An efficient synthesis of cycloalkane-1,3-dione-2-spirocyclopropanes from 1,3-cycloalkanediones using (1-aryl-2-bromoethyl)-dimethylsulfonium bromides: Application to a one-pot synthesis of tetrahydroindol-4(5H)-one

Article abstract of DOI:10.1016/j.tetlet.2015.05.069

An efficient synthesis of cyclohexane- and cyclopentane-1,3-dione-2-spirocyclopropanes from 1,3-cycloalkanediones using sulfonium salts was achieved. The reaction of 1,3-cycloalkanediones with (1-aryl-2-bromoethyl)-dimethylsulfonium bromides and powdered K₂CO₃ in EtOAc provided the corresponding spirocyclopropanes in high yields. Furthermore, a one-pot synthesis of tetrahydroindol-4(5H)-one from 1,3-cyclohexanedione was achieved using the present protocol and a sequential ring-opening cyclization of spirocyclopropane with a primary amine.

Full text of DOI:10.1016/j.tetlet.2015.05.069

Tetrahedron Letters 56 (2015) 4312–4315
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient synthesis of cycloalkane-1,3-dione-2-spirocyclopropanes
from 1,3-cycloalkanediones using (1-aryl-2-bromoethyl)-
dimethylsulfonium bromides: application to a one-pot
synthesis of tetrahydroindol-4(5H)-one
⇑
⇑
Hisanori Nambu , Masahiro Fukumoto, Wataru Hirota, Naoki Ono, Takayuki Yakura
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of cyclohexane- and cyclopentane-1,3-dione-2-spirocyclopropanes from
1,3-cycloalkanediones using sulfonium salts was achieved. The reaction of 1,3-cycloalkanediones with
(1-aryl-2-bromoethyl)-dimethylsulfonium bromides and powdered K2CO3 in EtOAc provided the
corresponding spirocyclopropanes in high yields. Furthermore, a one-pot synthesis of tetrahydroindol-
4(5H)-one from 1,3-cyclohexanedione was achieved using the present protocol and a sequential ring-
opening cyclization of spirocyclopropane with a primary amine.
Received 18 March 2015
Revised 12 May 2015
Accepted 19 May 2015
Available online 5 June 2015
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Cyclopropane
1,3-Cyclohexanediones
Sulfonium salts
Indole
One-pot synthesis
Doubly activated cyclopropanes represent versatile intermedi-
ates for the synthesis of a variety of carbo- and heterocyclic com-
pounds.1 In this context, a ring-opening cyclization reaction of
doubly activated cyclopropanes with primary amines is one of
the most powerful methods for the construction of pyrrole skele-
tons.2 Very recently, we reported the first example of the formation
of indole skeletons by employing the ring-opening cyclization of
spirocyclopropanes. The reaction of cyclohexane-1,3-dione-2-
spirocyclopropanes 3, derived from 1,3-cyclohexanediones 1, with
primary amines proceeded smoothly at room temperature to give
high yields of tetrahydroindol-4(5H)-ones 4, one of which was
easily converted to 4-hydroxyindole 5 (Scheme 1).3 This procedure
provides a useful method for the synthesis of 4-hydroxyindoles.
However, there is still a need for improvement in the yields of
spirocyclopropanes 3 in Rh(II)-catalyzed cyclopropanation4–6 with
2-diazo-1,3-cyclohexanediones 2 (27–48% yields). The reaction of
alkenes and diazo substrates derived from active methylene com-
pounds in the presence of an Rh(II) catalyst is widely employed for
the synthesis of a variety of doubly activated cyclopropanes. In the
case of the preparation of spirocyclopropanes, the Rh(II)-catalyzed
reaction also produced several cyclopropanes easily but in low
yields and was accompanied by a large amount of by-products.
For example, the reaction of an excess amount of styrene with
2-diazo-1,3-cyclohexanedione (2a) using a catalytic amount of
Rh2(OAc)4 gave spirocyclopropane 3a in 43% yield and tetrahy-
drobenzofuran-4(5H)-one 6a7 as
a by-product in 27% yield
(Scheme 1).6 Furthermore, this protocol is a two-step conversion
from 1,3-cyclohexanediones 1 and requires a potentially explosive
diazo compound. These drawbacks led us to develop a concise and
practical route to spirocyclopropanes 3 from 1,3-cyclohexane-
diones 1. Herein, we report an efficient synthesis of 1-arylspiro
[2.5]octane-4,8-diones 3 using (1-aryl-2-bromoethyl)-dimethyl-
sulfonium bromides 7 (Scheme 2).
The reaction of active methylene compounds such as malonate
and b-ketoester with sulfonium salts has been established2b,8–10 as
an alternative approach to doubly activated cyclopropanes.
Recently, Chandrasekaran and Gopinath reported that the reaction
of 2,4-pentanedione with (2-bromo-1-phenylethyl)dimethylsulfo-
nium bromide (7a) and K2CO3 in CH2Cl2/H2O (1:1) gave the corre-
sponding cyclopropane in 65% yield.9 Lu and co-workers applied
this reaction to a cyclic alkanedione system, in which the reaction
was conducted using DBU in DMSO, although the yield was very
low.10 At the outset, we examined the reaction of 1,3-cyclohexane-
dione (1a) with sulfonium salt 7a for the synthesis of 1-phenyl-
spiro[2.5]octane-4,8-dione (3a) according to Chandrasekaran’s
procedure (Table 1, entry 1). The reaction of 1a with 1.5 equiv of
⇑
Corresponding authors. Tel.: +81 76 434 7555/7556; fax: +81 76 434 5053.
E-mail addresses: nambu@pha.u-toyama.ac.jp (H. Nambu), yakura@pha.u-toyama.
ac.jp (T. Yakura).
http://dx.doi.org/10.1016/j.tetlet.2015.05.069
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

