Synthesis of phenanthro[9,10-b]indolizidin-9-ones, phenanthro[9,10-b] quinolizidin-9-one, and related benzolactams by Pd(OAc)2-catalyzed direct aromatic carbonylation

Article abstract of DOI:10.1002/ejoc.200801047

Phenanthro[9,10-b]indolizidin-9-ones, phenanthro[9,10-b]-quinolizidin-9- one, and related benzolactams were synthesized by benzolactam ring formation using Pd(OAc)₂-catalyzed direct aromatic carbonylation. This also constitutes a formal synthesis of the representative phenanthroindolizidine and -quinolizidine alkaloids (±)-tylophorine, (±)-antofine, and (±)-cryptopleurine. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Full text of DOI:10.1002/ejoc.200801047

FULL PAPER
DOI: 10.1002/ejoc.200801047
Synthesis of Phenanthro[9,10-b]indolizidin-9-ones,
Phenanthro[9,10-b]quinolizidin-9-one, and Related Benzolactams by
Pd(OAc)2-Catalyzed Direct Aromatic Carbonylation
Satoshi Yamashita,[a] Nobuhito Kurono,[b] Hisanori Senboku,[c] Masao Tokuda,[a] and
Kazuhiko Orito*[a]
Keywords: Palladium / Carbonylation / Benzolactams / Nitrogen heterocycles
Phenanthro[9,10-b]indolizidin-9-ones, phenanthro[9,10-b]-
quinolizidin-9-one, and related benzolactams were synthe-
sized by benzolactam ring formation using Pd(OAc)2-cata-
lyzed direct aromatic carbonylation. This also constitutes a
formal synthesis of the representative phenanthroindolizid-
ine and -quinolizidine alkaloids (Ϯ)-tylophorine, (Ϯ)-antof-
ine, and (Ϯ)-cryptopleurine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
tibiotic activities, as well as activities as inhibitors of protein
synthesis (peptide bond formation), as insecticides, and as
insect antifeedants – many efforts have been made to de-
velop methods for synthesizing these alkaloids and related
compounds.[3–8]
Introduction
Since tylophorine (1) was first isolated in 1935,[1] over 60
phenanthroindolizidine and -quinolizidine alkaloids,[2] in-
cluding their seco analogues, have been isolated from plants
of the Asclepiadaceae[2b] and Moraceae[2c] families. Because
of their interesting biological properties[2d–2h] – including
vesicant, mitotic, antitumor, anticancer, and antileukemic,
anti-Candida albicans, antiinflammatory, selective antifun-
gal, antiamoebic, antibacterial, antiviral, cytotoxic, and an-
Results and Discussion
Here we report a route to the syntheses of tylophorine
(1), antofine (2), and cryptopleurine (3) through the forma-
tion of benzolactam rings by Pd(OAc)2-catalyzed direct
aromatic carbonylation.[9,10] It has already been reported
that the benzolactam target compounds 4a, 4b, and 5 in
these syntheses are readily transformable into the represen-
tative alkaloids 1, 2, and 3, respectively, by hydride re-
duction (Figure 1).[3a,3n,4d–4f,5c,5e,6f,7a,8a,8b,8g]
[a] Laboratory of Organic Synthesis, Division of Molecular Chem-
istry, Graduate School of Engineering, Hokkaido University,
Sapporo 060-8628, Japan
Fax: +81-11-761-5383
E-mail: orito@eng.hokudai.ac.jp
[b] Division of Chemical Process Engineering, Graduate School of
Engineering, Hokkaido University,
Figure 1. Hydride reduction of benzolactams 4a, 4b and 5.
Sapporo 060-8628, Japan
E-mail: chrono@eng.hokudai.ac.jp
Several methods for the construction of the phenan-
threne ring components in syntheses of the alkaloids[2d–2h]
have been developed.[3–8] Direct oxidative cyclizations of
[c] Division of Chemical Process Engineering, Graduate School of
Engineering, Hokkaido University,
Sapporo 060-8628, Japan
E-mail: senboku@eng.hokudai.ac.jp
[3]
stilbenes with VOF3 or Tl(OAc)3,[4] photocyclization of
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
stilbenes in the presence of I2,[5] or indirect cyclization
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S. Yamashita, N. Kurono, H. Senboku, M. Tokuda, K. Orito
FULL PAPER
either with diazotized stilbenes through Pschorr reactions[6]
The (Z)-cinnamic acids 6a and 6b (Figure 2) were pre-
or with halogenated stilbenes by radical cyclization[7] have pared according to the reported methods,[4b,6b,11] by con-
been carried out either at the early or at the very last stages densation of (3,4-dimethoxyphenyl)acetic acid with vera-
of the syntheses. It was reported that the phenanthrenes, traldehyde or 4-methoxybenzaldehyde in the presence of
8a, 8b, and 10a were obtained in 75–100% yields by treat- Et3N and Ac2O, and their methyl esters 7a and 7b were
ment of 7a, 7b, and 9a with the expensive reagent VOF3 in quantitatively obtained by Fischer esterification. A photo-
CF3COOH,[3a,3d,3e] but this was reported to be unsuccessful cyclization of methyl ester 7a to phenanthrene 8a based on
for the preparation of less electrophilic substrates such as Herbert’s method[5a] was examined in cyclohexane or ben-
the trimethoxy derivative 10b.[3e] It was reported by Herbert zene in the presence of catalytic amounts of iodine, either
et al. that photocyclization of 7a gave methyl phenanthrene- with air being bubbled or with a limited amount of oxygen
9-carboxylate 8a in 31% yield.[5a] We were interested in this in a Pyrex flask open to air, but without agitation or bub-
method because of its potential economical advantages, and bling. The latter method resulted in more efficient forma-
we tried to improve the yield in order also to use it for the tion of phenanthrene 8a (Figure 2), in 65% yield, together
preparation of analogous compounds.
with the regioisomer 8c (8%). However, this method did
Figure 2. Photocyclization of α-phenylcinnamates and related nitriles.
