Cyclization of alk-5-ynyl ketones promoted by Tf2NH and In(OTf)3: selective synthesis of 5- and 7-membered carbocycles

Article abstract of DOI:10.1016/j.tetlet.2016.10.003

Combined use of Tf₂NH and In(OTf)₃effectively promotes the cyclization of alk-5-ynyl ketones to cyclopent-1-enyl ketones at 30?°C. Single use of Tf₂NH or In(OTf)₃requires heating at 50?°C for efficient cyclizati

Full text of DOI:10.1016/j.tetlet.2016.10.003

Accepted Manuscript
Cyclization of alk-5-ynyl ketones promoted by Tf2NH and In(OTf)3: selective
synthesis of 5- and 7-membered carbocycles
Hidenori Kinoshita, Chika Miyama, Katsukiyo Miura
PII:
S0040-4039(16)31297-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.003
TETL 48173
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
30 August 2016
26 September 2016
3 October 2016
Please cite this article as: Kinoshita, H., Miyama, C., Miura, K., Cyclization of alk-5-ynyl ketones promoted by
Tf2NH and In(OTf)3: selective synthesis of 5- and 7-membered carbocycles, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.10.003
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Graphical Abstract
Cyclization of alk-5-ynyl ketones promoted
by Tf2NH and In(OTf)3: selective synthesis of
5- and 7-membered carbocycles
Hidenori Kinoshita, Chika Miyama, and Katsukiyo Miura*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Cyclization of alk-5-ynyl ketones promoted by Tf2NH and In(OTf)3: selective
synthesis of 5- and 7-membered carbocycles
Hidenori Kinoshita, Chika Miyama, and Katsukiyo Miura∗
Department of Applied Chemistry, Graduate School of Science and Engineering, Saitama University, 255 Shimo-ohkubo, Sakura-ku, Saitama 338-8570, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Combined use of Tf2NH and In(OTf)3 effectively promotes the cyclization of alk-5-ynyl ketones
to cyclopent-1-enyl ketones at 30 °C. Single use of Tf2NH or In(OTf)3 requires heating at 50 °C
for efficient cyclization. The In(OTf)3–promoted reaction of certain alk-5-ynyl ketones gives
cyclohept-2-enones mainly.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Conia-ene reaction
Cyclization
Lewis acid
Brønsted acid
Intramolecular addition of enolizable carbons to alkenes and
alkynes is valuable for the synthesis of functionalized
carbocycles.1 The original reaction developed by Conia and
coworkers, known as the Conia-ene reaction, requires extended
heating at 300-400 °C.2 Since the pioneering work, much effort
has been devoted to improving the harsh reaction conditions.
Some Lewis acids and transition metal catalysts have been found
to effectively promote the conversion of α-alkynyl-β-ketoesters
and alkynylmalonates into the corresponding Conia-ene products
at lower temperatures (Scheme 1).3,4 However, in most cases, the
known methods for the Conia-ene cyclization are not applicable
to less enolizable alkynyl ketones not bearing another electron-
withdrawing group at the enolizable carbon.5 We herein report
that the use of Tf2NH and/or In(OTf)3 enables the cyclization of
the less enolizable substrates. Double catalysis by a Brønsted
acid and a mercury salt is known to be effective in the Conia-ene
reaction of simple alkynyl ketones.6 Gold Lewis acids can also be
used for this purpose.7 The present reaction systems are
characterized by no use of the toxic or expensive metal. In
addition, we disclose a novel cyclization of certain alkynyl
ketones to 7-membered carbocycles with In(OTf)3.
Nakamura and coworkers have recently disclosed that In(OTf)3
and In(NTf2)3 are effective in the Conia-ene reaction of α-
alkynyl-β-ketoesters.4 We therefore selected these indium salts as
promoters, and initially examined the cyclization of alkynyl
ketone 1a (Table 1). The treatment of 1a with In(OTf)3 or
In(NTf2)3 (0.2 equiv) in CH2Cl2 (rt, 24 h) gave no desired
products (entries 1 and 2). Enolization of the ketone moiety
should be crucial in promoting the Conia-ene reaction of 1a. To
facilitate the enolization, we next attempted combined use of a
Brønsted acid with In(OTf)3 (entries 3-5). As a result, the
reaction using Tf2NH (1 equiv) and In(OTf)3 (0.2 equiv) gave the
cyclized product 2a in 60% yield. The formation of 2a is
probably due to acid-catalyzed isomerization of β,γ-unsaturated
ketone 2a'.9 Use of PhCF3 as solvent and elevated temperatures
improved the yield of 2a (entries 6-9). Detailed analysis of the
products obtained in entry 8 revealed the formation of cyclohept-
2-enone 3a. Tf2NH promoted the cyclization even in the absence
of In(OTf)3 although the use of In(OTf)3 increased the reaction
rate (entries 8 vs. 10). At 50 °C the Tf2NH-promoted reaction
gave 2a in a good yield (entry 11). Although the increased
temperature without In(OTf)3 gave a positive effect in this case,
the reaction conditions using In(OTf)3 at 30 °C (entry 8) were
effective in suppression of side reactions and superior for
efficient cyclization in other cases (vide infra). When 1a was
treated with only In(OTf)3 (0.2 equiv) in PhCF3 at 50 °C, 2a and
3a were obtained in 52% and 16% yields, respectively (entry 12).
Scheme 1. Conia-ene reaction
Our research interest has been focused on the development of
new synthetic methods utilizing In(III) catalysis.8 In addition,
———
∗ Corresponding author. Tel.: +81-48-858-3514; fax: +81-48-858-3516; e-mail: kmiura@apc.saitama-u.ac.jp

