trans-Cyclooctenes as Halolactonization Catalysts

Article abstract of DOI:10.1002/anie.201808320

The strained olefins in trans-cyclooctenes serve as efficient catalysts for halolactonizations, including bromolactonizations and iodolactonizations. The trans-cyclooctene framework is essential for excellent catalytic performance, and the substituents also play important roles in determining efficiency. These results are the first demonstration of catalysis by a trans-cyclooctene.

Full text of DOI:10.1002/anie.201808320

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: trans-Cyclooctenes as Halolactonization Catalysts
Authors: Shunsuke Einaru, Kenta Shitamichi, Tagui Nagano, Akira
Matsumoto, Keisuke Asano, and Seijiro Matsubara
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808320
Angew. Chem. 10.1002/ange.201808320
Link to VoR: http://dx.doi.org/10.1002/anie.201808320
http://dx.doi.org/10.1002/ange.201808320

10.1002/anie.201808320
Angewandte Chemie International Edition
COMMUNICATION
trans-Cyclooctenes as Halolactonization Catalysts
Shunsuke Einaru+, Kenta Shitamichi+, Tagui Nagano, Akira Matsumoto, Keisuke Asano,* and Seijiro
Matsubara*
Abstract: The strained olefins in trans-cyclooctenes serve as
efficient
catalysts
for
halolactonizations,
including
bromolactonizations and iodolactonizations.
The trans-
cyclooctene framework is essential for excellent catalytic
performance, and the substituents also play important roles in
determining efficiency.
These results represent the first
demonstration of catalysis by a trans-cyclooctene; hence, these
findings offer new functional-group-design entries for molecular
catalysts.
trans-Cycloalkenes have garnered considerable attention since the
discovery of their unique refractive indices and densities owing to their
strained structures.[1] Their structural features have been extensively
studied,[2] and their optically active forms, which are based on planar
chirality, have been isolated[3] and used as chiral synthetic
intermediates.[4] In addition, strained olefins exhibit high reactivities
and chemoselectivities in organic reactions such as inverse-electron-
demand Diels–Alder reactions, which are applicable to orthogonal
bioconjugation reactions.[5] However, to the best of our knowledge,
their catalytic behavior is unknown despite their potential as novel
molecular-catalyst platforms that result from their unique reactivities,
chemoselectivities, and fascinating chirality. In this context, we
envisaged that the soft Lewis basicities of olefins would be useful for
activating electrophilic halogenating reagents; the strained olefins of
trans-cyclooctenes would be more Lewis basic than normal olefins
(Figure 1). Herein, we describe the catalytic activities of trans-
cyclooctenes in halolactonization reactions. This study offers new
functional-group-design entries for catalysis, as olefins have hardly
been used in this manner.[6]
Figure 1. trans-Cyclooctenes as Lewis-base catalysts during electrophilic
halogenation.
This study was initiated by the synthesis of trans-cyclooctenes
bearing substituents[7] that are capable of tuning the steric and
electronic properties of the trans-cyclooctene core (Scheme 1).
Starting from cyclooctanone (1), alkylation with a Grignard reagent
followed by dehydration yielded the alkylated cis-cyclooctene 2a.
Subsequent epoxidation and ring opening with lithium
diphenylphosphide followed by oxidation gave the corresponding
phosphine oxide 4a. Finally, treatment with sodium hydride afforded
trans-cyclooctene 5a, on a gram-scale, in 21% overall yield. In order
to confirm the olefin geometry, platinum complex 6a was synthesized
in order to prepare a single crystal for X-ray analysis (Figure 2).[8] The
ORTEP drawing unambiguously identifies the alkene as the trans-
isomer. Analogues 5b–5d (Table 1) bearing other substituents were
also synthesized via the same synthetic route (see Supporting
Information for details).
[*]
S. Einaru,[+] K. Shitamichi,[+] T. Nagano, A. Matsumoto, Prof. Dr. K
Asano, Prof. Dr. Seijiro Matsubara
Department of Material Chemistry, Graduate School of Engineering
Kyoto University
Kyotodaigaku-katsura, Nishikyo, Kyoto 615-8510 (Japan)
E-mail: asano.keisuke.5w@kyoto-u.ac.jp
matsubara.seijiro.2e@kyoto-u.ac.jp
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Synthesis of trans-cyclooctene 5a.
This article is protected by copyright. All rights reserved.