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Eur. J. Org. Chem. 2009, 1173–1180

Phenanthro[9,10-b]indolizidin-9-ones and -quinolizidin-9-one
not work for cyclization of the acids 6a and 6b. Attempts phenanthromethyl bromide 17a gave only a complex mix-
to prepare methyl ester 7a directly by condensation of ture, whereas interaction with bromide 17b gave only a
methyl (3,4-dimethoxyphenyl)acetate with 3,4-dimeth- small amount of (phenanthromethyl)pyrrolidine 21b (6%)
oxybenzaldehyde in the presence of Et3N/Ac2O[5a] or Na- after treatment of the reaction mixture containing N-Boc
OEt in EtOH[6b] failed. On the other hand, condensation product 20b with TFA. Under the same conditions, the use
of (3,4-dimethoxyphenyl)acetonitrile with the correspond- of aldehydes 18a or 18b in place of bromides 17a or 17b
ing aldehydes in the presence of NaOEt in EtOH resulted resulted in complete recovery of 18a or 18b. In contrast, an
in exclusive formation of the (Z)-cinnamonitriles 9a and 9b, alternative coupling with N-nitrosopyrrolidine lithium salt
photocyclization of which proceeded slowly to give either (2 equiv., prepared with LDA in THF, –78 °C) according to
phenanthronitrile 10a (71% yield) together with its re- Fraser’s report[14] based on Seebach’s method[15] produced
gioisomer 10c (25% yield) or 10b (78% yield).
(N-nitrosopyrrolidinomethyl)phenanthrenes 21a, 21b, and
The pyridine analogues 11 and 13 were also obtained by 21c in 81%, 93%, and 90% yields, respectively. Removal of
the same method (NaOEt in EtOH) and were subjected to the nitroso groups by subsequent treatment with HCl gas
photocyclization to give azaphenanthrenes 12 in 52% yield provided 2-(9-phenanthromethyl)pyrrolidine hydrochlorides
and 14 and 15 in 35% and 33% yields, respectively. The 22a·HCl, 22b·HCl, and 22c·HCl.
regioselectivity of this cyclization seems to be due to steric
factors rather than electronic effects.
LiAlH4 reduction of the esters 8a and 8b, followed by
treatment of the resultant hydroxy groups with PBr3 at
room temperature, afforded bromides 17a, 17b, and 17c in
excellent yields, as shown in Figure 3 (see also the Support-
ing Information). Alcohols 16a, 16b, and 16c were also ob-
tained in excellent yields by treatment of the phenanthroni-
triles 10a, 10b, and 10c with DIBAL and then aqueous acid,
followed by NaBH4 reduction of the resultant aldehyde
group.
Figure 4. Preparation of 2-(phenanthromethyl)pyrrolidines 22a,
22b, and 22c.
Similar reaction sequences with analogous – or dif-
ferently N-protected – piperidines[16–19] in place of pyrroli-
dines did not work for the preparation of compounds such
as the 2-(9-phenenthromethyl)piperidine 25. In a modifica-
tion of Eichen’s method,[20] however, Pd0-catalyzed cross-
coupling between 2-bromopyridine (1.2 equiv.) and ben-
zylzinc bromide (1 equiv., prepared from BnBr and Zn) in
the presence of Pd(PPh3)4 afforded 2-benzylpyridine (23) in
90% yield (Figure 5). Bromide 17b under the same condi-
tions, however, failed to give the desired coupling product 26.
Stille coupling[21] with tributyl(2-pyridinyl)stannane[22]
(1.1 equiv.) and bromide 17b (1 equiv.) in the presence of
Figure 3. Transformation of phenanthrenes 8a, 8b, 10a, 10b, and
Pd(PPh3)4 (1 mol-%) (at reflux in THF for 8 h) produced
26 in 58% yield, together with pyridinium salt 27. The yield
10c to bromides 17a, 17b, and 17c. Reaction conditions: (a) LiAlH4
in THF at reflux, 2 h. (b) PBr3 in CHCl3. (c) (1) DIBAL in CH2Cl2;
(2) aq. HCl. (d) NaBH4 in MeOH/CH2Cl2 (1:10).
of 26 was higher than the yields of couplings performed
[23]
with other catalytic systems such as Pd2dba3/P(2-furyl)3
In order to introduce an α-pyrrolidinomethyl group into PdCl2(PPh3)2,[24] PdCl2(dppb)2/CuO,[25] and Pd(OAc)2/
the phenanthrene at its 9-position, the reaction behavior of Cu(OAc)2/K2CO3.[26] In addition, an anionic reaction in-
N-protected pyrrolidinyl carbanions was examined. As volving treatment of 2-bromopyridine with tBuLi at
shown in Figure 4, coupling between N-Boc-pyrrolidine[12] –78 °C[27] and subsequent trapping of the resultant lithium
lithium salt and benzyl bromide in THF gave the 2-benzyl- salt with bromide 17b or aldehyde 18b failed to produce the
pyrrolidine 19 in 73% yield in a modification of the method desired 26. Catalytic hydrogenation of 2-benzylpyridine 23
reported by Beak.[13] However, a similar interaction with [PtO2 (8 mol-%), H2 (1.5 kgcm–2), concd. HCl/EtOH
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S. Yamashita, N. Kurono, H. Senboku, M. Tokuda, K. Orito
FULL PAPER
(1:20), room temp., 2 h][28] produced the corresponding oxotylophorine (4a) in 26% yield and (Ϯ)-9-oxocrypto-
piperidine 24 quantitatively. Under the same conditions, hy- pleurine (5) in 31% yield.[30] As described above, it has been
drogenation of hydrochloride 26 never went to completion. reported that hydride reactions converted these compounds
After many trials, the use of free amine 26 under hydrogen into the corresponding alkaloids (Figure 1). (Ϯ)-9-Oxo-
(25 kgcm–2) with PtO2 (20 mol-%) in AcOH at 140 °C for tylocrebrine (4c) was obtained in 17% yield.
