Construction of pyrrolophenanthridinone scaffolds mediated by samarium(II) diiodide and access to natural product synthesis

Article abstract of DOI:10.1016/j.tet.2015.06.067

Pyrrolophenanthridinone derivatives including the natural products were readily synthesized by samarium(II)-mediated reductive cyclization of aryl radical onto a benzene ring under mild reaction conditions. This methodology was applied to the concise synt

Full text of DOI:10.1016/j.tet.2015.06.067

Tetrahedron 71 (2015) 5513e5519
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Tetrahedron
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Construction of pyrrolophenanthridinone scaffolds mediated by
samarium(II) diiodide and access to natural product synthesis
Kenji Suzuki, Hiroki Iwasaki, Reika Domasu, Naho Hitotsuyanagi, Yuka Wakizaka,
*
Mao Tominaga, Naoto Kojima, Minoru Ozeki, Masayuki Yamashita
Kyoto Pharmaceutical University, Misasagi-Shichonosho 1, Yamashina, Kyoto 607-8412, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 May 2015
Received in revised form 15 June 2015
Accepted 16 June 2015
Available online 21 June 2015
Pyrrolophenanthridinone derivatives including the natural products were readily synthesized by
samarium(II)-mediated reductive cyclization of aryl radical onto a benzene ring under mild reaction
conditions. This methodology was applied to the concise synthesis of anhydrolycorinone, a natural
pyrrolophenanthridinone and a precursor of hippadine and anhydrolycorine.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Radical cyclization
Heterocycles
Pyrrolophenanthridinone scaffolds
Samarium diiodide
1. Introduction
Phenanthridinone scaffolds possessing a condensed 6-6-6-
tricyclic skeleton that includes a -lactam structure, are the one
d
of important nuclei found in natural products and biologically ac-
tive molecules.1 Reactions for the construction of phenan-
thridinones are classified into six major types: (1) intramolecular
CeC (10ae10b) bond formation by transition-metal-catalyzed an-
nulation2 or radical cyclization;3 (2) intramolecular CeN (5e6)
bond formation by cyclization of nitrocarbonyl-biphenyls and
subsequent reductive lactamization;4 (3) intramolecular CeN
(4ae5) bond formation by transition-metal-catalyzed annulation5
or microwave-assisted anionic ring closure reaction;6 (4) in-
termolecular CeC (10ae10b) and CeN (4ae5) bond formation by
transition-metal-catalyzed annulation;7 (5) C(sp2)-H amino-
carbonylation of o-arylanilines;8 and (6) intermolecular double
CeC (6e6a and 10ae10b) bond formation by transition-metal-
catalyzed annulation (Scheme 1).9 However, in some of those,
harsh conditions such as a high reaction temperature, use of
a strong acid and/or base, and/or a long reaction time, are required.
Therefore, the development of novel, practical, and mild pro-
cedures is desired.
Scheme 1. Methods for the construction of phenanthridinones.
widely found in natural products, particularly Amaryllidaceae al-
kaloids, such as anhydrolycorinone 1a, hippadine 1c, oxoassoanine
1e, and pratosine 1g (Fig.1). Because they possess diverse biological
activities, including antitumor, antilymphoma, and antiviral activ-
ities,10 the development of efficient synthetic methods has been
a fascinating research topic.11
Samarium(II) diiodide (SmI2) is an important reductant for
versatile single electron transfer (SET) reactions due to its low
toxicity, ease of preparation, tunable reactivity by changing addi-
tives, and usefulness under mild reaction conditions.12,13 Recently,
we have reported an intramolecular reductive cyclization of aryl
Pyrrolophenanthridinones, which have a condensed 5-6-6-6-
tetracyclic skeleton that includes a dihydroindole structure, are
* Corresponding author. Tel.: þ81 75 595 4640; fax: þ81 75 595 4775; e-mail
address: yamasita@mb.kyoto-phu.ac.jp (M. Yamashita).
http://dx.doi.org/10.1016/j.tet.2015.06.067
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

5514
K. Suzuki et al. / Tetrahedron 71 (2015) 5513e5519
X
2. Results and discussion
X
N
N
2.1. Cyclization of 1-(2-halobenzoyl)-2,3-dihydroindoles
O
O
O
O
Because the substrates could be easily prepared by condensation
of commercially available substrates, we first examined the aryl
radical coupling reaction of 1-(2-halobenzoyl)-2,3-dihydroindole 5,
which has a halogen atom on the benzoyl site.2j,3a The reaction of 1-
(2-bromobenzoyl)-2,3-dihydroindole 5a mediated by SmI2
(5.0 equiv) in THF at ꢀ40 ꢁC with HMPA as the additive14 gave
desired product 6a in low yield (Table 1, entry 1). That reaction,
which was attempted at 0 ꢁC, was not efficient and afforded 6a in
13% yield (entry 2). Next, we examined the cyclization reaction of 1-
(2-iodobenzoyl)-2,3-dihydroindole 5b under the same reaction
conditions as those of entry 2, and obtained 6a in 13% yield (entry
3). In general, the treatment of aryl iodide with SmI2 produces aryl
radical species more easily than that of aryl bromide. However, the
halogen species did not affect the yield of this reaction. The addi-
tion of i-PrOH as the proton source also did not improve the yield
(entry 4). Decreasing the amount of SmI2 to 3.0 equiv slightly im-
proved the yield of 6a, whereas the reaction with 2.4 equiv of SmI2
X = O, anhydrolycorinone (1a)
X = H, H, anhydrolycorine (1b)
X = O, hippadine (1c)
X = H, H, dehydroanhydrolycorine (1d)
X
O
N
N
MeO
R O
R O
MeO
X = O, oxoassoanine (1e)
X = H, H, assoanine (1f)
R
R
= R = Me, pratosine (1g)
= Me, R = H, pratorinine (1h)
Fig. 1. Pyrrolophenanthridinone-based Amaryllidaceae alkaloids.
radicals onto an aromatic ring mediated by SmI2 for the synthesis of
spirocycles 3 as the major product and fused rings 4 as the minor
product (Scheme 2).14 That was the first example of the selective
synthesis of spirocycles by aryl radical addition to an aromatic ring.
However, product distribution is dependent on the reaction con-
Table 1
Screening for reaction conditions
O
O
N
N
SmI2, Additive
THF, Temp.
X
5a-b
6a
Yieldb (%)
a
Entry
Starting material
SmI2 (equiv)
Additive
Temp (ꢁC)
X
1
2
3
4
5
6
7
8
9
5a:
5a:
5b:
5b:
5b:
5b:
5b:
5b:
5b:
5b:
Br
Br
I
I
I
I
I
I
I
5.0
5.0
5.0
5.0
3.0
2.4
3.0
3.0
3.0
3.0
HMPA
HMPA
HMPA
HMPA, i-PrOH
HMPA
ꢀ40
0
0
0
0
0
rt
0
0
0
7
13
13
12
22
HMPA
0c
HMPA
19
TMEDAd
39 (65% b.r.s.m.)
