Preparation of cyclophanes by room-temperature ring-closing alkyne metathesis with Lmidazolin-2-iminato tungsten alkylidyne complexes

Article abstract of DOI:10.1021/ol800154y

Room-temperature ring-closing alkyne metathesis of 1,2-, 1,3-, and 1,4-bis(3-pentynyloxymethyl)benzenes has been investigated in the presence of catalytic amounts of an imidazolin-2-iminato tungsten alkylidyne complex. The m- and p-diynes selectively form the respective [10]metacyclophane or [10.10]paracyclophane, respectively, whereas a mixture of monomeric and dimeric cycloalkynes is obtained in the case of the o-diyne. DFT calculations reveal that the different selectivities can be attributed to the relative thermodynamic stability of the emerging cyclophanes.

Full text of DOI:10.1021/ol800154y

ORGANIC
LETTERS
2008
Vol. 10, No. 5
981-984
Preparation of Cyclophanes by
Room-Temperature Ring-Closing Alkyne
Metathesis with Imidazolin-2-iminato
Tungsten Alkylidyne Complexes
Stephan Beer,† Kai Brandhorst,†,‡ Jorg Grunenberg,‡ Cristian G. Hrib,†
1
Peter G. Jones,† and Matthias Tamm*,†
Institut fu¨r Anorganische und Analytische Chemie and Institut fu¨r Organische Chemie,
Technische UniVersita¨t Carolo-Wilhelmina, Hagenring 30, D-38106 Braunschweig,
Germany
m.tamm@tu-bs.de
Received January 22, 2008
ABSTRACT
Room-temperature ring-closing alkyne metathesis of 1,2-, 1,3-, and 1,4-bis(3-pentynyloxymethyl)benzenes has been investigated in the presence
of catalytic amounts of an imidazolin-2-iminato tungsten alkylidyne complex. The m- and p-diynes selectively form the respective
[10]metacyclophane or [10.10]paracyclophane, respectively, whereas a mixture of monomeric and dimeric cycloalkynes is obtained in the case
of the o-diyne. DFT calculations reveal that the different selectivities can be attributed to the relative thermodynamic stability of the emerging
cyclophanes.
Alkene metathesis has revolutionized both organic chemistry
and material science in an extraordinary fashion.1 In par-
ticular, ring-closing metathesis (RCM) of dienes has emerged
during the past decade as an excellent tool for the synthesis
of complex natural products, although the lack of stereo-
control of the newly formed double bond is still a shortcom-
ing.2 This drawback can be avoided by the application of
ring-closing alkyne metathesis (RCAM) of diynes, which
allows a subsequent semireduction of the C-C triple bond
in the cycloalkyne either by Lindlar reduction or by hy-
† Institut fu¨r Anorganische und Analytische Chemie.
‡ Institu¨t fu¨r Organische Chemie.
(1) For reviews, see: (a) Clavier, H.; Grela, K.; Kirschning, A.; Mauduit,
M.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 6786-6801. (b) Schrock,
R. R.; Czekelius, C. AdV. Synth. Catal. 2007, 349, 55-77. (c) Chauvin, Y.
Angew. Chem., Int. Ed. 2006, 45, 3740-3747. (d) Schrock, R. R. Angew.
Chem., Int. Ed. 2006, 45, 3748-3759. (e) Grubbs, R. H. Angew. Chem.,
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2005, 176, 89-119. (g) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140.
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S. T.; Giessert, A. J. Chem. ReV. 2004, 104, 1317-1382. (j) Schrock, R.
R.; Hoveyda, A. H. Angew. Chem. 2003, 115, 4740-4782; Angew. Chem.,
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2003, 115, 1944-1968; Angew. Chem., Int. Ed. 2003, 42, 1900-1923. (l)
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10.1021/ol800154y CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/06/2008

