Iodide-Catalyzed Ring-Opening Cyclization of Cyclohexane-1,3-dione-2-spirocyclopropanes

Article abstract of DOI:10.1002/adsc.201800551

The ring-opening cyclization of 2′,3′-nonsubstituted and 2′-electron-withdrawing group (EWG)-substituted cyclohexane-1,3-dione-2-spirocyclopropanes was accomplished using iodide as a catalyst. The nonsubstituted derivatives afforded 3,5,6,7-tetrahydro-1-benzofuran-4(2H)-ones in high yields in the presence of trimethylsilyl iodide at room temperature. The EWG-substituted spirocyclopropanes, in turn, underwent regioselective ring opening followed by cyclization, which gave rise to 2-substituted tetrahydrobenzofuran-4-ones when a combination of tetrabutylammonium iodide catalyst and trifluoromethanesulfonic acid was used, whereas calcium iodide afforded the 3-substituted derivatives. (Figure presented.).

Full text of DOI:10.1002/adsc.201800551

Title: Iodide-Catalyzed Ring-Opening Cyclization of Cyclohexane-1,3-
dione-2-spirocyclopropanes
Authors: Hisanori Nambu, Yuta Onuki, Naoki Ono, and Takayuki
Yakura
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Advanced Synthesis & Catalysis
10.1002/adsc.201800551
Very Important Publication
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iodide-Catalyzed Ring-Opening Cyclization of Cyclohexane-
,3-dione-2-spirocyclopropanes
1
a,
a
a
a,
Hisanori Nambu, * Yuta Onuki, Naoki Ono, and Takayuki Yakura, *
a
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama 930-0194, Japan
Fax: (+81)-76-434-5053; phone: (+81)-76-434-7555, 7556
E-mail: nambu@pha.u-toyama.ac.jp, yakura@pha.u-toyama.ac.jp
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The ring-opening cyclization of 2',3'- spirocyclopropanes 3 and 5 to find that the presence
nonsubstituted and 2'-electron-withdrawing group (EWG)- of an iodide ion was crucial for the ring-opening
substituted cyclohexane-1,3-dione-2-spirocyclopropanes cyclization. Consequently, we herein report the
was accomplished using iodide as a catalyst. The iodide-catalyzed ring-opening cyclization of 2',3'-
nonsubstituted derivatives afforded 3,5,6,7-tetrahydro-1- nonsubstituted and 2'-EWG-substituted cyclohexane-
benzofuran-4(2H)-ones in high yields in the presence of
trimethylsilyl iodide at room temperature. The EWG-
substituted spirocyclopropanes, in turn, underwent
regioselective ring opening followed by cyclization,
which gave rise to 2-substituted tetrahydrobenzofuran-4-
ones when a combination of tetrabutylammonium iodide
catalyst and trifluoromethanesulfonic acid was used,
whereas calcium iodide afforded the 3-substituted
derivatives.
1
,3-dione-2-spirocyclopropanes 3 and 5 (Scheme 1,
B).
Keywords: iodide catalysts; cyclopropanes; ring opening;
cyclization; benzofurans
Doubly activated cyclopropanes are known to be
versatile synthetic intermediates for the synthesis of a
wide variety of carbo- and heterocyclic
compounds.[ In this context, we recently reported
the ring-opening cyclization of cyclohexane-1,3-
dione-2-spirocyclopropanes for the construction of
1,2]
indole[ and benzofuran skeletons. In the case of
the benzofuran derivatives, we disclosed that the
acid-catalyzed ring-opening cyclization of 2'-aryl-
3]
[4]
substituted
spirocyclopropanes
tetrahydro-1-benzofuran-4(2H)-ones
cyclohexane-1,3-dione-2-
afforded 2-aryl-3,5,6,7-
1
2
in
a
regioselective manner in excellent yields (Scheme 1,
A).[ Both Brønsted and Lewis acids, such as p-
4]
toluenesulfonic acid monohydrate (TsOHH
boron trifluoride (BF OEt ), trimethylsilyl
trifluoromethanesulfonate (TMSOTf), and
scandium(III) trifluoromethanesulfonate [Sc(OTf) ],
2
O),
3
2
3
proved to be effective activators for the reaction. The
reaction was proposed to proceed through a stable
benzylic carbocation intermediate, which provided
excellent regioselectivity. As a logical extension of
this catalytic process, we investigated the ring-
opening cyclization of a variety of nonsubstituted and
Scheme 1. Ring-opening cyclization of a variety of
cyclohexane-1,3-dione-2-spirocyclopropanes 1, 3 and 5.