2
Tetrahedron
Table 1. Cyclization of alkynyl ketone 1a.a
Table 2. Cyclization of several alkynyl ketones.a
entry substrate, methoda
product, isolated yield (%)
temp
isolated yield
entry
X in InX3
acid
solvent
(ºC)
rt
(%)
0
1
2
3
method A
method B
method C
85
60
65
4
4
1
2
OTf
NTf2
OTf
OTf
OTf
OTf
NTf2
OTf
OTf
none
none
OTf
none
none
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
rt
0
14
3
CF3CO2H
TfOH
rt
0
4
rt
48
5
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
Tf2NH
none
rt
60
6
rt
67
7
rt
65
8
30
50
30
50
50
74, 2b
77
4
5
6
method A
method B
method C
84
9
91
14b
10
11
55, 23c
74
12
52, 16b
a
Conditions: 1a (0.50 mmol), InX3 (0.10 mmol), an acid (0.50 mmol),
solvent (2.5 mL). b Yield of 3a. c Recovery of 1a.
7
8
9
method A
method B
method C
52
40
52, 80c
37
0, 0c
42
The scope of the present Conia-ene reaction was next
investigated (Table 2). Alkynyl ketone 1b derived from dimethyl
malonate was smoothly cyclized to cyclopentenyl ketone 2b in
the presence of Tf2NH and In(OTf)3, at 30 °C (method A, entry
1). As in the case of 1a, 7-membered carbocycle 3b was
obtained. The Tf2NH-promoted reaction at 50 °C (method B)
dropped the yield of 2b by unidentified side reactions (entry 2).
Under catalysis by In(OTf)3 at 50 °C (method C), the cyclization
of 1b to 2b became less efficient by competition with the
formation of 3b (entry 3). Dimethyl-substituted alkynyl ketone
1c was efficiently converted into 2c by either method A or B
(entries 4 and 5). The corresponding 7-membered product 3c was
not obtained even by method C (entry 6). The reaction of methyl
ketone 1d by method A formed the desired product 2d with a
considerable amount of 3d (entry 7). No formation of 3d was
observed by method B (entry 8). The yield of 2d, however,
remained moderate due to side reactions. When the treatment of
1d was conducted with a twofold amount of Tf2NH at 30 °C, the
cyclization to 2d proceeded efficiently. On the other hand, 3d
was the main product in the reaction of 1d by method C (entry 9).
The reaction of 1e gave a mixture of 2e and its regioisomer 2e'
(entries 10 and 11). The application of method B achieved a good
combined yield with selective formation of 2e. The cyclization of
1f, bearing an internal C-C triple bond, competed with complex
side reactions, and resulted in low to moderate yields of 2f
(entries 12 and 13). Interestingly, the reaction of 1g, bearing a
phenyl group at the sp-carbon, gave 1,2-dihydro-3H-fluorene 4
mainly (entries 14-16). o-Phenylene-tethered alkynyl ketone 1h
showed high reactivity, and method C worked well for the
cyclization of 1h to 2h (entries 17-19).10
10
11
method A
method B
28
68
35
18
12
13
method A
method B
37
51
14
15
16
method A
method B
method C
67
41
52, 88%d