10.1002/anie.201808320
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Catalytic performance of different alkenes in bromolactonization of
7a.[a]
Figure 2. Synthesis and ORTEP drawing of platinum complex 6a.
The catalytic performance of trans-cyclooctenes
5
was
subsequently investigated during halolactonizations that are facilitated
by catalytic amounts of Lewis bases.[9] Several alkenes (5a–5d, 2b,
and 10) were examined as catalysts for (E)-5-phenylpent-4-enoic acid
(7a) in the presence of N-bromoacetamide (NBA, 8) in CH2Cl2 at –
30 °C for 6–48 h (Table 1). While the reaction was slow in the absence
of any catalytic alkene or in the presence of 5a (Table 1, entries 1–4),
the use of the benzyl-bearing 5b promoted the reaction efficiently to
provide product 9a in 88% yield after 6 h (Table 1, entry 5). Reaction-
time investigations revealed that the yield in the reaction of 5b was
quantitative after 12 h (Table 1, entry 6), while the reaction in the
absence of the catalyst resulted in only 9% yield even after 48 h (Table
1, entry 2).[10] Moderate acceleration of the reaction was also observed
using 5a, which provided 9a in 71% yield after 48 h (Table 1, entry 4);
however, 5b was much more efficient than 5a. trans-Cyclooctenes 5c
and 5d bearing additional phenyl groups on the benzyl group afforded
lower yields than 5b (Table 1, entries 7 and 8). These results suggest
that trans-cyclooctenes have catalytic activities, and that their
substituents play roles that determine catalytic performance, which is
probably due to steric interactions. Moreover, cis-cyclooctene 2b and
acyclic trisubstituted alkene 10 were much less effective (Table 1,
entries 9 and 10). These results clearly indicate that the trans-
cyclooctene skeleton is responsible for catalytic efficiency during the
bromolactonization of 7a. In addition, the affect of acetamide (11),
which is generated from 8 during the course of the reaction, was also
investigated. The reaction was very slow in the presence of 11 instead
of the olefin catalyst (Table 1, entry 11); the use of 11 in combination
with 5a also resulted in a low yield (Table 1, entry 12). Hence, 11 was
revealed not to be involved as an active catalytic species.
Entry
1
Catalyst
None
None
5a
Time [h]
Yield [%][b]
6
3
2
48
6
9
3
2
4
5a
48
6
71
88
99
59
4
5
5b
6
5b
12
6
7
5c
8
5d
6
9
2b
6
1
10
11
12[c]
10
6
7
11
6
4
5a + 11
6
1
[a] Reactions were run using 7a (0.10 mmol), 8 (0.12 mmol), and the catalyst
(0.010 mmol) in CH2Cl2 (1.0 mL). [b] NMR yields. [c] Reaction was run
using 5a (0.010 mmol) and 11 (0.010 mmol).
This article is protected by copyright. All rights reserved.

10.1002/anie.201808320
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Bromolactonizations of 7.[a]
–30 °C under the conditions examined. In all cases, only the trans-
isomers of δ-valerolactones 9 were obtained. Moreover, the reaction of
(Z)-5-phenylpent-4-enoic acid (12) catalyzed by 5b afforded cis-δ-
valerolactone 13 along with γ-butyrolactone 13’, while trans-δ-
valerolactone 9a was not observed (Scheme 2). Hence, these reactions
were revealed to proceed stereospecifically, which implies the
intermediacy of putative cyclic bromiranium ions generated in situ
from substrates 7 and 12 during catalysis.[12] Furthermore, the
regioselectivity (13:13’) was affected by the Lewis-base catalysts; the
regioselectivity of the reaction using 5b was different from those
without catalyst; it was also different from those using triethylamine
and triphenylphosphine as Lewis-base catalysts. These results suggest
that 5b is also involved in the step of lactonization of the bromiranium
ion intermediates generated from the substrates.[9a]
Scheme 2. Bromolactonization of (Z)-5-phenylpent-4-enoic acid (12).
The effects of the amounts of 5a and 5b were next investigated
(Figure 3). In the case of 5b, the yield increased at catalyst loadings up
to 20 mol %; however, the yield decreased in the presence of more than
20 mol % of 5b. These results indicate that the olefin-to-olefin
transfers of bromiranium ions take place between two molecules of 5b
at higher concentrations of 5b, resulting in slower reactions.
Furthermore, 5a was less catalytically active than 5b over the entire
range of loadings, indicating that 5a is more likely to inactivate the
bromiranium ions by olefin-to-olefin transfer between trans-
cyclooctenes. Hence, the dramatic substituent effect of 5b observed in
Table 1 is attributed to the well-balanced bulkiness of the benzyl group
that inhibits unfavorable bimolecular association while maintaining the
approach of the substrate.
[a] Reactions were run using 7 (0.10 mmol), 8 (0.12 mmol), and 5b (0.010
mmol) in CH2Cl2 (1.0 mL). [b] 7b was recovered in 31% yield. [c] Reaction
was run on a 0.50 mmol scale. Yields were determined by 1H NMR analysis
using 1,1,2,2-tetrachloroethane as the internal standard.
parentheses represent material isolated after silica-gel
chromatography.
Yields in
column
High catalytic activity was also observed when other substrates 7
were investigated using 5b as the catalyst (Table 2). While the
reaction of electron-rich substrate 7b was slow,[11] the reaction of
electron-deficient substrate 7c was efficiently accelerated. In addition,
reactions of substrates 7d and 7e bearing 4-bromophenyl and 2-
naphthyl groups, respectively, were also accelerated by 5b. Similarly,
substrates 7f and 7g bearing 4-tolyl and 4-(tert-butyl)phenyl groups,
respectively, were efficiently transformed in the presence of 5b.
Substrate 7h bearing an aliphatic group also exhibited similar reaction
outcomes, although the product was obtained as a mixture of
regioisomers 9h and 9h’. Furthermore, similar effects involving 5b
were also observed during the bromolactonization of (E)-2-
styrylbenzoic acid (7i); the reaction proceeded quantitatively in the
presence of catalyst 5b, while it failed in the absence of the catalyst at
This article is protected by copyright. All rights reserved.

