Samarium(II)-mediated spirocyclization by intramolecular aryl radical addition onto an aromatic ring

Article abstract of DOI:10.1021/jo800656a

(Chemical Equation Presented) Samarium(II)-mediated spirocyclization by intramolecular addition of aryl radicals onto an aromatic ring was achieved by the reaction of N-(2-iodophenyl)-N-alkylbenzamides with SmI₂ in the presence of HMPA, yielding spirocyclic indolin-2-one derivatives. The ether congeners afford spirocyclic benzofuran derivatives in moderate yields by aryl radical addition onto a benzene ring without having an electron-withdrawing group. The reaction with other aryl groups such as naphthalene and indole rings is also described.

Full text of DOI:10.1021/jo800656a

Samarium(II)-Mediated Spirocyclization by Intramolecular Aryl
Radical Addition onto an Aromatic Ring
Hiroki Iwasaki, Toru Eguchi, Nozomi Tsutsui, Hiroaki Ohno,† and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka UniVersity, 1-6 Yamadaoka, Suita,
Osaka 565-0871, Japan
t-tanaka@phs.osaka-u.ac.jp
ReceiVed March 28, 2008
Samarium(II)-mediated spirocyclization by intramolecular addition of aryl radicals onto an aromatic ring
was achieved by the reaction of N-(2-iodophenyl)-N-alkylbenzamides with SmI2 in the presence of HMPA,
yielding spirocyclic indolin-2-one derivatives. The ether congeners afford spirocyclic benzofuran derivatives
in moderate yields by aryl radical addition onto a benzene ring without having an electron-withdrawing
group. The reaction with other aryl groups such as naphthalene and indole rings is also described.
Introduction
tertiary cyclic radicals to an alkene6 or alkyne,7 or cyclization
of a radical species possessing a preformed quaternary carbon
center.8 In contrast, synthesis of spirocycles by a radical attack
onto an aromatic ring is relatively limited, except for intramo-
lecular radical addition onto the para-position of phenol
derivatives, which is a convenient approach to spirocyclic
cyclohexadienones.9 Recently, some examples of the synthesis
of spirocyclic compounds using the radical reaction onto an
indole or benzofuran ring mediated by tributyltin hydride have
been reported.10 However, there are some problems with these
reactions such as the toxicity of the tin reagent, harsh reaction
Recently, the synthesis of spirocycles has attracted a great
deal of attention due to their unique structure and diverse
biological activities.1 A variety of methods for the synthesis of
spirocyclic compounds are reported, such as transition-metal-
catalyzed cyclization,2 rearrangement of epoxides or cyclopro-
panes,3 and cycloaddition reactions.4 Among them, radical
cyclization is one of the important methods for spirocyclization:
spirocycles can be efficiently synthesized by an intramolecular
radical attack onto a cyclic olefin,5 intramolecular addition of
† Present address: Graduate School of Pharmaceutical Sciences, Kyoto
University, Sakyo-ku, Kyoto 606-8501, Japan.
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10.1021/jo800656a CCC: $40.75
Published on Web 08/13/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7145–7152 7145

Iwasaki et al.
cyclization).13,14 (2) The reaction at carbon B followed by facile
aryl migration of the unstable spirocyclohexadienyl radical
intermediate 4 gives biaryl compound 5.15 On the other hand,
trapping of the intermediate 4 by hydrogen radical or reduction-
protonation affords the spirocyclic compounds such as 6.16 (3)
Ipso substitution via attack of the aryl radical at carbon C
followed by elimination of the X radical gives the fused ring
8.17 In general, the aryl radical cyclization onto an aromatic
ring to form spirocycles such as 6 is extremely difficult,
producing a considerable amount of the cine-cyclized product
of the type 3,16 except for the reaction of indole derivatives.10
Presumably this is because spirocyclohexadienyl radical inter-
mediate 4 is extremely unstable in the reversible radical
reactions, and in some cases, rearrangement readily takes place
to form a fused-ring radical such as 2 or 7.13,15c We expected
that SmI2 in the presence of a proton source would effectively
trap the key intermediate 4 by single electron transfer followed
by protonation, which could realize the spirocyclization via
reductive biaryl coupling.10 Herein, we present a full account
of our investigation into the aryl radical spirocyclization onto
various aromatic rings mediated by SmI2.18
SCHEME 1
conditions, and the difficulty to obtain spiro compounds
selectively due to the unstable spirocyclic radical intermediates.
