Synthesis of [2]- and [3]rotaxanes through Sonogashira coupling

Article abstract of DOI:10.1016/j.tetlet.2009.07.101

The synthesis of new [2]- and [3]rotaxanes through Sonogashira coupling has been accomplished in the aim to built oligo(phenyleneethynylene) (OPE) encircled by crown ethers. Optimization of the Sonogashira coupling for the formation of the [2]rotaxane (ca

Full text of DOI:10.1016/j.tetlet.2009.07.101

Tetrahedron Letters 50 (2009) 5497–5500
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Tetrahedron Letters
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Synthesis of [2]- and [3]rotaxanes through Sonogashira coupling
Jean-Benoît Giguère, Dominic Thibeault, Francis Cronier, Jean-Sébastien Marois, Michèle Auger,
*
Jean-François Morin
Département de chimie and Centre de Recherche sur les Matériaux Avancés, 1045 Ave de la Médecine, Pavillon Alexandre-Vachon, Université Laval, Québec (Qc), Canada G1V 0A6
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of new [2]- and [3]rotaxanes through Sonogashira coupling has been accomplished in the
aim to built oligo(phenyleneethynylene) (OPE) encircled by crown ethers. Optimization of the Sonogash-
ira coupling for the formation of the [2]rotaxane (capping reaction) is presented and the best method has
been applied for the synthesis of the longer [3]rotaxane.
Received 14 May 2009
Revised 14 July 2009
Accepted 15 July 2009
Available online 22 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The preparation of synthetic molecular machines mimicking
functions of those found in nature is one of the biggest challenges
in nanoscience.1 In the past decades, chemists exploited a large
variety of organic reactions to construct simple and complex nan-
oarchitectures able to perform tasks upon chemical2 or physical3
stimulation. Rotaxane is undoubtedly the most used supramolecu-
lar assembly for the preparation of functional nanomachines.
derivatives, which are well-known building blocks for the prepara-
tion of molecular machines.11 Few examples of oligo(phenylenee-
thynylene) (OPE)-based rotaxane have been reported so far,12 but
none of them was prepared using crown ether macrocycle. Thus,
we report herein the first synthetic efforts to prepare [2]- and
[3]rotaxanes (Fig. 1) based on ammonium-crown ether conjugate
through Sonogashira coupling. Because there is no report of such
reaction for rotaxane formation and end-capping, we investigated
different reaction conditions for the capping of a [2]rotaxane to
optimize the yield of reaction. The best conditions have been ap-
plied for the synthesis of the [3]rotaxane.
The rod of the rotaxane bearing the ammonium group was syn-
thesized in four steps as depicted in Scheme 1. First, 4-hydroxy-
benzaldehyde was alkylated with propargyl bromide in acetone
to give compound 4 in quantitative yield. Then, a condensation
reaction between compounds 513 and 3 in refluxing toluene in a
Dean–Stark apparatus followed by a reduction of the imine to a
secondary amine using LiAlH4 provided 6 in 92% yield (two steps).
The amine was finally protonated using HCl followed by an ion ex-
change with NH4PF6 to give the ammonium-containing rod 7 in
68% yield.
Rotaxane consists of
a dumbbell-shaped rod encircled by a
mechanically interlocked macrocycle than can move along the
rod in a translational fashion upon stimulation.1a,e,4 Over the past
ten years, several synthetic methods have been developed to en-
able the preparation of different types of rotaxane and to allow
the introduction of functional groups. This is especially true for
rotaxanes having an ammonium-crown ether conjugate and par-
ticular attention has been given to the development of new meth-
odologies to end-cap these rotaxanes. These include, among others,
the formation of urethane with isocyanate,5 ester from anhydride
derivatives,6disulfide,7 triazole via click chemistry,8 and alkene
by ruthenium-catalyzed metathesis9 and Wittig reaction.10 How-
ever, to the best of our knowledge, an end-capping reaction using
palladium-catalyzed C–C cross-coupling has never been reported
to end-cap rotaxane. The rather harsh reaction conditions, espe-
cially the presence of strong base, polar solvents and the high tem-
perature needed to achieve cross-coupling reaction are
incompatible with the formation of rotaxanes based on ammo-
nium-crown ether conjugate that rely solely on hydrogen bonds.