10.1002/anie.201808320
Angewandte Chemie International Edition
COMMUNICATION
bromosuccinimide (NBS, 17) was used as the brominating reagent.
Moreover, iodolactonization with N-iodosuccinimide (NIS, 18) was
also accelerated by 5b, although the effect was moderate under the
conditions examined.
Scheme 4. Halolactonizations of 7a with N-halosuccinimides.
Figure 3. The effects of 5a and 5b loadings.
In summary, we demonstrated the catalytic behavior of trans-
cyclooctenes in halolactonizations; these strained olefins efficiently
facilitate the halolactonizations. The trans-cyclooctene framework is
essential for good catalytic performance. In addition, substituents play
important roles in determining efficiency, which reveals the potential
of the substitutent to tune catalytic activity. The developed catalysts
are useful in bromolactonization and iodolactonization reactions.
These findings offer avenues for the design of novel molecular
catalysts for synthetic transformations. Studies on the detailed reaction
mechanism and applications in asymmetric catalysis[14] are currently
underway in our laboratory.
On the basis of the above-mentioned results, we propose a
mechanism involving a catalytic cycle, as shown in Scheme 3. First,
the bromiranium ion 14 is generated from 5 and 8, after which
association with another molecule of 5 makes the bromiranium ion
shuttle between 14 and 15. The olefin-to-olefin transfers of the
bromiranium ion between two molecules of 5 retard the reaction;
therefore, a key to increasing the catalytic efficiency is the inhibition of
the unfavorable bimolecular association of 5. Olefin-to-olefin transfer
of the bromiranium ion with 7a then takes place to stereospecifically
form 16; subsequent lactonization of 16, in which 5 is still present,
provides 9a and regenerates 5.[13]
Acknowledgements
We thank Professor Takuya Kurahashi (Kyoto University) for X-ray
crystallographic analysis. This work was supported financially by the
Japanese Ministry of Education, Culture, Sports, Science and
Technology (15H05845, 16K13994, 17K19120, 18K14214, and
18H04258). K.A. also acknowledges the Asahi Glass Foundation,
Toyota Physical and Chemical Research Institute, Tokyo Institute of
Technology Foundation, the Naito Foundation, Research Institute for
Production Development, the Tokyo Biochemical Research Foundation,
the Uehara Memorial Foundation, the Kyoto University Foundation,
the Institute for Synthetic Organic Chemistry, and Toyo Gosei
Memorial Foundation. A.M. also acknowledges the Japan Society for
the Promotion of Science for Young Scientists for the fellowship
support.
Keywords: trans-cyclooctene • strained olefin • Lewis base •
halolactonization • organocatalyst
Scheme 3. Proposed catalytic cycle.
[1] A. T. Blomquist, L. H. Liu, J. C. Bohrer, J. Am. Chem. Soc. 1952, 74,
3643.
Furthermore, 5b also exerted
a large influence on the
halolactonizations of 7a using other halogenating reagents (Scheme 4).
A remarkable improvement in yield was observed with 5b when N-
[2] For reviews, see: a) J. A. Marshall, Acc. Chem. Res. 1980, 13, 213;
b) M. Nakazaki, K. Yamamoto, K. Naemura, Top. Curr. Chem. 1984,
125, 1; c) K. Schlögl, Top. Curr. Chem. 1984, 125, 27; d) E. L. Eliel,
This article is protected by copyright. All rights reserved.