H. Nambu et al. / Tetrahedron Letters 56 (2015) 4312–4315
4313
Table 1
Reaction of 1,3-cyclohexanedione (1a) with sulfonium salt 7aa
Entry
Base
Solvent
Time (h)
Yieldb (%)
3a
6a
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
tBuOK
DBU
CH2Cl2/H2O (1:1)
CH2Cl2
CH3CN
iPrOH
THF
DMF
DMSO
EtOAc
EtOAc
EtOAc
EtOAc
8
24
9
20
24
4
30
Trace
14
9
7
26
35
81
Trace
20
Trace
6
Trace
9
Trace
28
Scheme 1. Synthesis of 4-hydroxyindole 5 employing a ring-opening cyclization of
cyclohexane-1,3-dione-2-spirocyclopropane 3 with amine.
2
23
1.5
24
0.5
1
Trace
Trace
7
10
11
c
K2CO3
92
Trace
a
b
c
All reactions were performed on a 0.5 mmol scale.
Isolated yield.
Powdered K2CO3 was used.
Scheme 2. Syntheses of spirocyclopropanes 3 from 1,3-cyclohexanediones 1 and
sulfonium salts 7.
7a using K2CO3 in CH2Cl2/H2O (1:1) at room temperature provided
3a in 30% yield. To enhance the yield of 3a, we then screened other
solvents. Switching the solvent to CH2Cl2 made the reaction messy
to give tetrahydrobenzofuran-4(5H)-one 6a in 6% yield without 3a
Table 2
Reaction of 1,3-cyclohexanediones 1a–d with sulfonium salts 7a–ca
i
(entry 2). The use of CH3CN, PrOH, and THF resulted in low yields
of 3a (7–14% yields, entries 3–5). We considered that the poor sol-
ubility of sulfonium salt 7a led to low product yields. With the
highly polar solvents DMF and DMSO, spirocyclopropane 3a was
obtained in 26% and 35% yields, respectively, along with 6a in
28% and 23% yields, respectively (entries 6 and 7). Surprisingly,
the reaction in EtOAc proceeded smoothly to completion within
1.5 h and gave 3a in 81% yield (entry 8), although 7a is almost
insoluble in EtOAc. A survey of bases revealed that K2CO3 was
the optimal base for this transformation (entry 8 vs entries 9 and
10). To our delight, the use of powdered K2CO3, which was finely
ground in a mortar, instead of granular K2CO3 increased the pro-
duct yield of 3a (92% yield, entry 11).
With the optimal conditions in hand,11 we investigated the
scope of the reaction of a variety of 1,3-cyclohexanediones 1a–d
with several sulfonium salts 7a–c prepared from styrene deriva-
tives and bromodimethylsulfonium bromide12,13 (Table 2). The
reaction of 1a with 7b and 7c bearing p-bromo or p-methyl sub-
stituents on the benzene ring provided the corresponding spirocy-
clopropanes 3b and 3c14 in 92% and 74% yields, respectively. High
yields of 3d–f14 (84–94% yields) were consistently obtained in the
reaction of dimedone (1b) with 7a–c. The reaction of 5-methyl-
and 5-phenyl-1,3-cyclohexanediones (1c and 1d) with 7a afforded
diastereomeric mixtures (ca. 1:1) of spirocyclopropanes 3g and 3h
in 89% and 81% yields, respectively. We then examined the Rh(II)-
catalyzed cyclopropanation of the corresponding styrene deriva-
tives with 2-diazo-1,3-cyclohexanediones derived from 1a–d, and
the yields are shown in square brackets in Table 2. In all cases,
the yields of 3a–h (38–47% yields) were lower than those obtained
by the reactions of 1 and 7.
a
All reactions were performed on a 0.5 mmol scale with 1.5 equiv of
sulfonium salts 7a–c and 3 equiv of powdered K2CO3 in EtOAc.
b Yields in square brackets were obtained in the reactions of large amounts
of the corresponding styrene derivatives with 2-diazo-1,3-cyclohexane-
diones derived from 1a–d in the presence of 1 mol % of Rh2(OAc)4.
c Ref. 3.
We next turned our attention to the reaction of 5-membered
carbocycles with sulfonium salt 7a (Scheme 3). The reaction of
1,3-cyclopentanedione (8) with 1.5 equiv of 7a using powdered
K2CO3 in EtOAc provided the corresponding spirocyclopropane 9
d The products 3g and 3h were isolated as a diastereomeric mixture (ca. 1:1).

