The first samarium(II)-mediated aryl radical cyclisation onto an aromatic ring

Article abstract of DOI:10.1039/b410457a

Intramolecular arylation of aryl radicals was mediated by SmI ₂/HMPA in the presence of i-PrOH to give spirocycles and/or reduced cine-cyclised products, while the reaction in the absence of i-PrOH gave the rearomatised fused rings.

Full text of DOI:10.1039/b410457a

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The first samarium(II)-mediated aryl radical cyclisation onto an
aromatic ring
Hiroaki Ohno, Hiroki Iwasaki, Toru Eguchi and Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871,
Japan
Received (in Cambridge, UK) 8th July 2004, Accepted 23rd July 2004
First published as an Advance Article on the web 23rd August 2004
Intramolecular arylation of aryl radicals was mediated by
unstable intermediate 4 rearranges to a fused-ring radical such as
2 or 7.2,4c Based on our previous results, we expected that
samarium(II) iodide would effectively trap the intermediate 4 by
single electron transfer, which could realize the spirocyclisation.
In this communication, we report a selective synthesis of spirocycles
10 and fused rings 11 mediated by samarium(II) iodide, by simply
changing the substrate structure and reaction conditions
(Scheme 2). This is the first example of samarium(II)-mediated
arylation of aryl radicals.
SmI2/HMPA in the presence of i-PrOH to give spirocycles
and/or reduced cine-cyclised products, while the reaction in
the absence of i-PrOH gave the rearomatised fused rings.
Aryl radical addition onto an aromatic ring has become an
important tool in organic synthesis. The traditional method is
heavy metal-mediated oxidative radical arylation of arenes through
the cation radical intermediates, which is a useful procedure for the
biaryl coupling of electron-rich arenes.1 Recently, intramolecular
reductive radical arylation using Bu3SnH or other hydrogen
sources has been extensively studied. As shown in Scheme 1, the
intramolecular addition of aryl radical 1 can take place at three
different carbons (A, B, and C). (1) The reaction at the carbon A
forms the cyclohexadienyl radical intermediate 2, which was
converted into the fused ring 3 by hydrogen abstraction.2,3 (2)
Attack at the carbon B generates the unstable spirocyclohexadienyl
radical intermediate 4, which easily undergoes aryl migration to
give 5.4 Otherwise, the intermediate 4 was trapped to give the
spirocyclic compounds such as 6.5 (3) Attack of the aryl radical at
the carbon C followed by elimination of the X radical gives the
cyclised product 8.6 In some cases, the intramolecular radical
arylation suffers from low regioselectivity of the radical addition.7
Recently, synthesis of spirocycles has attracted a great deal of
attention due to their unique molecular structure and diverse
biological activities.8 In our ongoing study on samarium(II)-
mediated9 cyclisation reaction onto an aromatic ring,10,11 we
planned to synthesize the spirocycles by radical aryl coupling.
Generally, the aryl radical cyclisation onto an aromatic ring to
form spirocycles such as 6 is extremely difficult, producing a
considerable amount of the cine-cyclisation product 3,5 except for
the reaction of indole derivatives.12 This is presumably due to both
the instability of spirocyclohexadienyl radical intermediate 4 and
the reversible nature of the radical addition. In some cases, the
Scheme 2 Reaction conditions: (a) SmI2, HMPA, i-PrOH, THF, 235 uC;
(b) SmI2, HMPA, THF, 0 uC.
We prepared various aryl radical precursors and investigated the
samarium(II)-mediated intramolecular biaryl coupling reaction.
First, we examined the reaction of 2-iodophenyl benzoate or N-(2-
iodophenyl)benzamide with SmI2/HMPA and obtained a complex
mixture of unidentified products. However, we found that treat-
ment of N-methylbenzamide derivative 9a with SmI2 and HMPA
in the presence of i-PrOH (2 equiv.) gave spirocycle 10a in 34%
yield (Table 1, entry 1). Although increased loading of i-PrOH
(20 equiv., entry 2) or lowering of the reaction temperature to
