Palladium-catalyzed annulation of 2,2′-diiodobiphenyls with alkynes: Synthesis and applications of phenanthrenes

Article abstract of DOI:10.1021/jo302013x

A range of phenanthrene derivatives were efficiently synthesized by the palladium-catalyzed annulation of 2,2′-diiodobiphenyls with alkynes. The scope, limitations and regioselectivity of the reaction were investigated. The described method was adopted to synthesize 9,10-dialkylphenanthrenes, sterically overcrowded 4,5-disubstituted phenanthrenes and phenanthrene-based alkaloids. Reactions of highly methoxy-substituted biphenyls with 2-(2-propynyl)pyrrolidine and 2-(2-propynyl)piperidine gave 2-(9-phenanthylmethyl)pyrrolidines and 2-(9-phenanthylmethyl)piperidines, respectively. The products were transformed to phenanthroindolizidine and phenanthroquinolizidine alkaloids by the Pictet-Spengler reaction.

Full text of DOI:10.1021/jo302013x

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pubs.acs.org/joc
Palladium-Catalyzed Annulation of 2,2′-Diiodobiphenyls with
Alkynes: Synthesis and Applications of Phenanthrenes
Yu-De Lin, Chun-Lung Cho, Chih-Wei Ko, Anna Pulte, and Yao-Ting Wu*
Department of Chemistry, National Cheng Kung University, No. 1 Ta-Hsueh Road, 70101 Tainan, Taiwan
S
* Supporting Information
ABSTRACT: A range of phenanthrene derivatives were
efficiently synthesized by the palladium-catalyzed annulation
of 2,2′-diiodobiphenyls with alkynes. The scope, limitations
and regioselectivity of the reaction were investigated. The
described method was adopted to synthesize 9,10-dialkylphe-
nanthrenes, sterically overcrowded 4,5-disubstituted phenan-
threnes and phenanthrene-based alkaloids. Reactions of highly
methoxy-substituted biphenyls with 2-(2-propynyl)pyrrolidine
and 2-(2-propynyl)piperidine gave 2-(9-phenanthylmethyl)pyrrolidines and 2-(9-phenanthylmethyl)piperidines, respectively.
The products were transformed to phenanthroindolizidine and phenanthroquinolizidine alkaloids by the Pictet−Spengler
reaction.
Chart 1. Representative Examples of Phenanthrene-Based
Alkaloids
INTRODUCTION
■
The phenanthroindolizidine and phenanthroquinolizidine
alkaloids are formed by the fusion of a highly oxygenated
phenanthrene ring to a saturated N-heterocycle,1 of which
tylophorine (1), tylocrebrine (2), antofine (3), cryptopleurine
(4) and boehmeriasin A (5) are representative examples,
known for their strong biological properties, including the
antitumor, anti-immune and anti-inflammatory properties.2
With respect to their antitumor properties, many members of
these alkaloids are very powerful growth inhibitors (GI50 < 10−8
M) in the 60 cell-line assay of the National Cancer Institute
(NCI) test. (−)-Boehmeriasin A (5) is 1−2 orders of
magnitude more potent than Paclitaxel (Taxol) in assays for
cytotoxicity on a panel of 12 cancer cell lines.3 However, the
cytotoxic potency and the antitumor mechanism of these
families of alkaloids are largely unknown,4 mostly because of
their insufficient availability. Many methods for synthesizing
these alkaloids have been developed,5 but a synthetic strategy
that involves a LEGO-type combination of various building
blocks efficiently yields numerous alkaloids. Phenanthrenes are
ideal target molecules in the proposed strategy because they can
be easily converted to both phenanthroindolizidine and
phenanthroquinolizidine alkaloids (Chart 1).
Scheme 1 presents several methods for preparing phenan-
threnes. Under irradiation6 or by transition metal-mediated
oxidative coupling,7 stilbenes are transformed to phenanthrenes
(M1). Unlike the cyclization of stilbenes, the annulation of
biphenyls is widely carried out to synthesize phenanthrenes. In
the presence of Lewis acids, for example, 2-ethynylbiphenyl
derivatives undergo cyclization to give (iodo)phenanthrenes
(M2).8 Additionally, the base-catalyzed cyclization of a 2-(1-
propynyl)biphenyl also yields a phenanthrene via an allenyl
intermediate.9 In addition to the aforementioned examples,
various metal-catalyzed annulations of biphenyl derivatives with
alkynes have been reported upon. The biphenyl reactants
include 2-iodobiphenyls (M3),10 2-phenylbenzoic acids
(M3),11 2,2′-diiodobiphenyls (M4),12 and 2-biphenylmagne-
sium bromide (M5).13 Bis(pinacolatoboryl)alkenes14 can be
regarded as surrogates of alkynes, and they readily undergo
palladium-catalyzed Suzuki reactions with 2,2′-dibromobiaryls
(M6) to yield phenanthrenes.15 Alternatively, phenanthrenes
can be formed by the cycloaddition of an alkyne with a 9-
metallafluorene, which is prepared in situ by either the
treatment of 2,2′-dilithiobiphenyl with chromium chloride
(M7)16 or by the nickel/iridium-catalyzed ring-opening of a
biphenylene (M8).17 Moreover, palladium-catalyzed [2+2+2]
cycloadditions of arynes with alkynes18a or allyl chlorides18b
also yield phenanthrenes (M9). Protocols M3 and M4 are the
most efficient for preparing various phenanthrene-based
alkaloids for the following reasons: (1) most of their reactants
or reagents are either commercially available or easily prepared,
(2) the desired product can be obtained with few synthetic
Received: September 19, 2012
Published: October 18, 2012
© 2012 American Chemical Society
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Despite the potential advantages of M4, the goals of this
investigation include (1) enlarging the scope of the palladium-
catalyzed annulation of 2,2′-diiodobiphenyls with an alkyne, (2)
reducing the complexity of the regioselectivity, and (3)
applying this developed protocol in the synthesis of natural
and unnatural phenanthrene-based alkaloids. Notably, the
original protocol M4 cannot be utilized to synthesize
phenanthrene-based alkaloids owing to its inefficiency (less
than 10% yields for all examples) and narrow scopes.12
Scheme 1. Preparation of Phenanthrene Derivatives
RESULTS AND DISCUSSION
■
Heating biphenyl 6a with 5-decyne (7a) under palladium-
catalyzed conditions generated a mixture of 8aa and 9aa (Table
1). The ligand, silver salts and the reaction temperature
strongly affected the reaction efficiency and the 8aa/9aa ratio.
AgOAc appeared to outperform Ag2CO3 in terms of both
reaction efficiency and the selective formation of 8aa, whose
yield was also increased as the reaction temperature was
reduced (entries 2, 3, 11, and 13 in Table 1). Ligands IPr, PPh3,
PCy3, PCy2Bp, and P(t-Bu)2Bp were observed to convert more
6a than P(t-Bu)3 did, but they exhibited low chemoselectivity in
the formation of 8aa (entries 4−8 in Table 1). Mixed ligands
IPr and P(t-Bu)3 did not suffer as much from this problem, and
gave 8aa in 76% yield with 98% chemoselectivity (entry 13 in
Table 1).
steps, and (3) as in other palladium-catalyzed protocols, the
reaction conditions tolerate many functional groups. In the
synthesis of phenanthrene-based alkaloids, reactions must be
performed with methoxy-substituted biphenyls.19
Efficient synthesis of phenanthrene-based alkaloids depends
on the regioselective and chemoselective formation of 9-alkyl-
and 9,10-dialkylphenanthrenes. The regioselective formation of
phenanthrenes by protocols M3−M8 has been rarely
investigated, but it is known to be complicated. For example,
the reaction of a biphenyl derivative IV with an unsymmetrical
alkyne yields up to three regioisomeric products, depending on
the reaction conditions (Scheme 2). The expected product is I.
Numerous alkyl-substituted acetylenes 7 under the optimal
conditions in this study gave the corresponding phenanthrenes
in moderate to good yields with excellent chemoselectivity
(Table 2). Only 4-methyl-2-pentyne (7h) furnished a
significant amount of 9ah (entry 8 in Table 2). Reactions
with sterically congested alkynes 7c and 7g or biphenyl 6e had
to be performed at high temperature (entries 3, 7, and 19 in
Table 2). Alkyne 7g formed the desilylated product 8ag′ (entry
7 in Table 2). Unlike p-xylene that was used in most of
reactions, toluene was a suitable solvent in the reactions of
biphenyls 6b and 6d, because p-xylene underwent side
reactions with alkynes to produce dimethylnaphthalene
derivatives.21 These unwanted side reactions were prevented
by carefully conducting them in toluene or a mixture of toluene
and 1,4-dioxane at low temperature for a longer reaction time
(entries 11−14, 17, and 18 in Table 2). Increasing ligand
loading also improved the reaction efficiency. This reaction is
associated with high chemoselectivity toward aryl iodide, and so
the reaction conditions herein can tolerate aryl bromide
(entries 17 and 18 in Table 2). Moreover, 2,2′-diiodobiphenyls
show unique reactivity in this protocol; their analogues, such as
2-bromobiphenyl or 2,2′-dibromobiphenyl, did not undergo the
annulation with 5-decyne (7a) to yield 9,10-di-n-butylphenan-
threne. Dimethyl acetylenedicarboxylate, an electron-deficient
alkyne, is not suitable for this reaction because its reaction with
biphenyl 6a generated the corresponding phenanthrene in very
low yield (less than 10%).