More recently, we have reported samarium(II)-mediated
spirocyclization through the addition of a ketyl radical onto an
aromatic ring.11,12 On the basis of this study, we next turned
our attention to samarium(II)-mediated spirocyclization by the
intramolecular addition of an aryl radical with an aromatic ring.
As shown in Scheme 1, (1) the intramolecular addition of aryl
radical 1 onto carbon A forms the cyclohexadienyl radical
intermediate 2, which is easily converted into the fused ring 3
by abstraction of a hydrogen atom on the carbon A (cine
Results and Discussion
SmI2-Mediated Spirocyclization of Benzoate Derivatives.
First, we examined the aryl radical coupling reaction of
2-iodophenyl benzoates 9a and 9b mediated by SmI2 with
HMPA. However, the reaction in the presence or absence of
i-PrOH led to decomposition of the starting materials, without
producing any detectable amounts of the desired spirocyclic
product (Scheme 2).
Considering that the phenyl ester moiety of 9a and 9b would
be labile under the reductive reaction conditions, we next
investigated the reaction of the N-methylbenzamide derivatives
10a-h in the presence of i-PrOH. The results are summarized
in Table 1. Fortunately, the reaction of 10a without a substituent
on the benzene ring could act as a radical acceptor with the
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7146 J. Org. Chem. Vol. 73, No. 18, 2008

Samarium(II)-Mediated Spirocyclization
TABLE 1. Samarium(II)-Mediated Spirocyclization Reactions in the Presence of i-PrOHa
product yield (%)
entry
substrate
R1
R2
R3
i-PrOH (equiv)
T (°C)
11
12
1
2
3
4
5
6
7
10a
10a
10a
10b
10c
10d
10e
H
H
H
Me
OMe
Br
H
H
H
H
H
H
H
H
2
20
2
2
2
0
0
34
39
36
89
89
34b
tr
28
30
6
9
0
H
H
H
H
H
H
-35
-35
-35
-35
-35
2
2
NO2
no reaction
8
9
10
10f
10g
10h
H
H
H
Me
H
H
H
Me
OMe
2
2
2
-35
-35
-35
29
31
65c
53
complex mixture
a All reactions were carried out in THF using Sml2 (5 equiv) and HMPA (18 equiv). b Gave a known biaryl compound A (40%). c Obtained as a
mixture of regioisomers 12fA and 12fB (1:1).
SCHEME 2
compound (40%) (entry 6). Similarly, the reaction of 10e having
a nitro group at the ortho-position at -35 °C did not give any
cyclized products leading to recovery of unchanged starting
material (entry 7).20 Comparing entries 4 and 5 with entries 6
and 7, the electron-rich benzene ring is more appropriate as a
radical acceptor in the samarium(II)-mediated aryl coupling
reaction than the electron-deficient benzene ring. Interestingly,
a methyl substituent at the meta- (entry 8) or para-position (entry
9) increased the yields of the fused rings 12. Compared to other
radical aryl coupling reactions using Bu3SnH/AIBN,13b,c,14b,c
which mainly yield biaryl products, formation of the spirocycles
11 and fused rings 12 with a loss of aromaticity is a unique
reactivity of the SmI2/HMPA/i-PrOH system. This can be
attributed to facile trapping of the unstable bicyclic hexadienyl
radical intermediates by SmI2 as the single electron transfer
reductant (vide infra).