Thus, it is a real challenge to prepare such rotaxane using the stan-
dard cross-coupling methods.
Using compound 7 and 3,5-dimethyliodobenzene, several at-
tempts to form a [2]rotaxane were performed and the results are
summarized in Table 1.
As a starting point, we have studied the reaction under standard
Sonogashira coupling conditions using PdCl2(PPh3)2 as the catalyst
and NEt3 as the base (entry 1). Because rotaxane formation is pos-
sible only in aprotic solvents that are unable to interact through
hydrogen bonding with the ammonium, we used CH3CN rather
than THF or DMF. Unfortunately, the yield obtained when 2.2 equiv
of NEt3 was used is rather low (12%). Interestingly, by decreasing
the amount of triethylamine to 1.1 equiv, the reaction yield dou-
bled to reach 25% (entry 2). The presence of NEt3 is likely to be
responsible for the poor yield since it is known to efficiently
deprotonate the ammonium group once the rotaxane is formed.13
Thus, we decided to use a modified method developed by Verkade
As a part of our research program aiming at preparing rotaxane-
based supramolecular rotors working in the solid state, we decided
to investigate the feasibility of Sonogashira coupling to prepare
[2]- and [3]rotaxanes. Sonogashira coupling has been chosen
among others since it allows the synthesis of phenylacetylene
* Corresponding author.
E-mail address: jean-francois.morin@chm.ulaval.ca (J.-F. Morin).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.101

5498
J.-B. Giguère et al. / Tetrahedron Letters 50 (2009) 5497–5500
O
O
O
-
PF6
O
O
O
O
N
+
H2
O
O
[2]rotaxane (1)
O
O
O
O
O
O
+H2N
R
O
-
O
PF6
O
O
O
O
-
PF6
O
O
+
NH2
O
O
O
O
[3]rotaxane (3)
Figure 1. Structure of the [2]- and [3]rotaxanes obtained by Sonogashira couplig.
NH2
O
OH
1)
2)
5
Br
PhMe, reflux
K2CO3, acetone
Quant.
LiAlH4
0°C - rt, 3h
92% (two steps)
O
O
4
-
PF6
+
1) HCl, MeOH
N
H
N
H2
2) NH4PF6
68%
O
O
6
7
Scheme 1. Synthetic route for the synthesis of the ammonium-containing rod.
et al. using tetrabutylammonium acetate (Bu4NOAc) as a weak
base for Sonogashira coupling (entries 3–6).14 It should be noted
that Me4NOAc has been used instead of Bu4NOAc since the methyl
derivative is much easier to remove in the workup than the butyl
one. The use of acetate as the base provided lower reaction yields
than NEt3 (entries 3 and 4), even when other palladium catalysts
were used (entries 5 and 6). Different bases were thus tried (entries
7–11), but only trace amounts of the desired product was obtained.
Therefore, we decided to investigate a more hindered base having a
structural similarity to NEt3, namely N-isopropyl-N-methyl-tert-
butylamine (iPMtBA). The reaction with 2.0 equiv of base provided
the desired rotaxane in 18% yield (entry 12). The yield of the reac-
tion can further be increased (26%) by decreasing the amount of
base down to 1.08 equiv (entry 16). Adding more DB24C8 to the
reaction mixture to drive the reaction (entry 13), adding the base
dropwise to the reaction mixture (entry 17) or starting the reaction
at 0 °C to drive the formation of the pseudo[2]rotaxane in solution
(entry 18) do not increase the reaction yield. The low yields ob-
tained for the capping reaction of a rotaxane by Sonogashira cou-
pling can be explained in different ways. First, the steric
hindrance near the alkyne can be responsible in part for the low
yield. In fact, steric hindrance due to the crown ether macrocycle
is known to be responsible for low yields in many types of rotaxane
transition metal-mediated capping reactions.9 Many attempts to
cap a [2]rotaxane using Sonogashira coupling with an ammonium
derivative having an alkyne directly attached to the phenyl group
were all unsuccessful. This suggests that the proximity of the al-
kyne to the macrocycle is an important factor for the success of this
reaction. Moreover, the choice of solvent and base to optimize the
reaction is rather limited since rotaxanes can be formed only in
specific conditions of pH (no strong bases), temperature (no heat),
and polarity (no hydrogen bond).
