Orthogonal π-bridges in [2.2]paracyclophanes

Article abstract of DOI:10.1055/s-0030-1259088

Orthogonal π-bridges have been introduced into [2.2]paracyclophanes by the reaction of the pseudo-geminal bisacetylene with various monoacetylenes and nitriles. The reactions with bistrimethylsilylacetylene and dimethylacetylenedicarboxylate take place even in the absence of a catalyst. This procedure can incorporate not only aromatic but also heteroaromatic bridges, as in pyridine-annulated cyclophane. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259088

LETTER
259
Orthogonal p-Bridges in [2.2]Paracyclophanes
O
rthogonal
p-Bridges
.in[2.2]Parac
L
yclophane
s
ucian Birsa,*a,b Peter G. Jones,c Henning Hopfb
a
b
c
Received 20 October 2010
tion’ of pseudo-geminal bisacetylene 1 with triple bonds,
could provide interesting orthogonal p-systems in which a
1,3,5-cyclohexatrienoid structure might appear. The
bridging of the ortho positions of a benzene ring, thereby
Abstract: Orthogonal p-bridges have been introduced into
[2.2]paracyclophanes by the reaction of the pseudo-geminal
bisacetylene with various monoacetylenes and nitriles. The reac-
tions with bistrimethylsilylacetylene and dimethylacetylenedicar-
boxylate take place even in the absence of a catalyst. This procedure leading to bond fixation, has been observed before in the
can incorporate not only aromatic but also heteroaromatic bridges,
electrophilic aromatic chemistry of indanes and tetra-
lins.13
as in pyridine-annulated cyclophane.
Key words: [2.2]paracyclophane, cyclotrimerization, acetylenes,
We wish to report here the synthesis of orthogonal p-sys-
nitriles, aromatic bridges
tems by the cyclotrimerization of bisacetylene 1 with a
third reactive group, including alkynes and nitriles.
As a first experiment, we decided to use the transition-
[2.2]Paracyclophanes constitute an intriguing class of
metal-mediated [2+2+2] cycloaddition, such as in the
compounds, which have attracted particular interest since
well-known Vollhardt reaction.14,15 For instance, the reac-
tion of bisacetylene 1 with an excess of bis(trimethyl-
silyl)acetylene (BTMSA), in the presence of a catalytic
amount of CpCo(CO)2, was performed under high dilu-
tion conditions (Scheme 1, Table 1, entry 1).16 Purifica-
tion by column chromatography on silica gel using
dichloromethane–pentane (1:1) as eluent provided com-
pound 3a in 63% isolated yield (86% based on recovered
bisacetylene 1).17 1H and 13C NMR monitoring revealed
the disappearance of the acetylenic carbon signals and the
presence of the characteristic low field signal for the para-
hydrogen atoms of the orthogonal bridge (d = 7.74 ppm).
It should be noted that, despite the original Vollhardt pro-
tocol, no additional light was needed during the reaction.
In a separate experiment the use of a stoichiometric
amount of BTMSA relative to bisacetylene 1 rather than
an excess resulted only in intractable, presumably poly-
meric, material.
their first appearance in the literature.1–3 So far most stud-
ies have involved the structural characteristics of
[2.2]paracyclophanes, particularly their geometry and
steric properties, transannular interactions, and ring
strain; further investigations have concerned the electron-
ic interactions between the parallel aromatic rings, their
influence on reactivity in electrophilic aromatic substitu-
tion reactions, and their implications for charge-transfer
complex formation.4–7 Much interest still centers on the
development of new synthetic methods for functionalized
[2.2]paracyclophanes and the design of appropriately sub-
stituted [2.2]paracyclophanes that can serve as polycyclic
hydrocarbon precursors or as chiral templates or auxilia-
ries.8 However, the introduction of new bridges, especial-
ly aromatic, heterosubstituted, and functionalized bridges,
has been neglected so far.
Cyclophanes are ideal model systems to investigate
whether and how functionalized groups can interact and
react with each other. Because of the rigid molecular
framework provided by the paracyclophane moiety and its
short interannular distance, functional groups in pseudo-
geminally substituted [2.2]paracyclophanes are often held
in such a position as to allow highly specific reactions to
take place between them. In one such application, unsat-
urated cyclophane bisesters undergo intramolecular pho-
tocyclization to the corresponding ladderane isomers.9–11
The pseudo-geminal bisacetylene 1 is an interesting build-
ing block for molecular scaffolding,12 since the ethynyl
functions can easily be connected by various coupling re-
actions. One such application, the formal ‘cyclotrimeriza-
R1
R1
R2
CpCo(CO)2
C
C
+
Δ
R2
1
2a–d
3a–d
a: R1 = R2 = TMS; b: R1 = R2 = COOMe;
c: R1 = R2 = Ph; d: R1 = COOEt, R2 = H
Scheme 1
In order to prove the generality of this type of cycloaddi-
tion we performed the same reaction using dimethyl acet-
ylenedicarboxylate (DMAD) as an activated alkyne.
