Practical synthesis and Diels-Alder chemistry of [4]dendralene

Article abstract of DOI:10.1021/ja053772+

Spectacular new atom efficient domino cycloaddition sequences involving [4]dendralene, the simplest cross-conjugated tetraene, are reported. Up to eight stereocenters, three new rings, and six C-C bonds are generated in one synthetic operation. The site s

Full text of DOI:10.1021/ja053772+

Published on Web 08/13/2005
Practical Synthesis and Diels-Alder Chemistry of [4]Dendralene
Alan D. Payne, Anthony C. Willis,† and Michael S. Sherburn*
Research School of Chemistry, Australian National UniVersity, Canberra, ACT 0200, Australia
Received June 9, 2005; E-mail: sherburn@rsc.anu.edu.au
Scheme 2. Exhaustive Reaction of [4]Dendralene with NMMa
Acyclic cross-conjugated polyenessthe dendralenessare fasci-
nating compounds with enormous untapped potential in chemical
synthesis.1-4 As formulated by Hopf,2-4 the Diels-Alder chemistry
of [4]dendralenes should be multifaceted, with up to three dieno-
philes uniting with one molecule of the hydrocarbon, in principle,
resulting in the very rapid assembly of functionalized polycyclic
frameworks. Until now, the chemistry of [4]dendralene remains
largely unexplored5 since the hydrocarbon has not been available
in synthetically useful amounts. Several ingenious routes to [4]-
dendralene 1 have been developed, but only one provides more
than a few milligrams of the hydrocarbon.6-13 The exception is a
patented procedure involving the dimerization of 4-chloro-1,2-
butadiene.14 Herein, we report an undemanding preparation of [4]-
dendralene, employing standard laboratory equipment and methods
based upon this early procedure. We show that the hydrocarbon
undergoes a rich variety of domino cycloaddition reactions to form
polycyclic systems, and we reveal methods to control the regio-
chemical outcomes of Diels-Alder reaction sequences involving
[4]dendralene.
The synthesis of [4]dendralene 1 (Scheme 1) avoids protection,
proceeds in one step, and uses the cheap and widely available
starting material, chloroprene.15 Thus, the chloroprene Grignard
reagent16 is converted into the organocopper species by the addition
of anhydrous copper(I) chloride at -78 °C. Slow introduction of
the oxidizing agent CuCl2•2LiCl at -78 °C17 followed by aqueous
workup and vacuum distillation affords [4]dendralene in 26% yield.
We routinely prepare 10 g batches of [4]dendralene using this
procedure. [4]Dendralene is considerably more stable than expected.
Indeed, the hydrocarbon can be stored as a neat liquid at room
temperature with minimal decomposition over several weeks!
Scheme 1. Practical Synthesis of [4]Dendralene 1
[4]Dendralene reacts with an excess of N-methylmaleimide
(NMM) under kinetically controlled conditions at room temperature
in THF to furnish a mixture of five products: a single mono-adduct
3, two diastereomeric bis-adducts 4 and 5, and two diastereomeric
tris-adducts 8 and 9 (Scheme 2).18 The mono-adduct results from
dienophile addition to the internal diene site of 1; this compound
does not undergo further reaction at room temperature. The other
four products result from an initial cycloaddition to one of the two
equivalent terminal diene sites of the hydrocarbon to give unsym-
metrical [3]dendralene 2, which reacts with more dienophile at each
of the two available diene sites to yield four bis-adducts, two of
which (6 and 7) are receptive toward a third cycloaddition. The
two remaining bis-adducts 4 and 5 are inert toward further reaction
at ambient temperature and pressure.
a Some hydrogens are omitted from X-ray crystal structures for clarity.
The second cycloaddition reaction involving mono-adduct 2
proceeds with ca. 5:3 site selectivity in favor of the semicyclic diene.
Not surprisingly, this major pathway, which gives 4 and 5, exhibits
strong π-diastereofacial selectivity for dienophile approach to the
convex face of semicyclic diene (i.e., to give 5). The minor pathway
flowing from mono-adduct 2 leads to bis-adducts 6 and 7, which
result from endo-mode additions to the acyclic diene site of 2, a
† To whom correspondence should be addressed regarding crystal structures.
E-mail: willis@rsc.anu.edu.au.
9
12188
J. AM. CHEM. SOC. 2005, 127, 12188-12189
10.1021/ja053772+ CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 5. Controlling the Cycloaddition Site Selectivity
Scheme 3. Further Transformations of Mono-Adduct 3
This study demonstrates the rich cycloaddition chemistry of
[4]dendralene. The extremely rapid assembly of structurally
complex bridged and fused tricyclic systems common to natural
products is a striking feature of this work. Thus, operationally simple
one-flask sequences involving the union of four molecules, the
construction of up to six new C-C bonds, and eight stereocenters
has been demonstrated. Importantly, methods have been developed
to steer precursors through the fascinating pathway of bond forming
events such that any one of the many possible products can be
obtained in high selectivity. The challenge now is to apply these
very powerful complexity-generating sequences in target synthesis.
process which proceeds with no π-diastereofacial selectivity. Bis-
adducts 6 and 7 undergo a third cycloaddition with NMM to give
