Synthesis of the syn and anti isomer of 1,4,5,8,9,12-hexahydro-2,3,6,7,10,11-hexamethylidene-1,4:5,8:9,12- trimethanotriphenylene and Diels-Alder reactivity of the syn isomer

Article abstract of DOI:10.1016/S0040-4039(02)02533-9

The title compounds, new members in the class of tris-annelated benzenes with [2.2.1] bicyclic rings, were obtained in high yields by coupling of 2-bromo-3-trimethyltin-5,6-dimethylenenorborn-2-ene with copper(I) 2-thiophenecarboxylate (CuTC). The syn iso

Full text of DOI:10.1016/S0040-4039(02)02533-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 561–563
Synthesis of the syn and anti isomer of
1,4,5,8,9,12-hexahydro-2,3,6,7,10,11-hexamethylidene-1,4:5,8:9,12-
trimethanotriphenylene and Diels–Alder reactivity of
the syn isomer
Giuseppe Borsato,a Ottorino De Lucchi,b Fabrizio Fabris,b Vittorio Lucchini,a,* Marco Pasqualottia
and Alfonso Zambona
aDipartimento di Scienze Ambientali, Universita` Ca’ Foscari di Venezia, Dorsoduro 2137, I-30123 Venezia, Italy
bDipartimento di Chimica, Universita` Ca’ Foscari di Venezia, Dorsoduro 2137, I-30123 Venezia, Italy
Received 30 October 2002; accepted 12 November 2002
Abstract—The title compounds, new members in the class of tris-annelated benzenes with [2.2.1] bicyclic rings, were obtained in
high yields by coupling of 2-bromo-3-trimethyltin-5,6-dimethylenenorborn-2-ene with copper(I) 2-thiophenecarboxylate (CuTC).
The syn isomer was reacted with 3 equiv. of the dienophiles TCNE, DMAD, PTAD and norbornadiene to afford the
corresponding cycloadducts. © 2002 Elsevier Science Ltd. All rights reserved.
Benzene rings annelated with three [2.2.1] bicyclic moi-
eties present excellent characteristics as potential host
molecules in the field of supramolecular chemistry.
These compounds come into two configurations, syn
(where the methano bridges are co-oriented) and anti.
Quite evidently, the syn isomers offer better features as
host structures.
The synthesis of the tris-annelated benzenes 1 was
accomplished by cyclotrimerization of the monomer 5.
In turn, the monomer was obtained with the synthetic
path presented in Scheme 1.
The Diels–Alder addition of the E:Z mixture of 1,4-
dichloro-2-butene to cyclopentadiene gave the two iso-
mers of 5,6-di(chloromethyl)bicyclo[2.2.1]hept-2-ene 2.2
Bromination afforded the mixture of dibromides 3,3
that was subjected to exhaustive dehydrohalogenation
with KOH in refluxing ethanol, yielding 4 as the sole
species. Bromide 4 was lithiated by a twofold excess of
lithium diisopropylamide in the presence of trimethyltin
chloride to give the properly functionalized triene 5.
These molecules can be synthesized by coupling of three
vic-bromotrimethylstannyl[2.2.1]bicyclo olefins, medi-
ated by copper salts.1 The statistical 1:3 syn to anti ratio
is frequently even more in favour of the anti isomer
because of the steric hindrance of the ‘arms’. Therefore,
syn trimers with long and functionalized ‘arms’, which
appear as most interesting host molecules, may be
generated in negligible quantity with respect to the anti
isomers. One possible way out of this problem is the
synthesis of syn trimers with short ‘arms’, however
functionalized with groups which may allow their
lengthening. The feasibility of this project was tested
with the title compound 1 in the syn configuration, by
the reaction of the heterocyclic dienic groups with
selected dienophiles.
The cyclotrimerization reaction was a crucial step.
Early attempts with the Cu(NO3)2·3H2O promoter
failed to afford the desired cyclotrimers, leading to the
formation of complex mixtures of products (the charac-
terized products were the protodestannylated monomer
4 and the dibromodimers 6, in the Cs and C2
configuration).
* Corresponding author. Tel.: 0039 41 2348619; fax: 0039 41 2348584;
e-mail: lucchini@unive.it
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02533-9

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G. Borsato et al. / Tetrahedron Letters 44 (2003) 561–563
Scheme 1. Reagents, conditions (yields): i: benzene, 175°C
(40%); ii: Br2, CCl4, 70°C (98%); iii: KOH, EtOH, reflux
(70%); iv: LDA, Me3SnCl, THF, rt (90%); v: CuTC, NMP, rt
(98%).
Figure 1. Part of the NOESY spectrum of syn-10. The dipo-
lar interactions between proton H8a and protons H4 are
highlighted.
At variance, the reaction of the monomer 5 with a
stoichiometric amount of copper(I) 2-thiophenecar-
boxylate (CuTC)4,5 in NMP afforded a 1:4 mixture of
syn and anti cyclotrimers 1 in almost quantitative
yield.6 Because of the small steric hindrance exerted by
the exocyclic dienic system, the isomer ratio is not too
far from the statistical 1:3 ratio. The isomers were
separated by chromatography (silica gel, eluant
dichloromethane–hexanes 3:7) and recrystallized from
methanol.
The characterization of the two isomers rests on
NMR.6 Particularly informative are the patterns and
the number of signals in 1H and 13C spectra which
reflect the C3v and Cs symmetries of syn-1 and anti-1.
The Diels–Alder reactivity of syn-1 was tested toward
strong dienophiles, as TCNE, dimethylacetylene dicar-
1
boxylate (DMAD), PTAD and O2, and also toward
the weaker norbornadiene. Conditions and results are
reported in Table 1. The tris-adducts syn-7, syn-8,
syn-9 and syn-10 have been fully characterized by the
usual NMR techniques.6
drastic conditions. The reaction with 1O2, by irradiation
of syn-1 in CDCl3 for 2 h with visible light (100 W)
under O2 bubbling and in the presence of catalytic
amounts of TPP, led to the formation of non-symmetri-
cal intermediates that decomposed upon further
irradiation.
syn-1 Proved to be less reactive than the monomeric
subunits 5,6-dimethylidenebicyclo[2.2.1]hept-2-ene or
2,3-dimethylidene-1:4-methanonaphthalene,7 requiring
Table 1. Results of the Diels–Alder additions to syn-1
Dienophile
Solvent
Dienophile:syn-1 ratio
Adduct
Temp. (°C), time (h)
Yield (%)
TCNE
CHCl3
CHCl3
CHCl3
CDCl3
Neat
3:1
3:1
3:1
Excess
Excess
syn-7
syn-8
25, 0.3
25, 0.3
100, 48
25, 2
100
100
50
–
70
DMAD
PTAD
syn-9
1O2
a
Norbornadiene
syn-10
100, 7
a Unrecognized decomposition products.