3
17
18
19
method A
method B
method C
68, 82e
54
achieved complete conversion of 1d (entry 2). The cyclization
was effectively accelerated by adding 1 equiv of MeOH and the
ratio of 3d was further improved (entry 3). To our surprise, the
use of 2 equiv of MeOH preferred the formation of 2d (entry 4).
The reactions using 0.2-0.5 equiv of MeOH succeeded in
efficient synthesis of 3d (entries 5 and 6). At 10 °C the selectivity
toward 3d increased; however, the reaction rate rather decreased
(entry 7).
90, 93f
a Conditions: 1 (0.50 mmol), PhCF3 (2.5 mL), 24 h. Method A: In(OTf)3
(0.10 mmol), Tf2NH (0.50 mmol), 30 °C. Method B: Tf2NH (0.50 mmol), 50
b
°C. Method C: In(OTf)3 (0.10 mmol), 50 °C. Determined by 1H NMR
c
analysis of the crude product. The substrate 1c was recovered in 52% yield.
Tf2NH (1.00 mmol), 30 °C, 48 h. d 80 °C, 48 h. e 3 h. f 80 °C.
Table 3. Cyclization of alkynyl ketone 1d.a
The cyclization of 1a using both Tf2NH and In(OTf)3 was
faster than that using either Tf2NH or In(OTf)3 under the same
conditions (Table 1). This fact suggests that the reaction
mechanism involves cooperative, simultaneous activation of both
the enolizable carbon and the C-C triple bond by the Brønsted
and Lewis acids (Scheme 2).11 Since these promoters can activate
either reaction site, their correct roles in the cyclization by
method A would be difficult to determine. The enolizable carbon
is possibly activated by proton- or In(OTf)3-promoted enolization
to 5a or 5a' (M = H) or by the formation of indium enolate 5a or
5a' (M = In(OTf)2).4b The activation of the C-C triple bond is
likely due to coordination to In(OTf)3 (5a)8c or the subsequent
formation of zuwitterionic species 5a'.12 Alternatively,
protonation forming alkenyl cation 5a'-H is possible for the
alkyne activation.13
entry
MeOH
(equiv)
0
temp
(°C)
30
time
(h)
24
72
12
12
24
24
24
isolated yield (%)
2d
23
28
27
65
26
25
9
3d
52b
64
71
34
73
75
58b
1
2
3
4
5
6
7
0
30
1.0
30
2.0
30
0.5
30
0.2
30
0.2
10
a Conditions: 1d (0.50 mmol), In(OTf)3 (0.50 mmol), and PhCF3 (2.5 mL).
b Recovery of 1d: 18% (entry 1) and 32% (entry 7).
When alk-5-ynyl methyl ketone 1i was treated with In(OTf)3
(1 equiv) and MeOH (0.5 equiv) in PhCF3, cyclohept-2-enone 3i
was obtained in a moderate yield (Scheme 4). The formation of
cyclohept-3-enone 3i' and cyclopetene 2i was also observed.
With 0.2 equiv of MeOH, the yield of 3i dropped to 46%.
Scheme 2. Possible mechanism for cyclization of 1a
The formation of an unexpected product 4 from 1g can be
explained as follows (Scheme 3). First, upon the action of Tf2NH
or In(OTf)3, intermediate 5g or 5g' was formed, and the sp-
carbon bearing a phenyl group becomes more electrophilic by its
cation-stabilizing effect.12 Then the enolic carbon adds to the
electrophilic carbon to form ketone 6. The acid-catalyzed
intramolecular Friedel-Crafts reaction of
dehydration gives 4.
6 followed by
Scheme 4. In(OTf)3-promoted cyclization of 1i
The cyclization to 3 is an intramolecular metathesis-type
reaction between alkynes and carbonyls.7,8a,14
A possible
mechanism involves nucleophilic addition of the terminal sp-
carbon to the ketone carbonyl by the aid of In(OTf)3 (Scheme 5).
MeOH serves for trapping the resultant zuwitterionic
intermediate 7 to prevent the inverse reaction. The 1,3-
rearrangement of intermediate 8 followed by elimination of
MeOH forms the 7-membered carbocycle.15 The need for an
equimolar amount of In(OTf)3 may be due to its deactivation by
coordination of the product.
Scheme 3. Possible mechanism for cyclization of 1g
As shown in entry 9 of Table 2, the In(OTf)3-promoted
cyclization of 1d provided 7-membered carbocycle 3d mainly.
This intriguing result induced us to explore new reaction
conditions toward more selective formation of 3d. When the
reaction of 1d was conducted with 1 equiv of In(OTf)3 at 30 °C
for 24 h, the ratio of 3d to 2d was improved but with 18%
recovery of 1d (Table 3, entry 1). Elongation of the reaction time