Interestingly, the yields obtained for compound 2 (end-capped
rod) are higher than those obtained for compound 1 meaning that

J.-B. Giguère et al. / Tetrahedron Letters 50 (2009) 5497–5500
5499
Table 1
Optimization of coupling reactiona
O
O
O
(1.1 eq)
I
-
-
PF6
PF6
O
O
O
O
+
N
N
+
H2
H2
CuI (4 mol%)
Catalyst (2 mol%)
DB24C8
O
O
O
7
Base, solvent, rt
1
+
-
PF6
N
+
H2
O
2
Entry
Catalyst
Base
Equiv of base
1 (%)
2g (%)
1
2
3
4
5
6
7
8
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(OAc)2
NEt3
NEt3
2.2
1.1
2.0
1.5
1.5
1.5
1.5
2.0
2.0
1.1
1.1
2.0
2.0
1.5
1.1
1.0
1.0
1.1
12
25
10
16
0
0
0
0
<5
<5
0
18
8
26
26
26
24
20
49
34
Me4NOAc
Me4NOAc
Me4NOAc
Me4NOAc
Imidazole
DBU
DABCO
2,6-lutidine
Me2NAre
iPMtBAf
iPMtBA
iPMtBA
iPMtBA
iPMtBA
iPMtBA
iPMtBA
PdCl2(dppf)
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
60
51
9
10
11
12
13b
14
15
16
17c
18d
59
a
Typical reaction uses CuI (0.04 equiv), Pd (0.02 equiv), DB24C8 (1.20 equiv) and base in acetonitrile (0.2 M) at room temperature.
2.0 equiv of DB24C8 were added for this entry.
The base was added dropwise to the reaction mixture.
The reaction was started at 0 °C for 1 h.
Me2NAr = N,N-dimethylaniline.
b
c
d
e
f
iPMtBA = N-isopropyl-N-methyl-tert-butylamine.
g
1H NMR yields.
the formation of the latter is rather limited by the low efficiency of
15, the best yield obtained for the preparation of the [3]rotaxane
(compound 3) is 15%. It is worth mentioning that compound 3
shows very similar Rf on silica TLC plate than that of DB24C8, mak-
ing the purification rather difficult. Column chromatography fol-
lowed by preparative size-exclusion chromatography (BioBeadsÒ
S-X3) was necessary to obtain compound 3 in good purity. Unfor-
tunately, all attempts to obtain single crystal from compound 3
failed. Counter-anion exchange and acetylation of compound 3 is
underway in order to get crystalline derivatives.
the pseudorotaxane formation under the various reaction condi-
tions used and not by the efficiency of the Sonogashira coupling it-
self. It is noteworthy that the yields reported in Table 1 for
compound 2 are NMR yields calculated by integrating the methyl
group of the blocker on the residual materials obtained after the
purification of compound 1. The purification of compound 2 by col-
umn chromatography proved to be unsuccessful because of the
great similarity in Rf values for compounds 2 and 7.
Although the best yield we obtained for the formation of com-
pound 1 is fairly low, we decided to proceed to the synthesis of
the [3]rotaxane using the conditions described in the entry 15 of
Table 1 (Scheme 2).15
First, we have attempted the reaction with 1,4-diiodobenzene
as the central rotaxane unit. Unfortunately, this compound is
poorly soluble in acetonitrile making the reaction very difficult to
proceed. Then, we have decided to use an unsymmetrical diiod-
ophenyl derivative, namely 2-fluoro-1,4-diiodobenzene, in order
to increase the solubility. Using the reaction conditions of entry
In conclusion, we successfully synthesized [2]- and [3]rotaxanes
using Sonogashira coupling. Even after optimization of the reaction
conditions, the yields are still moderately low. This can be attrib-
uted to the steric hindrance provided by the crown ether macrocy-
cle near the reaction site. Fortunately, this reaction was efficient
enough to provide our target molecules 1 and 3 in a good purity.