4314
H. Nambu et al. / Tetrahedron Letters 56 (2015) 4312–4315
the reaction of 1a with 1.05 equiv of 7a20 in EtOAc for 1 h, 2 equiv
of benzylamine was directly added to the reaction mixture. The
desired ring-opening cyclization reaction proceeded smoothly at
room temperature to afford 4a in 80% yield from 1a.
In conclusion, we have developed an efficient procedure for
the synthesis of cyclohexane-1,3-dione-2-spirocyclopropanes
from 1,3-cyclohexanediones using sulfonium salts. The reaction
of 1,3-cyclohexanediones with (1-aryl-2-bromoethyl)-dimethyl-
sulfonium bromides and powdered K2CO3 in EtOAc provided the
corresponding spirocyclopropanes in high yields. This method
was applicable to 1,3-cyclopentanedione, 1,3-indanedione and
acyclic 1,3-diones, affording the corresponding cyclopropanes in
high yields. In addition, a one-pot synthesis of tetrahydroindol-
4(5H)-one from 1,3-cyclohexanedione was achieved by exploiting
the present protocol and a sequential ring-opening cyclization of
spirocyclopropane with benzylamine. Further application of a
one-pot reaction to the synthesis of biologically active indole
alkaloids is currently in progress.
Scheme 3. Reactions of 1,3-cyclopentanedione (8) and 1,3-indanedione (10) with
sulfonium salt 7a.
in 83% yield (determined by 1H NMR analysis).15,16 The use of 1,3-
indanedione (10) as an active methylene compound afforded spiro-
cyclopropane 1117 in 85% yield. Thus, the present protocol can be
applied to the synthesis of spiro[2.4]heptane compounds.
Supplementary data
To expand the scope of the present protocol, we then examined
the reaction with acyclic 1,3-diones (Scheme 4). The reaction of
sulfonium salts 7a and 7b with 2 equiv of 2,4-pentanedione (12)
using powdered K2CO3 in EtOAc provided the corresponding dou-
bly activated cyclopropanes 13a9 and 13b18 in 80% and 88% yields,
respectively. The use of 1,3-diphenyl-1,3-propanedione (14) as an
acyclic 1,3-dione afforded cyclopropane 15 in 85% yield.19 Since
the yields of 13a and 15 were higher than those reported in the
literatures,9,19 these results clearly demonstrate that the combina-
tion of powdered K2CO3 as a base and EtOAc as a solvent is also
effective for the reaction with acyclic 1,3-diones.
Finally, we investigated a one-pot conversion from 1,3-cyclo-
hexanedione (1a) to tetrahydroindol-4(5H)-one 4a (Scheme 5). In
our previously reported ring-opening cyclization reaction of spiro-
cyclopropane with a primary amine (Scheme 1), obvious solvent
effects were not observed.3 The reactions were almost the same
in CH2Cl2, CH3CN, THF, and toluene. These observations indicate
that EtOAc would be usable in this ring-opening cyclization. After
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
069.
References and notes
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Scheme 4. Reactions of sulfonium salts 7a and 7b with acyclic 1,3-diones 12 and
14.
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Ferri, M.; Bernardinelli, G. ARKIVOC 2003, vii, 80.
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Scheme 5. One-pot synthesis of tetrahydroindol-4(5H)-one 4a from 1a.