1,10-Phenanthroline
None
0c
23
10
I
a
SmI2 (5.0 equiv) was prepared in situ with 6.7 equiv of Sm metal and 5.0 equiv of 1,2-diiodoethane.
Isolated yield.
Starting material was recovered.
TMEDA of 2.2 equiv relative to SmI2 was used.
b
c
d
ditions and the substrate. The reaction of benzamide derivatives in
did not proceed at all (entries 5 and 6). When the reaction of 5b was
conducted in the presence of tetramethylethylenediamine
(TMEDA) instead of HMPA, the yield of 6a was increased to 39%
(65% based on recovered starting material: b.r.s.m.) (entry 8).
However, the yield was not improved in the absence of an additive
or when 1,10-phenathroline was used (entries 9 and 10). The cy-
clization into the pyrrolophenanthridinone scaffold from 5, which
has a halogen atom on the benzoyl site, gave only low yields.
the absence of a proton source afforded phenanthridinone de-
rivatives in low yields. From the point of view of the synthesis of
phenanthridinone derivatives, our procedure has room for im-
provement in terms of generality and yield. Therefore, we devised
a method for the construction of pyrrolophenanthridinone scaf-
folds having a more complicated skeleton than phenanthridinone
scaffolds. That method was mediated by SmI2 under mild reaction
conditions, and was applied to the synthesis of natural products.
2.2. Cyclization of 1-benzoyl-2,3-dihydro-7-iodoindoles
Undaunted by our unsatisfactory results, the cyclization from 7,
which has a halogen atom on the dihydroindole site, was examined.
When the reaction was conducted with 7a2j under the optimum
conditions (SmI2 (3.0 equiv)/TMEDA/0 ꢁC) shown in Table 1, 6a was
obtained in only 22% yield along with the deiodinated product, 1-
benzoyl-2,3-dihydroindole, in 55% yield (Table 2, entry 1). Then,
re-optimization of the reaction conditions for the cyclization of 7a
Scheme 2. SmI2-mediated spirocyclization reaction.

K. Suzuki et al. / Tetrahedron 71 (2015) 5513e5519
5515
Table 2
cyclized into corresponding fused rings 6b and 6c in moderate
yields by treatment with SmI2 in the presence of HMPA, re-
spectively (entries 2 and 3). Benzamides 7def having an electron-
withdrawing group such as chlorine, trifluoromethyl, or methox-
ycarbonyl group gave 6 in low yields relative to benzamides having
an electron-donating group (entries 4e9 vs 2, 3). The reactions of
chlorine-substituted analogue 7d gave dechlorinated cyclized
product 6a in 42% yield together with 6d in 19% yield (entry 4). In
order to block the dechlorination reaction,16 the reaction of 7d
without HMPA was examined and found to afford 6d in 57% yield
(entry 5). Moreover, treatment of trifluoromethyl derivative 7e
afforded defluorinated cyclized product 6b in 2% yield together
with 6e in 41% yield (entry 6). Changing the additive to LiBr de-
creased the yield of 6e (entry 7). In addition, treatment of 7e
without an additive gave 6e in 50% yield (entry 8). It was found that
the reaction without an additive is efficient for deterring the
dehalogenation and improving the yield of the desired product 6e.
Meanwhile, the reaction of ortho-methyl-substituted benzamide 7g
gave desired product 6g in only 15% yield together with spirocycle
8g in 39% yield (entry 10). This result is in good accordance with our
previous report14 showing that the reaction of ortho-methyl-
substituted benzamide derivative 2 in the presence of i-PrOH gave
corresponding spirocycle 3 selectively. The formation of spirocycles
8 indicates that the aryl radical generated by SmI2 would undergo
5-exo-type intramolecular cyclization onto the benzene ring to
produce the unstable spirohexadienyl radical intermediate, and
that intermediate could be easily rearranged into the fused ring
intermediate to give desired cyclized product 6. Interestingly,
treatment of ortho-methoxy-substituted benzamide 7h with SmI2
and HMPA gave ipso-substituted cyclized product 6a in 45% yield
along with spirocycle 8h in 23% yield (entry 11). Previously, we
reported that the ketyl radical ipso substitution reaction of an ar-
omatic methoxy group is effectively promoted by SmI2 without
HMPA to afford cyclized products.17 Thus, we examined the re-
action of 7h with LiBr instead of HMPA or without an additive.
Unexpectedly, the yield of the ipso-substituted product was de-
creased or null compared with that when HMPA was used (entries
12 and 13 vs entry 11). We expected that this radical ipso sub-
stitution could be applied to the regioselective radical cyclization in
the cases that undesired regioisomers would be obtained. There-
fore, we explored the leaving group at the ortho-position of the
benzene ring for the ipso substitution reaction (entries 11e16), and
found that the methoxy group is the most efficient leaving group.
In order to investigate the steric effect of the substituent on the
dihydroindole moiety, we next examined the reaction of 1-benzoyl-
2,3-dihydro-7-iodo-2-methylindole 9a and 1-benzoyl-2,3-dihydro-
7-iodo-3-methylindole 9b (Table 4). The reaction of 9a and 9b gave
corresponding cyclized products 10a and 10b in moderate yields,
respectively (entries 1 and 2). When the reaction of 1-benzyl-2,3-
dihydro-7-iodoindole 9c containing an alkyl tether instead of
a carbonyl group was performed, 10c was obtained in only 6% yield
along with the deiodinated product of 9c in 48% yield and re-
covered 9c in 45% yield (entry 3). This result clearly shows that the
amide tether is essential for the samarium(II)-mediated cyclization
reaction, probably because it brings the aryl radical close to the
benzene ring as a radical acceptor, and/or stabilizes the radical
intermediates. Treatment of 1-benzoyl-7-iodoindole 9d with SmI2
and HMPA afforded no desired product along with the deiodinated
product of 9d in 25% yield and recovered of 9d in 9% yield (entry 4).
Next, we prepared starting material 9e that had a tetrahy-
droquinoline ring instead of a dihydroindole ring. It has been re-
ported that phenanthridinones possessing a condensed 6-6-6-6-
tetracyclic skeleton also exhibit biological activities.18 Therefore,
we examined the reaction of 1-benzoyl-1,2,3,4-tetrahydro-8-
iodoquinoline 9e and obtained 10e in 31% yield along with spiro-
cycle 11e in 28% yield (entry 5). When we decreased the amount of
Optimization of reaction conditions
O
O
N
N
SmI2, Additive
THF, Temp.