THF solution of SmI2 (5 equiv)19 in the presence of HMPA
and i-PrOH at 0 °C to give the desired spirocyclic compound
11 in 34% yield, as well as a trace amount of fused cyclic
compound 12 (entry 1). Increased loading of i-PrOH (20 equiv,
entry 2) or lowering of the reaction temperature to -35 °C (entry
3) was not effective for improvement of the yield of spirocycle
11, and a considerable amount of a reduced fused ring 12 was
obtained in both cases (28% and 30% yield, respectively). Next,
we investigated the spirocyclization of benzamides with a
substituent on the benzene ring and found that the reaction of
the o-methyl- or o-methoxy-substituted analogues 10b and 10c
(entries 4 and 5) afforded the spirocycle 11 both in high yields
(89%) and selectivities (ca. 11:12 ) 9:1). This is the first
example of selective spirocyclization by an aryl radical addition
onto a benzene ring. The reaction of benzamide derivative 10d,
which has a bromine atom at the ortho-position, afforded the
spirocycle 11d in low yield of 34% and a known biaryl
As shown in Table 2, when the reaction of 10a-h was
conducted in the absence of i-PrOH, the biaryl coupling products
13 were selectively obtained in low to moderate yields in almost
all cases (entries 1-8). For a reason that is unclear, the para-
substituted benzamide derivatives 10g and 10h afforded the
biaryl product 13 most efficiently in 57-60% yields, without
isolation of other cyclized products (entries 7 and 8). From these
results, we found that the cyclization mode (path A vs path B
in Scheme 1) could be completely controlled by simply changing
the reaction conditions and the substituent pattern (compare
Table 1, entries 4 and 5 vs Table 2, entries 7 and 8).
In order to investigate the steric effect of the substituent on
the nitrogen atom,21 we next examined the reaction of benza-
mide derivatives 14a-c, which have the sterically more hindered
N-alkyl substituent rather than a methyl group. The reaction of
(20) The reaction at a higher temperature (0 °C) gave a complex mixture of
unidentified products.
(21) The reaction of substrates having no substituent or Ms group on the
nitrogen atom led to decomposition of the starting materials without producing
the desired products.
(19) When the reaction was conducted with 2 equiv of SmI2, a considerable
amount of the unchanged starting materials was observed on TLC.
J. Org. Chem. Vol. 73, No. 18, 2008 7147

Iwasaki et al.
TABLE 2. Samarium(II)-Mediated Biaryl Coupling Reactions in
transfer (SET) to the iodide 18 by SmI2 generates the aryl
radical, which would undergo a 5-exo-type intramolecular
cyclization onto the benzene ring producing the spirohexadienyl
radical intermediate A. The unstable intermediate A can be
easily rearranged to the more stable intermediate C. However;
further SET and protonation of the resulting cyclohexadienyl
anion B would be promoted by SmI2 in the presence of i-PrOH
to afford the spirocyclic 1,4-cyclohexadiene 19. In contrast,
rearrangement of the unstable intermediate A to the fused ring
C followed by SET and the subsequent protonation would give
the reduced fused ring 21, while in the absence of i-PrOH, the
hydrogen abstraction from C yields the aromatized product 20.
The fact that the reaction in the absence of i-PrOH gave the
biaryl product 13 selectively (Table 2) indicates that i-PrOH
would promote the SET to B, by trapping this anionic
intermediate. The selective formation of spirocyclic compounds
11 from the ortho-substituted benzamide derivatives 10b and
10c (R1 ) Me or OMe; Table 1, entries 4 and 5) can be
explained by the unfavorable steric interaction in the rearrange-
ment of A to C as shown in the structure D. The relatively
long lifetime of A with an ortho-substituent would assist further
SET by SmI2 and the subsequent protonation to 19 without
rearrangement to C.
the Absence of i-PrOHa
entry
substrate
R1
R2
R3
13 (%)
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
OMe
26
26
15
Me
OMe
Br
NO2
H
35 (R1 ) H)
complex mixture
29b
60
10g
10h
H
H
H
57c
a All reactions were carried out in THF using Sml2 (5 equiv) and
HMPA (18 equiv). b Obtained as a mixture of regioisomers 13fA and
13fB (2:1). c The reaction was conducted at -78 °C, and
regioisomeric fused ring 13h′ was also formed.