Taking into account the thermal sensitivity of DMAD, the
above experimental procedure was modified in terms of
SYNLETT 2010, No. 2, pp 0259–0261
x
x.
x
x.
2
0
1
0
Advanced online publication: 07.12.2010
DOI: 10.1055/s-0030-1259088; Art ID: G29210ST
© Georg Thieme Verlag Stuttgart · New York

260
M. L. Birsa et al.
LETTER
syringe injection of the reagents to boiling xylene over 16
hours (Scheme 1, Table 1, entry 2). Purification by col-
umn chromatography over silica gel using dichlo-
romethane as the eluent provided compound 3b in 73%
isolated yield.18 The 1H NMR spectra again indicated the
characteristic signal for the para-hydrogen atoms of the
orthogonal bridge (d = 7.89 ppm).
Table 1 Reaction Conditions and Yields for Cyclotrimerization
Entry Acetylene
Solvent
p-xylene
p-xylene
p-xylene
toluene
Catalyst
yes
Yield (%)
1
2
3
4
5
6
BTMSA
63
73
28
43
18
24
DMAD
yes
PhC≡CPh
HC≡CCOOEt
BTMSA
yes
At this point, conformation of the structure of the pro-
posed cyclotrimerization products was considered a prior-
ity. Although the cyclophane diester 3b was found to be
disordered and the refinement of the crystal structure was
impossible, the molecular structure of compound 3a was
unambiguously proved by X-ray crystallography (Figure
1).19 The introduction of the new bridge does not greatly
influence the flattened boat form of the paracyclophane
rings, but instead renders them significantly nonparallel
(interplanar angle 13°); appreciable strain is also seen in
the angles C3–C22–C21 and C15–C17–C18 [both
125.9(1)°].
yes
p-xylene
p-xylene
no
DMAD
no
tions to less reactive triple bonds, such as nitriles. The in-
teraction of nitriles with bisacetylene 1 should provide a
new orthogonal p-system with a heteroatom in the aro-
matic bridge. Following the typical experimental proce-
dure described above, the pyridine-annulated
[2.2.2](1,2,4)cyclophanes 5a and 5b were indeed success-
fully obtained in the presence of the cobalt catalyst, the
latter being of crucial importance (Scheme 2). Compound
5a was obtained in 29% isolated yield using xylene as sol-
vent, whereas 5b was obtained in 25% isolated yield in
toluene. The structures of the pyridine-annulated cyclo-
phanes have been confirmed by analytical and spectral da-
ta. The mass spectra were consistent with the molecular
weight of 5a (C27H20N2O2, m/z = 404)20 and 5b
(C30H25NO2, m/z = 431), while the 1H and 13C NMR spec-
tra clearly indicate an asymmetric structure induced by the
pyridine nitrogen atom.
R
R
CpCo(CO)2
C
+
Δ
N
N
Figure 1 Molecular structure of 3a; ellipsoids represent 50% proba-
bility levels
1
4a,b
5a,b
a: R = 4-O2NC6H4
b: R = 4-EtOOCC6H4
Following the successful determination of the structure of
the cyclotrimerization products, we decided to explore the
limitations of this new synthetic method by using less ac-
tivated alkynes. Using the typical experimental procedure
the reaction of pseudo-geminal bisacetylene 1 with diphe-
nylacetylene provided compound 3c in 28% isolated yield
(pentane as eluent, Scheme 1, Table 1, entry 3). In a fourth
experiment compound 3d was obtained from bisacetylene
1 and ethyl propiolate using toluene as solvent (Scheme 1,
Table 1, entry 4).
Scheme 2
The reported cyclotrimerization reactions open the way
for new functionalized polycyclic structures. The trimeth-
ylsilyl groups from 3a can easily be replaced by bromine
or iodine; ester groups from 3b and 3d may be reduced to
the corresponding alcohols and then converted to various
substituted polycyclic compounds. It also should be
stressed that this reaction not only provides aromatic, but
also heteroaromatic bridges for the [2.2]paracyclophane
nucleus, the pyridine-annulated cyclophanes 5a,b being
the first reported compounds of the latter class. Further in-
vestigations will be focused on exploring the reactivity of
pseudo-geminal bisacetylene 1 towards other reactive
compounds such as olefins, cumulenes, and heterocumu-
lenes.