The synthesis of new derivatives with longer spacer between the
alkyne and the crown ether along with the solid-state NMR studies
of compound 3 are underway to test this new molecule as a supra-
molecular rotor.

5500
J.-B. Giguère et al. / Tetrahedron Letters 50 (2009) 5497–5500
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1)
BF3 Et2O
t-BuONO
I
NH2
R. W. J.; Veldman, N.; Spek, A. L.; Feringa, B. L. J. Org. Chem. 1997, 62, 4943; (b)
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Bull. Chem. Soc. Jpn. 2004, 77, 179; (b) Marois, J.-S.; Morin, J.-F. Org. Lett. 2008,
10, 33.
F
F
Et2O, -30°C
2) KI, MeCN
80%
I
9
I
I
I
-
PF6
R
+
N
H
6. (a) Kawasaki, H.; Kihara, N.; Takata, T. Chem. Lett. 1999, 1015; (b) Watanabe, N.;
Yagi, T.; Kihara, N.; Takata, T. Chem. Commun. 2002, 2720; (c) Kihara, N.;
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+
O
7
7. Furusho, Y.; Oku, T.; Hasegawa, T.; Tsuboi, A.; Kihara, N.; Takata, T. Chem. Eur. J.
2003, 9, 2895.
DB24C8
8. (a) Ashton, P. R.; Glink, P. T.; Stoddart, J. F.; Menzer, S.; tasker, P. A.; White, A. J.
P.; Williams, D. J. Tetrahedron Lett. 1996, 37, 6217; (b) Coutrot, F.; Busseron, E.
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PdCl2(PPh3)2, iPMtBA
CuI, CH3CN, rt, 24h
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Stoddart, J. F. Tetrahedron 2002, 58, 807.
R = H (no reaction)
R = F (15%) (3)
11. (a) Dominguez, Z.; Dang, H.; Jane Strouse, M.; Garcia-Garibay, M. A. J. Am. Chem.
Soc. 2002, 124, 2398; (b) Dominguez, Z.; Dang, H.; Jane Strouse, M.; Garcia-
Garibay, M. A. J. Am. Chem. Soc. 2002, 124, 7719; (c) Dominguez, Z.; Kuong, T.-A.
V.; Dang, H.; Sanrame, C. N.; Nunez, J. E.; Garcia-Garibay, M. A. J. Am. Chem. Soc.
2003, 125, 8827; (d) Godinez, C. E.; Zepeda, G.; Mortko, C. J.; Dang, H.; Garcia-
Garibay, M. A. J. Am. Chem. Soc. 2004, 69, 1652; (e) Gardinier, J. R.; Pellechia, P.
J.; Smith, M. D. J. Am. Chem. Soc. 2005, 127, 12448; (f) Akutagawa, T.; Shitagami,
K.; Nishihara, S.; Takeda, S.; Hasegawa, T.; Nakamura, T.; Hosokoshi, Y.; Inoue,
K.; Ikeuchi, S.; Miyazaki, Y.; Saito, K. J. Am. Chem. Soc. 2005, 127, 4397; (g)
Garcia-Garibay, M. A. Proc. Nat. Acad. Sci. 2005, 102, 10771; (h) Karlen, S. D.;
Ortiz, R.; Chapman, O. L.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 2005, 127,
6554; (i) Khuong, T.-A. V.; Nunez, J. E.; Godinez, C. E.; Garcia-Garibay, M. A. Acc.
