C-C bond-forming click synthesis of rotaxanes exploiting nitrile N-oxide

Article abstract of DOI:10.1021/ol101543x

A click end-capping reaction exploiting nitrile N-oxide to rotaxane was described with emphasis of productivity of the protocol via stable C-C bond formation. Establishment of a pH-driven molecular shuttling system was also demonstrated by practical neutralization of the sec-ammonium group of the rotaxane axle with potassium hydroxide.

Full text of DOI:10.1021/ol101543x

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3828-3831
C-C Bond-Forming Click Synthesis of
Rotaxanes Exploiting Nitrile N-Oxide
Tohru Matsumura, Fumitaka Ishiwari, Yasuhito Koyama,* and Toshikazu Takata*
Department of Organic and Polymeric Materials, Tokyo Institute of Technology,
2-12-1 (H-126), Ookayama, Meguro, Tokyo 152-8552, Japan
ttakata@polymer.titech.ac.jp; ykoyama@polymer.titech.ac.jp
Received July 6, 2010
ABSTRACT
A click end-capping reaction exploiting nitrile N-oxide to rotaxane was described with emphasis of productivity of the protocol via stable C-C
bond formation. Establishment of a pH-driven molecular shuttling system was also demonstrated by practical neutralization of the sec-
ammonium group of the rotaxane axle with potassium hydroxide.
Rotaxane is part of a fascinating class of supramolecules
consisting of interlocked macrocyclic and dumbbell-shaped
components. The rotaxane scaffolds are expected to be an
indispensable motif for nanoscale devices such as a molecular
motor or for polyrotaxane networks with specific character-
istics.1 Although synthetic studies directed toward the
versatile motifs have been reported,2 the synthesis of rotaxane
itself is still not easy owing to the need for multistep
elaborations or labor-intensive purification of the resulting
compound. Moreover, the skeleton often includes labile
linkages such as ester, urethane, and so on because of the
synthetic requirement to limit further modification of rotax-
ane. Hence, the development of productive and labor-saving
methods for the synthesis of interlocked molecules could
allow easy access to highly sophisticated supramolecular
systems. For this purpose, click chemistry,3 exploiting the
Huisgen dipolar cycloaddition of azides to alkynes, has
generated particular interest in the usefulness in the supramo-
lecular chemistry.4 However, the problems of safety of the
azide moiety concerning toxicity and explosiveness are some
of the limitations.5
Recognizing such issues, we became intrigued by the
potential usefulness of stable nitrile N-oxide as a substitute
(2) For reviews, see: (a) Fyfe, M. C. T.; Stoddart, J. F. AdV. Supramol.
Chem. 1999, 5, 1–53. (b) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.;
Sanders, J. K. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898–
952. (c) Kay, E. R.; Leigh, D. A. Top. Curr. Chem. 2005, 262, 133–177.
(d) Huang, F.; Gibson, H. W. Prog. Polym. Sci. 2005, 30, 982–1018. (e)
Takata, T. Polymer J. 2007, 38, 1–20. (f) Berna´, J.; Bottari, G.; Leigh,
D. A.; Perez, E. M. Pure Appl. Chem. 2007, 79, 39–54. (g) Champin, B.;
Mobian, P.; Sauvage, J.-P. Chem. Soc. ReV. 2007, 36, 358–366. (h) Griffiths,
K. E.; Stoddart, J. F. Pure Appl. Chem. 2008, 80, 485–506.
(1) (a) Molecular Electronics: Science and Technology; Aviram, A.,
Ratner, M., Eds.; New York Academy of Sciences: New York, 1998. (b)
Yu, H.; Luo, Y.; Beverly, K.; Stoddart, J. F.; Tseng, H.-R.; Heath, J. R.
Angew. Chem., Int. Ed. 2003, 42, 5706–5711. (c) Choi, J. W.; Flood, A. H.;
Steuerman, D. W.; Nygaard, S.; Braunschweig, A. B.; Moonen, N. N. P.;
Laursen, B. W.; Luo, Y.; DeIonno, E.; Peters, A. J.; Jeppesen, J. O.; Xu,
K.; Stoddart, J. F.; Heath, J. R. Chem.sEur. J. 2006, 12, 261–279. (d)
Green, J. E.; Choi, J. W.; Boukai, A.; Bunimovich, Y.; Johnston-Halperin,
E.; DeIonno, E.; Luo, Y.; Sheriff, A.; Xu, K.; Shin, Y. S.; Tseng, H.-R.;
Stoddart, J. F.; Heath, J. R. Nature 2007, 445, 414–417.
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Ed. 2001, 40, 2004–2021. (b) Tornøe, C. W.; Christensen, C.; Meldal, M.
J. Org. Chem. 2002, 67, 3057–3064.
10.1021/ol101543x  2010 American Chemical Society
Published on Web 08/02/2010