The parallel orientation of the triple bonds in the
[2.2]paracyclophane derivative 1 might constitute a pre-
requisite for an uncatalyzed cyclotrimerization. In order to
check this assumption, the previous four acetylenes were
separately added to a boiling solution of 1 in the absence
of the cobalt catalyst. Interestingly, the most reactive two
acetylenes, BTMSA and DMAD, successfully provided
the corresponding adducts 3a and 3b (Table 1, entries 5
and 6). This finding prompted us to extend our investiga-
Synlett 2010, No. 2, 259–261 © Thieme Stuttgart · New York

LETTER
Orthogonal p-Bridges in [2.2]Paracyclophanes
261
33.5 (t), 35.4 (t), 130.5 (d), 130.8 (d), 132.8 (d), 139.1 (d),
139.3 (s), 141.0 (s), 143.6 (s), 144.8 (s), 145.1 (s). MS (EI):
m/z (%) = 426 (100)[M+], 398 (81), 338 (41), 279 (34), 184
(22), 167 (23), 149 (40). Anal. Calcd for C28H34Si2: C, 78.81;
H, 8.03. Found: C, 78.52; H, 7.89.
Acknowledgment
Part of this work was supported by CNCSIS –UEFISCSU, project
number PNII – IDEI 2095/2008.
(18) Analytical Data of Compound 3b
References and Notes
Yield 145 mg (73%); mp 162–163 °C. IR (ATR): 2927,
1719, 1438, 1325, 1262, 1243, 1120, 1066, 952, 783, 614
cm–1. 1H NMR (200 MHz, CDCl3, TMS): d = 2.52 (m, 4 H,
2 CH2), 3.05 (m, 4 H, 2 CH2), 3.95 (s, 6 H, 2 CH3), 6.20 (d,
2 H, 4J = 2.0 Hz, 2 CHar), 6.39 (d, 2 H, 3J = 8.0 Hz, 2 CHar),
6.52 (dd, 2 H, 3J = 8.0 Hz, 4J = 2.0 Hz, 2 CHar), 7.89 (s, 2 H,
2 CHar). 13C NMR (50 MHz, CDCl3, TMS): d = 33.1 (t), 35.4
(t), 52.7 (q), 124.9 (d), 130.9 (s), 131.5 (d), 133.1 (d), 138.5
(d), 139.6 (s), 140.1 (s), 141.8 (s), 149.3 (s), 168.1 (s). MS
(EI): m/z (%) = 398 (100)[M+], 370 (60), 339 (35), 279 (39),
265 (32), 252 (23). Anal. Calcd for C26H22O4: C, 78.39; H,
5.52. Found: C, 78.61; H, 5.41.
(1) Brown, C. J.; Farthing, A. C. Nature (London) 1949, 164,
915.
(2) Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1951, 73, 5691.
(3) Vögtle, F.; Neumann, P. Synthesis 1973, 85.
(4) Staab, H. A.; Knaus, G. H.; Henke, H.-E.; Krieger, C. Chem.
Ber. 1983, 116, 2785.
(5) Boekelheide, V. Top. Curr. Chem. 1983, 113, 87.
(6) Hopf, H.; Marquard, C. In Strain and its Implications in
Organic Chemistry; de Meijere, A.; Blechert, S., Eds.;
Kluwer: Dordrecht, 1983, 297.
(7) Vögtle, F. Cyclophane Chemistry, Synthesis, Structure and
Reactions; Wiley: Chichester, 1993, 71.
(8) Rozenberg, V. I.; Sergeeva, E. V.; Hopf, H. In Modern
Cyclophane Chemistry; Gleiter, R.; Hopf, H., Eds.; Wiley-
VCH: Weinheim, 2004, Chap. 17, 435.
(9) Greiving, H.; Hopf, H.; Jones, P. G.; Bubenitschek, P.;
Desvergne, J.-P.; Bouas-Laurent, H. Eur. J. Org. Chem.
2005, 558.
(10) Hopf, H.; Greiving, H.; Beck, C.; Dix, I.; Jones, P. G.;
Desvergne, J.-P.; Bouas-Laurent, H. Eur. J. Org. Chem.
2005, 567.
(19) (a) Crystal Structure Determination of 3a – Crystal Data
Orthorhombic, space group P212121, a = 11.9328 (11),
b = 12.6273 (12), c = 15.8769 (15) Å, Z = 4, T = 100 K.