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Am. Chem. Soc. 2007, 129, 3110; (j) Nuez, J. E.; Natarajan, A.; Khan, S. I.; Garcia-
Garibay, M. A. Org. Lett. 2007, 9, 3559.
Scheme 2. Synthesis of [3]rotaxane-based rotors 1 and 3.
Acknowledgments
We thank Pierre Audet for his kind help with HRMS measure-
ments. We also thank Université Laval, the Fond Québécois sur la
Nature et les Technologies (FQRNT), and the National Sciences
and Engineering Research Council of Canada (NSERC) for their
financial support.
12. (a) Frampton, M. J.; Anderson, H. L. Angew. Chem., Int. Ed. 2007, 46, 1028; (b)
Daniell, H. W.; Klotz, E. J. F.; Odell, B.; Claridge, T. D. W.; Anderson, H. L. Angew.
Chem., Int. Ed. 2007, 46, 6845.
13. Tachibana, Y.; Kawasaki, H.; Kihara, N.; Takata, T. J. Org. Chem. 2006, 71, 5093.
14. Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 5752.
Supplementary data
Supplementary data (complete synthetic procedures and spec-
tral data for new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2009.07.101.
15. Synthetic procedure for compound 3. A 10 mL round-bottomed flask under
nitrogen atmosphere was charged with a magnetic stir bar, compound 7
(200 mg, 0.47 mmol), dibenzo-24-crown-8-ether (253 mg, 0.56 mmol) and
diiodide 9. Degassed acetonitrile (2.4 mL) was added and the solution was
stirred for 15 min prior to the addition of PdCl2(PPh3)2 (13 mg, 0.02 mmol) and
copper iodide (4 mg, 0,02 mmol). Degassed N-isopropyl-N-methyl-tert-
butylamine (67 mg, 0.52 mmol) was then added and the mixture was stirred
overnight at room temperature. Dichloromethane (30 mL) was added and the
organic layer was washed with water. The organic layer was dried over Na2SO4
and the solvent was removed under reduced pressure. The residue was purified
by preparative TLC on silica gel with 5% acetonitrile in dichloromethane as
eluent, followed by size exclusion chromatography on Bio-BeadsÒ S-X3 with
CHCl3 as eluent to afford 59 mg of [3]rotaxane (3) in 15% yield. 1H NMR
(CDCl3): 7.47 (br s, 4H), 7.38–7.30 (m, 5H), 7.16 (d, J = 8.7 Hz, 2H), 7.09 (d,
J = 9.3 Hz, 2H), 6.88–6.79 (m, 24H), 4.88 (s, 2H), 4.85 (s, 2H), 4.56 (q, J = 6.6 Hz,
4H), 4.41 (t, J = 11.0 Hz, 4H), 4.08 (br s, 16H), 3.74 (m, 16H), 3.44 (m, 16H), 2.12
(br s, 12H); 13C NMR (CDCl3): 162.2 (d, J = 252 Hz, 1C), 158.7 (2Â), 147.5 (8Â),
138.6 (4Â), 133.7, 131.6 (2Â), 131.1 (4Â), 130.6 (2Â), 127.8 (d, J = 3.4 Hz, 1C),
126.6 (4Â), 124.7 (2Â), 124.7 (2Â), 124.5 (d, J = 9.2 Hz, 1C), 121.6 (8Â), 118.6
(d, J = 22.8 Hz, 1C), 115.0 (4Â), 112.6 (8Â), 111.4 (d, J = 15.4 Hz, 1C), 90.8 (d,
J = 3.1 Hz, 1C), 86.9, 85.3 (d, J = 3.0 Hz, 1C), 80.2, 70.6 (8Â), 70.1 (8Â), 68.2 (8Â),
56.4 (2Â), 52.4, 52.0, 21.2 (4Â); 19F NMR (CDCl3): 73.6 (d, J = 714.5 Hz, 12F),
References and notes
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*
110.3 (dt, J = 7.2 Hz, J = 2.8 Hz, 1F); HRMS m/z 1548.7606 [M ÀP2F12]+, (calcd
for C92H109N2O18, 1548.7654).