Angewandte
Chemie
DOI: 10.1002/anie.201409910
Strained Molecules
Heteroatom-embedded Medium-Sized Cycloalkynes: Concise
Synthesis, Structural Analysis, and Reactions**
Runyan Ni, Naoto Mitsuda, Takeru Kashiwagi, Kazunobu Igawa,* and Katsuhiko Tomooka*
Dedicated to Professor Keisuke Suzuki on the occasion of his 60th birthday
Abstract: A variety of medium-sized cycloalkynes were
efficiently synthesized by the double Nicholas reaction of
cobalt complex and bis(hetero)substituted acyclic compound.
The alkyne moiety within the ring has a unique bent structure
and high reactivity toward cycloaddition reactions. Further-
more, preparation of multifunctionalized alkynes was achieved
by embedding the cycloalkyne within a peptide chain.
Figure 1. Heteroatom-embedded medium-sized cycloalkyne (1).
A
lkyne is one of the most important functional groups in
organic chemistry owing to its versatile synthetic utility. The
reactivity of an alkyne heavily depends on the electronic and
steric characteristics of the substituents.[1] It is also well known
that the reactivity of an alkyne is influenced by structural
strain. Indeed, bent medium-sized cycloalkynes such as
cyclooctyne or cyclononyne show remarkably high reactivity
in comparison with nonbent acyclic alkynes in a variety of
addition reactions.[2] In the last decade, highly reactive
medium-sized cycloalkynes have attracted considerable
attention as smart ligation molecules in the field of chemical
biology.[3] In 2004, Bertozzi and colleagues reported the
pioneering work on the catalyst-free Huisgen reaction of
cyclooctyne derivatives with azides and successfully utilized
this reaction in a bioimaging technique based on the
bioorthogonality.[3a] Thus, a variety of medium-sized bent
cycloalkynes have since been synthesized. However, some of
these are not applicable to chemical biological experiments
because of their instability.[4,5] Hence, imparting a suitable
reactivity to alkynes is an important issue not only for
structural organic chemistry and reaction chemistry, but also
for chemical biology.
on the endocyclic propargylic positions (Figure 1). We
expected the reactivity of the alkyne moiety to be adjustable
by varying the ring size and heteroatom functionalities.[6,7]
Furthermore, the heteroatom functionalities can be used as
connection points for a variety of functional units (FU), such
as tag molecules and probe molecules. The resulting multi-
functionalized cycloalkynes are valuable as novel smart
ligation molecules.
To realize the synthesis of 1, an efficient approach which
overcomes the inherent entropic disadvantages of cyclization
is needed to construct the strained ring system. A double
Nicholas reaction of the dicationic 2-butyne unit A, derived
from the alkyne/cobalt complex A’, and the bis-
(hetero)substituted acyclic unit B would be the most straight-
forward approach to 1 [Eq. (1)],[8–10] even though related
To this end, we planned to synthesize the medium-sized
cycloalkyne 1 with two heteroatom functionalities (X and Y)
reports could not obtain satisfactory results for medium-sized
cycloalkyne synthesis because of the difficulty in removal of
the cobalt moiety.[11–13] Based on this idea, we investigated and
found that the introduction of a sulfonamide moiety (X =
NSO2R) to B as a nucleophilic heteroatom functionality is the
key to success. Herein, we report the details of the synthesis,
structural analysis, and reactions of 1.
At the outset, we examined a BF3·OEt2-promoted double
Nicholas reaction of either the alkyne/cobalt complex 2a or
2b (2a: LG = OH, 2b: LG = OMe; LG = leaving group) with
the 1,3-diol 3a (X, Y= O) and 1,3-bis(benzamide) 3b (X, Y=
NBz; Bz = benzoyl) [Eq. (2)]. However, the reactions
afforded only complex mixtures including oligomers of 2. In
sharp contrast, similar reactions with the 1,3-bis(tosylamide)
3c (X, Y= NTs; Ts = p-toluenesulfonyl) and either 2a or 2b
provided the desired nine-membered 4c (X, Y= NTs) in
excellent yields (for 2a: 94%, for 2b: 97%).[14] The removal
[*] Dr. T. Kashiwagi, Dr. K. Igawa, Prof. Dr. K. Tomooka
Institute for Materials Chemistry and Engineering
Kyushu University
Kasuga-koen 6-1, Kasuga, Fukuoka 816-8580 (Japan)
E-mail: kigawa@cm.kyushu-u.ac.jp
Dr. R. Ni, N. Mitsuda
Department of Molecular and Material Sciences
Kyushu University (Japan)
[**] This research was supported by JSPS KAKENHI Grant Number
24106734, and MEXT Project of Integrated Research on Chemical
Synthesis. We thank Y. Tokito (Kyushu University) for assistance in
the HRMS measurements.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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