10.1002/anie.201808320
Angewandte Chemie International Edition
COMMUNICATION
S. H. Wilen, L. N. Mander, in Stereochemistry of Organic
Compounds, Wiley, New York, 1994, pp. 1172−1175.
[8] K. Tomooka, M. Shimada, K. Uehara, M. Ito, Organometallics 2010,
29, 6632.
[3] a) A. C. Cope, C. F. Howell, A. Knowles, J. Am. Chem. Soc. 1962,
84, 3190; b) A. C. Cope, C. R. Ganellin, H. W. Johnson, Jr. J. Am.
Chem. Soc. 1962, 84, 3191; c) A. C. Cope, C. R. Ganellin, H. W.
Johnson, Jr., T. V. Van Auken, H. J. S. Winkler, J. Am. Chem. Soc.
1963, 85, 3276; d) A. C. Cope, A. S. Mehta, J. Am. Chem. Soc. 1964,
86, 5626; e) A. C. Cope, K. Banholzer, H. Keller, B. A. Pawson, J. J.
Whang, H. J. S. Winkler, J. Am. Chem. Soc. 1965, 87, 3644; f) A. C.
Cope, B. A. Pawson, J. Am. Chem. Soc. 1965, 87, 3649. For selected
examples of enantioselective syntheses, see: g) Y. Inoue, T.
Yokoyama, N. Yamasaki, A. Tai, Nature 1989, 341, 225; h) K.
Tomooka, K. Uehara, R. Nishikawa, M. Suzuki, K. Igawa, J. Am.
Chem. Soc. 2010, 132, 9232; i) K. Igawa, N. Ichikawa, Y. Ano, K.
Katanoda, M. Ito, T. Akiyama, K. Tomooka, J. Am. Chem. Soc. 2015,
137, 7294; j) T. Miura, T. Nakamuro, C.-J. Liang, M. Murakami, J.
Am. Chem. Soc. 2014, 136, 15905; k) Y. Okayama, S. Tsuji, Y.
Toyomori, A. Mori, S. Arae, W.-Y. Wu, T. Takahashi, M.
Ogasawara, Angew. Chem. 2015, 127, 5009; Angew. Chem. Int. Ed.
2015, 54, 4927.
[4] For selected examples, see: a) K. Tomooka, N. Komine, D. Fujiki, T.
Nakai, S. Yanagitsuru, J. Am. Chem. Soc. 2005, 127, 12182; b) K.
Tomooka, M. Suzuki, K. Uehara, M. Shimada, T. Akiyama, Synlett
2008, 2518; c) K. Tomooka, T. Akiyama, P. Man, M. Suzuki,
Tetrahedron Lett. 2008, 49, 6327; d) K. Tomooka, C. Iso, K. Uehara,
M. Suzuki, R. Nishikawa-Shimono, K. Igawa, Angew. Chem. 2012,
124, 10501; Angew. Chem. Int. Ed. 2012, 51, 10355; d) O. V.
Larionov, E. J. Corey, J. Am. Chem. Soc. 2008, 130, 2954; e) M.
Royzen, G. P. A. Yap, J. M. Fox, J. Am. Chem. Soc. 2008, 130,
3760; f) B. Hurlocker, C. Hu, K. A. Woerpel, Angew. Chem. 2015,
127, 4369; Angew. Chem. Int. Ed. 2015, 54, 4295.
[5] For selected examples, see: a) F. Thalhammer, U. Wallfahrer, J.
Sauer, Tetrahedron Lett. 1990, 31, 6851; b) M. L. Blackman, M.
Royzen, J. M. Fox, J. Am. Chem. Soc. 2008, 130, 13518; c) N. K.
Devaraj, R. Weissleder, Acc. Chem. Res. 2011, 44, 816; d) F. Liu, Y.
Liang, K. N. Houk, J. Am. Chem. Soc. 2014, 136, 11483; e) D. N.
Kamber, Y. Liang, R. J. Blizzard, F. Liu, R. A. Mehl, K. N. Houk, J.
A. Prescher, J. Am. Chem. Soc. 2015, 137, 8388.
[6] For selected reviews on olefins as ligands for metal catalysts, see: a)
C. Defieber, H. Grützmacher, E. M. Carreira, Angew. Chem. 2008,
120, 4558; Angew. Chem. Int. Ed. 2008, 47, 4482; b) R. Shintani, T.
Hayashi, Aldrichimica Acta 2009, 42, 31; c) X. Feng, H. Du, Asian J.
Org. Chem. 2012, 1, 204; d) M. Nagamoto, T. Nishimura, ACS Catal.
2017, 7, 833.
[9] a) S. E. Denmark, M. T. Burk. Proc. Natl. Acad. Sci. USA 2010, 107,
20655; b) S. E. Denmark, W. E. Kuester, M. T. Burk, Angew. Chem.
2012, 124, 11098; Angew. Chem. Int. Ed. 2012, 51, 10938; c) S. E.
Denmark, G. L. Beutner, Angew. Chem. 2008, 120, 1584; Angew.
Chem. Int. Ed. 2008, 47, 1560. For selected reviews on recent