drosilylation/protodesilylation to obtain selectively the re-
spective Z- or E-alkenes.3 However, only a limited number
of well-defined alkylidyne complexes are known to date that
fulfill the expectations for an alkyne metathesis catalyst with
regard to its activity, substrate compatibility, and required
reaction temperature.4 Among these, the neopentylidyne
complex [Me3CCtW(OCMe3)3] represents the most widely
used tungsten-based species.5 In addition, several catalytically
active systems have been established that are based on
Mo(CO)6 and phenol additives6 or that rely on the activation
of molybdenum(III)triamido complexes of the general type
[Mo{N(tBu)Ar}3].7 Recently, we have introduced well-
defined imidazolin-2-iminato tungsten alkylidyne complexes
such as 1 (Scheme 1), which exhibit unprecedented catalytic
by alkyne metathesis would allow convenient access to
unsaturated derivatives of [10]cyclophanes, a class of
compounds originally established more than 50 years ago
by Cram and co-workers.9,10
The diynes 2 were prepared by Williamson etherification
of 3-pentyn-1-ol with the appropriate 1,2-, 1,3-, or 1,4-
dibromoxylenes, respectively. In a typical experiment,
RCAM was achieved by stirring a 4.5 mM solution of 2a-c
and the catalyst 1 (2 mol %) in hexane at room temperature
under reduced pressure (350 mbar) to remove 2-butyne
continuously. After 2 h, the reaction mixture was filtered
through alumina to remove the catalyst, and evaporation of
the solvent afforded white crystalline solids, which were
analyzed by NMR and GC/MS techniques. In the case of
2b, exclusive formation of a single product was observed,
1
which exhibits a characteristic H NMR resonance at 8.30
ppm in CDCl3 assignable to the arylic proton in the
2-position. This significant downfield shift can be attributed
to the penetration of this hydrogen atom into the deshielding
area of the C-C triple bond, an observation that clearly
suggested the formation of the [10]metacyclophane 3b in
an exceptionally selective manner.11 This assumption was
unequivocally confirmed by an X-ray diffraction analysis of
single crystals obtained in 93% yield by cooling of a hexane
solution to 4 °C. The molecular structure of 3b is shown in
Figure 1, revealing the existence of an unstrained 13-
Scheme 1
activity in alkyne cross-metathesis (ACM) of 1-phenylpro-
pynes at ambient temperature.8 Efficient RCAM to afford a
dioxacycloalkyne was also achieved and, in continuation of
this work, we present a comparative study of the impact of
the substitution pattern on the cyclization of o-, m- and p-bis-
(3-pentynyloxymethyl)benzenes, 2. Successful ring-closure
Figure 1. ORTEP diagrams of 3b (left) and 4c (right) with thermal
displacement parameters drawn at 50% probability. Selected bond
lengths [Å] and angles [deg] in 3b/4c: C1-C2 1.189(5)/1.188(5),
C1-C2-C3 178.1(4)/177.9(4), C2-C1-C12 177.9(4)/177.2(4).
(3) (a) Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. Chem. Eur. J. 2001,
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membered ring with C-H distances of 3.02 Å between the
hydrogen atom H7 and the alkyne carbon atoms C1 and C2.
It should be noted, however, that significantly shorter
intermolecular contacts are observed, e.g., C1‚‚‚H11 ) 2.86
Å and C2‚‚‚H11 ) 2.83 Å.
(7) (a) Fu¨rstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc.
1999, 121, 9453-9454. (b) Tsai, Y.-C.; Diaconescu, P. L.; Cummins, C.
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982
Org. Lett., Vol. 10, No. 5, 2008

