Complex polycyclic scaffolds by metathesis rearrangement of Himbert arene/allene cycloadducts

Article abstract of DOI:10.1021/ol302680m

The intramolecular arene/allene cycloaddition first described 30 years ago by Himbert and Henn permits rapid access to strained polycyclic compounds. Alkene metathesis processes cleanly rearrange appropriately substituted cycloadducts into complex, functi

Full text of DOI:10.1021/ol302680m

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5566–5569
Complex Polycyclic Scaffolds
by Metathesis Rearrangement
of Himbert Arene/Allene Cycloadducts
Jonathan K. Lam,† Yvonne Schmidt,† and Christopher D. Vanderwal*
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine,
California 92697-2025, United States
cdv@uci.edu
Received September 28, 2012
ABSTRACT
The intramolecular arene/allene cycloaddition first described 30 years ago by Himbert and Henn permits rapid access to strained polycyclic
compounds. Alkene metathesis processes cleanly rearrange appropriately substituted cycloadducts into complex, functional-group-rich
polycyclic lactams of potential utility for natural product synthesis and medicinal chemistry.
In certain instances, dearomatization of simple benzene
rings via pericyclic reactions can be facile. For example, the
aromatic Claisen rearrangement results in the transient
loss of aromaticity, and in some cases, the barrier to these
processes can be surprisingly low.1 Of course, in these
and related sigmatropic rearrangements, a facile me-
chanism for restoration of aromaticity is usually avail-
able, positively affecting the equilibrium of the overall
process. Cycloaddition reactions to aromatic rings are
also well-known but are most common in extended
aromatic systems or heteroaromatic rings with some-
what compromised aromatic stabilization, such as an-
thracene2 or furan,3 respectively, or those that provide
a postcycloadditionÀfragmentation pathway to gener-
ate a new aromatic system, as with six-membered-ring
azadienes.4 Certain transition metal complexes of benzene
also undergo DielsÀAlder reactions with potent dieno-
philes.5 On the other hand, direct thermal cycloadditions
to simple carbocyclic aromatic nuclei are rare, and it
seems reasonable to credit both high kinetic barriers
and unfavorable equilibria with the apparent dearth of
reports of these reactions.6À8
Three decades ago, Himbert and Henn disclosed a
fascinating thermal intramolecular DielsÀAlder cyclo-
addition of allenecarboxanilides (eq 1).9 This reaction
(5) For a representative example, see: Chordia, M. D.; Smith, P. L.;
Meiere, S. H.; Sabat, M.; Dean Harman, W. J. Am. Chem. Soc. 2001,
123, 10756–10757.
† These authors contributed equally.
(1) For example, the aromatic Claisen reaction of a tyrosine-derived
reverse-prenyl ether occurs under “physiological conditions” (37 °C in
aqueous buffers): McIntosh, J. A.; Donia, M. S.; Nair, S. K.; Schmidt,
E. W. J. Am. Chem. Soc. 2011, 133, 13698–13705.
(6) Photochemically induced cycloadditions to simple benzene rings,
especially the areneÀolefin photocycloaddition, are well-known but
most often provide the meta-regioisomer. For reviews, see: (a) Wender,
P. A.; Ternansky, R.; deLong, M.; Singh, S.; Olivero, A.; Rice, K. Pure
Appl. Chem. 1990, 62, 1597–1602. (b) Cornelisse, J. Chem. Rev. 1993, 93,
615–669. (c) Hoffmann, N. Synthesis 2004, 481–495. (d) Streit, U.;
Bochet, C. G. Beilstein J. Org. Chem. 2011, 7, 525–542.
(7) For a recent interesting intramolecular dearomatizing 1,3-dipolar
cycloaddition of a nitrile oxide to an unactivated benzene ring, see:
Yonekawa, M.; Koyama, Y.; Kuwata, S.; Takata, T. Org. Lett. 2012, 14,
1164–1167.
(2) See: Fringuelli, F.; Taticchi, A. Dienes in the DielsÀAlder Reac-
tion; Wiley & Sons: New York, 1990; Section 6.2 “Aromatic Hydrocarbons”;
pp 262À275.
(3) For a review of furan DielsÀAlder reactions, see: Kappe, C. O.;
Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53, 14179–14233.
(4) For a review of the cycloaddition reactivity of heterocyclic
azadienes, see: Boger, D. L. Chem. Rev. 1986, 86, 781–793.
r
10.1021/ol302680m
Published on Web 10/15/2012
2012 American Chemical Society