24 h finally led to the quantitative formation of 28.
Figure 6. Pd(OAc)2-mediated carbonylation of amines 22a, 22b,
22c and 28.
Table 1. Pd(OAc)2-mediated carbonylation of amines 22a, 22b, 22c,
and 28.
Entry Substrate Solvent Pd(OAc)2 Cu(OAc)2
CO
Time
Yield
[mol-%]
[mol-%]
1
2
3
4
5
6
7
8
9
22b
22b
toluene
dioxane
100
5
100
5
100
5
5
100
5
5
0
50
0
50
0
50
50
0
1 atm
1 atm
1 atm
1 atm
25 atm 2 h
25 atm 2 h
25 atm 24 h
25 atm 24 h 52% of 4a
25 atm 24 h 26% of 4a
25 atm 24 h 17% of 4c
2 h
2 h
2 h
2 h
0%
0%
22b·HCl toluene
22b·HCl toluene
22b·HCl toluene
22b·HCl toluene
22b·HCl dioxane
22a·HCl toluene
22a·HCl toluene
22c·HCl toluene
28·HCl toluene
53% of 4b
0%
70% of 4b
45% of 4b
7% of 4b
50
50
50
10
11
Figure 5. Preparation of 2-(phenanthromethyl)pyrrolidine 28.
5
25 atm 24 h
31% 5
Our recently reported[9,29] one-step preparation of five-
and six-membered benzolactams by a phosphane-free
Pd(OAc)2-catalyzed direct aromatic carbonylation pro-
cedure was examined with amine 22b and its HCl salt in
toluene or dioxane (Figure 6). As shown in Table 1, carbon-
ylation of free amine 22b with Pd(OAc)2 (5 mol-%) and
Cu(OAc)2 (50 mol-%) in boiling toluene under CO pro-
duced not the benzolactam, but the N-acetyl derivative of
the reactant (see the Supporting Information). Carbon-
ylation of 22b·HCl by electrophilic aromatic palladation[29]
(5 mol-%) with Cu(OAc)2 (50 mol-%) in boiling toluene un-
der CO also produced no benzolactam but the N-acetyl de-
rivative of the reactant (see the Supporting Information).
Carbonylation of 22b·HCl by electrophilic aromatic pallad-
ation[29] in the presence of a stoichiometric amount of
Pd(OAc)2, however, gave the desired benzolactam – (Ϯ)-9-
oxoantofine (4b) – in 53% yield (Entry 3 in Table 1). Under
CO gas (25 kgcm–2), the yield was improved to 70% (En-
try 5). A catalytic version of this carbonylation[9a] of
22b·HCl with Pd(OAc)2 (5 mol-%)/Cu(OAc) (50 mol-%)
under air containing CO (corresponding to 0.5 mol-equiv.
of O2) at 25 kgcm–2 produced 4b in 45% yield (Entry 6).
Use of a higher or lower pressure of CO decreased the yield.
Similarly, the N-propylbenzolactams 32 (26%) and 33
(43%) were obtained by carbonylation of the HCl salts of
N-propylamines 29 and 31. Amine 29 was prepared in 92%
yield from aldehyde 18b and propylamine, whereas amine
31 was obtained via nitrosoamine 30, which was obtained
in 90% yield from bromide 16c and N-nitrosopropylamine
(Figure 7).
Figure 7. Preparation and carbonylation of amines 29 and 31.
Conclusions
Phenanthro[9,10-b]indolizidin-9-ones, phenanthro[9,10-
Similar catalytic carbonylations of 22a and 28 gave (Ϯ)-9- b]quinolizidin-9-one, and related benzolactams were ob-
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Eur. J. Org. Chem. 2009, 1173–1180

Phenanthro[9,10-b]indolizidin-9-ones and -quinolizidin-9-one
350 (29.9), 281 (100). C22H24N2O4 (380.44): calcd. C 69.46, H 6.36,
N 7.36; found C 69.55, H 6.41, N 7.30.
tained from the corresponding amines by phosphane-free
Pd(OAc)2-catalyzed direct aromatic carbonylation. This
constitutes a formal synthesis of the representative phenan-
throindolizidine and -quinolizidine alkaloids (Ϯ)-tylophor-
ine, (Ϯ)-antofine, and (Ϯ)-cryptopleurine.
1-Nitroso-2-[(2,3,5,6-tetramethoxy-10-phenanthryl)methy]pyrrol-
idine (21c): Colorless crystals (90%) from bromide 17c, m.p. 124–
1
137 °C (EtOH). H NMR [rotational isomer A (60%)]: δ = 1.70–
2.30 (m, 4 H, 3- and 4-H), 3.13 (dd, J = 13.9, 10.6 Hz, 1 H, benzylic
H), 3.60–3.80 (m, 2 H, 5-H), 3.90–4.50 (m, 14 H, OMe, benzylic H
and 5-H), 4.95 (m, 1 H, 5-H), 7.20–7.65 (m, 3 H, Ar-H), 9.36 (s, 1
H, 4Ј-H) ppm; [rotational isomer B (40%)]: δ = 1.70–2.30 (m, 4 H,
3- and 4-H), 2.50 (dd, J = 13.2, 10.9 Hz, 1 H, benzylic H), 3.60–
3.80 (m, 1 H, 5-H), 3.90–4.50 (m, 14 H, OMe, benzylic H and 5-
H), 4.74 (m, 1 H, 2-H), 7.20–7.65 (m, 3 H, Ar-H), 8.20 (s, 1 H, 9Ј-
Experimental Section
General Remarks: Melting points were measured with a Yanagim-
oto micro melting point apparatus and are uncorrected. IR spectra
were recorded with a JASCO IR-810 infrared spectrophotometer.