Table 1. Click End-Capping Reaction Exploiting Nitrile N-Oxide for Rotaxane Synthesisa
entry
pseudorotaxane
end-capping agent
additive
temp /°C
time
[2]rotaxane
Yield /%
1
2
3
4
5
6
7
8b
4
4
4
4
4
5
5
5
6
6
6
6
7
7
7
7
Et3N
AgOTf
MS 4A
MS4A
-
rt
5 d
8
8
0
25
19
47
61
97
85
80
0 °C
rt
30 min
1 d
8
reflux
rt
13 d
20 h
1 d
2 h
20 min
8
9
10
10
10
-
rt
-
-
reflux
reflux
a General condition: A mixture of an axle component (0.18 mmol), DB24C8 (0.21 mmol), an end-capping agent (0.23 mmol), and additive was stirred
in CH2Cl2 (0.5 mL). b Solvent: ClCH2CH2Cl.
for azides, which would enable the efficient conversion of
not only alkynes but also alkenes and nitriles to selectively
give isoxazole, isoxazoline, and oxadiazole without any
catalyst.6,7 Since the end-capping reaction of pseudorotaxane
absolutely requires a mild condition to avoid decomposition
of the labile complex, the use of nitrile N-oxide as the end-
capping agent would provide a reliable synthetic method of
interlocked compounds.8 On the other hand, the resulting
rotaxane skeleton consists only of chemically stable linkages
and therefore enables versatile chemical modifications of the
rotaxane.9
Herein, we describe the effective synthesis of rotaxanes
via click reaction exploiting nitrile N-oxide to pseudorotaxane
possessing alkene, alkyne, or the nitrile group on the axle
terminal. A molecular shuttling system was fruitfully con-
structed by a simple neutralization of the resulting rotaxane
with potassium hydroxide (KOH).
Table 1 features the conversion of pseudorotaxane into
[2]rotaxane consisting of dibenzo-24-crown-8-ether (DB24C8,
3) and sec-ammonium salt as the axle moiety. Treatment of
sec-ammonium salt (1 or 2) in the presence of DB24C8 (3)
gave pseudorotaxane (4 or 5) possessing a terminal olefin
(4) (a) Aprahamian, I.; Miljanie´, O. S.; Dichtel, W. R.; Isoda, K.; Yasuda,
T.; Kato, T.; Stoddart, J. F. Bull. Chem. Soc. Jpn. 2007, 80, 1856–1869.
(b) Gonzalez, D.; Koivisto, B. D.; Leigh, D. A. Chem. Commun. 2007,
4218–4220. (c) Braunschweig, A. B.; Dichtel, W. R.; Miljanie´, O. S.; Olson,
M. A.; Spruell, J. M.; Khan, S. I.; Heath, J. R.; Stoddart, J. F. Chem. Asian
J. 2007, 2, 634–647. (d) Mobian, P.; Collin, J.-P.; Sauvage, J.-P. Tetrahedron
Lett. 2006, 47, 4907–4909. (e) Aprahamian, I.; Dichtel., W. R.; Ikeda, T.;
Heath, J. R.; Stoddart, J. F. Org. Lett. 2007, 9, 1287–1290. (f) Prikhod’ko,
A. I.; Durola, F.; Sauvage, J.-P. J. Am. Chem. Soc. 2008, 130, 448–449.
(g) Dichtel, W. R.; Miljanie´, O. S.; Spruell, J. M.; Heath, J. R.; Stoddart,
J. F. J. Am. Chem. Soc. 2006, 128, 10388–10390. (h) Aucagne, V.; Ha¨nni,
K. D.; Leigh, D. A.; Lusby, P. J.; Walker, D. B. J. Am. Chem. Soc. 2006,
128, 2186–2187
(5) Russell, K. E. J. Am. Chem. Soc. 1955, 67, 3487–3488
(6) (a) Quillico, A.; Speroni, G. Gazz. Chim. Ital. 1946, 76, 148–166.
(b) Quillico, A.; Stagno d’Alcontres, G.; Gru¨nanger, P. Gazz. Chim. Ital.
.
(8) For related reports concerning end-capping reaction of crown-sec-
ammonium salt type rotaxanes, see: (a) Kawasaki, H.; Kihara, N.; Takata,
T. Chem. Lett. 1999, 28, 1015–1016. (b) Furusho, Y.; Sasabe, H.; Natsui,
D.; Murakawa, K.; Harada, T.; Takata, T. Bull. Chem. Soc. Jpn. 2004, 77,
179–185. (c) Makita, Y.; Kihara, N.; Takata, T. Chem. Lett. 2007, 36, 102–
103. (d) Hsu, C.-C.; Chen, N.-C.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Chiu,
S.-H. Angew. Chem., Int. Ed. 2008, 47, 7475–7478. (e) Suzaki, Y.; Osakada,
K. Dalton Trans. 2007, 2376–2383. (f) Domoto, Y.; Fukushima, A.; Kasuga,
Y.; Sase, S.; Goto, K.; Kawashima, T. Org. Lett. 2010, 12, 2586–2589.
(9) For a selected review on isoxazoles, see: Lang, S. A.; Lin, Y.-I. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon: Oxford, 2000; Vol. 6, pp 1-144.
.
1950, 80, 479–495
.
(7) For our recent approach to polymerization reaction exploiting homo-
ditopic aromatic nitrile N-oxide, see: (a) Koyama, Y.; Yonekawa, M.;
Takata, T. Chem. Lett. 2008, 37, 918–919. (b) Lee, Y.-G.; Koyama, Y.;
Yonekawa, M.; Takata, T. Macromolecules 2009, 42, 7709–7717. (c) Lee,
Y.-G.; Yonekawa, M.; Koyama, Y.; Takata, T. Chem. Lett. 2010, 39, 420–
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.
Org. Lett., Vol. 12, No. 17, 2010
3829

