[2]Rotaxanes through palladium active-template oxidative heck cross-couplings

Article abstract of DOI:10.1021/ja075219t

Pd(II)-catalyzed cross-couplings have been utilized in the efficient synthesis of [2]rotaxanes via an active-metal template strategy. The reaction is efficient, mild, and substrate-tolerant and uses only catalytic amounts of the Pd(II) template. In contra

Full text of DOI:10.1021/ja075219t

Published on Web 09/18/2007
[2]Rotaxanes through Palladium Active-Template Oxidative Heck
Cross-Couplings
James D. Crowley, Kevin D. Ha¨nni, Ai-Lan Lee, and David A. Leigh*
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings, West Mains Road,
Edinburgh EH9 3JJ, United Kingdom
Received July 12, 2007; E-mail: david.leigh@ed.ac.uk
Scheme 1. Proposed Catalytic Cycle for the Oxidative Heck
Active-Template Synthesis of [2]Rotaxane 5 from 1, 3, and 4
Palladium-catalyzed cross-coupling reactions are extremely
powerful tools for organic synthesis, routinely proving the method
of choice for the construction of C-C bonds.1 Recently, Pd(II)-
catalyzed cross-couplings have been developed as a novel alternative
to the traditional Pd(0) systems, offering a change in both
mechanism and reaction parameters.2 Here we report on the utility
of the Pd(II)-catalyzed oxidative Heck cross-coupling over Pd(0)-
based methods in the active-metal template synthesis of [2]-
rotaxanes.
Active-template syntheses differ from classical template reactions
in that a single species acts as both a template AND a catalyst for
covalent bond formation.3 Combining these two roles within the
action of the same metal center(s) has several potential advantages
over conventional “passive” template syntheses, including inherent
efficiency, scope, the possibility of traceless assembly, andsif it
is able to turnover at the end of the catalytic cyclesonly
substoichiometric quantities of the template need to be employed.
The active-template concept has been demonstrated through the
synthesis of rotaxanes using reactions such as the Cu(I)-catalyzed
azide-alkyne cycloadditionsthe CuAAC “click” reactionsand
alkyne homocouplings.3,4 However, to make active-template strate-
gies truly attractive, it will be necessary to apply them to reactions
that are synthetically versatile and applicable to a wide variety of
different structural motifs. Palladium-catalyzed cross-couplings fit
these criteria perfectly, of course. However, our initial attempts to
make rotaxanes using Pd(0)-catalyzed reactions with various mono-,
bi-, and tridentate macrocycles were unsuccessful, producing only
the corresponding non-interlocked threads.5 We attributed this to
the Pd(0) not remaining attached to the macrocycle during key
stages of the catalytic cycle. Accordingly, we switched our attention
to the oxidative Heck cross-coupling2 since Pd(II) should be ligated
much more strongly than Pd(0) by nitrogen donor atoms6 in
macrocycles such as 1.
Palladium(II) complex 2 was formed in situ by mixing macro-
cycle 1 (1 equiv) with a catalytic quantity (10 mol %) of Pd(OAc)2
in 1:1 CHCl3/CH2Cl2. Addition of boronic acid 3 (2 equiv), alkene
4 (1 equiv), and benzoquinone (1 equiv), followed by simple stirring
under an atmosphere of oxygen at room temperature for 72 h,
pleasingly led to the desired [2]rotaxane 5 in 73% yield.7,8 These
base-free conditions produced much higher yields of rotaxane 5
than standard oxidative Heck procedures,2h presumably because the
formation of undesired homocoupled byproducts is reduced. Reduc-
ing the amount of Pd to 1 mol % still produced 66% [2]rotaxane
(i.e., the metal template turns over 65 times during the reaction),
albeit over a 16 day reaction time.
The proposed mechanism for rotaxane formation is shown in
Scheme 1. Transmetalation of the aryl boronic acid 3 with the Pd-
(II) complex 2, followed by π-coordination of alkene 4, affords
intermediate I. In order to achieve successful rotaxane formation,
the two building blocks that ultimately form the thread need to be
held on opposite faces of the macrocycle and the palladium needs
to retain the stoppered ligands until it has mediated a covalent bond-
forming reaction between them. Migratory insertion followed by
â-H elimination thus forms a mechanical as well as a covalent bond.
