A novel samarium(II)-mediated tandem spirocyclization onto an aromatic ring

Article abstract of DOI:10.1016/j.tetlet.2011.02.010

We report a samarium(II)-mediated tandem spirocyclization reaction to provide dispiro[4.2.4.2]tetradecadiene and dispiro[4.2.5.2]pentadecadiene skeletons. The reaction was achieved by intramolecular addition of a ketyl radical onto an aromatic ring bearin

Full text of DOI:10.1016/j.tetlet.2011.02.010

Tetrahedron Letters 52 (2011) 1770–1772
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A novel samarium(II)-mediated tandem spirocyclization onto an aromatic ring
Hiroki Iwasaki a, Nozomi Tsutsui b, , Toru Eguchi b, Hiroaki Ohno b,à, Masayuki Yamashita a,
,
⇑
Tetsuaki Tanaka b
a Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, 1 Misasagi-Shichono-cho, Yamashina-ku, Kyoto 607-8412, Japan
b Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a samarium(II)-mediated tandem spirocyclization reaction to provide dispiro[4.2.4.2]tetrade-
cadiene and dispiro[4.2.5.2]pentadecadiene skeletons. The reaction was achieved by intramolecular addi-
tion of a ketyl radical onto an aromatic ring bearing an electrophilic moiety followed by reductive capture
of the spirohexadienyl radical intermediate with SmI2 in the presence of HMPA.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 17 December 2010
Revised 27 January 2011
Accepted 2 February 2011
Available online 1 March 2011
Interest in spirocyclic systems derives from the unique molecu-
lar structure and diverse biological activities of this class of com-
pounds.1 A variety of methods for the synthesis of spirocyclic
compounds have been reported such as transition-metal catalyzed
cyclization,2 rearrangement of epoxides or cyclopropanes,3 and
cycloaddition reactions.4 Of these synthetic methods, those based
on radical cyclization are often effective because spirocycles can
be efficiently synthesized by the intramolecular addition of tertiary
cyclic radicals to an alkene5 or alkyne,6 or by cyclization of a radical
species possessing a preformed quaternary carbon center.7 In con-
trast, the synthesis of spirocycles by radical attack onto an aro-
matic ring is relatively limited8,9 despite the availability of a
wide range of aromatic compounds. This is presumably due to
the instability of the spirocyclohexadienyl radical intermediate A
(Scheme 1), and the reversible nature of the radical addition. Inter-
mediate A, generated by the intramolecular addition of the X rad-
ical (1) onto an aromatic ring, can be easily converted into the Y
radical (aryl migration) or the more stable rearranged product
3.10 To realize spirocyclization onto an aromatic ring, the spiro-
hexadienyl radical intermediate A should be effectively trapped
in an irreversible manner. Some examples of the formation of spi-
rocycle 4 accompanied by a loss of aromaticity by the capture of
intermediate A with an oxidant/nucleophile (ꢀeꢀ/Zꢀ)8 or a radical
species (ZÅ)9 have been reported. However, reductive trapping of A
(eꢀ/Z+) was unknown until recently.
Y
X
H
Y
Y
n
R
R
R
n
n
n
R
X
X
-e-/Z-
3
1
2
A
B
rearrangement
e-
Z
Y
Y
R
n
Z+
Y
R
n
X
X
Z
X
4
aryl migration
spirocyclisation
Scheme 1. Intramolecular addition onto an aromatic ring.
R1
SmI2
HMPA
O
O
O
OH
R2
R1
N
THF
–78 to 0 °C
N
CO2R3
n
R2
n
O
5: n = 1
6: n = 2
7: n = 1
8: n = 2
Scheme 2. Synthesis of dispiro[4.2.4.2]tetradecadiene and dispiro[4.2.5.2]penta-
decadiene skeletons.
We found that samarium(II)-mediated spirocyclization onto an
aromatic ring was promoted in the presence of HMPA, and that spi-
rocyclization proceeded through the formation of a cyclohexadie-
nyl anion intermediate and 1,4-reduction of the cyclohexadiene
intermediate.11 In addition, we captured the cyclohexadienyl anion
intermediate using electrophiles such as alkyl halides. On the basis
of these results, we expected that the tandem spirocyclization
reaction would proceed via the above mentioned reductive capture
of spirohexadienyl anion intermediate B by an intramolecular elec-
trophilic moiety (Scheme 1).
In this communication, we report a novel method for the forma-
tion of dispiro[4.2.4.2]tetradecadiene and dispiro[4.2.5.2]pentade-
cadiene skeletons mediated by samarium(II) iodide in the
presence of HMPA (Scheme 2).
⇑
Corresponding author.
E-mail address: yamasita@mb.kyoto-phu.ac.jp (M. Yamashita).
Present address: School of Pharmacy, Kinki University, 3-4-1 Kowakae, Higashi-
osaka, Osaka 577-8502, Japan.
à
Present address: Graduate School of Pharmaceutical Sciences, Kyoto University,
Sakyo-ku, Kyoto 606-8501, Japan.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.010