tris-adducts 8 and 9, respectively. C2V symmetric, chiral diene 6
can give only one endo-adduct, whereas achiral diene 7 can furnish
two; only one is formed in the latter case, however, presumably
for steric reasons.
Z-triene 3 can be coerced into direct cycloaddition with NMM
under high pressure at ambient temperature to furnish tetracycle
10 as the major product (Scheme 3).19 Alternatively, internal mono-
adduct 3 undergoes a 6π-electrocyclization/cycloaddition cascade
with N-phenylmaleimide (NPM) in refluxing toluene to give a single
diastereomeric pentacycle 12 in 70% yield. In the absence of
dienophile, electrocyclization product 11 is obtained in good yield.
Furthermore, the major product from the exhaustive room tem-
perature reaction between NMM and [4]dendralene, bis-adduct 5,
participates in a high yielding cycloaddition with NMM at ambient
temperature at 19 kbar pressure to afford tris-adduct 13 (Scheme
4). The same product is accessible directly from [4]dendralene and
NMM in a one-pot process in 34% isolated yield. This triple Diels-
Alder sequence occurs in a domino “diene transmissive” sense:
cycloadditions occur sequentially at diene residues from one end
of the hydrocarbon to the other.20
Finally, essentially complete control over [4]dendralene site
selectivity during the first and second cycloaddition events is
achieved by simply premixing the dienophile with different amounts
of simple Lewis acid promoters (Scheme 5). Thus, whereas the
uncatalyzed reaction gives predominantly the products of an initial
cycloaddition to the terminus of [4]dendralene (Scheme 2), high
selectivity for 3, the product of addition to the internal diene site,
is obtained by premixing a 1:1 molar ratio of NMM and MeAlCl2.
With a 1:2 complex of the dienophile and Lewis acid, the first
cycloaddition to 1 proceeds exclusively at the terminal diene site.
Moreover, while the thermal cycloaddition of mono-adduct 2 with
NMM proceeds preferentially through the semicyclic diene moiety
to form 4 and 5, this site selectivity is reversed with NMM•2MeAlCl2
to give tris-adducts 8 and 9 as sole products. Investigations into
the origin of this unusual reactivity profile are underway.
Acknowledgment. We thank the Australian Research Council
for funding.
Supporting Information Available: Synthetic details, crystal-
lographic data, and NMR spectra of key compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Hopf, H. In Organic Synthesis Highlights V; Schmalz, H.-G., Wirth, T.,
Eds.; Wiley-VCH: Weinheim, Germany, 2003; pp 419-427.
(2) Hopf, H. Classics in Hydrocarbon Chemistry: Syntheses, Concepts,
PerspectiVes; Wiley-VCH: Weinheim, Germany, 2000.
(3) Hopf, H. Angew. Chem., Int. Ed. 2001, 40, 705-707.
(4) Hopf, H. Angew. Chem., Int. Ed. Engl. 1984, 23, 948-960.
(5) Bailey and Neilsen treated 1 with maleic anhydride and benzoquinone to
give symmetrical bis-adducts (cf. 6 and 7, Scheme 2), which resisted
further reaction: Bailey, W. J.; Nielsen, N. A. J. Org. Chem. 1962, 27,
3088-3091. More recently, Hopf and Yildizhan exposed the hydrocarbon
to dimethyl acetylenedicarboxylate to obtain a tris-adduct, which was
isolated as the phenanthrene derivative upon oxidation.1
(6) Skattebøl, L.; Solomon, S. J. Am. Chem. Soc. 1965, 87, 4506-4513.
(7) Aufdermarsh, C. A., Jr. U.S. Patent 3264366, 1966; Chem. Abstr. 1966,
65, 107599.
(8) Grimme, W.; Rother, H. J. Angew. Chem., Int. Ed. Engl. 1973, 12, 505-
506.
(9) Bee, L. K.; Everett, J. W.; Garratt, P. J. Tetrahedron 1977, 33, 2143-
2150.
(10) Roth, W. R.; Scholz, B. P.; Breuckmann, R.; Jelich, K.; Lennartz, H. W.
Chem. Ber. 1982, 115, 1934-1946.
(11) Buchan, C. M.; Cadogan, J. I. G.; Gosney, I.; Henry, W. J. J. Chem.
Soc., Chem. Commun. 1985, 1785-1786. This paper describes a synthetic
equivalent of the hydrocarbon.
(12) Brain, P. T.; Smart, B. A.; Robertson, H. E.; Davis, M. J.; Rankin, D. W.
H.; Henry, W. J.; Gosney, I. J. Org. Chem. 1997, 62, 2767-2773.
(13) Fielder, S.; Rowan, D. D.; Sherburn, M. S. Angew. Chem., Int. Ed. 2000,
39, 4331-4333.
(14) See ref 7. The patent describes two related approaches for the coupling
of the Grignard reagent derived from 4-chloro-1,2-butadiene. No yields
are reported, and no indication of product purity is provided.
(15) Chloroprene is not commercially available in Australia. We prepare it by
the dehydrochlorination of 3,4-dichloro-1-butene with calcium hy-
droxide: Tassara, J.-P.; Baudoin, M. Eur. Pat. Appl. 94-202577, 1994;
Chem. Abstr. 1994, 122, 290321.
(16) Nunomoto, S.; Yamashita, Y. J. Org. Chem. 1979, 44, 4788-4791.
(17) Thermal decomposition of the organocopper reagent (occurring at about
-28 °C) affords [4]dendralene, but cleaner reactions were obtained with
CuCl2•2LiCl.
(18) As expected, all cycloadditions involving maleimide dienophiles were
found to proceed exclusively through the endo-mode.
Scheme 4. Preparation of Tris-Adduct 13
(19) This appears to be the first example of a Z-triene participating as a diene
in a Diels-Alder reaction.
(20) This is the first example of a double diene-transmissive Diels-Alder
sequence. For a review of diene-transmissive Diels-Alder reactions,
see: Winkler, J. D. Chem. ReV. 1996, 96, 167-176.
JA053772+
9
J. AM. CHEM. SOC. VOL. 127, NO. 35, 2005 12189