1H NMR spectra were obtained in CDCl3 (99.8 atom-% D, con-
taining 0.03% v/v TMS, Aldrich) with a JEOL EX-270 high-resolu-
tion spectrometer. Mass spectrometric data were recorded with a
JEOL JMS-FABmate or JMS-700TZ spectrometer at 70 eV. Pre-
parative TLC was run on Merck silica gel 60 PF-254 plates. Col-
umn chromatography was conducted with Cica reagent silica gel
60 (100–210 mm, spherical, Kanto Chemical Co., Inc.). See the
Supporting Information for the preparation of compounds 6–18,
23, and 24.
H), 9.32 (s, 1 H, 4Ј-H) ppm. IR (CHCl ): ν = 1602, 1528,
˜
3
1509 cm–1. EI-MS: m/z (%) = 410 (33.3) [M]+, 380 (28.2), 311 (100).
C23H26N2O5 (410.46): calcd. C 67.30, H 6.38, N 6.82; found C
67.17, H 6.52, N 6.88.
2-[(2,3,6,7-Tetramethoxy-9-phenanthryl)methyl]pyrrolidine Hydro-
chloride (22a·HCl). A General Procedure: HCl gas (generated from
NaCl and H2SO4) was introduced into a solution of nitrosoamine
21a (141.5 mg, 0.35 mmol) in benzene (25 mL) at reflux over 1 h,
and the mixture was then heated under N2 gas for 30 min. The
solvent was evaporated. Crystallization of the residue from CH2Cl2
gave 22a·HCl as colorless crystals (144 mg, 99%), m.p. 159–162 °C
(free amine: ref.[6d] m.p. 152 °C).
1-Nitroso-2-[(2,3,6,7-tetramethoxy-9-phenanthryl)methyl]pyrrolidine
(21a). A General Procedure: LDA (1.50 , THF solution, 0.67 mL,
1.00 mmol) was added under Ar at –78 °C to a stirred solution of
N-nitrosopyrrolidine (0.091 mL, 1.00 mmol) in dry THF (4 mL).
The mixture was stirred at –78 °C for 1 h. A solution of bromide
17a (195 mg, 0.5 mmol) in dry THF (8 mL) was added. The mix-
ture was stirred at –78 °C for 5 h and was then allowed to warm to
room temperature and diluted with CH2Cl2 (20 mL). The mixture
was washed with H2O (2ϫ50 mL) and dried (Na2SO4). The solvent
was evaporated, and the residue was purified by column
chromatography with AcOEt/CH2Cl2 (1:9) as eluent to give 21a as
colorless crystals (166 mg, 81%), m.p. 176–177 °C (benzene). 1H
NMR [rotational isomer A (67%)]: δ = 1.70–2.30 (m, 4 H, 3- and
4-H), 3.18 (dd, J = 13.9, 10.6 Hz, 1 H, benzylic H), 3.60–3.80 (m,
2 H, benzylic H and 5-H), 4.04, 4.05, 4.13, 4.14 (each s, each 3 H,
OMe), 4.00–4.20 (m, 1 H, 5-H), 4.90–5.00 (m, 1 H, 2-H), 7.20,
7.46, 7.59, 7.80, 7.86 (each s, each 1 H, Ar-H) ppm; [rotational
isomer B (33%)]: δ = 1.70–2.30 (m, 4 H, 3- and 4-H), 2.55 (dd, J
= 13.2, 10.9 Hz, 1 H, benzylic H), 3.92 (dd, J = 13.2, 2.6 Hz, 1 H,
benzylic H), 4.03, 4.12, 4.14, 4.34 (each s, each 3 H, OMe), 4.30–
4.50 (m, 2 H, 5-H), 4.70–4.90 (m, 1 H, 2-H), 7.17, 7.36, 7.78, 7.83,
2-[(2,3,6-Trimethoxy-10-phenanthryl)methyl]pyrrolidine Hydrochlo-
ride (22b·HCl): This compound was obtained as colorless crystals
(87%) from nitrosoamine 21b; m.p. 257–259 °C (dec. CHCl3) [free
amine: ref.[3q] m.p. 144–145 °C; ref.[6o] m.p. 145–146 °C; (R) form:
ref.[3l] m.p. 144–148 °C; picrate: ref.[6f] m.p. 229 °C].
2-[(2,3,5,6-Tetramethoxy-10-phenanthryl)methyl]pyrrolidine Hydro-
chloride (22c·HCl): This compound was obtained as a colorless oil
(99%) from nitrosoamine 21c (picrate: ref.[6e] m.p. 247–249 °C). It
was used for carbonylation without further purification.
2-[(2,3,6-Trimethoxy-10-phenanthryl)methyl]pyridine (26) and 1-
[(2,3,6-Trimethoxy-10-phenanthryl)methyl]pyridinium Bromide (27):
A solution of bromide 17b (360 mg, 1 mmol) and Pd(PPh3)4
(12 mg, 1 mol-%) in dry THF was stirred under N2 at room temp.
for 5 min. Tributyl(2-pyridyl)stannane [0.343 mL, 1.1 mmol, pre-
pared according to the reported method[22a] in 96% yield, b.p.