Decomplexation of the weakly binding Pd(0) liberates free rotaxane
5. Reoxidation of Pd(0) to Pd(II) regenerates the catalytically active
complex 2 and enables the reaction to be conducted using
substoichiometric amounts of palladium.
The 1H NMR spectrum of rotaxane 5 in CDCl3 (Figure 1b) shows
an upfield shift of several signals with respect to the non-interlocked
components (Figure 1a and c). The shielding, typical of interlocked
architectures in which the aromatic rings of one component are
positioned face-on to another component, occurs for all nonstopper
resonances of the axle (Hf-o), indicating that the macrocycle
accesses the full length of the thread in the rotaxane. However, the
resonances of the protons on the half of the axle bearing the aryl
ring (Hm-o) are shielded to a greater extend than those on the other
9
12092
J. AM. CHEM. SOC. 2007, 129, 12092-12093
10.1021/ja075219t CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
forming reaction, however, is sensitive to steric hindrancesalthough
trisubstituted alkenes can be formed in high yields using the
oxidative Heck method,2h the attempted coupling of disubstituted
alkene 13 with boronic acid 3 resulted in only traces of the
corresponding rotaxane 14.9 Alkene boronic acid 15 also proved
suitable as a substrate, giving butadiene [2]rotaxane 16 in 30%
yield.10
The introduction of active-template palladium cross-coupling
routes to [2]rotaxanes opens up the possibility of using one of the
most powerful bond-forming methodologies in organic chemistry
for the assembly of mechanically interlocked architectures. The
reaction is mild, substrate-tolerant, and essentially traceless with
respect to the thread, and as little as 1% of the catalytic Pd(II)
template is required.
Acknowledgment. This work was supported through the EU
project Hy3M and the EPSRC. D.A.L. is an EPSRC Senior
Research Fellow and holds a Royal Society Wolfson Research Merit
Award. J.D.C. is a British Centenary Ramsay Fellow. We thank
Roy T. McBurney for providing alkene 7.
Figure 1. 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a) macrocycle
1, (b) [2]rotaxane 5, (c) thread 6. The assignments correspond to the lettering
shown in Scheme 1.
Table 1. Substrate Scope in the Oxidative Heck Active-Template
Synthesis of [2]Rotaxanesa
Supporting Information Available: Full experimental procedures
and characterization of all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) (a) Tsuji, J. Palladium Reagents and Catalysis: New PerspectiVes for
the 21st Century, 2nd ed.; Wiley: Chichester, 2004. (b) Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, Germany, 2004.
(2) (a) Du, X.; Suguro, M.; Hirabayashi, K.; Mori, A. Org. Lett. 2001, 3,
3313-3316. (b) Parrish, J. P.; Jung, Y. C.; Shin, S. I.; Jung, K. W. J.
Org. Chem. 2002, 67, 7127-7130. (c) Jung, Y. C.; Mishra, R. K.; Yoon,
C. H.; Jung, K. W. Org. Lett. 2003, 5, 2231-2234. (d) Inoue, A.;
Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003, 125, 1484-1485.
(e) Andappan, M. M. S.; Nilsson, P.; von Schenck, H.; Larhed, M. J.
Org. Chem. 2004, 69, 5212-5218. (f) Andappan, M. M. S.; Nilsson, P.;
Larhed, M. Chem. Commun. 2004, 218-219. (g) Enquist, P.-A.; Lindh,
J.; Nilsson, P.; Larhed, M. Green Chem. 2006, 8, 338-343. (h) Yoo, K.
S.; Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384-
16393.
(3) (a) Aucagne, V.; Ha¨nni, K. D.; Leigh, D. A.; Lusby, P. L.; Walker, D. B.
J. Am. Chem. Soc. 2006, 128, 2186-2187. (b) Berna´, J.; Crowley, J. D.;
Goldup, S. M.; Ha¨nni, K. D.; Lee, A.-L.; Leigh, D. A. Angew. Chem.,
Int. Ed. 2007, 46, 5709-5713. (c) Aucagne, V.; Berna´, J.; Crowley, J.