Scheme 2. Possible Regioisomers and Byproducts Generated
by the Annulation of Biphenyls
One possible byproduct II is formed either by reversing the
regioselectivity of the alkyne insertion or via a new intermediate
V, which is furnished by the 1,4-Pd migration of initially
generated 2-palladabiphenyl.20 Another unwanted compound
III may be yielded in the ring-closure step. The chemo-
selectivity between VI and VII is also a serious problem. The
byproduct VII is formed by β-hydride elimination, which
competes with the regular ring-closure step concerning an aryl
C−H activation. The protocol M4 that involves 2,2′-
diiodobiphenyls should mitigate the formation of III and VII
because an aryl C−I activation in the ring-closure step should
outcompete an aryl C−H activation.
Unlike the parent phenanthrene,22 4,5-disubstituted phenan-
threnes exhibit significant out-of-plane distortion,17a,23 because
their bay regions are in an overcrowded environment.24
Accordingly, both product 8ei and natural occurring alkaloid
(R)-10, which was isolated from Tylophora indica,25 should
have had a twisted phenanthrenyl backbone. On the basis of the
number of signals in the 13C NMR spectrum, 8ei is indeed a
twisted molecule. The 2-tolyl substituent would have caused it
to contain two conformers (8ei-A and 8ei-B, see Chart 2),
which were expected to be observed because a similar
compound, 3,4,5,6-tetramethylphenanthrene, has a high
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a
Table 1. Optimization of Reaction Conditions for the Preparation of Phenanthrene 8aa
entry
ligand (mol %)
additive
T (°C)
conversion (%)
8aa:9aa
yield (%)
1
IPr·HCl (10)
IPr·HCl (10)
IPr·HCl (10)
PCy3 (10)
Ag2CO3
Ag2CO3
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
130
150
150
150
150
150
150
150
150
150
150
130
130
150
89
85
97
97
57
69
92
38
46
86
87
88
93
31
69:31
64:36
74:26
47:53
64:36
55:45
63:37
96:4
2
3
4
5
PPh3 (10)
6
PCy2Bp (10)
P(t-Bu)2Bp (10)
P(t-Bu)3·HBF4 (10)
P(t-Bu)3·HBF4 (10)
L1/L2 (10/10)
L1/L2 (5/5)
L1/L2 (5/5)
L1/L2 (5/5)
L1/L2 (3/6)
7
8
9
98:2
10
11
12
13
14
98:2
92:8
97:3
71
b
98:2
76
100:0
a
A reaction mixture comprised with biphenyl 6a (0.3 mmol), alkyne 7a (0.6 mmol), Pd(OAc)2 (10 mol %) and Ag2CO3 (1.0 equiv), or AgOAc (2.0
equiv) in p-xylene was heated if not otherwise mentioned. The ratio of products was determined by GC−MS analysis. Ligand L1 = IPr·HCl, L2 =
b
P(t-Bu)3·HBF4. Reaction for 24 h.
pseudorotation barrier (23.1 kcal/mol) to inverse the
configuration.23a However, 1H NMR experiments herein
could not distinguish the two conformers of 8ei, even at low
temperature (−80 °C).26
The regioselectivity of the above protocol was studied using
unsymmetrical biphenyl 6g and alkyne 7b, and the major
product was 8gb-I (Scheme 3). The structures of 8gb-I and
8gb-II were easily determined by conducting NOESY experi-
ments. The electronic effect of biphenyl 6g and the steric effect
of the substituents in alkyne 7b affected the regioselectivity
(Scheme 4).
On the basis of the literature, Scheme 4 describes a putative
mechanism for generating phenanthrene 8aa. Initially, Pd-
(OAc)2 oxidizes p-xylene to produce 2,5-dimethylphenylacetate
and 4-methylbenzyl acetate.27 The oxidative addition reaction
of the thus generated Pd(0) species with 2,2′-diiodobiphenyl 6a
gives complex 11. The syn-addition of the Ar−Pd bond in 11 to
the triple bond of alkyne 7a yields the alkenylpalladium
derivative 12. Cyclization of 12 furnishes palladadibenzocyclo-
heptatriene 13,28 which forms a mixture of phenanthrene 8aa
and PdI2 by reductive elimination. The reaction of PdI2 with
added AgOAc eventually reforms Pd(OAc)2. A side reaction of
complex 12 produces allene 14 by β-hydride elimination, and
the latter undergoes palladium-catalyzed cyclization to yield the
byproduct 9aa through β-hydride elimination of complex 15.
The regioselective formation of 8gb-I in Scheme 3 suggests
that the reaction intermediate is not 9-palladafluorene. The
mechanism proposed above explains the regioselectivity. The
oxidative addition step occurs mainly at the electron-deficient
position in 6g to form complex 16,29 which undergoes selective
alkyne insertion to yield 17,30 and subsequently to 8gb-I
(Scheme 4).
synthesize phenanthroindolizidine and phenanthroquinolizi-
dine alkaloids. As described above, 2-(9-phenanthylmethyl)-
pyrrolidines and 2-(9-phenanthylmethyl)piperidines were the
key intermediates in this investigation, and they should be
obtainable easily by the annulation of biphenyls with
corresponding alkynes. On the basis of the authors’ recent
study, alkyne (S)-7j was efficiently prepared by the cobalt-
catalyzed coupling reaction of (S)-2-(iodomethyl)pyrrolidine
(S)-18 with trimethylsilylethynylmagnesium (Scheme 5).5a
This coupling reaction retained the stereochemistry of the
pyrrolidinyl backbone. Unfortunately, alkyne (S)-7k could not
be synthesized similarly because iodination of the correspond-
ing alcohol did not yield N-Boc-protected (iodomethyl)-
piperidine. A modified Corey−Fuchs reaction formed the
racemic alkyne 7k upon the treatment of dibromoalkene 19
with n-butyllithium and was followed by the addition of
chlorotrimethylsilane.31
Alkynes 7j and 7k underwent annulation with numerous
biphenyls, forming the corresponding phenanthrenes in 45−
74% yields in six examples (Table 2). The results strongly
depended on the steric properties of both alkynes 7 and
biphenyls 6. Alkyne 7j produced the cycloadducts in higher
yields than 7k (entries 9, 10, 15, and 16 in Table 2). Relative to
other biphenyls, 6e and 6f gave unfavorable results (entries 20
and 21 in Table 2) because the former created an overcrowded
environment in the bay region of phenanthrenes23 and the
latter resulted in peri-repulsion between C-8 and C-9 positions
in the phenanthrenyl backbone.32
As presented in Schemes 3 and 4, the electronic effect of
biphenyl 6g and the steric effect of alkyne 7b were assumed to
control the regioselective formation of 8gb-I. Accordingly, the
annulation of biphenyl 6h with alkyne 7k was expected to
exhibit low selectively (Scheme 6), but products 8hk-I and 8hk-
II are the precursors of cryptopleurine (4)5g and boehmeriasin
Following the successful examples of the preparation of 9-
alkyl- and 9,10-dialkylphenanthrenes, attempts were made to
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a
Table 2. Synthesis Phenanthrenes from 2,2′-Diiodobiphenyls 6 and Alkynes 7
entry
biphenyl
alkyne
7a
ligand (mol %)
salt
solvent
T [°C]/t [h]
product (ratio)
yield (%)
1
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6b
6b
6b
6c
6c
6d
6d
6e
6e
6f
L1/L2 (5/5)
L1/L2 (5/5)
L1 (10)
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2CO3
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
p-xylene
toluene
130/24
130/24
150/24
130/24
130/24
130/24
150/24
130/24
150/16
150/24
90/48
8aa + 9aa (98:2)
76
73
74
75
63
51
68
91
2
7b
8ab
8ac
8ad
8ae
8af
3
7c
4
7d
L1/L2 (5/5)
L1/L2 (5/5)
L1/L2 (5/5)
L1 (10)
5
7e
6
7f
b
7
7g
8ag′
8
7h
L1/L2 (5/5)
L1 (10)
8ah + 9ah (67:33)
d
9
(S)-7j
(R/S)-7k
7a
(S)-8aj
74
10
11
12
13
14
15
16
17
18
19
20
21
L1 (10)
(R/S)-8ak
8ba + 9ba (98:2)
8ba + 9ba (90:10)
8bb
65
67
75
70
66
65
51
70
50
75
50
45
L1/L2 (10/10)
L1/L2 (10/5)
L1/L2 (10/10)
L1/L2 (10/10)
L1 (10)
c
7a
toluene
90/48
7b
toluene
toluene
p-xylene
p-xylene
90/48
7d
90/48
8bd
(S)-7j
(R/S)-7k
7a
150/48
150/48
90/72
(S)-8cj
L1 (10)
(R/S)-8ck
8da
c
L1/L2 (10/5)
L1/L2 (5/5)
L1/L2 (5/5)
L1 (10)
toluene
7b
toluene
p-xylene
p-xylene
p-xylene
130/48
160/48
150/48
150/48
8db
7i
8ei
(S)-7j
(S)-7j
(S)-8ej
L1 (10)
(S)-8fj
a
The reaction was conducted with biphenyl 6 (0.3 mmol), alkyne 7 (0.6 mmol) and AgOAc (2 equiv) or Ag2CO3 (1 equiv). The ratio of products
b
was determined by GC−MS analysis. Ligand L1 = IPr·HCl and L2 = P(t-Bu)3·HBF4. A desilylated product 8ag′ (R5 = H, R6 = n-Bu) was obtained.
c
d
The reaction was conducted with mixed solvents toluene and dioxane (ratio 4:1). Ref 5a.