Employing 2c also resulted in the clean formation of a
single product, which precipitated from hexane solution in
the course of the RCAM reaction. Recrystallization from
CHCl3 afforded a single-crystalline material in 68% yield,
which proved to be the [10.10]paracyclophane 4c by X-ray
diffraction analysis.12 The molecule resides on a crystal-
lographic inversion center, generating a highly symmetric
28-membered ring with coplanar aromatic rings and alkyne
moieties (Figure 1). At first, the absence of any detectable
amounts of monomeric 3c is somewhat surprising in view
of the large number of [10]paracyclophanes, including the
cycloalkyne 5-[10]paracyclophyne,9a which have been syn-
thesized by acyloin ring closure.9 However, this observation
is in agreement with a previous report on the cyclization of
xylylene-bridged bis(oxyphenylpropynes), which failed to
give the 14-membered tolane derivative in case of a para-
substituted diyne substrate.13 Furthermore, it should be
emphasized that the synthesis of the [10.10]paracyclophane
4c by alkyne metathesis resembles the method for the
preparation of naturally occurring [n,n]paracyclophanes
(cylindrocyclophanes) by olefin metathesis dimerization.14
In contrast to the selective RCAM reactions of 2b and
2c, the use of the ortho-substituted isomer 2a produced a
mixture of 3a and 4a in a 24:76 ratio, determined by
integration of the well-resolved 1H NMR resonances of the
benzylic and aliphatic CH2O hydrogen atoms. Both isomers
could be separated by fractional crystallization, and single
crystals of the [10]orthocyclophane 3a could be obtained
from the supernatant hexane solution after removal of dimeric
4a. An X-ray diffraction analysis confirmed the formation
of a 12-membered ring; however, the structure could not be
adequately refined because of modulation and twinning
effects. Attempts to interpret the data in a more satisfactory
manner are ongoing.
reaction,14a,b,16 it is reasonable to propose that the catalyst 1,
which is active at room temperature, is able to establish an
equilibrium between 3 and 4 by reversible ring-opening and
ring-closing metathesis (RORCM)17 reactions (eq 1)
3 + 3 h 4
(1)
and that the associated standard Gibbs free energies ∆G°
dictate the respective product ratios. Table 1 summarizes the
Table 1. Gibbs Free Energies ∆G° and Equilibrium Constants
Kc for the Reaction of Two Molecules 3 to Form Dimeric 4
∆G°
(kcal mol-1
Kc ) [4]/[3]2
(M-1
calcd
ratiob
exp.
ratioc
a
isomers
)
)
o- (3a, 4a)
m- (3b, 4b)
p- (3c, 4c)
-2,78
+4.00
-9.66
1.1 × 102
1.1 × 10-3
1.2 × 107
77:23
100:0
1:99
24:76
100:0
0:100
a ∆G° ) -RT ln Kc (T ) 298 K). b Calculated molar ratio for
c0(monomer) ) 4.5 mM. c Experimental molar ratio for c0(monomer) )
4.5 mM.
∆G° values and the corresponding equilibrium constants Kc
together with the calculated and experimental ratios. The
calculations fully confirm our experimental observations,
since the equilibrium should lie almost completely on the
(15) The gas-phase global minima were obtained by full conformational
analysis using the MMFF94 force field (Halgren, T. A J. Comp. Chem.
1996, 17, 490-519) together with a Monte Carlo torsional sampling as
implemented in the Macromodel 9.5 program (MacroModel, version 9.5;
Schro¨dinger, LLC: New York, 2007). The respective lowest-energy
conformation was optimized by applying density functional theory. The
B3LYP hybrid functional (Becke, A. D. J. Chem. Phys. 1993, 98, 5648-
5652) was employed, and all atoms were described by the 6-311G(d,p)
basis set. Enthalphic and entropic contributions were calculated by statistical
thermodynamics as implemented in the Gaussian03 set of programs (Frisch,
M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant,
J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.;
Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels,
A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian03,
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To rationalize the striking differences in the selectivity of
the RCAM reactions with 2a, 2b, and 2c, we carried out a
series of DFT calculations on all six cyclophanes 3 and 4.15
In analogy to the reversible nature of the olefin metathesis
(10) For books on cyclophanes, see: (a) Gleiter, R., Hopf, H., Eds.
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1993.
(11) For instance, the corresponding saturated all-carbon [10]metacy-
clophane could be obtained in 9% and 22% yield by using Suzuki-Miyaura
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Smith, B. B.; Hill, D. E.; Cropp, T. A.; Walsh, R. D.; Cartrette, D.; Hipps,
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Begley, M. J. J. Chem. Soc., Perkin Trans. I 1996, 1141-1151.
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to close 10 to 14 under different conditions failed with a variety of catalytic
in situ systems”. This is in conflict with an erroneous illustration in Scheme
1 of their report, which indicates a yield of 18% for the 14-membered cyclic
monomer.
(14) (a) Smith, A. B., III; Adams, C. M.; Kozmin, S. A.; Paone, D. V.
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Org. Lett., Vol. 10, No. 5, 2008
983

monomer side in case of 3b/4b and on the dimer side in
case of 3c/4c. In contrast, the calculations for the ortho
system reveal that both 3a and 4a should be present in
detectable amounts for an initial monomer concentration of
c0 ) 4.5 mM.
the monomer-to-dimer ratio for the ortho system 3a/4a. In
contrast, the meta monomer remains the only detectable
species at relevant concentrations (up to one mol L-1),
whereas significant amounts of the experimentally elusive
para monomer should only form under very high dilution
conditions. We emphasize that consideration of only mono-
mers and dimers represents an oversimplification, since a
more detailed description must also take into account the
formation of larger oligomeric species, in particular at higher
concentration. Furthermore, kinetic effects should also be
contemplated in the future, but we assume that the differences
in energy between relevant transition states are in a similar
order of magnitude as the energy differences between the
monomeric and dimeric cycloalkynes 3 and 4, so that their
relative thermodynamic stability is a good measure for
predicting the outcome of reversible ring-closing reactions.
Figure 2 shows the calculated ratios 3:4 against the initial
Figure 2. Molar fraction of [10]cyclophanes 3 as a function of
the initial monomer concentration c0.
Supporting Information Available: Full synthetic, char-
acterization, theoretical calculation, and X-ray structural
details. This material is available free of charge via the
Internet at http://pubs.acs.org.
monomer concentration in the range 10-7-104 M. As
expected, variation of the concentration most strongly affects
OL800154Y
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Org. Lett., Vol. 10, No. 5, 2008