a
Substrate Scope and Limitation. We next examined the
reaction of substrates 22a-g that contained an ether tether with
SmI2 in the absence of i-PrOH. Isomeric spirocyclic dienes 23
and 24 were obtained in only low yields (Table 4, entry 1);
however, this result clearly shows that the benzene ring without
an activating substituent such as a carbonyl group can also serve
as the acceptor of aryl radicals. Introduction of a methoxy
substituent at the ortho-position slightly improved the yield of
spirocycles 23 and 24 (entry 2), which is in good agreement
with the results with the amide congeners (Table 1). For a reason
that is unclear, formation of a fused ring was not observed with
the substrates having an ether tether. Instead, hydrodeiodination/
reduction products 25 were observed in most cases. We found
that introduction of a methyl group at the tether carbon also
improves the yield of the spirocycle (entry 5). This can be partly
attributed to stabilization of a favorable conformation for
spirocyclization due to the steric hindrance around the ether
tether, as with the N-alkylanilide derivatives. The best result
was gained with 22g, which has a methyl group at the ether
tether and a methoxy group at the para-position of the benzene
ring (entry 7).
TABLE 3. Steric Effect of Substituent on the Nitrogen Atoma
product yield (%)
entry substrate R1 R2 R3 i-PrOH (equiv) T (°C) 15
16
17
1
2
3
4
5
6
14a
14a
14b
14b
14c
14c
Bu Me H
Bu Me H
2
0
2
0
2
0
-35
0
-35
0
-35
0
75
0
27
0
75
0
tr
0
tr
0
tr
0
0
19b
0
Bu
Bu
H
H
Me
Me
46
0
i-Pr Me H
i-Pr Me H
4b
Next, we planned to investigate the reactivity of other
aromatic rings as the radical acceptor to expand the synthetic
utility of this reaction and explore the limitation of its scope.
First, we chose the indole ring as the radical acceptor10a and
investigated the reaction under the standard conditions for
spirocyclization (SmI2/HMPA/i-PrOH). Unfortunately, spiro-
cycle 27 and reduced fused ring 28 were obtained in low yields
(Table 5, entry 1). With this unsatisfactory result in terms of
both yield and selectivity, we next examined the reaction in
the presence of alkali metal salts, according to Flower’s report,
which uses LiBr or LiCl in a SmI2-mediated pinacol coupling
reaction.22 Use of LiBr and LiCl as an additive gave better
results in the spirocyclization, leading to formation of the desired
spirocycle 27 in 57% yield (entries 4-6). In contrast, other salts
such as LiI, NaBr, and KBr were ineffective (entries 7-9).
a All reactions were carried out in THF using Sml2 (5 equiv) and
HMPA (18 equiv). b A complex mixture of unidentified products was
also obtained.
N-alkyl derivatives 14a and 14c with an ortho-substituent gave
the corresponding spirocycles 15 in good yields (Table 3, entries
1 and 5). When the reaction of 14b was conducted in the absence
of i-PrOH, the expected biaryl coupling product was selectively
obtained in 46% yield (entry 4).
A plausible mechanism for the samarium(II)-mediated radical
aryl coupling reaction is shown in Scheme 3. Single electron
(22) (a) Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A., II.
Tetrahedron Lett. 1997, 38, 8157–8158. (b) Miller, R. S.; Sealy, J. M.; Shabangi,
M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A., II J. Am. Chem. Soc. 2000,
122, 7718–7722, They speculated that the addition of bromide or chloride to
samarium iodide would form another samarium halide species with improved
reducing ability.
We also examined the substrate 29 with an amide side chain
at the 3-position of the indole ring. The reaction of 29 with
SmI2 in the presence of LiBr at room temperature gave
7148 J. Org. Chem. Vol. 73, No. 18, 2008

Samarium(II)-Mediated Spirocyclization
TABLE 5. Reactions of Indole-2-carboxamide Derivative 26a
SCHEME 3
product yield (%)
entry
additiveb
T (°C)
27
28
1
2
HMPA, i-PrOH
HMPA
-35
16
17
0
complex mixture
3
none
rt
no reaction
4
5
6
7
LiBr
LiBr, i-PrOH
LiCl
rt
rt
rt
rt
57
57
57
8
0
0
Lil
no reaction
no reaction
no reaction
8
9
NaBr
KBr
rt
rt
a Reactions were carried out with 3.5 equiv (with HMPA) or 5 equiv
(with other additives) of Sml2 in THF. b HMPA (4 equiv relative to
Sml2), metal salts (8 equiv relative to Sml2), and i-PrOH (2 equiv
relative to 26) were used.