235 uC (entry 3) was not effective for improvement of the yield of
spirocycle 10a, a considerable amount of the reduced fused ring 12a
was obtained in both cases (28% and 30% yield, respectively). In
contrast, the radical coupling reaction of the corresponding ortho-
substituted analogues 9b (entry 4) and 9c (entry 5) afforded high
yields of spirocycles 10b and 10c, respectively, in good selectivities.
This is the first example of selective spirocyclisation by the aryl
radical addition onto a benzene ring. Interestingly, a methyl sub-
stituent at the meta- (entry 6) or para-position (entry 7) increased
the yields of the fused rings 12d and 12e, respectively. Compared to
other conditions for the radical aryl coupling reaction mainly
yielding biaryl products,2–7 formation of the spirocycles 10 and
fused rings 12 with a loss of aromaticity is a unique reactivity of
the SmI2/HMPA/i-PrOH system. When the reaction of 9a–e
was conducted in the absence of i-PrOH, the biaryl coupling
products 11a–e were selectively obtained in low to moderate yields
(entries 8–12). For a reason that is unclear, the para-substituted
benzamide derivative 9e showed the best result affording the biaryl
product 11e in 60% yield, without producing other cyclised pro-
ducts (entry 12). This type of intramolecular radical biaryl coupling
is also promoted by Bu3SnH or other reagents;2 however, it is
extremely interesting that the cyclisation mode can be completely
controlled by changing the reaction conditions and the substituent
pattern (compare entries 4 and 5 vs. 12).
A plausible mechanism for the samarium(II)-mediated radical
aryl coupling reaction is shown in Scheme 3. Single electron
transfer (SET) to the iodide 9 by SmI2 generates the aryl radical 13,
which would cyclise into the spirohexadienyl radical intermediate
Scheme 1 Intramolecular addition of aryl radical 1 onto an aromatic ring.
2 2 2 8
C h e m . C o m m u n . , 2 0 0 4 , 2 2 2 8 – 2 2 2 9
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 1 Samarium(II)-mediated aryl coupling reactiona
selectively obtained (entries 4 and 5, Table 1). This is presumably
due to the unfavourable steric interaction in the rearrangement of
14 to 16 as shown in the structure 17, which provides more time
to 14 for the SET and the subsequent protonation without
rearrangement to 16.
In conclusion, we have demonstrated a reductive cyclisation of
aryl radicals onto an aromatic ring mediated by SmI2/HMPA in
the presence of i-PrOH. This is the first example of the highly
selective synthesis of spirocycles by the aryl radical addition onto a
benzene ring.
Notes and references
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Product yield (%)
i-PrOH
R2 R3 (equiv.) T/uC 10 11
Entry Substrate R1
12
1
2
9a
9a
9a
9b
9c
9d
9e
9a
9b
9c
9d
9e
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
Me
H
H
2
20
2
2
2
2
2
0
0
0
0
34
39
0
0
0
0
0
trace
28
30
6
3
H
235 36
235 89
235 89
235 29
235 31
4
5
6
Me
OMe
H
9
0
0
65
53b
0
0
0
7
H
8
H
0
0
0
0
0
0
0
0
0
0
26
26
15
29c
60
9
Me
OMe
H
10
11
12
H
Me
H
H
H
Me
0
0
0
0
0
H
a All the reactions were carried out in THF using SmI2 (5 equiv.)
and HMPA (18 equiv.). b Obtained as a mixture of regioisomers
(1:1). c Obtained as a mixture of regioisomers (2:1).
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Scheme 3 A plausible mechanistic pathway.
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14. Further SET by SmI2 and the protonation of the resulting
cyclohexadienyl anion 15 by i-PrOH affords the spirocyclic 1,4-
cyclohexadiene 10. In contrast, rearrangement of the unstable
intermediate 14 to the fused ring 16 followed by SET and the
subsequent protonation would give the reduced fused ring 12,
while, in the absence of i-PrOH, the hydrogen abstraction from 16
yields aromatized product 11. The presence of i-PrOH would
promote the SET to 16, by trapping the anionic intermediate.11b
When the ortho-substituted benzamide derivatives 9b and 9c
(R1LMe or OMe) were used, the spirocycles 10b and 10c were
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C h e m . C o m m u n . , 2 0 0 4 , 2 2 2 8 – 2 2 2 9
2 2 2 9