Chart 2
and 5, have not yet been elucidated.33 To the best of the
authors’ knowledge, a natural phenanthroindolizidine with a
highly twisted phenanthrenyl moiety is very rare. Unexpectedly,
the analytic data concerning 10 prepared herein differ from
these in the literature,25 but the precise structure of the
synthesized product was confirmed by 2D NMR experiments.
Consequently, the structure of the alkaloid isolated from
Tylophora indica must be corrected.34
Scheme 3. Reaction of Biphenyl 6g with Alkyne 7b
CONCLUSION
■
The synthesis of phenanthrenes by the palladium-catalyzed
annulation of 2,2′-diiodobiphenyls with alkynes was inves-
tigated. This synthetic method was adopted to prepare
important phenanthroindolizidine and phenanthroquinolizidine
alkaloids. A significant advantage of this synthetic approach is
the LEGO-type combination of various biphenyls and
pyrrolidinyl or piperidinyl building blocks to give numerous
phenanthrene-based alkaloids. Evaluations of their antitumor
properties and a systematic study of their structure−activity
relationship are currently under way.
A (5), respectively (see below). Indeed, this annulation formed
the two regioisomers 8hk-I and 8hk-II in approximately equal
amounts in a total yield of 64%. Fortunately, they were easily
and completely separated from each other.
The Pictet−Spengler reaction converted phenanthrenes 8aj,
8ej and 8hk-II to alkaloids 1, 10, and 5, respectively (Scheme
7). The bioactivity and the synthesis of 10, unlike those of 1
EXPERIMENTAL SECTION
■
1
General Methods. H NMR spectra were recorded on 300, 400,
and 500 MHz spectrometers. 13C NMR spectra were recorded on 75,
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sodium D line (589 nm) using MeOH or CH2Cl2 as solvent. 2,2′-
Diiodo-4,4′,5,5′-tetramethoxybiphenyl (6a),35 2,2′-diiodo-4,4′,5,5′-tet-
ramethylbiphenyl (6b),35 2,2′-diiodo-4,4′-dibromo-5,5′-dimethoxybi-
phenyl (6d),36 1-phenyl-1-hexyne (7b),37 1-phenyl-3,3-dimethyl-1-
butyne (7c),38 1-cyclopropyl-2-phenylethyne (7d),39 1,4-dimethoxy-2-
butyne (7f),40 1-trimethylsilyl-1-hexyne (7g),41 1-methyl-2-
(phenylethynyl)benzene (7i),42 and (S)-(−)-tert-butyl 2-(3-trimethyl-
silyl-2-propynyl)pyrrolidine-1-carboxylate [(S)-7j]5a were synthesized
according to or similarly to published procedures. 5-Decyne (7a), 2-
butyne (7e) and 4-methyl-2-pentyne (7h) are commercially available.
2,2′-Diiodo-5,5′-dimethoxybiphenyl (6c). The title compound
was prepared by the lithium-mediated halogen exchange of 2,2′-
dibromo-5,5′-dimethoxybiphenyl. To a solution of 2,2′-dibromo-5,5′-
dimethoxybiphenyl43 (1.86 g, 5.0 mmol) in THF (50 mL) at −78 °C,
n-butyllithium (4.2 mL, 2.5 M in hexane, 10.5 mmol) was dropwise
added. The solution was stirred at the same temperature for 1 h and
then treated with a solution of I2 (2.67 g, 10.5 mmol) in THF (20
mL). The reaction mixture was warmed to room temperature and
stirred for 1 h. After adding a saturated aqueous solution of NH4Cl (30
mL), the aqueous phase was extracted with EA (3 × 20 mL). The
combined organic extracts were washed with a saturated aqueous
solution of Na2S2O3 (50 mL), and dried over MgSO4. The solvents of
the filtrate were removed under reduced pressure. The residue was
subjected to chromatography on silica gel. Eluting with hexane/EA
Scheme 4. Proposed Reaction Mechanism for the Formation
of 8aa, 8gb-I and 9aa
1
(10:1) gave 6c (2.10 g, 90%) as colorless solid: mp 136−137 °C; H
NMR (300 MHz, CDCl3, ppm) δ = 3.80 (s, 6H), 6.69 (dd, J = 8.7, 3.0
Hz, 2H), 6.76 (d, J = 3.0 Hz, 2H), 7.78 (d, J = 8.7 Hz, 2H); 13C NMR
(75.5 MHz, CDCl3, plus DEPT, ppm) δ = 55.5 (OCH3), 87.8 (Cquat),
115.6 (CH), 115.8 (CH), 139.4 (CH), 149.5 (Cquat), 159.6 (Cquat); EI
MS (70 eV), m/z (%) 466 (86) [M+], 339 (100) [M+ − I], 212 (27)
[M+ − 2I]; HRMS (EI) calcd for C14H12I2O2 465.8927, found
465.8932.
6,6′-Diiodo-2,2′,3,3′-tetramethoxybiphenyl (6e). The title
compound was prepared by iodination of 2,2′,3,3′-tetramethoxybi-
phenyl. A solution of 2,2′,3,3′-tetramethoxybiphenyl44 (5.48 g, 20.0
mmol) in AcOH (150 mL) was treated with a diluted solution of
H2SO4 (15 mL, 20% in water), KIO3 (1.90 g, 8.88 mmol) and I2 (5.58
g, 22.0 mmol). The reaction mixture was stirred a room temperature
for 2 d. A saturated aqueous solution of NH4Cl (200 mL) was added,
and the precipitate was collected and dissolved in ethyl acetate (150
mL). The solution was washed with aqueous Na2S2O3 (50 mL) and
brine (50 mL). The organic layer was dried over magnesium sulfate.
The solvents of the filtrate were removed under reduced pressure and
the residue was subjected to chromatography on silica gel. Eluting with
hexane/EA (8:1) gave 6e (6.00 g, 57%) as colorless solid.
Crystallization from ethanol yielded 6e as colorless crystals: mp
Scheme 5. Synthesis of Alkynes 7j and 7k
1
121−122 °C; H NMR (400 MHz, CDCl3, ppm) δ = 3.72 (s, 6H),
3.89 (s, 6H), 6.76 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3, plus DEPT, ppm) δ = 55.9 (CH3), 60.1
(CH3), 89.5 (Cquat), 114.1 (CH), 133.8 (CH), 140.3 (Cquat), 147.1
(Cquat), 153.2 (Cquat); EI MS (70 eV), m/z (%) 526 (100) [M+], 384
(28) 369 (14); HRMS (EI) calcd for C16H16I2O4 525.9138, found
525.9133.
2,2′-Diiodo-3,3′,4,4′,5,5′-hexamethoxybiphenyl (6f). The
title compound was prepared by iodination of 3,3′,4,4′,5,5′-
hexamethoxybiphenyl. A solution of 3,3′,4,4′,5,5′-hexamethoxy-
biphenyl45 (1.00 g, 3.0 mmol) in AcOH (15 mL) was treated with a
diluted solution of H2SO4 (1.5 mL, 20% in water), KIO3 (0.28 g, 1.32
mmol) and I2 (0.84 g 3.30 mmol). The reaction mixture was heated at
80 °C overnight. After cooling to room temperature, water (20 mL)
was added. The precipitate was collected and dissolved in ethyl acetate
(50 mL). The solution was washed with a saturated aqueous solution
of Na2S2O3 (30 mL) and brine (30 mL). The organic layer was dried
over Mg2SO4, and the solvent of filtrate was removed under reduced
pressure. The residue was subjected to chromatography on silica gel.