Data Collection
A crystal ca. 0.3 × 0.2 × 0.17 mm3 was used to record 89806
intensities to 2q 63° on a Bruker APEX-2 diffractometer
using Mo Ka radiation (l = 0.71073 Å).
Structure Refinement
The structure was refined anisotropically on F2 (program
SHELXL-97)17b to wR2 = 0.0861, R1 = 0.0320 for 277
parameters and 7929 unique reflexions. Data have been
deposited in Cambridge under the number CCDC-796776.
(b) Sheldrick, G. M. Acta Crystallogr., Sect. A.: Fundam.
Crystallogr. 2008, 64, 112.
(11) For a review, see: Hopf, H. Angew. Chem. Int. Ed. 2003, 42,
2822; Angew. Chem. 2003, 115, 2928.
(12) Bondarenko, L.; Dix, I.; Hinrich, H.; Hopf, H. Synthesis
2004, 2751.
(20) Analytical Data of Compound 5a
(13) Mills, W. H.; Nixon, I. G. J. Chem. Soc. 1930, 2510.
(14) Vollhardt, K. P. C. Acc. Chem. Res. 1977, 10, 1.
(15) Funk, R. L.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1980, 102,
5253.
(16) Typical Procedure for Cyclotrimerization
To a boiling solution of xylene (30 mL) a solution of
bisacetylene 1 (0.5 mmol), acetylene 2a–c (2.5 mmol), and
CpCo(CO)2 (5 mol%) in xylene (20 mL) was added with a
syringe pump over 16 h. The solvent was evaporated under
vacuum, and the residue purified by column
Yield 58 mg (29%); mp 133–134 °C. IR (ATR): 2930, 1595,
1517, 1460, 1336, 1317, 1105, 855, 721 cm–1. 1H NMR (600
MHz, CDCl3, TMS): d = 2.61–2.80 (m, 4 H, 2 CH2), 3.03–
3.13 (m, 4 H, 2 CH2), 2.95 (m, 4 H, 2 CH2), 6.26 (d, 1 H,
4J = 1.9 Hz, CHar), 6.29 (d, 1 H, 4J = 1.9 Hz, CHar), 6.46 (d,
1 H, 3J = 8.1 Hz, CHar), 6.48 (d, 1 H, 3J = 8.1 Hz, CHar), 6.57
(dd, 1 H, 3J = 8.1 Hz, 4J = 1.9 Hz, CHar), 6.59 (dd, 1 H,
3J = 8.1 Hz, 4J = 1.9 Hz, CHar), 8.03 (s, 1 H, CHar), 8.31 (d,
2 H, 3J = 8.0 Hz, 2 CHar), 8.39 (d, 2 H, 3J = 8.0 Hz, 2 CHar),
8.89 (s, 1 H, CHar). 13C NMR (150 MHz, CDCl3, TMS):
d = 33.0 (t), 33.3 (t), 35.3 (t), 35.4 (t), 117.1 (d), 124.1 (d),
127.8 (d), 131.7 (d), 131.8 (d), 133.3 (d), 133.5 (d), 137.7
(d), 139.2 (d), 139.6 (s), 139.7 (s), 140.0 (s), 140.3 (s), 140.5
(s), 141.3 (s), 141.9 (s), 144.9 (d), 145.3 (s), 148.2 (s), 154.1
(s), 155.9 (s). MS (EI): m/z (%) = 404 (100)[M+], 389 (15),
359 (45), 283 (12), 190 (86), 176 (31). Anal. Calcd for
C27H20N2O2: C, 80.20; H, 4.95. Found: C, 80.34; H, 4.79.
chromatography on silica gel.
(17) Analytical Data of Compound 3a
Yield 134 mg (63%); mp 158–159 °C. IR (ATR): 3342,
1611, 1432, 1342, 1297, 1031, 771, 755 cm–1. 1H NMR (400
MHz, CDCl3, TMS): d = 0.36 (s, 18 H, 6 CH3), 2.47 (m, 2 H,
CH2), 2.51 (m, 2 H, CH2), 2.95 (m, 4 H, 2 CH2), 6.24 (d, 2
H, 4J = 2.0 Hz, 2 CHar), 6.33 (d, 2 H, 3J = 7.9 Hz, 2 CHar),
6.42 (dd, 2 H, 3J = 7.9 Hz, 4J = 2.0 Hz, 2 CHar), 7.74 (s, 2 H,
2 CHar). 13C NMR (100 MHz, CDCl3, TMS): d = 2.2 (q),
Synlett 2010, No. 2, 259–261 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.