D.; Goldup, S. M.; Ha¨nni, K. D.; Leigh, D. A.; Lusby, P. J.; Ronaldson,
V. E.; Slawin, A. M. Z.; Viterisi, A.; Walker, D. B. J. Am. Chem. Soc.
2007, 129, 11950-11963.
(4) For stoichiometric active-metal template Ullman and Glaser coupling
rotaxane syntheses, in which the metal does not turnover, see: Saito, S.;
Takahashi, E.; Nakazono, K. Org. Lett. 2006, 8, 5133-5136.
(5) An outline of these macrocycle-Pd(0) investigations is given in the
Supporting Information. Pd(0)-catalyzed Suzuki reactions have been used
as the stoppering reaction in the synthesis of cyclodextrin rotaxanes; see:
(a) Terao, J.; Tang, A.; Michels, J. J.; Krivokapic, A.; Anderson, H. L.
Chem. Commun. 2004, 56-57. (b) Klotz, E. J. F.; Claridge, T. D. W.;
Anderson, H. L. J. Am. Chem. Soc. 2006, 128, 15374-15375. (c) Stone,
M. T.; Anderson H. L. Chem. Commun. 2007, 2387-2389.
_
a R ) (t-BuC6H4)3CC6H4O(CH2)3 . Reaction conditions: macrocycle 1
(1 equiv), Pd(OAc)2 (10 mol %), alkene (1 equiv), boronic acid (2 equiv),
and benzoquinone (1 equiv) in 1:1 CHCl3/CH2Cl2 were allowed to stir under
O2 at rt for 72 h. b Conditions as for other entries except alkene 4 (1.2
equiv), boronic acid 15 (3 equiv), no benzoquinone, 1:1 CHCl3/DMF as
solvent. All reactions were carried out at 16 mM concentration with respect
to 1 without the need for dried or distilled solvents.
(6) Studies2f-h suggest that bidentate N ligands such as bipyridine and
phenanthroline are the most effective at promoting oxidative Heck
reactions at room temperature. Carrying out the reaction in Table 1, entry
1, with a monodentate pyridine macrocycle resulted in no rotaxane
formation and only 10% conversion to the thread.
(7) Use of Cu(OAc)2 or I2 as the oxidant produced no rotaxane; O2 as the
sole oxidant produced only 26% rotaxane (other reagents and conditions
as per Table 1, entry 1). See Supporting Information for further details.
(8) According to Jung and co-workers,2h the base-free oxidative Heck cross-
coupling shows the greatest efficiency in polar aprotic solvents. However,
our rotaxane-forming reactions did not proceed efficiently in DMF (16%
yield of 5), probably due to the low solubility of the cross-coupling
partners. A 1:1 mixture of CHCl3/CH2Cl2 was found to be the optimal
solvent system for the studies presented here. See Supporting Information
for further details.
half (Hf-h). This preference of the macrocycle for the aromatic
region of the thread is probably a result of both π-stacking
interactions and solvation effects.
To examine if this new cross-coupling approach to [2]rotaxanes
is tolerant of a range of different cross-coupling partners, we
screened a number of alkene and boronic acid functionalized
stoppers, generating a variety of [2]rotaxanes (Table 1).9 Vinyl
ketone 7 and styrene derivative 8 can replace vinyl ester 4 as the
alkene cross-partner to produce the corresponding rotaxanes 9 and
10 in 70 and 50% yields, respectively. The electron-poor aryl
boronic acid 11 can also be used in place of the electron-rich aryl
boronic acid 3 without affecting the yield (12, 76%). The rotaxane-
(9) Much lower yields of rotaxane (<5%) were obtained using pinacol boronic
esters in place of boronic acids, even though the former generally gives
higher yields in base-free oxidative Heck reactions.2h This difference is
probably due to steric effects.
(10) Unoptimized yield. Rotaxane 16 proved difficult to isolate free from the
accompanying byproduct thread.
JA075219T
9
J. AM. CHEM. SOC. VOL. 129, NO. 40, 2007 12093