4
Tetrahedron
Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 9140. (q)
Li, W.; Liu, X.-Z.; Zhou, X.-F.; Lee, C.-S. Org. Lett. 2010, 12,
548.
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i.; Itoh, Y.; Endo, K.; Nakamura, M.; Nakamura, E. Angew.
Chem., Int. Ed. 2007, 46, 5350. (b) Itoh, Y.; Tsuji, H.; Yamagata,
K.-i.; Endo, K.; Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am.
Chem. Soc. 2008, 130, 17161. (c) Takahashi, K.; Midori, M.;
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2008, 47, 6244.
5. Recently, the Conia-ene reactions of alkynals have been achieved
successfully by using a secondary amine and a π-Lewis acid. (a)
Binder, J. T.; Crone, B.; Haug, T. T.; Menz, H.; Kirsch, S. F. Org.
Lett. 2008, 10, 1025. (b) Montaignac, B.; Vitale, M. R.; Michelet,
V.; Ratovelomanana-Vidal, V. Org. Lett. 2010, 12, 2582 and
references therein.
Scheme 5. Possible mechanism for cyclization of 1d to 3d
In conclusion, we have developed new methods for the Conia-
ene reaction of alkynyl ketones. The existing methods using
Lewis acids and metal catalysts are applicable to easily
enolizable carbonyls such as β-ketoesters. In contrast, the present
methods using Tf2NH and In(OTf)3 enable the Conia-ene
cyclization of less enolizable alkynyl ketones at relatively low
temperatures. This study has enhanced synthetic utility of the
Conia-ene reaction for carbocycle construction. In addition, we
have succeeded in finding a novel type of carbocyclization useful
for the construction of cyclohept-2-enones. Application of the
present methods to the synthesis of other carbocycles is now
under further investigation.
6. Boaventura, M. A.; Drouin, J.; Conia, J. M. Synthesis 1983, 801.
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2006, 1883.
9. Indeed, 2a' was quantitatively isomerized to 2a in the presence of
Tf2NH and In(OTf)3.
10. The cyclization of 1-phenylhept-6-yn-1-one by method A resulted
in failure. The Thorpe-Ingold effect (gem-dimethyl effect) seems
crucial for the present cyclization. For the Thorpe-Ingold effect,
see: Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735.
11. As a related reaction, Baba and coworkers have reported the
InBr3-promoted addition of silyl enolates to alkynes in an anti
fashion. Nishimoto, Y.; Takeuchi, M.; Yasuda, M.; Baba, A.
Angew. Chem., Int. Ed. 2012, 51, 1051.
References and notes
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Tsuchimoto, T.; Maeda, T.; Shirakawa, E.; Kawakami, Y. Chem.
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Shirakawa, E.; Kawakami, Y. Synlett 2000, 1777.
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15. To the best of our knowledge, the indium-promoted 1,3-migration
of an allylic hydroxy group is not known. However, Baba and
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Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at http://xxxxxxxxxxxxxxxxxxxxxxxxxxxx.

5
Highlights:
• In(OTf)3 and Tf2NH cooperatively promote the
Conia-ene cyclization.
• Less enolizable alk-5-ynyl ketones can be
cyclized to cyclopent-1-enyl ketones.
• In(OTf)3 promotes the cyclization of alk-5-ynyl
ketones to cyclohept-2-enones