Initially, we examined the ring-opening cyclization
of 2',3'-nonsubstituted cyclohexane-1,3-dione-2-
electron-withdrawing
group
(EWG)-substituted
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201800551
spirocyclopropane 3a[5] (Table 1). The reaction with
by the nucleophilic attack of the iodide ion on the
cyclopropane intermediate A to provide the alkyl
iodide intermediate B. Cyclization of B would, then,
occur rapidly to form tetrahydrobenzofuran-4-one 4,
with the concomitant regeneration of TMSI. It is
worth noting that the iodide ion would serve as a
good nucleophile to open the cyclopropane and as a
good leaving group to prompt the cyclization that
0
.1 equiv of Brønsted or Lewis acids such as
TsOHH O, trifluoromethanesulfonic acid (TfOH),
TMSOTf, or BF OEt in CH Cl at room temperature
hardly progressed even after 24 h (entries 1–4).
2
3
2
2
2
[6]
Therefore, the use of activators was investigated.
The reaction of 3a with a catalytic amount of MgI
2
proceeded smoothly at room temperature, giving
[11]
3
5
,5,6,7-tetrahydro-1-benzofuran-4(2H)-one 4a within
leads to the dihydrofuran.
.5 h in 79% yield (entry 5). In contrast, the reaction
with MgBr
2
required significantly longer times (10 h)
Table 2. TMSI-catalyzed ring-opening cyclization of
various spirocyclopropanes 1a, 3a–c, and 8.
to achieve completion and provided 4a in 75% yield
entry 6), indicating that the iodide ion is a more
(
effective activator of the present reaction than its
bromide counterpart is. Then, after screening various
activators, trimethylsilyl iodide (TMSI) was
established as the most effective activator for this
[7]
reaction, affording 4a in 96% yield (entry 7).
Time
(h)
Yield
Entry Substrate
1
Product
[a]
Table 1. Ring-opening cyclization of 2',3'-nonsubstituted
spirocyclopropane 3a.
(%)
2.5
96
(trace)
]
b]
]b]
(
24)
Entry Activator
Time (h)
Yield (%)[a]
trace
7
4
7
79
75
96
2
3
4
5
3
82
90
84
1
2
3
4
5
6
7
TsOHH
2
O
24
24
24
24
5.5
10
2.5
TfOH
TMSOTf
BF OEt
MgI
3
2
2
MgBr
TMSI
2
3.5
1.5
[
a]
Isolated yield.
With the optimal activator in hand, we investigated
the reactions of a range of spirocyclopropanes (Table
). The reaction of 2',3'-nonsubstituted
24)]b]
]b]
]b]
(
(72)
2
spirocyclopropanes 3b and 3c provided the
corresponding tetrahydrobenzofuran-4-ones 4b and
4
c in 82% and 90% yields, respectively (entries 2 and
[8]
3
). TMSI was also effective for the reaction of
0.5
(1)
98
(98)
]
b]
alkyl- and aryl-substituted spirocyclopropanes 8 and
1
a. Thus, the reaction of n-butyl-substituted
spirocyclopropane 8 under the same conditions (0.1
[
[
a]
b]
Isolated yield.
equiv of TMSI in CH
2
Cl at room temperature)
2
TsOHH
2
O (0.1 equiv) instead of TMSI was used as an
proceeded smoothly to completion within 1.5 h,
[
4]
activator.
affording the corresponding product 9 in 84% yield
(
entry 4). To provide comparison, the result of the
TsOH-catalyzed version has been included in the
table; in this case 9 was obtained in 72% yield after
4 h. Finally, the reaction of 1a[ finished within 0.5
9]
2
[
10]
h to give 2a in 98% yield (entry 5).
A plausible mechanism for the TMSI-catalyzed
ring-opening cyclization of 2',3'-nonsubstituted
spirocyclopropane 3 is shown in Scheme 2.
Accordingly, spirocyclopropane 3 would be activated
by silylation on the carbonyl oxygen atom with TMSI,
resulting in the cleavage of the cyclopropane moiety
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201800551
investigated the iodide-catalyzed reactions of 5a
(
entries 3–5). The reaction with TMSI afforded 6a
and 7a in 87% yield after 7.5 h. The regioselectivity
was the same as that of the reaction with TfOH;
however, 7a was obtained as the major product with
lower selectivity (6a:7a = 25:75, entry 3). On the
other hand, the use of MgI
the reaction strongly, affording products 6a and 7a in
0% yield after 4 h with poor regioselectivity that
2
was found to accelerate
9
followed the opposite trend (6a:7a = 59:41, entry 4).