122 °C/0.4 Torr (ref.[22b] b.p. 140–145 °C/0.3 Torr)] was then added,
and the mixture was heated at reflux for 8 h. The solvent was evap-
orated, and the residue was dissolved in hot AcOEt (20 mL). An
insoluble product was collected by suction filtration and recrys-
tallized from EtOH/CH2Cl2 to give 27 (110.8 mg, 25%), as color-
less crystals, m.p. 216 °C (dec.). 1H NMR: δ = 4.02, 4.03, 4.07 (each
s, each 3 H, OMe), 6.93 (s, 2 H, CH2), 7.18 (dd, J = 8.9, 2.3 Hz, 1
H, 7Ј-H), 7.34 (s, 1 H, 1Ј-H), 7.67–7.70 (m, 2 H, 5Ј- and 9Ј-H),
7.78 (d, J = 8.9 Hz, 1 H, 8Ј-H), 7.90 (t, J = 7.3 Hz, 2 H, 3- and 5-
H), 8.00 (s, 1 H, 4Ј-H), 8.29 (t, J = 7.6 Hz, 1 H, 4-H), 9.58 (d, J =
8.19 (each s, each 1 H, Ar-H) ppm. IR (CHCl ): ν = 1622,
˜
3
1509 cm–1. EI-MS: m/z (%) = 410 (20.1) [M]+, 380 (23.6), 349 (9.9),
326 (18.7), 311 (100). C23H26N2O5 (410.46): calcd. C 67.30, H 6.38,
N 6.82; found C 67.28, H 6.29, N 6.71.
1-Nitroso-2-[(2,3,6-trimethoxy-10-phenanthryl)methyl]pyrrolidine
(21b): Colorless crystals (93%) from bromide 17b, m.p. 165–167 °C
(benzene). 1H NMR [rotational isomer A (60%)]: δ = 1.70–2.30
(m, 4 H, 3- and 4-H), 3.13 (dd, J = 13.9, 10.6 Hz, 1 H, benzylic
H), 3.60–3.80 (m, 2 H, 2- and 5-H), 4.02, 4.05, 4.12 (each s, each
5.6 Hz, 2 H, 2- and 6-H) ppm. IR (CHCl ): ν = 1612, 1524,
˜
3
1511 cm–1. EI-MS: m/z (%) = 360 (8.6) [M – Br]+, 281 (100).
3 H, OMe), 4.00–4.20 (m, 1 H, benzylic H), 4.88–5.00 (m, 1 H, 5- C23H22BrNO3 (440.33): calcd. C 62.74, H 5.04, Br 18.15, N 3.90;
H), 7.20 (dd, J = 8.9, 2.3 Hz, 1 H, 7Ј-H), 7.46 (s, 1 H, 1Ј-H), 7.57 found C 62.55, H 5.16, Br 18.43, N 3.75. The filtrate was concen-
(s, 1 H, 9Ј-H), 7.74 (d, J = 8.9 Hz, 1 H, 8Ј-H), 7.84 (d, J = 2.3 Hz, trated, and the residue was purified by column chromatography on
1 H, 5Ј-H), 7.93 (s, 1 H, 4Ј-H) ppm; [rotational isomer B (40%)]:
δ = 1.70–2.30 (m, 4 H, 3- and 4-H), 2.51 (dd, J = 13.2, 10.9 Hz, 1
H, benzylic H), 3.88 (dd, J = 13.2, 2.6 Hz, 1 H, benzylic H), 4.01,
4.12, 4.35 (each s, each 3 H, OMe), 4.30–4.45 (br. s, 2 H, 5-H),
4.70–4.85 (br. s, 1 H, 5-H), 7.17 (dd, J = 8.9, 2.3 Hz, 1 H, 7Ј-H),
7.36 (s, 1 H, 1Ј-H), 7.71 (d, J = 8.9 Hz, 1 H, 8Ј-H), 7.83 (d, J =
silica gel with AcOEt as eluent to give 26 (207.6 mg, 58%), m.p.
166–167 °C (EtOH) as colorless crystals. H NMR: δ = 3.87, 4.04,
4.08 (each s, each 3 H, OMe), 4.61 (s, 2 H, CH2), 7.00–7.20 (m, 2
H, 3- and 5-H), 7.21 (dd, J = 8.6, 2.3 Hz, 1 H, 7Ј-H), 7.42 (s, 1 H,
1Ј-H), 7.47 (dt, J = 7.9, 2.0 Hz, 1 H, 4-H), 7.60 (s, 1 H, 9Ј-H), 7.79
(d, J = 8.6 Hz, 1 H, 8Ј-H), 7.86 (d, J = 2.3 Hz, 1 H, 5Ј-H), 7.90 (s,
1
2.3 Hz, 1 H, 5Ј-H), 7.90 (s, 1 H, 9Ј-H), 8.22 (s, 1 H, 4Ј-H) ppm. IR 1 H, 4Ј-H), 8.50–8.70 (m, 1 H, 6-H) ppm. IR (CHCl ): ν = 1611,
˜
3
(CHCl ): ν = 1611, 1525 cm–1. EI-MS: m/z (%) = 380 (33.0) [M]+,
1591, 1567, 1509 cm–1. EI-MS: m/z (%) = 359 (100) [M]+, 344
˜
3
Eur. J. Org. Chem. 2009, 1173–1180
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1177

S. Yamashita, N. Kurono, H. Senboku, M. Tokuda, K. Orito
FULL PAPER
(41.7). C23H21NO3 (359.42): calcd. C 76.86, H 5.89, N 3.90; found
C 76.75, H 6.03, N 4.11.
ture, and CH2Cl2 (20 mL) was added. The CH2Cl2 layer was
washed with H2O (2ϫ50 mL) and dried (Na2SO4). The solvent
was evaporated, and the residue was purified by column
chromatography with AcOEt/CH2Cl2 (1:9) as eluent to give 30
(315 mg, 82%), which was treated with EtOH to give colorless crys-
2-[(2,3,6-Trimethoxy-10-phenanthryl)methyl]piperidine (28): A solu-
tion of 26 (71.9 mg, 0.2 mmol) and PtO2 (9 mg, 20 mol-%) in
AcOH (1 mL) was stirred at 140 °C under H2 (25 kgcm–2) for 24 h.