TABLE 6. Reactions of Indole-3-carboxamide Derivative 29a
TABLE 4.
Reactions of Substrates Having an Ether Tethera
product yield (%)b
entry substrate R1
R2
R3
R4
23
24
25
product yield (%)
1
2
3
4
5
6
7
22a
22b
22c
22d
22e
22f
H
H
H
H
H
OMe
H
H
H
H
H
OMe
H
H
H
H
H
OMe
H
19
28
10
28
6
0
0
47
41
62
31
24
13
0
entry
T (°C)
30
31
32
1
2
3
4
rt
0
-30
-78
22
16
0
34
29
tr
28
41
tr
28
41c
38
Me
Me OMe
Me
no reaction
H
H
H
OMe
35
18
0
22g
H
67d
a All Reactions were carried out in THF using Sml2 (3.5 equiv) and
LiBr (8 equiv relative to Sml2).
a All reactions were carried out in THF using Sml2 (3 equiv) and
HMPA (10.8 equiv). b Yields were based on 1H NMR. c As a 23:18
d
mixture of diastereomers.
the radical acceptor in the aryl radical coupling reaction;
however, the spirocyclization by the aryl radical addition onto
an indole ring proceeds more easily at the 2-position.
We next evaluated naphthalene ring as the radical acceptor.
The standard conditions for the spirocyclization (SmI2/HMPA/
i-PrOH) yielded the spirocycle 34 in ca. 75% yield, although
isolation of 34 from the starting material was difficult (Table
7, entry 1). Interestingly, treatment of 33 with SmI2 and HMPA
in the absence of i-PrOH selectively gave spirocycle 35, which
has a conjugated double bond (entry 2), whereas the reaction
spirocycle 30, reduced fused ring 31, and dehalogenated product
32 without selectivity (Table 6, entry 1). Lowering the reaction
temperature did not improve the yield or selectivity (entries
2-4). These results revealed that the indole ring can work as
J. Org. Chem. Vol. 73, No. 18, 2008 7149

Iwasaki et al.
TABLE 7. Reactions of 1-Naphthamide Derivative 33a
SCHEME 5
product yield (%)
entry
additiveb
T (°C)
34
35
1
2
3
4
5
HMPA, i-PrOH
HMPA
LiBr
LiBr, i-PrOH
LiBr
-35
0
rt
rt
0
<75
0
75
74
0
58
0
0
no reaction
a Reactions were carried out with 3.5 equiv (with HMPA) or 5 equiv
(with LiBr) of Sml2 in THF. b HMPA (4 equiv relative to Sml2), metal
salts (8 equiv relative to Sml2) and i-PrOH (2 equiv relative to 33) were
used.
TABLE 8. Reactions of 2-Naphthamide Derivative 40a
SCHEME 4
product yield (%)
42
entry
1
additive
T (°C)
-78
41
43
HMPA, i-PrOH
complex mixture
2
3
HMPA
LiBr
-78
rt
14
22
15
complex mixture
4
LiBr
rt
complex mixture
a Reactions were carried out with 3.5 equiv (with HMPA) or 5 equiv
(with LiBr) of Sml2 in THF. b HMPA (4 equiv relative to Sml2), LiBr (8
equiv relative to Sml2) and i-PrOH (2 equiv relative to 40) were used.
formation of the organosamarium intermediate of type 37 would
be relatively difficult since the coordination site of samarium
can be saturated by HMPA. Accordingly, SET to the spiro
radical 36 by SmI2 followed by protonation by i-PrOH at the
less hindered position of the resulting anionic intermediate 38
gives spirocycle 34. In the absence of i-PrOH, protonation
occurred during workup at the less hindered position after
formation of the organosamarium species 39 to give the
spirocycle 35 having a conjugated double bond.23 It should be
noted that isomerization of 34 to the conjugated isomer 35 did
proceed to some extent (34:35 ) 4:1, Scheme 5) under the
cyclization conditions without i-PrOH, while the reverse reaction
from 35 was not observed under the protic conditions (SmI2/
HMPA/i-PrOH in THF). Accordingly, isomerization to 35 might
with SmI2/LiBr gave spirocycle 34 with an isolated double bond
in good yields, irrespective of the presence or absence of i-PrOH
(entries 3 and 4).