Scheme 1.
Synthesis of [2]Rotaxanes Comprising Hetero Aromaticsa
a The reactions were performed using axle component, DB24C8 (1.2 equiv per axle component), and stable nitrile N-oxide 7 (1.3 equiv per axle component).
moiety that hopefully served for the isoxazole formation to
give the corresponding rotaxane (8-10). However, initial
attempts using benzohydroxamoyl chloride derivative 6 were
not so productive. The combination of 6 with Et3N to
generate nitrile N-oxide in situ only afforded the dumbbell-
shaped molecule with a lack of the wheel component (Table
1, entry 1). Use of AgOTf or MS 4A10 resulted in relatively
low yields of rotaxane 8 as a single product (Table 1, entries
2-4). After considerable efforts, we found that [2]rotaxane
9 was nicely obtained by treatment of 4 with stable nitrile
N-oxide 711 through use fo bulky substituents in CH2Cl2
without any catalyst (Table 1, entries 5-8). Finally, treatment
of hexafluorophosphate salt 5 as the pseudorotaxane with 7
at room temperature afforded the rotaxane 10 in 97% yield
as a single product (Table 1, entry 6). The regiochemistry
of 8 and 10 was determined by the HMBC correlations.12
On the other hand, the elevated temperature shortened the
reaction time, though the yield was slightly lowered. The
decrease of yield clearly depends on the entropy-driven
dessociation of the pseudorotaxane (entries 7 and 8).
Having the stable nitrile N-oxide 7 as a crucial end-capping
agent in hand, we examined its utility for various [2]rotaxane
preparations. Scheme 1 shows the end-capping reactions of
pseudorotaxanes possessing various dipolarophiles at the axle
termini. According to the same procedure as for entry 7 of
Table 1, the vinylene terminus of 11 worked well to obtain
isoxazole-containing [2]rotaxane 12 in 98% yield at room
temperature after only 2 h. The high reactivity is probably
attributed to the steric hindrance of 11 being less than 5.
The use of acetylene 13 or 15 also underwent the click end-
capping to give the corresponding isoxazoline-containing
[2]rotaxane 14 or 16 as a single product in a high yield,
respectively (14: 78%, 16: 98%). On the other hand, the use
of cyano-functionalized 17 gave 1,2,4-oxadiazole-containing
[2]rotaxane 18 in 24% yield. DB24C8-free dumbbell-shaped
ammonium salt was obtained as the main product because
the basity of the oxadiazole formed probably causes the
decomposition of pseudorotaxane 17. Notably, all reactions
proceeded regioselectively, as evaluated by the HMBC
correlations,12 and importantly, the formation of [2]rotaxanes
was performed by the chemically stable C-C bond in the
cases of the pseudorotaxane having an alkene and an alkyne
terminus.
Figure 1 features the application to a molecular shuttling
1
system by showing the spectral change of H NMR from
(a) ammonium-type rotaxane 16 to (b) free amine-type
rotaxane 19. In spectrum a, the signal originating from the
isoxazole skeleton along with the disappearance of signal
of terminal alkyne of pseudorotaxane 15 afforded the direct
evidence for the formation of 16. In addition, the charac-
teristic signals of benzyl protons of the axle component of
16 appeared as broad peaks due to the geminal coupling,
strongly supporting the rotaxane formation in accordance
with the literatures.8 The neutralization reaction of the sec-
ammonium moiety in 16 was performed by pouring a DMSO
solution of 16 into 3 M aq KOH.13 The corresponding free
amine-type rotaxane 19 was quantitatively obtained. As
shown in the spectrum of 19, the signals of the benzyl protons
of the axle component were upfield-shifted, indicating the
neutralization of the ammonium moiety.14 Moreover, some
signals of the axle effected a deshielding effect from DB24C8
(10) (a) Kim, J. N.; Ryu, E. K. Heterocycles 1990, 31, 1693–1697. (b)
Pindur, U.; Haber, M. Heterocycles 1991, 32, 1463–1470. (c) Matsuura,
T.; Bode, J. W.; Hachisu, Y.; Suzuki, K. Synlett 2003, 1746–1748.
(11) (a) Grundmann, C.; Richter, R. J. Org. Chem. 1968, 33, 476–478.
(b) Beltrame, P.; Veglio, C.; Simonetta, M. J. Chem. Soc. B 1967, 867–
873. (c) Bode, J. W.; Hachisu, Y.; Matsuura, T.; Suzuki, K. Tetrahedron
Lett. 2003, 44, 3555–3558.
(13) The use of an excess amount of KOH in polar solvents such as
DMSO or DMF was absolutely needed in the neutralization process, strongly
suggesting the low acidity of the ammonium group surrounded by the crown
ether of 16. For a related report, see: Kihara, N.; Tachibana, Y.; Kawasaki,
H.; Takata, T. Chem. Lett. 2000, 29, 506–507.
(12) Structural assignments of 8, 10, 12, 14, 16, and 18 were based on
the HMBC correlations. The HMBC observed between the hetero ring
protons was diagnostic in each case.
(14) Nakazono, K.; Takata, T. Chem.sEur. J. 2010, . in press.
3830
Org. Lett., Vol. 12, No. 17, 2010