I
7a
6a
Yieldb (%)
a
Entry
SmI2 (equiv)
Additive
TMEDAc
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA, i-PrOH
None
Temp (ꢁC)
1
2
3
4
5
6
7
8
3.0
3.0
3.0
2.5
3.5
4.0
3.5
3.5
0
0
22d
75
60e
70
84
62
22
30
ꢀ30
0
0
0
0
0
a
SmI2 (3.5 equiv) was prepared in situ with 4.8 equiv of Sm metal and 3.5 equiv of
1,2-diiodoethane.
b
Isolated yield.
TMEDA of 2.2 equiv relative to SmI2 was used.
Deiodinated product of 7a was obtained in 55% yield.
Starting material was recovered in 18% yield.
c
d
e
was performed. The use of HMPA as an additive instead of TMEDA
dramatically improved the yield of 6a to 75% (entry 2). It was re-
ported that the SmI2/amine-mediated reaction without H2O on the
ketone reduction gave a low chemical yield, but the clear reason
was not mentioned.15 In the SmI2/TMEDA-mediated reaction
without a proton source, the similar result was obtained. The re-
action at ꢀ30 ꢁC was not efficient for the yield improvement of 6a
(entry 3). Screening for the amount of SmI2 revealed that 3.5 equiv
of SmI2 gave 6a in the highest yield (84%) (entry 5). The addition of
i-PrOH as the proton source or the absence of HMPA did not im-
prove the yield (entries 7 and 8). The reactions with other additives
such as H2O and N,N-dimethylpropyleneurea (DMPU) were exam-
ined, however, 6a was obtained in only low yields.
Next, we investigated the scope and limitations, and summa-
rized the results in Table 3. In para-substituted benzamides 7bef,
methyl- and methoxy-substituted benzamides 7b and 7c were
Table 3
Scope and limitationsa
O
O
R
R
O
R
R
N
N
N
SmI (3.5 equiv.), Additive
THF
C
R
I
R
7a-k
6a-k
8a-k
Entry Starting material
Additive Product yieldb (%)
R1
R2
6
8
7
1
2
3
4
7a
H
H
H
H
H
H
H
H
H
H
Me
HMPA
HMPA
HMPA
HMPA
None
6a: 84
6b: 72
6c: 62
0
0
0
0
0
0
0
0
0
0
7b Me
7b: 17
0
0
7d: 20
7e: 7
7e: 4
7e: 12
0
7c
OMe
7d Cl
7d Cl
6d: 19, 6a:42
6d: 57
6e: 41, 6b: 2
6e: 29, 6b: 10
6e: 50
5
6
7e
7e
7e
7f
7g
7h
7h
7h
7i
CF3
CF3
CF3
HMPA
LiBr
None
7c
8
9
CO2Me
HMPA
HMPA
6f: 35
6g: 15
10
11
12c
13
14
15
16
H
H
H
H
H
H
H
8g: 39 7g: 31
OMe HMPA
OMe LiBr
OMe None
OPh
CN
Cl
6a: 45
6a: 24
0
8h: 23
8h: 47
0
0
0
7h: 93
HMPA
HMPA
HMPA
6i/6a 36 (2.4:1)d 8i: 32
0
0
0
7j
7k
6a: 7
6a: 26
0
8k: 31
a
SmI2 (3.5 equiv) was prepared in situ with 4.8 equiv of Sm metal and 3.5 equiv of
1,2-diiodoethane.
b
Isolated yield.
c
The reaction was performed at room temperature.
d
The ratio was determined by 1H NMR measurement.

5516
K. Suzuki et al. / Tetrahedron 71 (2015) 5513e5519
Table 4
Samarium(II)-mediated cyclization reactions
Y
n
Y
Y
X
N
n
X
N
X
N
n
SmI2, Additive
THF, 0 ºC
I
9a-e
10a-e
11e
a
Entry
Starting material
X
SmI2 (equiv)
Additive
Product yieldb (%)
Y (C2eC3)
n
10
11
1
2
3
4
5
6
7
9a
9b
9c
9d
9e
9e
9e
CO
CO
CH2
CO
CO
CO
CO
CH(CH3)eCH2
CH2eCH(CH3)
CH2eCH2
CH]CH
CH2eCH2
0
0
0
0
1
1
1
3.5
3.5
3.5
3.5
3.5
3.0
3.5
HMPA
HMPA
HMPA
HMPA
HMPA
HMPA
LiBre
10a: 43
10b: 58
10c: 6c
10d: 0d
10e: 31
10e: 50
10e: 57
0
0
0
0
11e: 28
11e: 9
11e: 42
CH2eCH2
CH2eCH2
a
SmI2 (3.5 equiv) was prepared in situ with 4.8 equiv of Sm metal and 3.5 equiv of 1,2-diiodoethane.
Isolated yield.
Deiodinated product of 9c was obtained in 48% yield with recovery of 9c in 45% yield.
Deiodinated product of 9d was obtained in 25% yield with recovery of 9d in 9% yield.
The reaction was carried out at room temperature.
b
c
d
e
SmI2, the yield of 10e was increased to 50% and the yield of spiro-
3. Conclusion
cycle 11e was decreased to 9% (entry 6). Changing the additive to
LiBr dramatically increased the yields of 10e and 11e (entry 7).19 In
the case of 9e, even the reaction of the substrate without the
substituent at the ortho-position gave spirocycle 11e. This is prob-
ably due to the stability of the spirohexadienyl radical in-
termediates caused by ring size expansion.
We have demonstrated a samarium(II)-mediated synthesis of
pyrrolophenanthridinone derivatives from 1-benzoyl-2,3-dihydro-
7-iodoindole derivatives under mild reaction conditions, which
involves a reductive cyclization of aryl radicals onto a benzene ring
via a spirohexadienyl radical intermediate. The utility of our syn-
thetic method has been confirmed in the rapid total synthesis of
anhydrolycorinone and the formal total synthesis of pyrrolophe-
nanthridinone derivatives, such as anhydrolycorine and hippadine,
which are Amaryllidaceae alkaloids that have significant value in
biochemistry and medicinal chemistry. Studies aimed at extending
the scope of the regioselective cyclization reaction and improving
product yield are ongoing.