advance of halolactonization reactions, see: d) A. Sakakura, K.
Ishihara, Chem. Rec. 2015, 15, 728; e) Y. A. Cheng, W. Z. Yu, Y.-Y.
Yeung, Org. Biomol. Chem. 2014, 12, 2333; f) C. K. Tan, W. Z. Yu,
Y.-Y. Yeung, Chirality 2014, 26, 328; g) S. Zheng, C. M.
Schienebeck, W. Zhang, H.-Y. Wang, W. Tang, Asian J. Org. Chem.
2014, 3, 366; h) K. Murai, H. Fujioka, Heterocycles 2013, 87, 763; i)
C. K. Tan, Y.-Y. Yeung, Chem. Commun. 2013, 49, 7985; j) S. R.
Chemler, M. T. Bovino, ACS Catal. 2013, 3, 1076; k) U. Hennecke,
Chem. Asian J. 2012, 7, 456; l) A. Castellanos, S. P. Fletcher, Chem.
Eur. J. 2011, 17, 5766; m) C. K. Tan, L. Zhou, Y.-Y. Yeung, Synlett
2011, 1335.
[10] Reaction profiles using 5a and 5b, as well in the absence of catalyst,
were also monitored (see Scheme S1 in the Supporting Information
for details).
[11] Side products, such as compounds brominated on the aromatic ring,
were not isolated, although trace amounts were detected by HRMS.
[12] The olefin-to-olefin transfers of bromiranium and iodiranium ions
are known, see: a) A. J. Bennet, R. S. Brown, R. E. D. McClung, M.
Klobukowski, G. H. M. Aarts, B. D. Santarsiero, G. Bellucci, R.
Bianchini, J. Am. Chem. Soc. 1991, 113, 8532; b) R. S. Brown, R. W.
Nagorski, A. J. Bennet, R. E. D. McClung, G. H. M. Aarts, M.
Klobukowski, R. McDonald, B. D. Santarsiero, J. Am. Chem. Soc.
1994, 116, 2448; c) A. A. Neverov, R. S. Brown, J. Org. Chem. 1996,
61, 962; d) R. S. Brown, Acc. Chem. Res. 1997, 30, 131; e) S. E.
Denmark, M. T. Burk, A. J. Hoover, J. Am. Chem. Soc. 2010, 132,
1232.
[13] At this stage, all efforts to recover or detect catalysts 5 following
their reactions have failed. However, we believe that trans-
cyclooctenes 5 act as catalysts on the basis of the reasonable reaction
profiles displayed in Scheme S1 and the results of control
experiments summarized in Table 1 and Table S1 in the Supporting
Information.
[14] At this stage, optically active forms of trans-cyclooctenes 5 failed to
realize enantioselectivity in the halolactonization reactions presented
herein (see Scheme S3 in the Supporting Information for details).
We are currently optimizing catalyst structures for asymmetric
catalysis in our laboratory.
[7] a) E. Vedejs, K. A. Snoble, P. L. Fuchs, J. Org. Chem. 1973, 38,
1178; b) K. J. Shea, J.-S. Kim, J. Am. Chem. Soc. 1992, 114, 3044.
This article is protected by copyright. All rights reserved.

10.1002/anie.201808320
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Shunsuke Einaru, Kenta Shitamichi,
Tagui Nagano, Akira Matsumoto,
Keisuke Asano,* and Seijiro Matsubara*
Page No. – Page No.
trans-Cyclooctenes as
Halolactonization Catalysts
The strained olefins in trans-cyclooctenes serve as efficient catalysts for
halolactonizations, including bromolactonizations and iodolactonizations. The
trans-cyclooctene framework is essential for excellent catalytic performance, and
the substituents also play important roles in determining efficiency. These results
represent the first demonstration of catalysis by a trans-cyclooctene; hence, these
findings offer new functional-group-design entries for molecular catalysts.
This article is protected by copyright. All rights reserved.