The mixture was filtered through Celite to remove precipitates by
washing with CH2Cl2 (15 mL). The combined solution and wash-
ings were washed with Na2CO3 solution (5%) and H2O (2ϫ10 mL)
and dried (Na2SO4). The solvents were evaporated. Crystallization
of the residue from EtOH gave 28 as colorless crystals (73.0 mg,
99%), m.p. 110–116 °C [ref.[6o] m.p. 122–123 °C; ref.[3q] m.p. 136–
137 °C; (R) form: ref.[3l] m.p. 147–148 °C]. Its hydrochloride was
prepared as follows. A solution of 28 (36.5 mg, 0.1 mmol) in CHCl3
was treated with an HCl solution (2 ), dried, and concentrated.
Crystallization of the residue from CHCl3 gave 28·HCl as colorless
crystals (40.1 mg, 99%), m.p. 205–208 °C. 1H NMR: δ = 1.65–2.15
(m, 6 H, 3-, 4- and 5-H), 2.80–3.00 (m, 1 H, 6-H), 3.25–3.45 (m, 2
H, benzyl H), 3.60 (m, 1 H, 6-H), 3.99 (s, 3 H, OMe), 4.05 (s, 3 H,
OMe), 4.15–4.30 (m, 1 H, 2-H), 4.19 (s, 3 H, OMe), 7.14 (dd, J =
8.9, 2.3 Hz, 1 H, 7Ј-H), 7.40 (s, 1 H, 1Ј-H), 7.58 (s, 1 H, 9Ј-H), 7.66
(d, J = 8.9 Hz, 1 H, 8Ј-H), 7.74 (d, J = 2.3 Hz, 1 H, 5Ј-H), 7.82 (s,
1 H, 4Ј-H), 9.67, 10.40 (each br. s, each 1 H, NH and HCl) ppm.
1
tals, m.p. 108–111 °C. H NMR [rotational isomer A (73%)]: δ =
0.96 (t, J = 7.6 Hz, 3 H, Pr-CH3), 1.78 (sext, J = 7.6 Hz, 2 H, Pr-
CH2), 3.14 (t, J = 5.6 Hz, 2 H, N-CH2), 3.81 (t, J = 5.6 Hz, 2 H,
benzylic H), 3.95–4.10 (overlapping, 2 H, Pr-CH2N), 3.99, 4.10,
4.27 (each s, each 3 H, OMe), 7.10–7.95 (m, 6 H, Ar-H) ppm;
[rotational isomer B (27%)]: δ = 0.85 (t, J = 7.6 Hz, 3 H, Pr-CH3),
1.52 (sext, J = 7.6 Hz, 2 H, Pr-CH2), 3.44 (m, 2 H, benzylic H),
3.52 (m, 2 H, Pr-CH2N), 3.99, 4.00, 4.10, (each s, each 3 H, OMe),
4.43 (t, J = 5.6 Hz, 2 H, N-CH2), 7.10–7.95 (m, 6 H, Ar-H) ppm.
IR (CHCl ): ν = 1612, 1527, 1510 cm–1. EI-MS: m/z (%) = 382
˜
3
(27.3) [M]+, 394 (20.6), 281 (100). C22H26N2O4 (382.45): calcd. C
69.09, H 6.85, N 6.32; found C 69.20, H 6.63, N 6.54.
N-[2-(2,3,6-Trimethoxy-10-phenanthryl)ethyl]propylamine (31): This
compound was obtained as a colorless oil (95%) from 30. 1H
NMR: δ = 0.90 (t, J = 7.2 Hz, 3 H, Pr-CH3), 1.53 (q, J = 7.2 Hz,
2 H, Pr-CH2), 2.65 (t, J = 7.2 Hz, 2 H, benzylic H), 3.09, 3.29 (each
t, J = 7.2 Hz, each 2 H, CH2NCH2), 4.02, 4.06, 4.12 (each s, each
3 H, OMe), 7.19 (dd, J = 8.8, 2.3 Hz, 1 H, 7Ј-H), 7.45, 7.48 (each
s, each 1 H, 1Ј- and 9Ј-H), 7.75 (d, J = 8.8 Hz, 1 H, 8Ј-H), 7.85 (d,
J = 2.3 Hz, 1 H, 5Ј-H), 7.93 (s, 1 H, 4Ј-H) ppm.
IR (CHCl ): ν = 3650, 1610, 1526, 1511 cm–1. EI-MS: m/z (%) =
˜
3
365 (0.5) [M – HCl]+, 282 (28.3), 84 (100). C23H28ClNO3 (401.93):
calcd. C 68.73, H 7.02, Cl 8.82, N 3.48; found C 68.79, H 6.85, Cl
8.46, N 3.48.
1
Hydrochloride 31·HCl: H NMR: δ = 1.03 (t, J = 7.6 Hz, 3 H, Pr-
CH3), 2.00 (m, 2 H, Pr-CH2), 2.99, 3.30, 3.87 (each br. s, each 2
H, CH2NCH2), 3.99, 4.06, 4.15 (each s, each 3 H, OMe), 7.16 (dd,
J = 8.9, 2.3 Hz, 1 H, 7Ј-H), 7.47, 7.53 (each s, each 1 H, 1Ј- and
9Ј-H), 7.68 (d, J = 8.9 Hz, 1 H, 8Ј-H), 7.75 (d, J = 2.3 Hz, 1 H, 5Ј-
H), 7.82 (s, 1 H, 4Ј-H), 10.05 (br. s, 2 H, +NH2) ppm. This was
used for the carbonylation without further purification.