H. Nambu et al. / Tetrahedron Letters 56 (2015) 4312–4315
4315
Matlock, J. V.; Fritz, S. P.; Harrison, S. A.; Coe, D. M.; McGarrigle, E. M.;
Aggarwal, V. K. J. Org. Chem. 2014, 79, 10226.
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10. Lu and co-workers reported that the reaction of b-(trifluoromethyl)vinyl
diphenylsulfonium salt with 1,3-cyclohexanedione (1a) in the presence of DBU
in DMSO gave 1-trifluoromethylspiro[2.5]octane-4,8-dione in 22% yield. Lin,
H.; Shen, Q.; Lu, L. J. Org. Chem. 2011, 76, 7359.
11. Typical procedure for the synthesis of cyclohexane-1,3-dione-2-spirocyclopropanes
3 with sulfonium salts 7: 1-Phenylspiro[2.5]octane-4,8-dione (3a) (Table 1,
entry 11). Powdered K2CO3 (207 mg, 1.5 mmol) and 1,3-cyclohexanedione (1a)
14. The crude products of 3c and 3f were purified by recrystallizations due to the
instability of 3c and 3f on silica gel.
15. Determined by 1H NMR analysis of the crude reaction mixture using 1,3,5-
trimethoxybenzene as the internal standard.
16. The product 9 was obtained in 54% isolated yield. The crude product of 9 was
purified by column chromatography on silica gel despite the instability of 9 on
silica gel, because it is very difficult to isolate 9 by recrystallization.
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(56 mg, 0.5 mmol) were added to
a
suspension of (2-bromo-1-
19. Very recently, Feng and Liu reported that the reaction of sulfonium salts 7a
with 1.2 equiv of 1,3-diphenyl-1,3-propanedione (14) using 3 equiv of K2CO3 in
CH2Cl2/H2O (1:1) provided the corresponding doubly activated cyclopropane
15 in 68% yield. Xia, Y.; Liu, X.; Zheng, H.; Lin, L.; Feng, X. Angew. Chem. Int. Ed.
2015, 54, 227.
20. A slightly excess amount (1.05 equiv) of 7a was used in the one-pot reaction,
because sulfonium salts react with primary amines to give aziridines. See Ref.
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Chem. Lett. 2003, 32, 392; (b) Yamanaka, H.; Matsuo, J.; Kawana, A.;
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Shiosaki, M.; Azema, T.; Hanamoto, T. Org. Lett. 2010, 12, 2548.
phenylethyl)dimethylsulfonium bromide (7a) (245 mg, 0.75 mmol) in EtOAc
(5 mL). After stirring at room temperature for 1 h, the reaction mixture was
filtered through a Celite pad and the filter cake was rinsed with EtOAc (30 mL).
Combined filtrates were washed with water (10 mL) and the aqueous layer was
extracted with EtOAc (10 mL Â 2). The combined organic layer was washed
with brine (10 mL) and dried over anhydrous MgSO4. The filtrate was
concentrated in vacuo, and the crude product was purified by column
chromatography (silica gel, 25% EtOAc in hexane) to provide 3a (98 mg, 92%)
as a white solid.
12. Chow, Y. L.; Bakker, B. H. Synthesis 1982, 648.
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