In the case of the reaction of 5a with
tetrabutylammonium iodide (TBAI), the reaction
required 24 h to give a 46:54 mixture of 6a and 7a
Scheme 2. Plausible mechanism for 2',3'-nonsubstituted
spirocyclopropanes 3.
(
entry 5). This longer reaction time most likely stems
from the lower Lewis acidity of TBAI compared to
that of TMSI and MgI . We investigated a
combination of an iodide catalyst and a strong acid to
2
Next, we turned our attention to the ring-opening
[12]
obtain good yield and regioselectivity.
When 5a
cyclization
of
2'-EWG-substituted
was reacted with 0.2 equiv of TBAI and 1.0 equiv of
spirocyclopropanes (Table 3). The acid-induced
reactions of 2'-methoxycarbonyl-substituted
TfOH, a 20:80 mixture of 6a and 7a was produced in
8
7% yield after 22 h (entry 6). Increasing the TBAI
cyclohexane-1,3-dione-2-spirocyclopropane 5a were
first examined. The reaction of 5a with 1.0 equiv of
amount to 1.0 equiv was found to enhance the
reaction rate; however, decrease in the
regioselectivity was observed (6a:7a = 27:73, entry
). In contrast, the addition of 2.0 equiv of TfOH
a
TsOHH
2
O in CH
2
Cl at room temperature did not
2
proceed at all (entry 1). In contrast, a stronger
Brønsted acid, TfOH, provided a mixture of 2- and 3-
methoxycarbonyl-substituted tetrahydrobenzofuran-
7
resulted in an acceleration of the reaction (12 h) and
an improvement of the regioselectivity (6a:7a = 6:94,
entry 8). When 3.0 equiv of TfOH was used, the 3-
isomer 7a was obtained with the highest yield and
selectivity (87% yield, 6a:7a = 4:96, entry 9). Further
addition of TfOH (a total of 3.5 equiv) led to a
decrease in the yield (entry 10).
4
-ones 6a and 7a in 49% combined yield after 24 h
entry 2). Interestingly, this reaction showed the
opposite regioselectivity to that of the acid-catalyzed
(
[4]
reaction of 2'-aryl-substituted spirocyclopropane 1
and gave 3-substituted tetrahydrobenzofuran-4-one
a as the major product (6a:7a = 10:90). Next, we
7
Table 3. Ring-opening cyclization of 2'-methoxycarbonyl-substituted cyclohexane-1,3-dione-2-spirocyclopropane 5a.
Entry Activator (equiv)
Solvent
Temp.
Time (h)
Yield (%)[a]
6a:7a[b]
1
2
3
4
5
6
7
8
9
0
TsOHH
TfOH (1.0)
TMSI (0.2)
2
O (1.0)
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
24
7.5
4
24
22
1.5
12
4
No reaction
49
87
90
85
87
85
87
87
82
92
82
95
95
8
10:90
25:75
59:41
46:54
20:80
27:73
6:94
MgI
2
(0.2)
TBAI (0.2)
TBAI (0.2) + TfOH (1.0)
TBAI (1.0) + TfOH (1.0)
TBAI (0.2) + TfOH (2.0)
TBAI (0.2) + TfOH (3.0)
TBAI (0.2) + TfOH (3.5)
CH
CH
2
Cl
Cl
2
4:96
4:96
1
1
2
2
2
1
MgI
MgI
MgI
2
2
2
(0.2)
(0.2)
(0.2)
EtOAc
DMF
THF
THF
THF
THF
THF
THF
THF
0.5
12
0.5
0.5
24
0.5
0.5
0.5
1.5
73:27
77:23
83:17
70:30
50:50
93:7
96:4
97:3
96:4
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
9
BaI
ZnI
CaI
CaI
2
2
2
2
2H
2
O (0.2)
(0.2)
(0.2)
(0.1)
(0.1)
(0.05)
91
97
95
92
CaI
CaI
2
0 °C
0 °C
2
[
a]
Combined yield of 6a and 7a.
[
b]
1
Determined by H NMR analysis of the crude product.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201800551
Once the regioselective formation of the 3-isomer
a was accomplished, we tackled the optimization of
intermediate C, which would trigger the
regioselective cleavage of the cyclopropane to
provide an alkyl iodide intermediate D. The
subsequent cyclization of D would proceed smoothly
to form the 3-substituted product 7, along with the
release of the iodide ion. In contrast, the reaction of
2'-carbonyl group-substituted spirocyclopropanes 5,
such as ester and ketone, under condition B (cat.
7
[13]
the conditions for the synthesis of the 2-isomer 6a.
