6 H), 0.61 (s, 6 H).
Anal. Calcd for C28H32N2: C, 84.80; H, 8.13; N, 7.06. Found: C,
84.76; H, 8.12; N, 7.15.
Anal. Calcd for C28H34N2: C, 84.37; H, 8.60; N, 7.03. Found: C,
84.18; H, 8.58; N, 7.05.
References
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Ojiama, I. Catalytic
Asymmetric Synthesis; VCH: New York, 1993.
(2) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M.
Chem. Rev. 2000, 100, 2159.
Phenanthrolines 1–4; General Procedure
A suspension of 10% Pd/C (100 mg) in decahydronaphtalene (10
mL) containing dihydrophenanthroline 12 (or 16, 21, 26) (1.00
mmol) was refluxed for 3 h. After cooling, the suspension was fil-
tered, the solvent was removed under reduced pressure and the res-
idue was purified by flash chromatography (petroleum ether–
EtOAc, 8:2).
(3) (a) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102,
3129. (b) Gladiali, S.; Chelucci, G.; Madadu, M. T.; Gastaut,
M. G.; Thummel, R. P. J. Org. Chem. 2001, 66, 400.
(c) Chelucci, G.; Pinna, G. A.; Saba, A.; Sanna, G. J. Mol.
Catal. A 2000, 159, 423. (d) Chelucci, G.; Saba, A.; Sanna,
G.; Soccolini, F. Tetrahedron: Asymmetry 2000, 11, 3427.
(e) Chelucci, G.; Thummel, R. P. Synth. Commun. 1999, 29,
1665. (f) O’Neill, D.; Helquist, P. Org. Lett. 1999, 1, 1659.
(g) Riesgo, E. C.; Credi, A.; De Cola, L.; Thummel, R. P.
Inorg. Chem. 1998, 37, 2145. (h) Chelucci, G.; Saba, A.
Tetrahedron: Asymmetry 1998, 9, 2575. (i) Peña-Cabrera,
E.; Norrby, P.-A.; Sjgören, M.; Vitagliano, A.; De Felice, V.;
Oslob, J.; Ishii, S.; O’Neill, D.; Åkermark, B.; Helquist, P. J.
Am. Chem. Soc. 1996, 118, 4299. (j) Gladiali, S.; Pinna, L.;
Delogu, G.; De Martin, S.; Zassinovich, G.; Mestroni, G.
Tetrahedron: Asymmetry 1990, 1, 635. (k) Kandzia, C.;
Steckhan, E.; Knoch, F. Tetrahedron: Asymmetry 1993, 4,
39. (l) Chelucci, G.; Falorni, M.; Giacomelli, G.
Tetrahedron 1992, 48, 3653. (m) Gladiali, S.; Chelucci, G.;
Soccolini, F.; Delogu, G.; Chessa, G. J. Organomet. Chem.
1989, 370, 285. (n) Gladiali, S.; Chelucci, G.; Chessa, G.;
Delogu, G.; Soccolini, F. J. Organomet. Chem. 1987, 327, C
15.
(1R,3R, 10R,12R)-(+)-1,3,10,12-Dimethano-2,2,11,11-tetrame-
thyl-1,2,3,4,9,10,11,12-octahydrodibenzo[b,j][1,10]phenan-
throline (1)
Yield: 344 mg (93%); mp 104–106 °C; [ ]D +68.2 (c = 1.13,
CHCl3).
1H NMR: = 7.91 (s, 2 H), 7.63 (s, 2 H), 3.58 (t, 2 H, J = 5.7 Hz),
3.17 (m, 4 H), 2.80 (m, 2 H), 2.28 (m, 2 H), 1.46 (s, 6 H), 1.42 (d, 2
H, J = 9.9 Hz), 0.71 (s, 6 H).
13C NMR: = 167.2, 142.9, 134.2, 130.3, 127.4, 124.9, 51.4, 39.8,
39.2, 31.4, 31.0, 26.1, 21.5.
25
Anal. Calcd for C26H28N2: C, 84.74; H, 7.66; N, 7.60. Found: C,
84.55; H, 7.64; N, 7.58.
(2S,4S, 9S,11S)-(+)-2,4,9,11-Dimethano-3,3,10,10-tetramethyl-
1,2,3,4,6,7,9,10,11,12-decahydrodibenzo[b,j][1,10]phenan-
throline (2)
Yield: 336 mg (91%); mp 101–103 °C; [ ]D +117.1 (c = 0.74,
CHCl3).
25
1H NMR: = 7.67 (s, 2 H), 7.63 (s, 2 H), 3.58–3.56 (m, 4 H), 3.50–
3.46 (m, 2 H), 3.00 (t, 2 H, J = 5.7 Hz), 2.81–2.74 (m, 2 H), 2.52–
2.42 (m, 2 H), 1.46 (s, 6 H), 1.37 (d, 2 H, J = 9.6 Hz), 0.84 (s, 6 H).
13C NMR: = 158.8, 144.1, 141.3, 131.3, 126.3, 125.3, 46.9, 40.2,
39.7, 37.3, 32.1, 26.0, 21.5.
(4) Chelucci, G.; Gladiali, S.; Sanna, M. G.; Brunner, H.
Tetrahedron: Asymmetry 2000, 11, 3419.
(5) Chelucci, G.; Loriga, G.; Murineddu, G.; Pinna, G. A.
Tetrahedron Lett. 2002, 43, 3601.
(6) Mihelich, E. D.; Eickhoff, D. J. J. Org. Chem. 1983, 48,
4135.
Anal. Calcd for C26H28N2: C, 84.74; H, 7.66; N, 7.60. Found: C,
84.58; H, 7.68; N, 7.57.
(7) Woodward, R. B.; Pachter, I. J.; Scheinbaum, M. L. J. Org.
Chem. 1971, 36, 1137.
(8) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1991, 203.
(9) Cain, E. N.; Welling, L. L. Tetrahedron Lett. 1975, 1353.
(10) Wu, Y.-J.; Ding, W.-L.; Du, C.-X. Tetrahedron: Asymmetry
1998, 9, 4035.
(11) Gianini, M.; von Zelewsky, A. Synthesis 1996, 702.
(12) Bessière-Chrétien, Y.; Grison, C. Bull. Soc. Chim. Fr. 1970,
3103.
(13) Chelucci, G.; Delogu, G.; Gladiali, S.; Soccolini, F. J.
Heterocycl. Chem. 1986, 23, 1395.
(1S,2S,4S,9S,11S,12S)-(–)-2,4,9,11-Dimethano-1,3,3,10,10,12-
hexamethyl-1,2,3,4,9,10,11,12-octahydrodibenzo-
[b,j][1,10]phenanthroline (3)
This compound was purified by chromatography on neutral Al2O3
(petroleum ether–EtOAc, 95:5); yield: 345 mg (91%); mp 186–
188 °C; [ ]D25 –6.7 (c = 0.63, CHCl3).
1H NMR: = 7.64 (s, 2 H), 7.62 (s, 2 H), 3.49 (ddd, 2 H, J = 6.9,
5.1, 1.8 Hz), 2.99 (t, 2 H, J = 5.7 Hz), 2.68 (m, 2 H), 2.26 (dt, 2 H,
J = 5.7, 2.1 Hz), 1.73 (d, 6 H, J = 6.9 Hz), 1.46 (s, 6 H), 1.40 (d, 2
H, J = 9.9 Hz), 0.67 (s, 6 H).
Synthesis 2003, No. 1, 73–78 ISSN 0039-7881 © Thieme Stuttgart · New York