H. Iwasaki et al. / Tetrahedron Letters 52 (2011) 1770–1772
1771
Table 1
Samarium(II)-mediated tandem spirocyclization for the construction of the dispiro[4.2.4.2]tetradecadiene skeletona
SmI2
HMPA
O
O
O
OH
O
OH
Me
CO2R1
11
Me
N
Me
THF
N
CO2R1
N
Me
O
10
α
Me
9
Entry
Substrate
R1
i-PrOH (equiv)
T (°C)
Product yield (%)
10b
11
1
2
3
9a
9a
9b
Me
Me
Ph
0
2
0
ꢀ78 to 0
ꢀ78
35
0
15
0
65
8
ꢀ78
a
All the reactions were carried out in THF using SmI2 (5 equiv) and HMPA (18 equiv).
Obtained as a single stereoisomer.
b
Various benzamide derivatives12 bearing an alkyl ketone side
44% (Table 2, entry 1). Treatment of phenyl ester 12b with SmI2
in the presence of HMPA also gave product 13a in 44% yield, along
with several byproducts (entry 2). In order to investigate the steric
effect of the substituent on the amide side chain, we investigated
the reaction of 12c–e. In compound 12c bearing an isopropyl
substituent that was more sterically hindered than the methyl
group on the nitrogen atom in 12a, the corresponding spirocycle
13b was obtained in only 26% yield (entry 3). Interestingly, a
methyl substituent at the b-position (12d) increased the yield of
the tandem spirocyclization product 13c to 51% (entry 4). In these
cases (entries 1–3), the desired products were obtained as a single
chain were prepared and used as starting materials in the samar-
ium(II)-mediated tandem spirocyclization reaction. First, we
examined the reaction of methyl 2-{N-methyl-4-(4-oxopen-
tyl)benzoylamino}acetate 9a with SmI2 and HMPA in the absence
of i-PrOH as a proton source, and obtained tandem spirocyclization
product 10 as a single stereoisomer13 in 35% yield (Table 1, entry
1). In order to confirm the intermediate in this reaction, the reac-
tion of 9a in the presence of i-PrOH was conducted to selectively
give mono-cyclization product 11 in 65% yield (Table 1, entry 2).
This demonstrates that reduction of 9 by SmI2-HMPA through
two sequential electron transfers provides an intermediate an-
ion.14 Changing the electrophilic moiety to phenyl ester did not
improve the yield of spirocycle 10 (Table 1, entry 3).
stereoisomer.13 In contrast, a methyl substituent at the
a-position
(12e) decreased the yield and stereoselectivity to give 13d as a
stereoisomeric mixture (27%, isomeric ratio = 3:3:1:1, entry 5).
This is presumably due to the unfavorable steric interaction in
the second cyclization, in which intramolecular nucleophilic attack
occurs on the ester carbonyl.
Next, the tandem spirocyclization of various ketone substrates
was investigated (Table 3).16 Similar to methyl ketone 12a (Table
2, entry 1), ethyl and benzyl ketones 14 and 15 were cyclized into
spirocycles 18a/b and 19a/b, respectively (entries 1 and 2).
Sterically congested isopropyl ketone 16 also underwent tandem
spirocyclization under identical reaction conditions (entry 3). This
In these reactions, we observed a byproduct formed by C–N
bond cleavage at the
a
-position.15 This side reaction is likely the
major reason for the relatively low yields of the tandem spirocyc-
lization products. To avoid this reductive cleavage of the C–N bond,
we examined the reaction of the b-amino acid derivatives,
3-{N-methyl-4-(4-oxopentyl)benzoylamino}propanoates 12, with
SmI2 in the presence of HMPA. In this reaction, the six-membered
ring would be formed in the second cyclization. As expected, the
yield of the tandem spirocyclization product 13a increased to
Table 2
Table 3
Samarium(II)-mediated tandem spirocyclization for the construction of the dispi-
Tandem spirocyclization of various ketone substratesa
ro[4.2.5.2]tetradecadiene skeletona
Entry
Substrate
Product ratio (yield)b
SmI2
O
R1
R2
HMPA
R
O
O
O
OH
N
R3
Me
Me
N
THF
O
O
OH
β
N
O
R
R1
CO2R4
α
R3
R2
O
N
Me
CO2Me
12
13
1
2
3
14:R = Et
15:R = Bn
16:R = i-Pr
18a:18b = 29:4 (33%)
19a:19b = 15:9 (24%)
20a:20b = 17:3 (23%)
Entry
Substrate
R1
R2
R3
R4
Product yield (%)
13b
O
1
2
3
4
5
12a
12b
12c
12d
12e
Me
Me
i-Pr
Me
Me
H
H
H
Me
H
H
H
H
H
Me
Ph
Me
Me
Me
13a:44
13a:44
13b:26
13c:51
13d:27
Me
N
OH
O
O
O
Me
N
21a:21b = 17:3 (20%)
Me
CO2Me
The ratio could not be determined. Compound 13d was obtained as a stereoiso-
meric mixture. The ratio was determined by 1H NMR as 3:3:1:1.
4
17
a
All the reactions were carried out in THF using SmI2 (5 equiv) and HMPA
a
(18 equiv) at ꢀ78 to 0 °C.
All the reactions were carried out in THF using SmI2 (5 equiv) and HMPA
b
Compounds 13a and 13b were obtained as a single stereoisomer. Compound
(18 equiv) at ꢀ78 to 0 °C.
b
13c was obtained as stereoisomeric mixture.
Ratios were determined by 1H NMR.