Eluting with hexane/EA (3:1) gave 6f (1.55 g, 88%) as colorless solid:
mp 164−165 °C; 1H NMR (400 MHz, CDCl3, ppm) δ = 3.80 (s, 6H),
3.87 (s, 6H), 3.89 (s, 6H), 6.56 (s, 2H); 13C NMR (100 MHz, CDCl3,
plus DEPT, ppm) δ = 56.2 (OCH3), 60.9 (OCH3), 61.1 (OCH3), 87.7
(Cquat), 109.6 (CH), 141.4 (Cquat), 144.3 (Cquat), 153.1 (Cquat), 153.4
Scheme 6. Reaction of Biphenyl 6h with Alkyne 7k
100, and 125 MHz NMR spectrometers. High-resolution mass spectra
(HRMS) were obtained on a high resolution sector type double
focusing mass spectrometer (ionization mode: EI or FAB). Melting
points were measured by a hot stage melting point apparatus and are
uncorrected. Optical rotations were measured at 20 °C from the
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Scheme 7. Synthesis of Alkaloids 1, 5, and 10
(Cquat). FAB MS (70 eV), m/z (%) 586 (15) [M+], 127 (100); HRMS
(FAB) calcd for C18H20I2O6 585.9349, found 585.9343.
phenyl. A solution of 2-iodo-3′,4′,5-trimethoxybiphenyl5g (1.11 g, 3.0
mmol) in AcOH (15 mL) at room temperature was treated with a
diluted solution of H2SO4 (20% in water, 1.5 mL), KIO3 (0.14 g, 0.67
mmol) and I2 (0.42 g 1.65 mmol). The reaction mixture was heated at
50 °C for 2 d. After cooling to room temperature, water (20 mL) was
added. The precipitate was dissolved in ethyl acetate (50 mL), and the
solution was washed with a saturated aqueous solution of Na2S2O3 (30
mL) and brine (30 mL). After drying over MgSO4, the solvent of the
filtrate was removed under reduced pressure, and the residue was
subjected to chromatography on silica gel. Eluting with hexane/EA
2,2′-Diiodo-4,5-dimethoxybiphenyl (6g). (a) Synthesis of 2′-
Iodo-3,4-dimethoxybiphenyl. To a solution of 2′-bromo-3,4-
1
(5:1) gave 6h (1.34 g, 90%) as colorless solid: mp 144−145 °C; H
NMR (400 MHz, CDCl3, ppm) δ = 3.81 (s, 3H), 3.85 (s, 3H), 3.92 (s,
3H), 6.69 (dd, J = 8.8, 2.8 Hz, 1H), 6.70 (s, 1H), 6.78 (d, J = 2.8 Hz,
1H), 7.31 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3, plus DEPT, ppm) δ = 55.5 (OCH3), 56.0 (OCH3), 56.2
(OCH3), 87.3 (Cquat), 88.8 (Cquat), 112.7 (CH), 115.7 (CH), 116.1
(CH), 120.9 (CH), 139.4 (CH), 141.4 (Cquat), 149.0 (2 × Cquat),
149.5 (Cquat), 159.6 (Cquat); EI MS (70 eV), m/z (%) 496 (100) [M+],
369 (96) [M+ − I], 227 (33), 84 (28); HRMS (EI) calcd for
C15H14I2O3 495.9032, found 495.9031.
dimethoxybiphenyl5b (2.92 g, 10.0 mmol) in THF (30 mL) at −78
°C, n-butyllithium (4.0 mL, 2.5 M in hexane, 10.0 mmol) was
dropwise added. The mixture was stirred at the same temperature for 2
h and then treated with a solution of I2 (2.53 g, 10.0 mmol) in THF
(ca. 5 mL). The reaction mixture was warmed to room temperature
and stirred for 10 h. A saturated aqueous solution of NH4Cl (50 mL)
was added, and the precipitate was collected and dissolved in ethyl
acetate (100 mL). The solution was washed with a saturated aqueous
solution of Na2S2O3 (30 mL) and brine (30 mL). After drying over
MgSO4, the solvents of the filtrate were removed under reduced
pressure, and the residue was subjected to chromatography on silica
gel. Eluting with hexane/EA (8:1) gave 2′-iodo-3,4-dimethoxybiphenyl
(3.06 g, 90%) as colorless solid.
(b) Iodination of 2′-Iodo-3,4-dimethoxybiphenyl. A solution of 2′-
iodo-3,4-dimethoxybiphenyl (6.90 g, 20.0 mmol) in AcOH (150 mL)
was treated with a diluted solution of H2SO4 (15 mL, 20% in water),
KIO3 (0.94 g, 4.40 mmol) and I2 (2.78 g, 11.0 mmol). The reaction
mixture was heated at 80 °C overnight. After cooling to room
temperature, water (200 mL) was added. The precipitate was collected
and dissolved in ethyl acetate (150 mL), and the solution was washed
with a saturated aqueous solution of Na2S2O3 (50 mL) and brine (50
mL). After drying over MgSO4, the solvent of the filtrate was removed
under reduced pressure, and the residue was subjected to
chromatography on silica gel. Eluting with hexane/EA (8:1) gave 6g
(8.38 g, 90%) as colorless solid. Crystallization from ethanol yielded
6g as colorless crystals: mp 132−133 °C; 1H NMR (300 MHz, CDCl3,
ppm) δ = 3.85 (s, 3H), 3.92 (s, 3H), 6.70 (s, 1H), 7.08 (t, J = 7.5 Hz,
1H), 7.21 (d, J = 7.5 Hz, 1H), 7.31 (s, 1H), 7.41 (t, J = 7.5 Hz, 1H),
7.94 (d, J = 7.5 Hz, 1H); 13C NMR (75.5 MHz, CDCl3, plus DEPT,
ppm) δ = 56.0 (CH3), 56.1 (CH3), 87.5 (Cquat), 100.3 (Cquat), 112.8
(CH), 120.8 (CH), 127.9 (Cquat), 128.8 (CH), 129.3 (CH), 130.3
(CH), 138.9 (CH), 141.6 (Cquat), 148.8 (Cquat), 149.0 (Cquat); EI MS
(70 eV), m/z (%) 466 (100) [M+], 399 (93), 126 (54); HRMS (EI)
calcd for C14H12I2O2 465.8927, found 465.8922.
tert-Butyl 2-(3-trimethylsilyl-2-propynyl)piperidine-1-car-
boxylate (7k). To a solution of dibromide 1931 (2.39 g, 6.25
mmol) in THF (30 mL) at −78 °C, n-butyllithium (5.0 mL, 2.5 M in
hexane, 12.5 mmol) was dropwise added. The reaction mixture was
kept at the same temperature for 1 h. Then, the solution was warmed
to 0 °C and was treated with SiMe3Cl (1.01 g, 9.37 mmol). After
stirring at room temperature overnight, the reaction was quenched
with a saturated aqueous NH4Cl solution (20 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 50 mL). The combined organic
phases were dried over MgSO4 and the solvents of the filtrate were
removed under reduced pressure. The residue was subjected to
chromatography on silica gel. Eluting with hexane/EA (8:1) gave 7k
1
(1.66 g, 90%) as pale yellow solid: mp 59−60 °C; H NMR (400
MHz, CDCl3, ppm) δ = 0.10 (s, 9H), 1.40 (s, 9H), 1.44−1.60 (m,
5H), 1.80−1.87 (m, 1H), 2.33 (dd, J = 16.6, 9.5 Hz, 1H), 2.49 (dd, J =
16.6, 5.8 Hz, 1H), 2.67 (t, J = 12.7 Hz, 1H), 3.91 (br d, J = 12.7 Hz,
1H), 4.31 (br s, 1H); 13C NMR (100 MHz, CDCl3, plus DEPT, ppm)
δ = 0.0 (SiMe3), 18.6 (CH2), 20.9 (CH2), 25.1 (CH2), 26.6 (CH2),
28.4 (CH3), 39.1 (CH2), 49.6 (CH), 79.3 (Cquat), 86.1 and 104.2 (C
C), 154.7 (Cquat); EI MS (70 eV), m/z (%) 296 (<1) [M+], 128
(100), 84 (76); HRMS (EI) calcd for C16H29NO2Si 295.1968, found
295.1969.
Representative Procedure for Preparation of Phenanthrene
8 from 2,2′-Diiodobiphenyl 6 and Alkyne 7. A mixture of the
appropriate diiodobiphenyl 6 (0.30 mmol), alkyne 7 (0.60 mmol),
Pd(OAc)2 (6.7 mg, 0.30 μmol), IPr·HCl (6.4 mg, 15 μmol), P(t-
Bu)3·HBF4 (4.5 mg, 15 μmol), AgOAc (99.0 mg, 0.60 mmol) and p-
xylene (2 mL) in a thick-walled Pyrex tube was purged with nitrogen
for 5 min. The sealed tube was kept in an oil bath at 130 °C for 24 h.
After cooling to room temperature, the solvents of the filtrate were
2,2′-Diiodo-4,5,5′-trimethoxybiphenyl (6h). The title com-
pound was prepared by iodination of 2-iodo-3′,4′,5-trimethoxybi-
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removed under reduced pressure. The residue was subjected to
chromatography on silica gel, eluting with hexane/EtOAc. The analytic
data for phenanthrenes (S)-8aj5a and 8hk-I5g have been described
previously.