Since MgI
2
had been shown to favor the formation of
6
a over 7a (entry 4), we examined a series of solvents
with MgI
2
and found that tetrahydrofuran (THF) gave
the best results for the selective formation of the 2-
isomer 6a (6a:7a = 83:17, entry 13 vs entries 4, 11,
and 12). After screening of other iodides such as
CaI
2
) would generate a seven-membered ring
BaI
2
2H
2
O, ZnI
2
, and CaI
2
(entries 14–16), CaI was
2
intermediate E formed by the bidentate chelation of
found to be the most effective catalyst for the
the two carbonyl oxygen atoms by CaI
intramolecular attack of the iodide ion of CaI
2
. The
on the
selective synthesis of the 2-isomer 6a (91% yield,
2
14]
6
a:7a = 93:7, entry 16).[ Furthermore, the optimal
carbon atom next to the substituted carbonyl group
would lead to the regioselective cleavage of the
cyclopropane to provide the -iodo carbonyl
compound F. Subsequently, cyclization of F would
occur, affording the 2-substituted product 6, with the
conditions were established as 0.1 equiv of CaI
2
at
0
°C of reaction temperature, which furnished the
combined product of 6a and 7a in 95% yield with
excellent regioselectivity (6a:7a = 97:3, entry 18 vs
entries 16, 17, and 19).
concomitant regeneration of CaI . On the other hand,
2
Having optimized the reaction conditions for the
selective formation of the 2- and 3-isomers, we then
addressed the reaction of a variety of 2'-EWG-
the reactions of cyano and trifluoromethyl-substituted
5g and 5h would take place without the formation of
the seven-membered ring intermediate, providing the
3-isomers 7 by the nucleophilic attack of an
substituted spirocyclopropanes
5
under either
conditions A or B (Table 4). The reaction of methyl
esters 5b and 5c under condition A (cat. TBAI and
intermolecular iodide ion from CaI on the less
2
hindered carbon atom in G. Again, according to the
proposed mechanism, the iodide ion would act in the
reaction of EWG-substituted spirocyclopropanes 5 as
a good nucleophile to open the cyclopropane and as a
good leaving group to trigger the cyclization that
TfOH in CH
2
Cl
2
at rt) provided 3-substituted
tetrahydrobenzofuran-4-ones 7b and 7c as major
products, respectively (entries 3 and 5), whereas the
reaction of 5b and 5c under condition B (cat. CaI in
2
[16]
THF at 0 °C) afforded the respective 2-substituted
ultimately affords the dihydrofuran.
products 6b and 6c as major products (entries 4 and
6
). Although tert-butyl ester 5d led to decomposition
under condition A (entry 7), the reaction of 5d under
condition B resulted in an excellent regioselectivity
(
8
6d:7d = 98:2), and the 2-isomer 6d was obtained in
1% yield (entry 8). Moreover, the reaction of methyl
and phenyl ketones 5e and 5f under condition A
furnished a 19:81 mixture of 2-isomers (6e and 6f)
and 3-isomers (7e and 7f) in 76% and 81% combined
yields, respectively (entries 9 and 11). On the other
hand, the 2-isomers 6e and 6f were obtained as sole
products in 93% and 91% yields from 5e and 5f,
respectively, under condition B (entries 10 and 12).
Unfortunately, nitrile 5g quickly decomposed under
condition A (entry 13). In surprising contrast, the
reaction of 5g under condition B provided 3-isomer
7
g as the major product (85% combined yield, 6g:7g
=
17:83, entry 14). Furthermore, trifluoromethyl-
[15]
substituted spirocyclopropane 5h
afforded the 3-
isomer 7h as a sole product under both conditions A
and B in 85% and 80% yields, respectively (entries
15 and 16). These results suggested that the presence
of a carbonyl group in the 2'-EWG substitution
strongly affects the regioselectivity.
Scheme 3. Plausible mechanism for EWG-substituted
spirocyclopropanes 5.
For the iodide-catalyzed ring-opening cyclization
of 2'-EWG-substituted spirocyclopropanes 5, we
envisaged the mechanism depicted in Scheme 3.
Under condition A (cat. TBAI and TfOH),
spirocyclopropane
5
would be activated by
protonation on the carbonyl oxygen atom with TfOH,
followed by the nucleophilic attack of the iodide ion
from TBAI on the less hindered carbon atom in
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201800551
Table 4. Ring-opening cyclization of 2'-EWG-substituted cyclohexane-1,3-dione-2-spirocyclopropane 5a–h.