2.3. Application to synthesis of anhydrolycorinone
For the synthesis of natural products, we chose 12 as the sub-
strate. Hayama et al. reported that anhydrolycorinone 1a was ob-
tained as the minor product in 15% yield along with 13 in 60% yield
when 12 was treated with Pd(OAc)2 and P(o-tol)3.2h We examined
the reaction of 12 with 3.5 equiv of SmI2 in the presence of HMPA as
the additive, and obtained 1a as the major product in 39% yield
along with regioisomer 13 in 25% yield (Table 5, entry 1). De-
creasing the equivalents of SmI2 gave 1a in 48% yield along with
regioisomer 13 in 22% yield (entry 2).20 Synthetic 1a displayed
spectral properties that were in good agreement with those of re-
ported 1a.3a The SmI2-mediated formation of pyrrolophenan-
thridinone could be an efficient method for the synthesis of natural
products in terms of regioselectivity. Cyclized product 1a is readily
4. Experimental section
4.1. General
All reactions were performed using dried glasswares under an
atmosphere of argon. Anhydrous THF was purchased from Kanto
Chemicals Inc. and used without further purification. HMPA was
distilled from CaH2 under reduced pressure. All other chemicals
were purchased at the highest commercial grade and used without
further purification. Melting points were measured with a Yanaco
MP micro-melting apparatus and uncorrected. NMR spectra were
measured on JEOL JNM-LA-500 (1H: 500 MHz; 13C: 125 MHz), JEOL
ECS-400 (1H: 400 MHz; 13C: 100 MHz), JEOL AL-300 (1H: 300 MHz;
13C: 75.5 MHz), and Varian INOVA 400NB (1H: 400 MHz, 13C:
100 MHz) spectrometers with tetramethylsilane as an internal
standard. Chemical shifts are reported in parts per million (ppm). IR
spectra were taken with Shimadzu FTIR-8400 spectrophotometers,
and only noteworthy absorptions are listed. A JEOL JMS-GC mate
spectrometer was used for low-resolution and high-resolution
electron ionizations MS (LR-EIMS and HR-EIMS). Silica gel 60N
(60-230 mesh, Kanto Chemical Co., Inc.) for column chromatogra-
phy, silica gel 60 F254 pre-coated glass plates (0.25 mm-thickness,
Merck) for analytical thin-layer chromatography (TLC), and silica
gel 60 F254 (0.5 mm and 1.0 mm-thickness, Merck) for preparative
TLC were used. Compound 12 was prepared according to reported
procedures.2j Cyclized products 1a, 6a, 6b, 6c, 10e, and 13 were
known compound.3a,4a,19a,23
3f,21
transformed into anhydrolycorine 1b by reduction with LiAlH4
and hippadine 1c by oxidation with DDQ.22
Table 5
Synthesis of anhydrolycorinone
O
O
O
N
N
N
O
O
SmI2, HMPA
THF, 0 ºC
O
I
O
O
O
12
anhydrolycorinone (1a)
13
a
Entry
SmI2 (equiv)
Product yieldb (%)
1a
13
1
2
3.5
3.0
39
48
25
22
a
SmI2 (3.0 equiv) was prepared in situ with 4.1 equiv of Sm metal and 3.0 equiv of
1,2-diiodoethane.
b
Isolated yield.

K. Suzuki et al. / Tetrahedron 71 (2015) 5513e5519
5517
4.2. General procedure for samarium(II)-mediated cycliza-
tion. Synthesis of 4H-pyrrolo[3,2,1-de]phenanthridin-7(5H)-
one (6a) (Table 2, entry 5)
(d, J¼8.0 Hz, 1H), 8.06 (s, 1H), 8.42 (d, J¼8.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 27.2, 46.4, 115.6, 119.8, 121.9, 123.4, 125.2, 125.6,
128.0, 129.9, 130.9, 135.1, 138.6, 140.1, 159.2; MS (EI) m/z (%) 255
(Mþ, 100.0), 191 (15), 219 (23), 254 (80), 256 (42), 257 (33); HRMS
(EI) calcd for C15H10ClNO (Mþ): 255.0451; found: 255.0446.
The reaction was carried out under positive pressure of argon,
and glassware and syringes were dried prior to use. A mixture of
samarium (144 mg, 0.960 mmol) and 1,2-diiodoethane (197 mg,
0.700 mmol) in THF (6.7 mL) was stirred for 1.5 h at room tem-
perature. After cooling to 0 ꢁC, HMPA (0.44 mL, 2.52 mmol) was
added to the mixture, and stirring was continued for 20 min at this
temperature. A solution of 7a (70.0 mg, 0.200 mmol) in THF
(4.9 mL) was added to the mixture, and the mixture was stirred for
30 min. After the mixture was exposed to air, saturated NaHCO3
was added to the mixture, and the whole was extracted with Et2O.
The extract was washed with saturated NaHCO3 and brine. After
drying the extract over MgSO4, the filtrate was concentrated under
reduced pressure to leave a residue, which was purified by column
chromatography over silica gel with n-hexane/EtOAc (2:1) to give
6a (37.3 mg, 84% yield).
4.5. 10-Trifluoromethyl-4H-pyrrolo[3,2,1-de]phenanthridin-
7(5H)-one (6e)
Compound 6e was synthesized with a similar manner to 6a
except without HMPA. Colorless prisms (24.4 mg, 50%):
mp 239e240 ꢁC (EtOAc); IR (KBr, cmꢀ1): 1649; 1H NMR (400 MHz,
CDCl3)
d
3.47 (t, J¼8.4 Hz, 2H), 4.51 (t, J¼8.4 Hz, 2H), 7.27 (dd, J¼8.0,
7.2 Hz, 1H), 7.39 (dd, J¼7.2, 0.8 Hz, 1H), 7.80 (dd, J¼8.0, 0.8 Hz, 1H),
7.94 (d, J¼8.0 Hz,1H), 8.44 (br s,1H), 8.66 (d, J¼8.0 Hz,1H); 13C NMR
(100 MHz, CDCl3)
d
27.3, 46.6, 115.9, 119.4 (q, J¼4.0 Hz), 120.0,
123.80, 123.81 (q, J¼271.5 Hz), 123.9 (q, J¼3.5 Hz), 125.5, 129.4,
129.6, 131.0, 133.7 (q, J¼32.3 Hz), 134.1, 140.1, 159.0; MS (EI) m/z (%)
289 (Mþ, 100.0), 191 (11), 240 (9); HRMS (EI) calcd for C16H10F3NO
(Mþ): 289.0715; found: 289.0718.
Compound 6a:3a 1H NMR (400 MHz, CDCl3)
d
3.45 (t, J¼11.2 Hz,
2H), 4.51 (t, J¼11.2 Hz, 2H), 7.23 (t, J¼10.0 Hz, 1H), 7.34 (dd, J¼10.0,
1.6 Hz, 1H), 7.60 (dt, J¼10.0, 1.6 Hz, 1H), 7.77 (dt, J¼10.0, 1.6 Hz, 1H),
7.94 (d, J¼10.0 Hz, 1H), 8.23 (d, J¼10.0 Hz, 1H), 8.57 (dd, J¼10.0,
1.6 Hz, 1H); MS (EI) m/z (%) 221 (Mþ, 100.0), 96 (12), 165 (13), 191
(24), 220 (98); HRMS (EI) calcd for C15H11NO (Mþ): 221.0841;
found: 221.0845.
4.6. Methyl-4H-pyrrolo[3,2,1-de]phenanthridin-7(5H)-one-
10-carboxylate (6f)
Compound 6f was synthesized with a similar manner to 6a.