N-[(2,3,6-Trimethoxy-10-phenanthryl)methyl]propylamine (29): A
mixture of aldehyde 18b (444 mg, 1.5 mmol), propylamine
(0.25 mL, 3 mmol), and Na2SO4 (50 mg) in CH2Cl2 (15 mL) was
stirred at room temperature for 19 h. A solution of NaBH4
(121.6 mg, 3 mmol) in MeOH (15 mL) was added. After 1 h, the
solvent was evaporated, and the residue was dissolved in CH2Cl2
(100 mL). The CH2Cl2 layer was washed with H2O (2ϫ100 mL)
and dried (Na2SO4). The solvent was evaporated, and the residue
was crystallized from EtOH to give 29 as colorless crystals (467 mg,
(؎)-9-Oxotylophorine (4a): A mixture of 22a (21 mg, 0.05 mmol),
Pd(OAc)2 (0.6 mg, 5 mol-%), and Cu(OAc)2 (4.6 mg, 50 mol-%) in
toluene (2.5 mL) was stirred at 140 °C under air (3 mL) containing
92%), m.p. 142–143 °C. 1H NMR: δ = 0.97 (t, J = 7.3 Hz, 1 H, Pr- CO (25 kgcm–2) for 25 h. The reaction mixture was filtered through
CH3), 1.60, 2.68 (each sext, J = 7.3 Hz, each 2 H, Pr-CH2), 4.02,
4.06, 4.12 (each s, each 3 H, OMe), 4.20 (s, 2 H, benzylic H), 7.19
(dd, J = 8.6, 2.3 Hz, 1 H, 7Ј-H), 7.58 (s, 2 H, 1- and 9Ј-H), 7.77
a pad of powdered MgSO4. The precipitates were washed with
CHCl3 (10 mL). The combined organic layers were washed with
NaOH solution (0.5 , 1 mL) and H2O (10 mL), dried (Na2SO4),
(d, J = 8.6 Hz, 1 H, 8Ј-H), 7.85 (d, J = 2.3 Hz, 1 H, 5Ј-H), 7.92 (s, and concentrated. The residue (18 mg) was purified by preparative
1 H, 4Ј-H) ppm. IR (CHCl ): ν = 2926, 1656, 1611, 1561, 1523, TLC on silica gel with AcOEt and crystallized from EtOH to give
˜
3
1509 cm–1. EI-MS: m/z (%) = 339 (33.4) [M]+, 282 (87.2), 281 (100). 4a (5.3 mg, 26%) as colorless crystals, which melted at 200 °C, then
C21H25NO3 (339.43): calcd. C 74.31, H 7.42, N 4.13; found C
74.04, H 7.48, N 3.96.
solidified, and remelted at 283–289 °C [ref.[5d] m.p. 237–238 °C;
ref.[5e] m.p. 280–281 °C; ref.[4d] m.p. 282–283 °C; ref.[3n] m.p. 284–
286 °C; (R) form: ref.[4e] m.p. 286–289 °C].
Hydrochloride 29·HCl: Colorless crystals (92 %) from 29, m.p.
110 °C. 1H NMR: δ = 0.87 (t, J = 7.6 Hz, 3 H, Pr-CH3), 1.86 (sext,
J = 7.6 Hz, 2 H, Pr-H), 2.65–2.85 (m, 2 H, Pr-CH2), 3.87, 3.94
(each s, each 3 H, OMe), 4.10–4.20 (m, 2 H, benzylic H), 4.15 (s,
3 H, OMe), 7.13 (dd, J = 8.9, 2.3 Hz, 1 H, 7Ј-H), 7.20 (s, 1 H, 1Ј-
H), 7.51 (d, J = 2.3 Hz, 1 H, 5Ј-H), 7.65, 7.69 (each s, each 1 H,
9Ј- and 4Ј-H), 7.75 (d, J = 8.9 Hz, 1 H, 8Ј-H), 9.76 (br. s, 2 H,
+NH ) ppm. IR (CHCl ): ν = 2924, 1527, 1510 cm–1. EI-MS: m/z
(؎)-9-Oxoantofine (4b): Colorless crystals (45%) from 22b·HCl,
m.p. 262–264 °C (benzene) (ref.[8g] m.p. 183–184 °C; ref.[6m] m.p.
254–256 °C; ref.[8h] m.p. 265–270 °C).
(؎)-9-Oxotylocrebrine (4c): Colorless crystals (6%) from 22c·HCl,
m.p. 231–235 °C (EtOH) (ref.[5d,5e] dec. 207 °C). 1H NMR: δ =
1.85–2.05 (m, 2 H, 12- and 13-H), 220–2.50, 2.40–2.55 (each m,
each 1 H, 12- and 13-H), 2.92 (dd, J = 15.8, 13.3 Hz, 1 H, 15-H),
3.55 (dd, J = 15.8, 4.0 Hz, 1 H, 15-H), 3.70–4.20 (m, 3 H, 11- and
14-H), 3.88, 4.05, 4.07, 4.09 (each s, each 3 H, OMe), 7.33 (dd, J
= 9.3 Hz, 1 H), 7.36 (s, 1 H, 1-H), 7.33 (d, J = 9.3 Hz, 1 H, 7-H),
7.36 (s, 1 H, 1-H), 9.10 (d, J = 9.3 Hz, 1 H, 8-H), 9.37 (s, 1 H, 4-
˜
2
3
(%) = 339 [M – HCl]+ (52.3), 282 (87.5), 281 (100). C21H26ClNO3
(375.89): calcd. C 67.10, H 6.97, Cl 9.43, N 3.73; found C 66.99,
H 7.16, Cl 9.18, N 3.77.