A possible rationalization for the observed results with the
naphthalene derivative 33, in which the position of the double
bond was controlled by changing the reaction conditions, is
shown in Scheme 4. In the presence of LiBr, the generated
22
SmBr2 would react with the radical species 36, coordinating
with the amide oxygen to produce an organosamarium inter-
mediate 37, and the spirocycle 34 was then formed by
subsequent protonation. In contrast, in the case using HMPA,
(23) The key intermediate 39 would be formed only in the absence of proton
source, because isopropanol could protonate the intermediate 38 leading to 34,
before formation of 39.
7150 J. Org. Chem. Vol. 73, No. 18, 2008

Samarium(II)-Mediated Spirocyclization
Compound 12a: pale yellow oil; IR (KBr) cm-1 1666 (CdO);
1H NMR (500 MHz, CDCl3) δ 3.32-3.36 (m, 1H, CH), 3.37 (s,
3H, NMe), 3.78 (ddd, J ) 9.0, 3.0, 3.0 Hz, 1H, CH), 5.77 (ddd, J
) 9.0, 4.0, 3.5 Hz, 1H, CdCH), 5.96-5.99 (m, 1H, CdCH),
6.08-6.15 (m, 2H, CHdCH), 6.98 (d, J ) 8.0 Hz, 1H, Ar),
7.05-7.08 (m, 1H, Ar), 7.22-7.31 (m, 2H, Ar); 13C NMR (75.5
MHz, CDCl3) δ 29.8, 35.6, 39.3, 114.4, 123.1, 124.2, 125.5, 125.7,
126.5, 127.6 (2C), 127.8, 139.8, 170.2; MS (FAB) m/z (%) 212
(MH+, 49), 210 (100); HRMS (FAB) calcd for C14H14NO (MH+)
212.1075, found 212.1084.
General Procedure for Samarium(II)-Mediated Spirocycliza-
tion in the Absence of i-PrOH. Synthesis of 5-Methylphenan-
thridin-6(5H)-one (13a) (Table 2, entry 1). A mixture of samarium
(293 mg, 1.95 mmol) and 1,2-diiodoethane (423 mg, 1.50 mmol)
in THF (15.0 mL) was stirred for 1.5 h. After cooling to 0 °C,
HMPA (0.939 mL, 5.40 mmol) was added to the mixture, and
stirring was continued for 20 min at this temperature. A solution
of amide 10a (100 mg, 0.300 mmol) in THF (3.0 mL) was added
to the mixture, and the mixture was stirred for 30 min at this
temperature. 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 and dried 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 (6:1) to give
a biaryl coupling product 13a (16.2 mg, 26% yield): colorless oil;
IR (KBr) cm-1 1651 (CdO); 1H NMR (500 MHz, CDCl3) δ 3.80
(s, 3H, NMe), 7.31 (ddd, J ) 8.0, 8.0, 1.5 Hz, 1H, Ar), 7.39 (d, J
) 8.5 Hz, 1H, Ar), 7.52-7.59 (m, 2H, Ar), 7.74 (ddd, J ) 7.5,
7.5, 1.5 Hz, 1H, Ar), 8.25 (dd, J ) 7.5, 4.5 Hz, 2H, Ar), 8.54 (dd,
J ) 8.0, 1.5 Hz, 1H, Ar); 13C NMR (75.5 MHz, CDCl3) δ 29.9,
115.0, 119.2, 121.6, 122.4, 123.2, 125.5, 127.9, 128.8, 129.5, 132.3,
133.5, 138.0, 161.6; MS (FAB) m/z (%) 210 (MH+, 60), 154 (100);
HRMS (FAB) calcd for C14H12NO (MH+) 210.0919, found
210.0916.