Colorless prisms (16.6 mg, 35%): mp 188e189 ꢁC (EtOAc); IR (KBr,
cmꢀ1): 1719, 1647; 1H NMR (400 MHz, CDCl3)
d
3.47 (t, J¼8.4 Hz,
4.3. General procedure for samarium(II)-mediated cyclization
in the presence of LiBr. Synthesis of 5,6,-dihydropyrido[3,2,1-
de]phenanthridin-8(4H)-one (10e) and 50,60-dihydrospiro[cy-
clohexa[2,5]diene-1,10-pyrrolo[3,2,1-ij]quinolin]-20(40H)-one
(11e) (Table 4, entry 7)
2H), 4.02 (s, 3H), 4.52 (t, J¼8.4 Hz, 2H), 7.27 (t, J¼7.6 Hz, 1H), 7.38 (d,
J¼7.2 Hz, 1H), 8.03 (d, J¼8.0 Hz, 1H), 8.20 (dd, J¼8.0, 1.2 Hz,1H), 8.62
(d, J¼8.0 Hz, 1H), 8.91 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 27.2,
46.5, 52.6, 116.3, 120.1, 123.6, 123.9, 125.0, 127.9, 128.6, 130.2, 130.8,
132.9, 133.7, 139.8, 159.2, 166.4; MS (EI) m/z (%) 279 (Mþ, 100.0), 96
(12), 219 (14), 278 (51); HRMS (EI) calcd for C17H13NO3 (Mþ):
279.0895; found: 279.0890.
The reaction was carried out under positive pressure of argon,
and glassware and syringes were dried prior to use. A mixture of
samarium (139 mg, 0.926 mmol) and 1,2-diiodoethane (191 mg,
0.676 mmol) in THF (6.4 mL) was stirred for 2 h at room temper-
ature. After cooling to 0 ꢁC, a solution of LiBr (469 mg, 5.40 mmol) in
THF (5.1 mL) was added to the mixture, and stirring was continued
for 40 min at room temperature. A solution of 9e (70.0 mg,
0.193 mmol) in THF (2.9 mL) was added to the mixture, and the
mixture was stirred for 30 min. After the mixture was exposed to
air, saturated Na2S4O7 was added to the mixture, and the mixture
was extracted with Et2O. The extract was washed with saturated
NaHCO3 and brine. After drying the extract over MgSO4, the filtrate
was concentrated under reduced pressure to leave a residue, which
was purified by column chromatography over silica gel with n-
hexane/EtOAc (2:1) to give 10e (25.8 mg, 57% yield) and 11e
(19.1 mg, 42%).
4.7. 8-Methyl-4H-pyrrolo[3,2,1-de]phenanthridin-7(5H)-one
(6g) and 2-methyl-40,50-dihydro-20H-spiro[cyclohexa[2,5]di-
ene-1,10-pyrrolo[3,2,1-hi]indol]-20-one (8g)
Compounds 6g and 8g were synthesized with a similar manner
to 6a. Compound 6g. Colorless prisms (6.7 mg, 15%):
mp 176.6e177.1 ꢁC (EtOAc); IR (KBr, cmꢀ1): 1641; 1H NMR
(400 MHz, CDCl3)
d
3.00 (s, 3H), 3.40 (t, J¼8.4 Hz, 2H), 4.45 (t,
J¼8.4 Hz, 2H), 7.18 (t, J¼7.6 Hz,1H), 7.28e7.32 (m,1H), 7.32e7.37 (m,
1H), 7.59 (t, J¼7.6 Hz, 1H), 7.89 (dd, J¼7.6, 0.4 Hz, 1H), 8.10 (d,
J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.2, 27.1, 46.6, 116.8,
120.1, 120.3, 123.0, 124.4, 125.6, 130.4, 131.2, 131.6, 135.4, 139.8,
142.6, 161.3; MS (EI) m/z (%) 235 (Mþ, 100.0), 83 (12), 191 (12), 204
(10), 219 (11), 234 (95); HRMS (EI) calcd for C16H13NO (Mþ):
235.0997; found: 235.0999.
Compound 11e: colorless prisms: mp 148e149 ꢁC (EtOAc); IR
(KBr, cmꢀ1): 1713; 1H NMR (400 MHz, CDCl3)
d
2.03 (quin, J¼6.0 Hz,
Compound 8g. Colorless prisms (17.6 mg, 39%): mp 120e121 ꢁC
2H), 2.80 (t, J¼6.0 Hz, 2H), 2.77e3.04 (m, 2H), 3.73 (t, J¼6.0 Hz, 2H),
5.42 (dt, J¼10.4, 1.6 Hz, 2H), 6.13 (dt, J¼10.4, 3.2 Hz, 2H), 6.92e6.99
(EtOAc); IR (KBr, cmꢀ1): 1661; 1H NMR (400 MHz, CDCl3)
d 2.06 (s,
3H), 3.10e3.27 (m, 3H), 3.87e3.93 (m, 1H), 3.99e4.16 (m, 2H), 5.44
(dd, J¼9.3, 3.2 Hz, 1H), 5.89e5.93 (m, 1H), 5.99 (ddd, J¼9.3, 5.3,
3.2 Hz, 1H), 6.96 (t, J¼7.6 Hz, 1H), 7.05 (d, J¼7.6 Hz, 1H), 7.10 (dd,
(m, 2H), 7.01e7.07 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 21.1, 24.5,
25.7, 39.2, 52.9, 120.1, 122.3 (2C), 123.8 (2C), 127.1, 127.2 (2C), 132.8,
138.8, 176.8; MS (EI) m/z (%) 237 (Mþ, 41.6), 220 (12), 236 (100);
HRMS (EI) calcd for C16H15NO (Mþ): 237.1154; found: 237.1159.
J¼7.6, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 24.0, 27.7, 37.2, 45.4,
45.5, 120.8, 122.1, 123.55, 123.64, 124.86, 124.88, 126.0, 128.9, 133.3,
140.6, 167.3; MS (EI) m/z (%) 237 (Mþ, 80.8), 193 (15), 208 (31), 222
(56), 236 (100); HRMS (EI) calcd for C16H15NO (Mþ): 237.1154;
found: 237.1147.
4.4. 10-Chloro-4H-pyrrolo[3,2,1-de]phenanthridin-7(5H)-one
(6d)
Compound 6d was synthesized with a similar manner to 6a
except without HMPA. Colorless prisms (26.7 mg, 57%):
mp 211e212 ꢁC (EtOAc); IR (KBr, cmꢀ1): 1643; 1H NMR (400 MHz,
4.8. 2-Methoxy-40,50-dihydro-20H-spiro[cyclohexa[2,5]diene-
1,10-pyrrolo[3,2,1-hi]indol]-20-one (8h)
CDCl3)
d
3.41 (t, J¼8.4 Hz, 2H), 4.44 (t, J¼8.4 Hz, 2H), 7.20 (t,
Compound 8h was synthesized with a similar manner to 6a.