9-n-Butyl-2,3,6,7-tetramethoxyphenanthrene (8ag′). Color-
less solid: mp 80−81 °C; 1H NMR (300 MHz, CDCl3, ppm) δ = 1.01
(t, J = 7.3 Hz, 3H), 1.47−1.57 (m, 2H), 1.75−1.86 (m, 2H), 3.05 (t, J
= 7.4 Hz, 2H), 4.03 (s, 3H), 4.03 (s, 3H), 4.11 (s, 3H), 4.12 (s, 3H),
7.13 (s, 1H), 7.40 (s, 1H), 7.41 (s, 1H), 7.78 (s, 1H), 7.84 (s, 1H); 13C
NMR (75.5 MHz, CDCl3, plus DEPT, ppm) δ = 14.0 (CH3), 22.8
(CH2), 32.1 (CH2), 33.1 (CH2), 55.8 (2 × OCH3), 56.0 (OCH3),
56.1 (OCH3), 102.8 (CH), 103.4 (CH), 104.8 (CH), 107.9 (CH),
123.4 (Cquat), 123.5 (CH), 124.9 (Cquat), 125.5 (Cquat), 126.5 (Cquat),
134.3 (Cquat), 148.4 (Cquat), 148.6 (2 × Cquat), 148.8 (Cquat); EI MS
(70 eV), m/z (%) 354 (98) [M+], 311 (100); HRMS (EI) calcd for
C22H26O4 354.1831, found 354.1836.
9,10-Di-n-butyl-2,3,6,7-tetramethoxyphenanthrene (8aa).
Colorless solid: mp 170−171 °C; 1H NMR (300 MHz, CDCl3,
ppm) δ = 1.07 (t, J = 7.2 Hz, 6H), 1.56−1.71 (m, 8H), 3.10 (t, J = 8.4
Hz, 4H), 4.05 (s, 6H), 4.12 (s, 6H), 7.43 (s, 2H), 7.83 (s, 2H); 13C
NMR (75.5 MHz, CDCl3, plus DEPT, ppm) δ = 14.0 (CH3), 23.4
(CH2), 29.2 (CH2), 32.6 (CH2), 55.8 (OCH3), 56.0 (OCH3), 103.4
(CH), 105.4 (CH), 123.9 (Cquat), 125.8 (Cquat), 131.5 (Cquat), 148.2
(Cquat), 148.6 (Cquat); EI MS (70 eV), m/z (%) 410 (100) [M+], 325
(66); HRMS (EI) calcd for C26H34O4 410.2457, found 410.2446.
9-n-Butyl-2,3,6,7-tetramethoxy-10-phenylphenanthrene
(8ab). Colorless solid: mp 173−174 °C; 1H NMR (300 MHz, CDCl3,
ppm) δ = 0.84 (t, J = 7.3 Hz, 3H), 1.25−1.35 (m, 2H), 1.58−1.71 (m,
2H), 2.77−2.82 (m, 2H), 3.70 (s, 3H), 4.06 (s, 3H), 4.11 (s, 3H), 4.15
(s, 3H), 6.65 (s, 1H), 7.30−7.33 (m, 2H), 7.42−7.47 (m, 4H), 7.85 (s,
1H), 7.90 (s, 1H); 13C NMR (75.5 MHz, CDCl3, plus DEPT, ppm) δ
= 13.8 (CH3), 23.1 (CH2), 30.3 (CH2), 32.7 (CH2), 55.5 (OCH3),
55.8 (OCH3), 56.09 (OCH3), 56.1 (OCH3), 102.8 (CH), 103.4
(CH), 105.7 (CH), 108.0 (CH), 123.4 (Cquat), 124.6 (Cquat), 125.3
(Cquat), 126.9 (Cquat), 127.0 (CH), 128.3 (CH), 130.3 (CH), 132.3
(Cquat), 134.8 (Cquat), 140.9 (Cquat), 148.3 (Cquat), 148.5 (Cquat), 148.7
(Cquat), 148.8 (Cquat); EI MS (70 eV), m/z (%) 430 (100) [M+], 387
(13), 356 (28) HRMS (EI) calcd for C28H30O4 430.2144, found
430.2141.
9-tert-Butyl-2,3,6,7-tetramethoxy-10-phenylphenanthrene
(8ac). Colorless solid: mp 142−143 °C; 1H NMR (300 MHz, CDCl3,
ppm) δ = 1.46 (s, 9H), 3.60 (s, 3H), 4.07 (s, 3H), 4.10 (s, 3H), 4.15
(s, 3H), 6.56 (s, 1H), 7.31−7.42 (m, 5H), 7.79 (s, 1H), 7.87 (s, 1H),
8.00 (s, 1H); 13C NMR (75.5 MHz, CDCl3, plus DEPT, ppm) δ =
35.1 (CH3), 38.2 (Cquat), 55.3 (OCH3), 55.8 (OCH3), 55.9 (OCH3),
56.1 (OCH3), 102.3 (CH), 103.3 (CH), 108.6 (CH), 111.0 (CH),
123.6 (Cquat), 125.8 (Cquat), 126.1 (Cquat), 126.9 (CH), 127.4 (CH),
127.9 (Cquat), 131.7 (CH), 134.6 (Cquat), 138.5 (Cquat), 143.5 (Cquat),
146.4 (Cquat), 147.9 (Cquat), 148.0 (Cquat), 148.7 (Cquat); EI MS (70
eV), m/z (%) 430 (100) [M+], 415 (22), 369 (12); HRMS (EI) calcd
for C28H30O4 430.2144, found 430.2134.
9-Cyclopropyl-2,3,6,7-tetramethoxy-10-phenylphenan-
threne (8ad). Colorless solid: mp 150−151 °C; 1H NMR (300 MHz,
CDCl3, ppm) δ = 0.30−0.35 (m, 2H), 0.75−0.81 (m, 2H), 1.99−2.08
(m, 1H), 3.72 (s, 3H), 4.08 (s, 3H), 4.12 (s, 3H), 4.15 (s, 3H), 6.98 (s,
1H), 7.37−7.50 (m, 5H), 7.85 (s, 1H), 7.87 (s, 1H), 8.09 (s, 1H); 13C
NMR (75.5 MHz, CDCl3, plus DEPT, ppm) δ = 9.5 (CH2), 13.3
(CH), 55.5 (OCH3), 55.8 (OCH3), 56.08 (OCH3), 56.09 (OCH3),
102.7 (CH), 103.0 (CH), 106.9 (CH), 107.7 (CH), 124.0 (Cquat),
124.2 (Cquat), 126.3 (Cquat), 126.7 (CH), 127.5 (Cquat), 127.9 (CH),
131.0 (CH), 131.4 (Cquat), 136.8 (Cquat), 140.7 (Cquat), 148.3 (Cquat),
148.4 (Cquat), 148.7 (Cquat), 148.8 (Cquat), EI MS (70 eV), m/z (%)
414 (58) [M+], 383 (100), 352 (18); HRMS (EI) calcd for C27H26O4
414.1831, found 414.1829.
2,3,6,7-Tetramethoxy-9,10-dimethylphenanthrene (8ae).
Colorless solid: mp 210−211 °C; 1H NMR (300 MHz, CDCl3,
ppm) δ = 2.68 (s, 6H), 4.06 (s, 6H), 4.12 (s, 6H), 7.40 (s, 2H), 7.83
(s, 2H); 13C NMR (75.5 MHz, CDCl3, plus DEPT, ppm) δ = 16.2
(CH3), 55.8 (OCH3), 56.0 (OCH3), 103.3 (CH), 105.3 (CH), 123.4
(Cquat), 126.6 (Cquat), 126.9 (Cquat), 148.2 (Cquat), 148.6 (Cquat); EI
MS (70 eV), m/z (%) 326 (100) [M+], 268 (16); HRMS (EI) calcd
for C20H22O4 326.1518, found 326.1517.
9,10-Di-n-butyl-2,3,6,7-tetramethlyphenanthrene (8ba). Col-
1
orless solid: mp 82−83 °C; H NMR (300 MHz, CDCl3, ppm) δ =
1.03 (t, J = 7.1 Hz, 6H), 1.56−1.67 (m, 8H), 2.48 (s, 6H), 2.50 (s,
6H), 3.08 (t, J = 8.7 Hz, 4H), 7.79 (s, 2H), 8.40 (s, 2H); 13C NMR
(75.5 MHz, CDCl3, plus DEPT, ppm) δ = 14.1 (CH3), 20.3 (CH3),
20.5 (CH3), 23.4 (CH2), 28.8 (CH2), 32.9 (CH2), 123.1 (CH), 124.9
(CH), 127.9 (Cquat), 129.6 (Cquat), 132.4 (Cquat), 134.0 (Cquat), 134.9
(Cquat); EI MS (70 eV), m/z (%) 346 (55) [M+], 261 (100); HRMS
(EI) calcd for C26H34 346.2661, found 346.2654.