G. Borsato et al. / Tetrahedron Letters 44 (2003) 561–563
563
Although a weak dienophile, norbornadiene added to
syn-1 with satisfactory yield. Remarkably, the reaction
is highly stereoselective: the tris-adduct syn-10 could be
recovered as major product, where the methano bridge
belonging to former syn-1 and the methano bridge
belonging to former norbornadiene are co-oriented.
The orientation is demonstrated by the detection (by
NOESY, see Fig. 1) of dipolar interactions between the
‘inner’ proton of the methano bridge in the norbornene
moiety (H8a in structure syn-10) and two methylene
protons of the cyclohexene ring (H4). For steric rea-
sons, norbornadiene can only approach the exo face of
the dienic systems of syn-1. Stabilizing secondary
orbital interactions (phase concordance) are possible
between the LUMO of the dienic system of syn-1 and
the HOMO of norbornadiene, either with the contribu-
tion to this orbital of the outer p(CHꢀCH) system (endo
approach of norbornadiene), or with the p(CH2) contri-
bution (exo approach).8 The exo approach appears to
be sterically less demanding, leading to the tris-adduct
syn-10.
2. (a) Bowe, M. A. P.; Miller, R. G. J.; Rose, J. B.; Wood,
D. G. M. J. Chem. Soc. 1960, 1541; (b) Toda, T.; Ohaya,
T.; Mukai, T. Bull. Chem. Soc. Jpn. 1972, 45, 1561.
3. Wilt, J. W.; Chenier, P. J. J. Org. Chem. 1970, 35, 1562.
4. (a) Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem.
1997, 62, 2312; (b) Allred, G. D.; Liebeskind, L. S. J.
Am. Chem. Soc. 1996, 118, 2748.
5. Borsato, G.; De Lucchi, O.; Fabris, F.; Groppo, L.; Luc-
chini, V.; Zambon, A. J. Org. Chem. 2002, 67, 7894.
6. syn-1: mp 250°C (dec.); 1H NMR (CDCl3, 400 MHz) l
5.05 (6H, s), 4.91 (6H, s), 3.84 (6H, t, J=1.6 Hz), 2.05
(3H, dt, J=8.6, 1.6 Hz), 1.91 (3H, dt, J=8.6, 1.6 Hz);
13C NMR (CDCl3, 100 MHz) l 148.10, 135.65, 101.87,
51.27, 50.25. anti-1: mp 230°C (dec.); 1H NMR (CDCl3,
400 MHz) l 5.18 (2H, s), 5.113 (2H, s), 5.107 (2H, s),
5.05 (2H, s), 5.01 (2H, s), 4.96 (2H, s), 3.86 (2H, m),
3.837 (2H, m), 3.833 (2H, m), 2.01 (2H, dt, J=8.6, 1.5
Hz), 1.95 (1H, dt, J=8.6, 1.5 Hz) 1.89 (2H, dt, J=8.6,
1.6 Hz), 1.86 (1H, dt, J=8.6, 1.7 Hz); 13C NMR (CDCl3,
100 MHz) l 149.25, 149.08, 148.15, 136.56, 135.82,
135.80, 101.89, 101.72, 101.57, 50.98, 50.74, 50.33, 50.27,
50.17. syn-10: mp 215°C (dec.); 1H NMR (CDCl3, 400
MHz) l: 5.99 (6H, m, H7), 3.51 (6H, t, H2, J=1.6 Hz),
2.42 (6H, t, H6, J=1.8 Hz), 2.23 (6H, m, H4%), 2.14 (3H,
dt, H9a, J=6.9, 1.6 Hz), 2.02 (6H, m, H4), 2.01 (3H, dt,
H9s, J=6.9, 1.6 Hz), 1.63 (3H, dt, H8a, J=8.3, 1.7 Hz),
1.30 (6H, m, H5), 1.29 (3H, dt, H8s, J=8.3, 1.7); 13C
NMR (CDCl3, 100 MHz) l: 146.23 (6C, C3), 137.27 (6C,
C7), 137.10 (6C, C1), 62.44 (3C, C9), 50.86 (6C, C6), 50.56
(6C, C2), 44.29 (3C, C8), 37.83 (6C, C5), 29.73 (6C, C4).
The assignments refer to the non-IUPAC numbering
reported with the structure.
Acknowledgements
This work was cofunded by MURST (Rome) within
the national project ‘Stereoselezione in Sintesi Organ-
ica. Metodologie e Applicazioni’.
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