J¼7.6 Hz, 1H), 7.33 (d, J¼7.2 Hz, 1H), 7.49 (dd, J¼8.8, 1.2 Hz, 1H), 7.77
Colorless oil (22.1 mg, 47%); IR (CHCl3, cmꢀ1): 1663; 1H NMR

5518
K. Suzuki et al. / Tetrahedron 71 (2015) 5513e5519
(400 MHz, CDCl3)
d
3.10e3.31 (m, 3H), 3.72 (s, 3H), 3.99e4.16 (m,
J¼7.5 Hz, 1H), 8.56 (d, J¼7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
3H), 5.17 (d, J¼6.0 Hz, 1H), 5.19 (dd, J¼9.2, 2.8 Hz, 1H), 6.01 (ddd,
d
20.7, 34.7, 54.4, 116.7, 120.1, 122.1, 123.47, 123.53, 127.4, 127.8,
128.4, 132.0, 133.9, 136.0, 139.2, 160.1; MS (EI) m/z (%) 235 (Mþ,
69.1), 191 (14), 220 (100), 221 (17); HRMS (EI) calcd for C16H13NO
(Mþ): 235.0997; found: 235.0994.
J¼9.2, 6.0, 2.8 Hz, 1H), 6.97 (t, J¼7.6 Hz, 1H), 7.06 (d, J¼7.6 Hz, 1H),
7.11 (dd, J¼7.6, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 27.7, 38.4,
45.7, 45.9, 55.2, 93.9, 119.9, 121.7, 123.6, 123.7, 124.9, 125.5, 129.1,
140.5, 155.4, 165.8; MS (EI) m/z (%) 253 (Mþ, 100.0), 210 (15), 222
(38), 224 (38), 225 (44), 238 (31); HRMS (EI) calcd for C16H15NO2
(Mþ): 235.1103; found: 235.1100.
4.13. 5,7-Dihydro-4H-pyrrolo[3,2,1-de]phenanthridine (10c)
Compound 10c was synthesized with a similar manner to 6a.
Colorless prisms (2.4 mg, 6%): mp 73e75 ꢁC (EtOAc); IR (KBr, cmꢀ1):
4.9. 2-Phenoxy-40,50-dihydro-20H-spiro[cyclohexa[2,5]diene-
1,10-pyrrolo[3,2,1-hi]indol]-20-one (8i)
1601; 1H NMR (400 MHz, CDCl3)
d
3.02 (t, J¼8.0 Hz, 2H), 3.34 (t,
J¼8.0 Hz, 2H), 4.15 (s, 2H), 6.77 (t, J¼7.6 Hz, 1H), 7.04 (d, J¼7.6 Hz,
1H), 7.13 (d, J¼7.6 Hz,1H), 7.19 (t, J¼7.6 Hz,1H), 7.29 (t, J¼7.6 Hz,1H),
7.42 (d, J¼7.6 Hz, 1H), 7.67 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
Compound 8i was synthesized with a similar manner to 6a.
Colorless oil (15.9 mg, 32%); IR (CHCl3, cmꢀ1): 1663; 1H NMR
(500 MHz, CDCl3)
d
3.10e3.30 (m, 2H), 3.50 (d, J¼8.5 Hz, 1H),
CDCl3)
d 28.9, 53.4, 55.5, 118.8, 119.6, 120.1, 121.9, 124.1, 127.07,
127.13, 127.7, 128.8, 131.4, 132.1, 150.3; MS (EI) m/z (%) 207 (Mþ,
3.99e4.09 (m, 1H), 4.12e4.22 (m, 2H), 5.11 (d, J¼6.0 Hz, 1H), 5.21
(dd, J¼9.5, 2.5 Hz, 1H), 5.90 (ddd, J¼9.0, 6.0, 3.0 Hz, 1H), 7.00 (t,
J¼7.5 Hz, 1H), 7.10 (d, J¼7.5 Hz, 1H), 7.14 (d, J¼7.5 Hz, 1H), 7.16 (t,
J¼7.8 Hz, 1H), 7.28 (d, J¼7.8 Hz, 2H), 7.36 (t, J¼7.8 Hz, 2H); 13C NMR
47.7), 102 (11), 103 (14), 204 (19), 206 (100); HRMS (EI) calcd for
C
15H13N (Mþ): 207.1048; found: 207.1042.
(100 MHz, CDCl3)
d 27.7, 38.9, 44.8, 45.7, 100.6, 121.4 (2C), 121.5,
Acknowledgements
121.6, 123.8, 123.9, 124.6, 125.08, 125.10, 129.3, 129.6 (2C), 140.6,
155.1 (2C), 165.9; MS (EI) m/z (%) 315 (Mþ, 100.0), 193 (26), 198 (10),
221 (11), 222 (50), 287 (35), 314 (70); HRMS (EI) calcd for
This work was financially supported in part by a Strategic Re-
search Foundation Grant-in-Aided Project for Private Universities
from the Ministry of Education, Culture, Sports, Science, and
Technology of Japan (MEXT) Grant no. S0801063 and the Kyoto
Pharmaceutical University Fund for the Promotion of Scientific
Research.
C
21H17NO2 (Mþ): 315.1259; found: 315.1263.
4.10. 2-Chloro-40,50-dihydro-20H-spiro[cyclohexa[2,5]diene-
1,10-pyrrolo[3,2,1-hi]indol]-20-one (8k)
Compound 8k was synthesized with a similar manner to 6a.
Colorless prisms (14.6 mg, 31%): mp 194.4e195.0 ꢁC (EtOAc); IR
Supplementary data
(KBr, cmꢀ1): 1657; 1H NMR (400 MHz, CDCl3)
d 3.11e3.29 (m, 2H),
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.06.067.
3.48 (d, J¼8.8 Hz, 1H), 4.00e4.09 (m, 1H), 4.11e4.20 (m, 2H), 5.52
(dd, J¼9.2, 2.9 Hz, 1H), 5.97 (ddd, J¼9.2, 5.6, 2.9 Hz, 1H), 6.30 (d,
J¼5.6 Hz, 1H), 6.99 (t, J¼7.6 Hz, 1H), 7.06 (d, J¼7.6 Hz, 1H), 7.13 (dd,
References and notes
J¼7.6, 0.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 27.7, 38.7, 45.8, 47.8,
1. (a) Aprile-Garcia, F.; Antunica-Noguerol, M.; Budzinski, M. L.; Liberman, A. C.;
Arzt, E. Endocr. Connect. 2014, 3, 1; (b) Nasrabady, S. E.; Kuzhandaivel, A.;
Mladinic, M.; Nistri, A. Cell. Mol. Neurobiol. 2011, 31, 503; (c) Jin, Z. Nat. Prod. Rep.