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H. Iwasaki et al. / Tetrahedron Letters 52 (2011) 1770–1772
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spirocyclization is useful for direct synthesis of tetracyclic spirocy-
cles 21a/b using cyclohexanone derivative 17 as a substrate,
although the yield is relatively low (20%, entry 4).
In conclusion, we have developed a tandem spirocyclization
method mediated by SmI2 in the presence of HMPA, which
proceeded via ketyl radical attack on the aromatic ring, single elec-
tron transfer, and nucleophilic attack of the resulting dienyl anion
to the ester group. This reaction can provide a stereoselective syn-
thetic route to dispiro[4.2.4.2]tetradecadienes and dispiro[4.2.5.2]
tetradecadienes.
References and notes
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13. General procedure for samarium(II)-mediated tandem spirocyclization:
preparation of 10 as an example.
A mixture of samarium (168 mg,
1.12 mmol) and 1,2-diiodoethane (242 mg, 5.86 mmol) in THF (8.5 mL) was
stirred for 1.5 h. After cooling to 0 °C, HMPA (0.51 mL, 3.09 mmol) was added
to the mixture, and stirring was continued for 20 min at that temperature.
After cooling to ꢀ78 °C, a solution of the amide 9a (50 mg, 0.17 mmol) in THF
(1.5 mL) was added dropwise to the mixture for 30 min, and the mixture was
stirred for 20 min at 0 °C. After the mixture was exposed to air, EtOAc was
added to the mixture. The mixture was washed with saturated NaHCO3 and
brine, dried over MgSO4, and concentrated under reduced pressure. The
residue was purified by column chromatography over silica gel with n-hexane-
EtOAc (1:4) to give spirocycle 10 (14.9 mg, 33% yield).
Compound 10: colorless solid; IR (KBr) cmꢀ1: 3461 (OH), 1774 (C@O), 1678
[C(O)N]; 1H NMR (300 MHz, CDCl3) d: 1.25 (s, 3H, CMe), 1.75–2.05 (m, 6H,
3 ꢁ CH2), 3.11 (s, 3H, NMe), 4.00 (s, 2H, NCH2), 5.46 (dd, J = 9.9, 2.1 Hz, 1H,
C@CH), 5.52 (dd, J = 9.9, 2.1 Hz, 1H, C@CH), 5.95 (dd, J = 9.9, 1.8 Hz, 1H, C@CH),
6.15 (dd, J = 9.9, 1.8 Hz, 1H, C@CH); 13C NMR (75 MHz, CDCl3) d: 19.5, 25.3,
29.8, 38.0, 38.7, 51.5, 57.1, 57.2, 82.5, 118.9, 119.0, 135.6, 136.2, 172.0, 205.8;
MS (FAB) m/z (%): 262 (MH+, 49), 154 (100); HRMS (FAB) calcd for C15H20NO3
(MH+): 262.1443; found: 262.1448. Determination of the stereochemistry of
the products is currently in progress.
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benzyl, isopropyl, and cyclohexyl group compared with methyl group of
substrate 12a, which may be the reason why stereoisomeric mixtures were
obtained in Table 3. In order to clarify this reason, the investigation is in
progress.