9-n-Butyl-2,3,6,7-tetramethyl-10-phenylphenanthrene
(8bb). Colorless solid: mp 155−156 °C; 1H NMR (300 MHz, CDCl3,
ppm) δ = 0.81 (t, J = 7.3 Hz, 3H), 1.12−1.32 (m, 2H), 1.55−1.59 (m,
2H), 2.27 (s, 3H), 2.49 (s, 3H), 2.51 (s, 3H), 2.55 (s, 3H), 2.79 (t, J =
7.3 Hz, 2H), 7.00 (s, 1H), 7.27−7.30 (m, 2H), 7.44−7.52 (m, 3H),
7.85 (s, 1H), 8.43 (s, 1H), 8.48 (s, 1H); 13C NMR (75.5 MHz, CDCl3,
plus DEPT, ppm) δ = 13.8 (CH3), 20.1 (CH3), 20.3 (CH3), 20.4
(CH3), 20.5 (CH3), 23.1 (CH2), 30.0 (CH2), 33.0 (CH2), 122.5
(CH), 123.2 (CH), 125.3 (CH), 126.7 (CH), 127.4 (Cquat), 127.5
(CH), 128.2 (CH), 128.5 (Cquat), 129.1 (Cquat), 130.0 (CH), 130.7
(Cquat), 133.4 (Cquat), 134.5 (Cquat), 134.86 (Cquat), 134.89 (Cquat),
135.2 (Cquat), 135.5 (Cquat), 141.0 (Cquat); EI MS (70 eV), m/z (%)
366 (100) [M+], 323 (57), 308 (55), 308 (55), 293 (42); HRMS (EI)
calcd for C28H30 366.2348, found 366.2338.
9-Cyclopropyl-2,3,6,7-tetramethyl-10-phenylphenanthrene
(8bd). Colorless solid: mp 175−176 °C; 1H NMR (300 MHz, CDCl3,
ppm) δ = 0.28−0.30 (m, 2H), 0.74−0.77 (m, 2H), 1.94−2.12 (m,
1H), 2.30 (s, 3H), 2.50 (s, 3H), 2.53 (s, 3H), 2.56 (s, 3H), 7.30 (s,
1H), 7.34−7.52 (m, 5H), 8.42 (s, 1H), 8.44 (s, 1H), 8.46 (s, 1H); 13C
NMR (75.5 MHz, CDCl3, plus DEPT, ppm) δ = 9.5 (2 × CH2), 13.2
(CH), 20.2 (CH3), 20.3 (CH3), 20.4 (CH3), 20.5 (CH3), 122.5 (CH),
122.9 (CH), 126.4 (CH), 126.5 (CH), 127.1 (CH), 127.8 (2 × CH),
127.9 (Cquat), 128.2 (Cquat), 130.1 (Cquat), 131.1 (Cquat), 131.2 (2 ×
CH), 132.5 (Cquat), 134.8 (Cquat), 134.9 (Cquat), 137.5 (Cquat), 140.7
(Cquat). One Cquat cannot be observed due to signals overlap; EI MS
(70 eV), m/z (%) 350 (64) [M+], 335 (100) [M+ − CH3], 320 (46)
[M+ − 2 × CH3 ]; HRMS (EI) calcd for C27H26 350.2035, found
350.2028.
2,7-Dibromo-9,10-di-n-butyl-3,6-dimethoxyphenanthrene
(8da). Colorless solid: mp 167−168 °C; 1H NMR (300 MHz, CDCl3,
ppm) δ = 1.04 (t, J = 7.1 Hz, 6H), 1.57−1.67 (m, 8H), 3.02 (t, J = 8.9
Hz, 4H), 4.11 (s, 6H), 7.85 (s, 2H), 8.23 (s, 2H); 13C NMR (75.5
MHz, CDCl3, plus DEPT, ppm) δ = 14.0 (CH3), 23.3 (CH2), 28.9
(CH2), 32.9 (CH2), 56.4 (OCH3), 103.8 (CH), 113.3 (Cquat), 127.5
(Cquat), 129.2 (Cquat), 129.8 (CH), 131.7 (Cquat), 153.4 (Cquat); EI MS
(70 eV), m/z (%) 510/508/506 (25/100/27) [M+], 425/423/421
(23/91/24); HRMS (EI) calcd for C24H28Br2O2 508.0436, found
508.0432.
2,7-Dibromo-9-n-butyl-3,6-dimethoxy-10-phenylphenan-
threne (8db). Colorless solid: mp 134−135 °C; 1H NMR (300 MHz,
CDCl3, ppm) δ = 0.80 (t, J = 7.3 Hz, 3H), 1.23−1.28 (m, 2H), 1.50−
1.55 (m, 2H), 2.72 (t, J = 7.1 Hz, 2H), 4.12 (s, 3H), 4.16 (s, 3H), 7.24
(s, 1H), 7.46−7.75 (m, 5H), 7.88 (s, 1H), 7.93 (s, 1H), 8.29 (s, 1H);
13C NMR (75.5 MHz, CDCl3, plus DEPT, ppm) δ = 13.7 (CH3), 23.0
2,3,6,7-Tetramethoxy-9,10-bis(methoxymethyl)-
1
phenanthrene (8af). Colorless solid: mp 187−188 °C; H NMR
(300 MHz, CDCl3, ppm) δ = 3.52 (s, 6H), 4.06 (s, 6H), 4.11 (s, 6H),
5.03 (s, 4H), 7.59 (s, 2H), 7.80 (s, 2H); 13C NMR (75.5 MHz, CDCl3,
plus DEPT, ppm) δ = 55.8 (OCH3), 56.0 (OCH3), 58.1 (OCH3), 68.4
(CH2), 102.9 (CH), 106.0 (CH), 125.3 (Cquat), 125.6 (Cquat), 129.2
(Cquat), 148.8 (Cquat), 149.3 (Cquat); EI MS (70 eV) m/z (%) 386
(100) [M+], 354 (43), 339 (64); HRMS (EI) calcd for C22H26O6
386.1729, found 386.1720.
(CH2), 30.0 (CH2), 30.1 (CH2), 56.49 (OCH3), 56.52 (OCH3) 103.2
(CH), 103.8 (CH), 113.2 (Cquat), 113.6 (Cquat), 127.0 (Cquat), 127.4
(CH), 128.5 (CH), 128.6 (Cquat), 128.7 (Cquat), 130.0 (Cquat), 130.2
(CH), 130.4 (CH), 132.3 (CH), 132.7 (Cquat), 134.6 (Cquat), 139.5
(Cquat), 153.7 (Cquat), 154.0 (Cquat); EI MS (70 eV), m/z (%) 530/
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528/526 (28/100/29) [M+], 406/404 (66/65); HRMS (EI) calcd for
C26H24Br2O2 528.0123, found 528.0117.
(CH2), 22.5 (CH2), 27.3 (CH2), 28.2 (CH3), 33.6 (CH2), 38.8 (CH2),
50.6 (CH), 55.5 (2 × OCH3), 79.1 (Cquat), 104.2 (CH), 105.0 (CH),
116.2 (CH), 116.5 (CH), 125.1 (CH), 126.3 (CH), 126.4 (Cquat),
127.0 (Cquat), 129.6 (CH), 130.5 (Cquat), 130.9 (Cquat), 131.6 (Cquat),
155.0 (Cquat), 157.76 (Cquat), 157.81 (Cquat); EI MS (70 eV), m/z (%)
435 (100) [M+], 362 (58), 334 (19); HRMS (EI) calcd for
C27H33NO4 435.2410, found 435.2406.
3,4,5,6-Tetramethoxy-9-phenyl-10-(o-tolyl)phenanthrene
(8ei). Colorless solid: mp 163−164 °C; 1H NMR (400 MHz, CDCl3,
ppm) δ = 1.95 (s, 3H), 3.78 (s, 3H), 3.79 (s, 3H), 3.99 (s, 6H), 6.91−
7.25 (m, 13H); 13C NMR (100 MHz, CDCl3, plus DEPT, ppm) δ =
20.0 (CH3), 56.81 (OCH3), 56.84 (OCH3), 60.9 (2 × OCH3), 113.6
(CH), 120.9 (CH), 120.5 (CH), 122.3 (Cquat), 122.5 (Cquat), 125.1
(CH), 126.4 (CH), 126.9 (CH), 127.4 (CH), 127.6 (CH), 128.6
(Cquat), 129.3 (Cquat), 129.4 (CH), 129.6 (CH), 131.1 (CH), 131.5
(CH), 134.0 (Cquat), 134.4 (Cquat), 136.9 (Cquat), 138.9 (Cquat), 139.5
(Cquat), 147.7 (Cquat), 150.78 (Cquat), 150.84 (Cquat). One CH and one
Cquat cannot be observed due to signals overlap; EI MS (70 eV), m/z
(%) 464 (100) [M+], 418 (13); HRMS (EI) calcd for C31H28O4
464.1988, found 464.1982.