2009, 26, 363; (d) Patil, S.; Kamath, S.; Sanchez, T.; Neamati, N.; Schinazi, R. F.;
Buolamwini, J. K. Bioorg. Med. Chem. 2007, 15, 1212; (e) Ishida, J.; Yamamoto, H.;
Kido, Y.; Kamijo, K.; Murano, K.; Miyake, H.; Ohkubo, M.; Kinoshita, T.; War-
izaya, M.; Iwashita, A.; Mihara, K.; Matsuoka, N.; Hattori, K. Bioorg. Med. Chem.
2006, 14, 1378; (f) Ishida, J.; Hattori, K.; Yamamoto, H.; Iwashita, A.; Mihara, K.;
Matsuoka, N. Bioorg. Med. Chem. Lett. 2005, 15, 4221; (g) Bellocchi, D.; Mac-
chiarulo, S.; Costantino, G.; Pellicciari, R. Bioorg. Med. Chem. 2005, 13, 1151; (h)
Harayama, T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.; Akiyama, T.; Abe, H.;
Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 2001, 523; (i) Michael, J. P. Nat. Prod.
Rep. 1995, 12, 465.
120.4, 123.3, 124.0, 124.1, 124.9, 125.0, 127.0, 129.3, 129.5, 140.3,
164.7; MS (EI) m/z (%) 257 (Mþ, 88.2), 96 (13), 165 (14), 193 (31), 222
(100), 228 (26), 256 (94), 258 (44), 259 (30); HRMS (EI) calcd for
C
15H12ClNO (Mþ): 257.0607; found: 257.0609.
4.11. 5-Methyl-4H-pyrrolo[3,2,1-de]phenanthridin-7(5H)-one
(10a)
Compound 10a was synthesized with a similar manner to 6a.
Colorless oil (19.3 mg, 43%); IR (CHCl3, cmꢀ1): 1641; 1H NMR
2. (a) De, S.; Mishra, S.; Kakde, B. N.; Dey, D.; Bisai, A. J. Org. Chem. 2013, 78, 7823;
(b) Nervig, C. S.; Waller, P. J.; Kalyani, D. Org. Lett. 2012, 14, 4838; (c) Yu, Q.;
Zhang, N.; Tang, Y.; Lu, H.; Huang, J.; Wang, S.; Du, Y.; Zhao, K. Synthesis 2012,
2374; (d) Parhi, A.; Kelly, C.; Kaul, M.; Pilch, D. S.; LaVoie, E. J. Bioorg. Med. Chem.
Lett. 2012, 22, 4221; (e) Zhang, G.; Zhao, X.; Yan, Y.; Ding, C. Eur. J. Org. Chem.
2012, 669; (f) Shen, Z.; Ni, Z.; Mo, S.; Wang, J.; Zhu, Y. Chem.dEur. J. 2012, 18,
4859; (g) Nunez, A.; Sanchez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron 2007,
63, 6774; (h) Harayama, T.; Hori, A.; Abe, H.; Takeuchi, Y. Heterocycles 2006, 67,
385; (i) Harayama, T.; Sato, T.; Hori, A.; Abe, H.; Takeuchi, Y. Heterocycles 2005,
66, 527; (j) Harayama, T.; Toko, H.; Hori, A.; Miyagoe, T.; Sato, T.; Nishioka, H.;
Abe, H.; Takeuchi, Y. Heterocycles 2003, 61, 513; (k) Hara, H.; Hoshino, O.;
Umezawa, B. Tetrahedron Lett. 1972, 49, 5031.
(500 MHz, CDCl3)
d
1.64 (d, J¼6.5 Hz, 3H), 2.99 (dd, J¼16.5, 3.5 Hz,
1H), 3.65 (dd, J¼16.5, 9.5 Hz, 1H), 5.13 (dqd, J¼9.5, 6.5, 3.5 Hz, 1H),
7.24 (t, J¼7.5 Hz, 1H), 7.32 (d, J¼7.5 Hz, 1H), 7.56 (t, J¼7.5 Hz, 1H),
7.76 (t, J¼7.5 Hz, 1H), 7.94 (d, J¼7.5 Hz, 1H), 8.22 (d, J¼7.5 Hz, 1H),
8.56 (d, J¼7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 20.6, 36.3, 56.0,
ꢀ~
ꢀ
116.8, 119.9, 122.0, 123.4, 124.7, 127.8 (2C), 128.4, 129.5, 132.0, 133.9,
139.2, 160.0; MS (EI) m/z (%) 235 (Mþ, 57.9), 191 (12), 220 (100), 221
(17); HRMS (EI) calcd for C16H13NO (Mþ): 235.0997; found:
235.0994.
3. (a) De, S.; Ghosh, S.; Bhunia, S.; Sheikh, J. A.; Bisai, A. Org. Lett. 2012, 14, 4466;
(b) Bhakuni, B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J. A.; Konar, S.; Kumar, S.
Org. Lett. 2012, 14, 2838; (c) Curran, D. P.; Keller, A. I. J. Am. Chem. Soc. 2006, 128,
13706; (d) Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M. Org. Lett. 2005,
7, 1943; (e) Tsuge, O.; Hatta, T.; Tsuchiyama, H. Chem. Lett. 1998, 155; (f) Lauk, U.;
4.12. 4-Methyl-4H-pyrrolo[3,2,1-de]phenanthridin-7(5H)-one
(10b)
€
Dorst, D.; Fischer, W. Tetrahedron Lett. 1991, 32, 65.
Compound 10b was synthesized with a similar manner to 6a.
Colorless prisms (26.1 mg, 58%): mp 140e141 ꢁC (EtOAc); IR (KBr,
4. (a) Riahi, A.; Shkoor, M.; Fatunsin, O.; Yawer, M. A.; Hussain, I.; Fischer, C.;
Langer, P. Tetrahedron 2009, 65, 9300; (b) Yawer, M. A.; Hussain, I.; Iqbal, I.;
Spannenberg, A.; Langer, P. Tetrahedron Lett. 2008, 49, 4467; (c) Banwell, M. G.;
Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O. Org. Lett. 2004, 6, 2741.
5. Peron, F.; Fosssey, C.; Cailly, T.; Fabis, F. Org. Lett. 2012, 14, 1827.
cmꢀ1): 1641; 1H NMR (500 MHz, CDCl3)
d
1.48 (d, J¼7.0 Hz, 3H),
3.78 (sext, J¼7.0 Hz, 1H), 4.03 (dd, J¼12.5, 5.5 Hz, 1H), 4.66 (dd,
J¼12.5, 9.5 Hz, 1H), 7.25 (t, J¼7.5 Hz, 1H), 7.32 (d, J¼7.5 Hz, 1H), 7.59
(t, J¼7.5 Hz, 1H), 7.75 (t, J¼7.5 Hz, 1H), 7.93 (d, J¼7.5 Hz, 1H), 8.21 (d,
6. (a) Dubost, E.; Magnelli, R.; Cailly, T.; Legay, R.; Fabis, F.; Rault, S. Tetrahedron
2010, 66, 5008; (b) Cailly, T.; Fabis, F.; Rault, S. Tetrahedron 2006, 62, 5862.