Entry Substrate
Conditions Products
Time (h) Yield (%)[a] 6:7[b]
1
2
A
B
+
4
0.5
87
95
4:96
97:3
3
4
A
B
+
+
4
0.5
91
98
5:95
97:3
5[
6
c]
A
B
4
0.5
83
93
[d]
[d]
4:96
95:5
[
c]
7
8
A
B
+
+
+
+
+
0.5
0.5
Decomp.
81
[
e]
98:2
9
0
A[f]
B
0.3
0.5
76
93
19:81
100:0
1
1
1
1
2
A
B
1.5
0.5
81
91
19:81
100:0
1
1
3
4
A
0.5
2.5
Decomp.
85
[
g]
B
17:83
1
1
5
6
A
B
1
24
85
80
0:100
0:100
[
[
[
[
[
[
[
a]
Combined yield of 6 and 7.
Determined by H NMR analysis of the crude product.
A diastereomeric mixture (ca. 1:1) of starting material 5c was used.
The products 6c and 7c were isolated as a diastereomeric mixture (ca. 1:1).
Isolated yield of 6d.
b]
c]
d]
e]
f]
1
Performed at 0 °C.
Performed at room temperature.
g]
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201800551
In summary, we have developed an iodide-
catalyzed ring-opening cyclization of 2',3'-
nonsubstituted and 2'-EWG-substituted cyclohexane-
,3-dione-2-spirocyclopropanes. The reaction of
nonsubstituted spirocyclopropanes provided
column chromatography (silica gel, 80% EtOAc in
hexane) to provide a 97:3 mixture of 6a and 7a (37 mg,
9
5%).
1
Acknowledgements
tetrahydrobenzofuran-4-ones in high yields in the
presence of a catalytic amount of trimethylsilyl
iodide at room temperature. Moreover, the
regioselective ring-opening of 2'-carbonyl group-
This research was supported, in part, by a Grant-in-Aid for
Scientific Research (C) (Grant No. JP15K07853) from the Japan
Society for the Promotion of Science (JSPS) and JSPS Core-to-
Core Program, B. Asia-Africa Science Platforms.
substituted
spirocyclopropanes
followed
by
cyclization was achieved by using an iodide catalyst.
In this case, a combination of tetrabutylammonium
iodide catalyst and trifluoromethanesulfonic acid
afforded the 2-substituted products, whereas calcium
iodide gave the 3-substituted derivatives. Further
application of this method to the synthesis of a
variety of benzofuran and 2,3-dihydrobenzofuran
natural products is currently in progress.
References
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Experimental Section
Typical Procedure for the Ring-Opening Cyclization of
2
',3'-Nonsubstituted Spirocyclopropane 3a with TMSI
TMSI (4 mg, 0.020 mmol) was added to a solution of
spiro[2.5]octane-4,8-dione (3a) (28 mg, 0.20 mmol) in
2 2
CH Cl (1 mL) at room temperature. After stirring for 2.5
h, the reaction was quenched by addition of water (3 mL),
and the resulting mixture was extracted with EtOAc (3 x
1
0 mL). The combined organic layers were washed with
4
brine (10 mL) and dried over anhydrous MgSO . Filtration
2
015, 13, 655–671; k) B. L. Pagenkopf, N. Vemula,
and evaporation in vacuo furnished the crude product,
which was purified by column chromatography (silica gel,
6
Eur. J. Org. Chem. 2017, 2561–2567; l) E. M.
Budynina, K. L. Ivanov, I. D. Sorokin, M. Y.
Melnikov, Synthesis 2017, 49, 3035–3068; m) X. Liu,
H. Zheng, Y. Xia, L. Lin, X. Feng, Acc. Chem. Res.
2017, 50, 2621–2631.
0% EtOAc in hexane) to provide 4a (27 mg, 96%).
Typical Procedure for the Selective Synthesis of 3-
Substituted Tetrahydrobenzofuran-4-one 7a with a
Combination of TBAI Catalyst and TfOH (condition
A)
[
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2 2
added to a solution of TBAI (15 mg, 0.040 mmol) and
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8
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4
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8
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4
. Filtration and evaporation in vacuo
6
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Advanced Synthesis & Catalysis
10.1002/adsc.201800551
1
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[
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7
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Advanced Synthesis & Catalysis
10.1002/adsc.201800551
UPDATE
Iodide-Catalyzed Ring-Opening Cyclization of
Cyclohexane-1,3-dione-2-spirocyclopropanes
Adv. Synth. Catal. Year, Volume, Page – Page
a,
a
a
Hisanori Nambu, * Yuta Onuki, Naoki Ono, and
a,
Takayuki Yakura, *
8
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