N-Nitroso-N-[2-(2,3,6-trimethoxy-10-phenanthryl)ethyl]propylamine
(30): BuLi (1.58 , hexane solution, 1.26 mL, 2 mmol) was added
under Ar at –78 °C to a stirred solution of N-nitrosopropylamine
(0.21 mL, 2 mmol) in dry THF (4 mL). The mixture was stirred at
–78 °C for 1 h. A solution of bromide 17b (360 mg, 1 mmol) in dry
THF (8 mL) was added dropwise, and the mixture was stirred at
–78 °C for 5 h. The mixture was allowed to warm to room tempera-
H) ppm. IR (CHCl ): ν = 1635, 1603, 1524, 1512 cm–1. EI-MS: m/z
˜
3
(%) = 407 (100) [M]+, 392 (40.8), 339 (36.4).
(؎)-9-Oxocryptopleurinone (5): Colorless crystals (30%) from
28·HCl, m.p. 190–192 °C (benzene) [ref.[5c,8a,8b] m.p. 194–195 °C;
ref.[5e] m.p. 194–196 °C; ref.[6m] m.p. 197–198.5 °C; (R) form: ref.[7a]
m.p. 194–195.5 °C; (R) form: ref.[5f] m.p. 196–197 °C].
1178
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1173–1180

Phenanthro[9,10-b]indolizidin-9-ones and -quinolizidin-9-one
[4]
[5]
[6]
For Tl(OCOCF3)3, see: a) R. B. Herbert, J. Chem. Soc., Chem.
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581–588; d) T. R. Govindachari, M. V. Lakshmikantham, S.
Rajadurai, Chem. Ind. 1960, 664; T. R. Govindachari, M. V.
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1962, 1008–1014; f) T. R. Govindachari, I. S. Ragade, N. Vis-
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2573–2578; h) B. Chauncy, E. Gellert, Aust. J. Chem. 1970, 23,
2503–2516; i) W. Wiegrebe, L. Faber, H. Budzikiewicz, Justus
Liebigs Ann. Chem. 1970, 733, 125–140; j) S. Földeák, Tetrahe-
dron 1971, 27, 3465–3476; k) L. Faber, W. Wiegrebe, Helv.
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rahedron 1978, 34, 641–643; m) M. Iwao, M. Watanabe, S. O.
de Silva, V. Sniekus, Tetrahedron Lett. 1981, 22, 2349–2352; M.
Iwao, K. K. Mahalanabis, M. Watanabe, S. O. de Silva, V.
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A. Couture, E. Deniau, P. Grandclaudon, Tetrahedron 1999,
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2006, 14, 6560–6569. See also ref.[3e]
2,3,6-Trimethoxy-N-propylphenanthro[9,10-c]pyrrolidin-9-one (32):
Colorless crystals (26%) from 29, m.p. 205–206 °C (EtOH). 1H
NMR: δ = 1.02 (t, J = 7.3 Hz, 3 H, Pr-CH3), 1.79 (sext, J = 7.3 Hz,
2 H, Pr-CH2), 3.68 (t, J = 7.3 Hz, 2 H, Pr-CH2), 4.02, 4.04, 4.12
(each s, each 3 H, OMe), 4.56 (s, 2 H, 11-H), 7.03 (s, 1 H, 1-H),
7.32 (dd, J = 8.9, 2.3 Hz, 1 H, 7-H), 7.83 (d, J = 2.3 Hz, 1 H, 5-
H), 7.85 (s, 1 H, 4-H), 9.29 (d, J = 8.9 Hz, 1 H, 8-H) ppm. IR
(CHCl ): ν = 1675, 1606, 1526 cm–1. EI-MS: m/z (%) = 365 (86)
˜
3
[M]+, 336 (100). C22H23NO4 (365.42): calcd. C 72.31, H 6.34, N
3.83; found C 72.18, H 6.25, N 3.78.
2,3,6-Trimethoxy-N-propylphenanthro[9,10-c]piperidin-9-one (33):
1
Colorless crystals (43%) from 31·HCl, m.p. 67–71 °C (EtOH). H
NMR: δ = 1.03 (t, J = 7.3 Hz, 3 H, Pr-CH3), 1.75 (sext, J = 7.3 Hz,
2 H, Pr-CH2), 3.28 (t, J = 6.6 Hz, 2 H, 12-H), 3.60–3.75 (m, 4 H,
Pr-CH2 and 3-CH2), 4.01, 4.05, 4.13 (each s, each 3 H, OMe), 7.25
(dd, J = 9.2, 2.6 Hz, 1 H, 7-H), 7.32 (s, 1 H, 1-H), 7.86 (d, J =
2.6 Hz, 1 H, 5-H), 7.96 (s, 1 H, 4-H), 9.26 (d, J = 9.2 Hz, 1 H, 8-
H) ppm. IR (CHCl ): ν = 1633, 1619, 1510 cm–1. EI-MS: m/z (%)
˜
3
= 379 (84) [M]+, 350 (100). C23H25NO4 (379.45): calcd. C 72.80, H
6.64, N 3.59; found C 72.72, H 6.77, N 3.60.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures for compounds 6a–18c, 23,
1
and 24 and H NMR spectra for compounds 4–18, 21–24, 26–33,
and carbamates of amines 22a, 22b, and 28.
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[7]
[8]
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Received: October 27, 2008
Published Online: January 22, 2009
1180
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1173–1180