1
Figure 1. Spectral change of the molecular shuttling system: H NMR spectra of (a) rotaxane 16 and (b) free amine-type rotaxane 19
(DMSO-d6, 400 MHz, 298 K).
and were the most characteristic toward understanding the
translation of the wheel component: Signals a-c around
DB24C8 were upfield-shifted; on the contrary, signals f-h
located far from DB24C8 were downfield-shifted. On the
other hand, the signals of the Ar-CH3 and Ar-OCH3 protons
of the end groups showed inverse behavior to such signals,
probably depending on the shielding effect from DB24C8.
Again, treatment of 19 with satd aq NH4PF6 furnished 16,
suggesting the establishment of a pH-driven molecular
shuttling system.15
tion to a molecular switch, with emphasis of productivity of
the protocol via stable C-C bond formation. Further studies
directed toward the functionalization of the resulting rotax-
anes by the chemical modifications of the heteroaromatics
are currently underway.
Acknowledgment. This work was financially supported
by a Grant-in-Aid for Scientific Research from MEXT, Japan
(Nos. 18064008 and 19655013), Global COE program
(Tokyo Institute of Technology), and the Mizuho Foundation
for the Promotion of Science.
In conclusion, the present paper has disclosed a simple
and powerful synthetic method of various heteroaromatics-
containing [2]rotaxanes without any catalyst and its applica-
Supporting Information Available: Full experimental
1
details for all compounds, including H NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) For related reviews of molecular shuttling systems, see: (a)
Rescifina, A.; Zagni, C.; Iannazzo, D.; Merino, P. Curr. Org. Chem. 2009,
13, 448–481. (b) Silvi, S.; Venturi, M.; Credi, A. J. Mater. Chem. 2009,
19, 2279–2294.
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3831