General Procedure for Samarium(II)-Mediated Spirocycliza-
tion in the Presence of LiBr. Synthesis of 1,1′-Dimethyl-2,3′-
spirobi[indolin]-2-one (27) and (()-(6aR,11bR)-5,7-Dimethyl-
5,6a,7,11b-tetrahydroindolo[2,3-c]quinolin-6-one (28) (Table 5,
entry 4). A mixture of samarium (90 mg, 0.599 mmol) and 1,2-
diiodoethane (131 mg, 0.466 mmol) in THF (4.6 mL) was stirred
for 2 h. After cooling to 0 °C, a solution of LiBr (323 mg, 3.72
mmol) in THF (3.5 mL) was added to the mixture, and stirring
was continued for 40 min at room temperature. A solution of indole
26 (50 mg, 0.133 mmol) in THF (2.0 mL) was added to the mixture,
and the mixture was stirred for 30 min at this temperature. After
the mixture was exposed to air, Na2S4O7 was added to the mixture,
and the whole was extracted with Et2O. The extract was washed
with Na2S4O7 and brine and dried 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 (10:1). Further purification by recrystallization
from EtOAc gave the spirocycle 27 (20.1 mg, 57% yield) and fused
cyclic compound 28 (2.8 mg, 8% yield).
partly assist the selective formation of 35 in the absence of
i-PrOH, although it has been proven that formation of 34 using
i-PrOH is kinetically controlled.24
Finally, we examined substrate 40 with an amide side chain
at the 2-position of the naphthalene ring. The reaction of 40
with SmI2/HMPA gave fused ring 41 (formed by the rearrange-
ment of the carbonyl group to the 1-position), fused ring 42
(formed by the rearrangement of the phenyl group to the
1-position), and fused ring 43 (formed by the rearrangement of
the phenyl ring to the 3-position) (Table 8, entry 2). We have
revealed that the spirocyclization by the aryl radical addition
onto a naphthalene ring proceeds more efficiently with substrate
33 having an amide side chain at the 1-position of the
naphthalene ring.
Conclusions
We have demonstrated a reductive cyclization of aryl radicals
onto an aromatic ring mediated by SmI2 and an appropriate
additive such as HMPA, i-PrOH, and LiBr. When ortho-
substituted benzamide derivatives were used, the corresponding
spirocyclic compounds were selectively obtained. This is the
first example of the synthesis of spirocycles by the aryl radical
addition onto a benzene ring. It has also been revealed that an
indole or naphthalene ring can work as the radical acceptor,
yielding various spirocycles and reduced fused ring compounds.
The radical cyclization reaction with the substrates having an
ether tether also proceeds to give spirocycles, and we found
that introduction of a substituent onto the tether is effective for
improvement of the yield of the spirocycles. These results
demonstrate that product distribution is highly dependent on
the reaction conditions and substrate structure; however, sa-
marium(II)-mediated cyclization of appropriate substrates is
useful for the synthesis of various spirocycles.
Experimental Section
General Procedure for Samarium(II)-Mediated Spirocycliza-
tion. Synthesis of 1′-Methylspiro[cyclohexa[2,5]diene-1,3′-indo-
lin]-2′-one (11a) and 5-Methyl-6a,10a-dihydrophenanthridin-
6(5H)-one (12a) (Table 1, entry 3). A mixture of samarium (232
mg, 1.54 mmol) and 1,2-diiodoethane (335 mg, 1.19 mmol) in THF
(12 mL) was stirred for 1.5 h. After cooling to 0 °C, HMPA (0.742
mL, 4.27 mmol) was added to the mixture, and stirring was
continued for 20 min at this temperature. After cooling to -35 °C,
a solution of the amide 10a (80 mg, 0.237 mmol) and i-PrOH (0.036
mL, 0.474 mmol) in THF (2 mL) was added to the mixture, and
the mixture was stirred for 15 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 and dried 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 (6:1) to give spirocycle 11a (18 mg, 36% yield)
and fused cyclic compound 12a (15 mg, 30% yield).