(S)-(+)-tert-Butyl 2-[(3,4,5,6-tetramethoxyphenanthrene-9-
yl)methyl]pyrrolidine-1-carboxylate [(S)-8ej, two diaster-
1
eomers]. Pale yellow oil: H NMR (400 MHz, CD2Cl2, ppm) 1.53
(s, 9H), 1.55 (s, 9H), 1.64−1.74 (m, 2H), 1.71−1.82 (m, 4H), 1.92−
2.04 (m, 2H), 2.60−2.73 (m, 2H), 3.28−3.59 (m, 6H), 3.67 (s, 6H),
3.71 (s, 6H), 4.00 (s, 6H), 4.03 (s, 6H), 4.19−4.36 (m, 2H), 7.19 (s,
2H), 7.31 (d, J = 8.5 Hz, 3H), 7.44 (d, J = 8.5 Hz, 3H), 7.97 (d, J = 8.5
Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H); 13C NMR (100 MHz, CD2Cl2, plus
DEPT, ppm) δ = 21.9 (CH2), 22.8 (CH2), 27.8 (CH3), 27.9 (CH3),
28.4 (CH2), 29.1 (CH2), 36.8 (CH2), 37.4 (CH2), 45.8 (CH2), 46.2
(CH2), 56.0 (CH), 56.1 (OCH3), 56.2 (OCH3), 56.5 (CH), 58.87
(OCH3), 59.94 (OCH3), 78.1 (Cquat), 78.7 (Cquat), 112.6 (CH), 112.9
(CH), 113.5 (CH), 118.3 (CH), 118.8 (CH), 120.8 (CH), 120.9
(CH), 121.4 (Cquat), 122.7 (Cquat), 125.1 (CH), 125.6 (CH), 127.8
(Cquat), 128.3 (Cquat), 130.5 (Cquat), 130.8 (Cquat), 147.2 (Cquat), 147.3
(Cquat), 147.5 (Cquat), 150.3 (Cquat) 153.8 (Cquat) 154.0 (Cquat); EI MS
(70 eV), m/z (%) 481 (100) [M+], 408 (20); HRMS (EI) calcd for
9-n-Butyl-2,3-dimethoxy-10-phenylphenanthrene (8gb-I).
1
Colorless oil: H NMR (400 MHz, CDCl3, ppm) δ = 0.81 (t, J =
7.3 Hz, 3H), 1.26−1.35 (m, 4H), 2.81−2.85 (m, 2H), 3.68 (s, 3H),
4.11 (s, 3H), 6.67 (s, 1H), 7.31−7.34 (m, 2H), 7.44−7.54 (m, 3H),
7.59−7.66 (m, 2H), 8.06 (s, 1H), 8.14 (d, 3J = 8.0 Hz, 1H), 8.62 (d, 3J
= 8.4 Hz, 1H); 13C NMR (A mixture of 8gb-I and 8gb-II, 100 MHz,
CDCl3, plus DEPT, ppm) δ = 13.7 (CH3), 23.1 (CH2), 29.7 (CH2),
30.1 (CH2), 30.3 (CH2), 32.6 (CH2), 33.1 (CH2), 55.4 (OCH3), 56.0
(OCH3), 103.0 (CH), 103.7 (CH), 105.6 (CH), 107.9 (CH), 121.8
(CH), 122.5 (CH), 123.9 (Cquat), 125.3 (CH), 125.6 (CH), 125.7
(CH), 126.9 (CH), 127.0 (CH), 127.5 (Cquat), 127.6 (CH), 128.2
(CH), 128.3 (CH), 129.8 (Cquat), 130.1 (CH), 130.2 (Cquat), 130.4
(CH), 133.1 (Cquat), 136.2 (Cquat), 140.7 (Cquat), 148.6 (Cquat), 148.8
(Cquat); EI MS (70 eV), m/z (%) 370 (100) [M+], 327 (37), 296 (36),
191 (41); HRMS (EI) calcd for C26H26O2 370.1933, found 370.1933.
tert-Butyl 2-[(2,3,6,7-tetramethoxyphenanthrene-9-yl)-
methyl]piperidine-1-carboxylate (8ak). Colorless solid: mp
C28H35NO6 481.2464, found 481.2451. [α]20 +30.7 (c 0.021,
D
MeOH).
(S)-(+)-tert-Butyl 2-[(1,2,3,6,7,8-hexamethoxyphenanthrene-
9-yl)methyl]pyrrolidine-1-carboxylate [(S)-8fj, two diaster-
1
eomers]. Pale yellow oil: H NMR (400 MHz, CD2Cl2, ppm) 0.81
(br s, 9H), 1.61−1.80 (m, 2H), 1.83−1.91 (m, 1H), 1.96−2.05 (m,
1H), 3.01−3.08 (m, 1H) 3.34−3.46 (m, 2H), 3.53−3.62 (m, 1H), 3.92
(s, 3H), 3.94 (s, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 4.04 (s, 3H), 4.05 (s,
3H), 4.30−4.41 (m, 1H), 7.53 (br s, 1H), 7.60 (s, 1H), 7.71 (s, 1H);
13C NMR (100 MHz, CD2Cl2, plus DEPT, ppm) δ = 22.7 (CH2), 23.5
(CH2), 27.4 (CH3), 28.1 (CH3), 40.0 (CH2), 40.14 (CH2), 41.07
(CH2), 45.35 (CH2), 46.3 (CH2), 55.8 (OCH3), 56.0 (OCH3), 58.3
(OCH3), 58.9 (OCH3), 60.6 (OCH3), 60.9 (OCH3), 61.3 (OCH3),
61.5 (OCH3), 77.8 (Cquat), 99.3 (CH), 100.2 (CH), 121.46 (CH),
121.59 (Cquat), 121.67 (Cquat), 125.7 (Cquat), 127.7 (Cquat), 131.2
(Cquat), 141.4 (Cquat), 142.4 (Cquat), 148.2 (Cquat), 151.4 (Cquat), 152.2
(Cquat), 152.6 (Cquat), 154.3 (Cquat); EI MS (70 eV), m/z (%) 541 (11)
[M+], 371 (21), 57 (100); HRMS (EI) calcd for C30H39NO8 541.2676,
1
162−163 °C; H NMR (300 MHz, CDCl3, ppm) 1.20 (brs, 9H),
1.41−1.89 (m, 7H), 3.09 (dd, J = 12.9, 2.1 Hz, 1H), 3.21−3.35 (m,
2H), 4.02 (s, 3H), 4.10 (s, 3H), 4.12 (s, 3H), 4.14 (s, 3H), 4.67−4.78
(m, 1H), 7.15 (s, 1H), 7.34 (s, 1H), 7.77 (s, 1H), 7.75−7.83 (m, 1H),
7.83 (s, 1H); 13C NMR (75.5 MHz, CDCl3, plus DEPT, ppm) δ =
18.9 (CH2), 25.6 (CH2), 28.1 (CH3), 34.0 (CH2), 39.4 (CH2), 50.2
(CH), 55.8 (OCH3), 56.0 (OCH3), 56.1 (OCH3), 56.3 (OCH3), 79.9
(Cquat), 102.8 (CH), 103.3 (CH), 105.6 (CH), 107.9 (CH), 123.8
(Cquat), 124.9 (Cquat), 125.2 (CH), 125.9 (Cquat), 126.2 (Cquat), 131.2
(Cquat), 148.72 (Cquat), 148.84 (Cquat), 148.88 (Cquat), 148.90 (Cquat),
155.0 (Cquat). One CH2 was not observed due to signals overlap; EI
MS (70 eV), m/z (%) 495 (5) [M+], 312 (80), 128 (75), 84 (100);
HRMS (EI) calcd for C29H37NO6 495.2621, found 495.2615.
found 541.2673. [α]20 +2.6 (c 0.121, MeOH).
D
tert-Butyl 2-[(2,3,6-trimethoxyphenanthren-9-yl)methyl]-
piperidine-1-carboxylate (8hk-II). Pale yellow solid: mp 160−161
°C; 1H NMR (300 MHz, CDCl3, ppm) δ = 1.16 (br s, 9H), 1.39−1.62
(m, 4H), 1.69−1.80 (m, 2H), 3.08 (td, J = 13.2, 2.6 Hz, 1H), 3.23 (dd,
J = 13.7, 8.1 Hz, 1H), 3.31 (dd, J = 13.7, 7.0 Hz, 1H), 4.02 (s, 3H),
4.03 (s, 3H), 4.10 (s, 3H), 4.14−4.20 (m, 1H), 4.64−4.74 (m, 1H),
7.15 (s, 1H), 7.24 (dd, J = 7.6, 2.3 Hz, 1H), 7.30 (s, 1H), 7.85 (s, 1H),
7.91 (d, J = 2.3 Hz, 1H), 8.16 (br d, J = 7.6 Hz, 1H); 13C NMR (75.5
MHz, CDCl3, plus DEPT, ppm) δ = 19.0 (CH2), 25.6 (CH2), 27.5
(CH2), 28.1 (CH3), 33.7 (CH2), 38.8 (CH2), 50.6 (CH), 55.5
(OCH3), 55.8 (OCH3), 56.0 (OCH3), 79.1 (Cquat), 103.3 (CH), 104.6
(CH), 107.9 (CH), 115.0 (CH), 123.7 (Cquat), 124.6 (CH), 125.4
(Cquat), 126.3 (CH), 127.4 (Cquat), 131.65 (Cquat), 131.70 (Cquat),
148.7 (Cquat), 149.5 (Cquat), 155.0 (Cquat), 157.8 (Cquat); EI MS (70
eV), m/z (%) 465 (2) [M+], 281 (20), 185 (10), 128 (58), 57 (100);
HRMS (EI) calcd for C28H35NO5 465.2515, found 465.2521.