K. Suzuki et al. / Tetrahedron 71 (2015) 5513e5519
5519
7. (a) Lu, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem. 2012, 77, 8648; (b) Wang,
G.-W.; Yuan, T.-T.; Li, D.-D. Angew. Chem., Int. Ed. 2011, 50, 1380; (c) Karthikeyan,
J.; Cheng, C.-H. Angew. Chem., Int. Ed. 2011, 50, 9880; (d) Donati, L.; Leproux, P.;
Prost, E.; Michel, S.; Tillequin, F.; Gandon, V.; Poree, F.-H. Eur. J. Chem. 2011, 17,
12809; (e) Furuta, T.; Kitamura, Y.; Hashimoto, A.; Fujii, S.; Tanaka, K.; Kan, T.
Org. Lett. 2007, 9, 183.
8. (a) Liang, D.; Hu, Z.; Peng, J.; Huang, J.; Zhu, Q. Chem. Comuun 2013, 49, 173; (b)
Rajeshkumar, V.; Lee, T.-H.; Chuang, S.-C. Org. Lett. 2013, 15, 1468; (c) Liang, Z.;
Zhang, J.; Liu, Z.; Wang, K.; Zhang, Y. Tetrahedron 2013, 69, 6519; (d) Kumazawa,
E.; Tokuhashi, T.; Horibata, A.; Kurono, N.; Senboku, H.; Tokuda, M.; Ohkuma, T.;
Orito, K. Eur. J. Org. Chem. 2012, 4622.
Krief, A.; Laval, A. M. Chem. Rev. 1999, 99, 745; (g) Kagan, H. B.; Namy, J. L. Top.
Organomet. Chem. 1999, 2, 155.
14. (a) Iwasaki, H.; Eguchi, T.; Tsutsui, N.; Ohno, H.; Tanaka, T. J. Org. Chem. 2008, 73,
7145; (b) Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. Chem. Commun. 2004,
2228.
ꢁ
ꢀ
15. (a) Dahlen, A.; Nilsson, A.; Hilmersson, G. J. Org. Chem. 2006, 71, 1576; (b)
ꢀ
ꢀ
Dahlen, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393; (c) Dahlen, A.; Hil-
mersson, G. Tetrahedron Lett. 2002, 43, 7197.
16. (a) Inanaga, J. Rev. Heteroat. Chem. 1990, 3, 75; (b) Inanaga, J.; Ishikawa, M.;
Yamaguchi, M. Chem. Lett. 1987, 1485; (c) Otsubo, K.; Kawamura, K.; Inanaga, J.;
Yamaguchi, M. Chem. Lett. 1987, 1487.
9. Yang, Y.; Huang, H.; Wu, L.; Liang, Y. Org. Biomol. Chem. 2014, 12, 5351.
10. (a) Evdokimovaaa, N. M.; Lamoral-Theys, D.; Mathieu, V.; Andolfi, A.; Frolova, L.
V.; Pelly, S. C.; van Otterlo, W. A. L.; Magedov, I. V.; Kiss, R.; Evidente, A.; Kor-
nienko, A. Bioorg. Med. Chem. 2011, 19, 7252; (b) Ghosal, S.; Lochan, R.; Ashu-
tosh; Kumar, Y.; Srivastava, R. S. Phytochemistry 1985, 24, 1825; (c)
Chattopadhyay, U.; Mathur, P. P.; Saini, K. S.; Ghosal, S. Planta Med. 1983, 49, 252.
11. (a) Umemoto, H.; Dohshita, M.; Hamamoto, H.; Miki, Y. Heterocycles 2011, 83,
1111; (b) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
4068; (c) Mentzel, U. V.; Tanner, D.; Tonder, J. E. J. Org. Chem. 2006, 71, 5807; (d)
Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7, 4777; (e) Zhou, Q. J.; Worm, K.;
Dolle, R. E. J. Org. Chem. 2004, 69, 5147; (f) Hartung, C. G.; Fecher, A.; Chapell, B.;
Snieckus, V. Org. Lett. 2003, 5, 1899.
17. Ohno, H.; Wakayama, R.; Maeda, S.; Iwasaki, H.; Okumura, M.; Iwasata, C.;
Mikamiyama, H.; Tanaka, T. J. Org. Chem. 2003, 68, 5909.
18. (a) Tomita, K.; Taoda, Y.; Iwaki, T.; Kawasuji, T.; Akiyama, T.; Sugiyama, S.; Ta-
mura, Y.; Iwatsu, M. PCT Int. Appl. WO 2014119636 A1 20140807, 2014; (b) Zee,
C.; Robert, K. Y.; Yan, S. J.; Cheng, C. C. J. Med. Chem. 1978, 21, 199.
19. In Ref. 2i, the biaryl coupling reaction of 1-(2-iodobenzoyl)-2,3-dihydroindole
and 1-(2-iodobenzoyl)-1,2,3,4-tetrahydroquinoline using Pd reagent was ex-
amined. In the case of 1-(2-iodobenzoyl)-1,2,3,4-tetrahydroquinoline, the high
yield of 10e was obtained, however, in the case of 1-(2-iodobenzoyl)-2,3-
dihydroindole, the only low yield of 6e was done.
20. In Ref. 2k, the photochemical biaryl coupling reaction of 1-(2-bromo-4,5-
methylenedioxybenzoyl)-2,3-dihydroindole, which did not give regioisomer
13, was performed to afford 1a in 67% yield.
12. (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693; (b)
Namy, J. L.; Girard, P.; Kagan, H. B. Nouv. J. Chim. 1977, 1, 5.
ꢀ
ꢀ
21. Gonzalez, C.; Guitian, E.; Castedo, L. Tetrahedron 1999, 55, 5195.
22. (a) Hutchings, R. H.; Meyers, A. I. J. Org. Chem. 1996, 61, 1004; (b) Meyers, A. I.;
Hutchings, R. H. Tetrahedron Lett. 1993, 34, 6185; (c) Black, D. C.; Keller, P. A.;
Kumar, N. Tetrahedron Lett. 1989, 30, 5807.
13. For recent reviews of SmI2-mediated reactions: (a) Szostak, M.; Fazakerley, N. J.;
Parmar, D.; Procter, D. J. Chem. Rev. 2014, 114, 5959; (b) Kagan, H. B. Tetrahedron
€
2003, 59, 10351; (c) Banik, B. K. Eur. J. Org. Chem. 2002, 2431; (d) Holemann, A.
Synlett 2002, 1497; (e) Steel, F. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727; (f)
23. Zhang, W.; Pugh, G. Tetrahedron 2003, 59, 3009.