Compound 27: colorless crystals; mp 176-178 °C; IR (KBr)
1
cm-1 1716 (CdO); H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H,
NMe), 3.21 (d, J ) 15.6 Hz, 1H, CHH), 3.25 (s, 3H, NMe), 3.54
(d, J ) 15.6 Hz, 1H, CHH), 6.47 (d, J ) 7.8 Hz, 1H, Ar), 6.72
(ddd, J ) 7.5, 7.5, 1.0 Hz, 1H, Ar), 6.88 (d, J ) 7.5 Hz, 1H, Ar),
7.01 (ddd, J ) 7.5, 7.5, 1.0 Hz, 1H, Ar), 7.06-7.17 (m, 3H, Ar),
7.33 (ddd, J ) 7.5, 7.5, 1.2 Hz, 1H, Ar); 13C NMR (75.5 MHz,
CDCl3) δ 26.3, 30.6, 40.8, 73.9, 106.6, 108.3, 118.1, 123.0, 123.4,
124.1, 126.8, 127.9, 129.3, 129.5, 143.0, 151.9, 176.9; MS (FAB)
m/z (%) 287 (MNa+, 73), 264 (100); HRMS (FAB) calcd for
C17H16N2NaO (MNa+) 287.1130, found 287.1154.
1
Compound 11a: colorless oil; IR (KBr) cm-1 1716 (CdO); H
NMR (500 MHz, CDCl3) δ 2.82-3.01 (m, 2H, CH2), 3.23 (s, 3H,
NMe), 5.39 (ddd, J ) 10.5, 2.0, 2.0 Hz, 2H, 2 × CdCH),
6.12-6.15 (m, 2H, 2 × CdCH), 6.83-6.85 (m, 1H, Ar), 7.05-7.13
(m, 2H, Ar), 7.26-7.30 (m, 1H, Ar); 13C NMR (75.5 MHz, CDCl3)
δ 25.7, 26.6, 51.8, 108.0, 122.9, 123.8 (2C), 124.7, 127.2, 128.4
(2C), 134.2, 143.0, 177.9; MS (FAB) m/z (%) 212 (MH+, 100);
HRMS (FAB) calcd for C14H14NO (MH+) 212.1075, found
212.1077.
1
Compound 28: colorless oil; IR (KBr) cm-1 1668 (CdO); H
NMR (300 MHz, CDCl3) δ 2.96 (s, 3H, NMe), 3.42 (s, 3H, NMe),
4.01 (d, J ) 8.1 Hz, 1H, 11b-H), 4.49 (d, J ) 8.1 Hz, 1H, 6a-H),
6.56 (d, J ) 8.1 Hz, 1H, Ar), 6.82 (ddd, J ) 7.5, 7.5, 0.6 Hz, 1H,
(24) As we expected, isomerization from 35 to 34 or its reverse reaction did
not proceed under SmI2/HMPA in the presence of i-PrOH.
J. Org. Chem. Vol. 73, No. 18, 2008 7151

Iwasaki et al.
Ar), 6.99-7.06 (m, 2H, Ar), 7.18 (ddd, J ) 7.5, 7.5, 1.2 Hz, 1H,
Ar), 7.23-7.28 (m, 1H, Ar), 7.33-7.36 (m, 2H, Ar); 13C NMR
(75.5 MHz, CDCl3) δ 29.7, 35.3, 42.0, 68.4, 108.5, 114.7, 119.0,
122.9, 123.2, 124.8, 127.9, 128.5, 128.7, 130.5, 138.5, 151.8, 166.6;
MS (FAB) m/z (%) 287 (MNa+, 75), 264 (100); HRMS (FAB)
calcd for C17H16N2NaO (MNa+) 287.1160, found 287.1158.
Ministry of Education, Culture, Sports, Science and Technol-
ogy of Japan.
Supporting Information Available: Synthetic procedure,
1
characterization, and H NMR for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (B) (T.T.) and for
Encouragement of Young Scientists (A) (H.O.) from the
JO800656A
7152 J. Org. Chem. Vol. 73, No. 18, 2008