Preparation of Phenanthroindolizidine and Phenanthroqui-
nolizidine Alkaloids from Phenanthrenes by the Pictet−
Spengler Reaction. According to the procedure developed by
Herr and co-workers,5e phenanthrenes 8aj, 8ej and 8hk-II were
transformed to alkaloids 1, 10, and 5, respectively. The reactions were
conducted on a 0.20 mmol scale. 1H NMR spectra of 15a,g and 55n are
identical to those previously reported in literatures.
(S)-(+)-tert-Butyl 2-[(3,6-dimethoxyphenanthren-9-yl)-
methyl]pyrrolidine-1-carboxylate [(S)-8cj]. Colorless solid: mp
1
121−22 °C; H NMR (300 MHz, CDCl3, ppm) δ = 1.56 (s, 9H),
1.61−1.71 (m, 1H), 1.74−1.87 (m, 2H), 1.90−2.06 (m, 1H), 2.72 (dd,
J = 13.2, 10.6 Hz, 1H), 3.34−3.53 (m, 2H), 3.68−3.81 (m, 1H), 4.01
(s, 3H), 4.02 (s, 3H), 4.22−4.34 (m, 1H), 7.17−7.32 (m, 2H), 7.34 (s,
1H), 7.73 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H),
8.29−8.47 (m, 1H); 13C NMR (75.5 MHz, CDCl3, plus DEPT, ppm)
δ = 22.7 (CH2), 28.7 (CH3), 29.3 (CH2), 38.1 (CH2), 46.0 (CH2),
55.52 (OCH3), 55.54 (OCH3), 57.1 (CH), 79.5 (Cquat), 104.3 (CH),
104.9 (CH), 116.1 (CH), 116.6 (CH), 125.5 (CH), 126.4 (Cquat),
127.0 (CH), 129.5 (CH), 130.5 (Cquat), 131.2 (Cquat), 131.5 (Cquat),
154.7 (Cquat), 157.8 (Cquat). Two Cquat was not observed due to signals
overlap; EI MS (70 eV), m/z (%) 421 (14) [M+], 251 (83), 114 (70),
70 (100); HRMS (EI) calcd for C26H31NO4 421.2253, found
421.2258. [α]20 +4.9 (c 0.138, CH2Cl2).
D
tert-Butyl 2-[(3,6-dimethoxyphenanthren-9-yl)methyl]-
piperidine-1-carboxylate (8ck). Colorless solid: mp 121−122 °C;
1H NMR (400 MHz, CDCl3, ppm) δ = 1.20 (br s, 9H), 1.40−1.67 (m,
4H), 1.70−1.86 (m, 2H), 3.09 (dd, J = 13.2, 2.9 Hz, 1H), 3.24 (dd, J =
13.6, 8.5 Hz, 1H), 3.31 (dd, J = 13.6, 7.0 Hz, 1H), 4.00 (s, 3H), 4.02
(s, 3H), 4.15 (d, J = 12.1 Hz, 1H), 4.63−4.73 (m, 1H), 7.21 (dd, J =
8.7, 2.5 Hz, 1H), 7.29 (dd, J = 8.7, 2.1 Hz, 1H), 7.34 (s, 1H), 7.71 (d, J
= 8.8 Hz, 1H), 7.92 (d, J = 2.1 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 8.18
(br s, 1H); 13C NMR (100 MHz, CDCl3, plus DEPT, ppm) δ = 18.9
(+)-(13aS)-9,11,12,13,13a,14-Hexahydro-3,4,5,6-
tetramethoxydibenzo[f,h]pyrrolo[1,2-b]isoquinoline [(+)-10].
Colorless solid: mp 82−83 °C; 1H NMR (300 MHz, DMSO-d6,
CF3CO2H, ppm) δ = 1.56−1.74 (m, 1H), 1.77−1.96 (m, 2H), 2.08−
2.23 (m, 1H), 2.26−2.42 (m, 2H), 2.66−2.83 (m, 1H), 3.14−3.26 (m,
9986
dx.doi.org/10.1021/jo302013x | J. Org. Chem. 2012, 77, 9979−9988

The Journal of Organic Chemistry
Featured Article
1H), 3.45−3.56 (m, 2H), 3.62 (s, 3H), 3.63 (s, 3H), 3.96 (s, 6H), 4.42
(d, J = 15.6 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.7 Hz,
1H), 7.53 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.7 Hz, 1H); 1H NMR (500
MHz, CD2Cl2, ppm) δ = 1.65−1.73 (m, 1H, 13-H), 1.84−1.91 (m,
1H, 12-H), 1.92−2.01 (m, 1H, 12-H), 2.15−2.22 (m, 1H, 13-H), 2.37
(q, J = 8.8 Hz, 1H, 11-H), 2.40−2.44 (m, 1H, 13a-H), 2.81 (dd, J =
15.5, 11.0 Hz, 1H, 14-H), 3.20 (dd, J = 15.5, 1.5 Hz, 1H, 14-H), 3.36
(td, J = 8.8, 2.0 Hz, 1H, 11-H), 3.56 (d, J = 15.0 Hz, 1H, 9-H), 3.63
and 3.64 (each s and 3H, 4,5-OCH3), 3.98 and 3.99 (each s and 3H,
3,6-OCH3), 4.42 (d, J = 15.0 Hz, 1H, 9-H), 7.28 (d, J = 9.0 Hz, 1H, 7-
H), 7.30 (d, J = 9.0 Hz, 1H, 2-H), 7.45 (d, J = 9.0 Hz, 1H, 8-H), 7.60
(d, J = 9.0 Hz, 1H, 1-H); 13C NMR (125 MHz, CD2Cl2, plus DEPT,
ppm) δ = 11.8 (C-12), 21.4 (C-13), 23.7 (C-14), 44.1 (C-9), 45.2 (C-
11), 46.8 and 46.9 (3,6-OCH3), 50.5 (C-13a), 50.8 (4,5-OCH3), 103.7
(C-7), 103.8 (C-2), 106.2 (C-8), 107.2 (C-1), 112.0 (C-4b), 112.2 (C-
4a), 116.5 (C-8b), 116.8 (C-14a), 117.4 (C-8a), 118.7 (C-14b), 138.1
(C-4), 138.3 (C-5), 140.7 (C-3), 140.8 (C-6); EI MS (70 eV), m/z
(%) 393 (31) [M+], 324 (100); HRMS (EI) calcd for C24H27NO4
2011, 13, 196. (c) Mai, D. N.; Wolfe, J. P. J. Am. Chem. Soc. 2010, 132,
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393.1940, found 393.1933. [α]20 +17.5 (c 0.032, MeOH).
D
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectral data of all new compounds, 5, 8aj and
8hk-I. This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
(6) For reviews, see: (a) Mattay, J.; Griesbeck, A. G. Photochemical
Key Steps in Organic Synthesis; VCH: Weinheim, 1994. (b) Mallory, F.
B.; Mallory, C. W. Org. React. 1984, 30, 1.
(7) [Tl(III)]: (a) Taylor, E. C.; Andrade, J. G.; Rall, G. J. H.;
McKillop, A. J. Am. Chem. Soc. 1980, 102, 6513. [Pb(IV)]:
(b) Feldman, K. S.; Ensel, S. M. J. Am. Chem. Soc. 1994, 116, 3357.
[V(V)]: (c) Evans, D. A.; Dinsmore, C. J.; Evrard, D. A.; DeVries, K.
M. J. Am. Chem. Soc. 1993, 115, 6426. (d) Wang, K.; Wang, Q.;
Huang, R. J. Org. Chem. 2007, 72, 8416. [Fe(III)]: (e) Wang, K.-L.;
AUTHOR INFORMATION
Corresponding Author
*Fax: +886-6-2740552. E-mail: ytwuchem@mail.ncku.edu.tw.
■
Notes
Lu, M.-Y.; Wang, Q.-M.; Huang, R.-Q. Tetrahedron 2008, 64, 7504.
̈
(f) Wang, K.; Lu, M.; Yu, A.; Zhu, X.; Wang, Q. J. Org. Chem. 2009,
̈
The authors declare no competing financial interest.
74, 935. For a review, see: (g) Lessene, G.; Feldman, K. S. In Modern
Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002; p 479.
(8) For iodonium-induced carbocyclization, see: (a) Yao, T.; Campo,
M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677. (b) Yao, T.; Campo, M.
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C.-I.; Liao, H.-Y.; Chaudhuri, R.; Liu, R.-S. J. Org. Chem. 2007, 72,
9203. For transition metal-catalyzed cyclization, see: [Pt(II)]:
ACKNOWLEDGMENTS
■
This work was supported by the National Science Council of
Taiwan (NSC 98-2113-M-006-002-MY3) and the German
Academic Exchange Service (DAAD for A.P.). We also thank
Prof. P.-L. Wu (National Cheng Kung University, Taiwan) for
useful discussion and suggestions.
(d) Mamane, V.; Hannen, P.; Furstner, A. Chem.Eur. J. 2004, 10,
̈
4556. (e) Furstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264.
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barrier, compared to 3,4,5,6-tetramethylphenanthrene. The effective
Van der Waals radius of a methoxy group (1.51 Å) is smaller than that
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(27) In the presence of oxygen and catalytic amounts of Pd(OAc)2,
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9988
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