efficiently dearomatized the unactivated benzene ring
without recourse to oxidative, reductive, or photochemical
conditions, nor did it take advantage of an arene with low
aromatic stabilization or with the ability to engage in a
post-cycloaddition thermodynamically favored process.10
This unusual reaction rejects the conventional wisdom that
“normal” benzene rings do not readily behave as dienes in
the DielsÀAlder reaction. Furthermore, it provides easy
access to complex polycycles from readily available start-
ing materials. The scope of the reaction is relatively broad
with respect to substitution both on the arene and on the
allene; furthermore, ester, thioester, imide, phosphina-
mide, and phosphinic ester tethers can be used in place of
the amide.11 Extensive studies of the reaction character-
istics can be found in more than 20 publications from the
Himbert group since their first disclosure;11À13 this signifi-
cant body of work has apparently gone largely unappre-
ciated by organic chemists;to date, we are unaware of any
applications of this complexity-generating transformation.
Our laboratory is interested in underutilized processes
that permit the conversion of readily available aromatic
systems into complex organic scaffolds.14 In that context,
we became intrigued by the idea of using Himbert cycload-
ducts as starting points for the synthesis of topologically
and stereochemically complex molecules that might find
application in natural product synthesis and medicinal
chemistry. Our first efforts involved alkene-metathesis-
based rearrangement reactions of these cycloadducts;15,16
our initial results are described in this communication.
The Himbert group used a variety of methods to access
theallene-containing cycloaddition substrates. Mostoften,
they performed Wittig olefination reactions on in situ
generated ketenes,11a,b and they also took advantage of
the reactivity of silylated ynamines with ketenes that they
had developed themselves.11c While these methods cer-
tainly enabled access to a variety of substrates, we sought
more general preparations of a broad range of allenecar-
boxylic acid derivatives. We have found that readily avail-
able deconjugated alkynoic amides can be easily iso-
merized to the desired allenes (4a f 5a, Scheme 1).17 As
a result, acylation of the corresponding aniline provides
straightforward accesstoalleneprecursors. Anin situbase-
catalyzed isomerization/cycloaddition reaction serves to con-
vert alkynes of type 4 directly into the Himbert cycloadducts;
for example, 6a is generated in good yield on gram scale in
this manner. With the appropriately tethered alkene included
in the cycloaddition substrate, the cycloadduct is poised
for rearrangement via alkene metathesis. After significant
screening efforts, we found that the HoveydaÀGrubbs-type
ruthenium catalyst 718 smoothly converted the lactam cy-
cloadduct 6a into the complex polycyclic product 8a.
Scheme 1. Facile Synthesis of Cycloaddition Precursors,
Tandem in Situ Allene Formation and Cycloaddition, and
Metathesis Rearrangement
(12) Please see the Supporting Information for the complete listing of
the Himbert group references that describe this body of work.
(13) The Orahovats group also studied related cycloadditions in
work that began after that of the Himbert group: (a) Trifonov, L. S.;
Orahovats, A. S. Helv. Chim. Acta 1986, 69, 1585–1587. (b) Trifonov,
L. S.; Orahovats, A. S. Helv. Chim. Acta 1987, 70, 262–270. (c) Trifonov,
L. S.; Simova, S. D.; Orahovats, A. S. Tetrahedron Lett. 1987, 28, 3391–
3392. (d) Trifonov, L. S.; Orahovats, A. S. Helv. Chim. Acta 1987, 70,
1732–1736. (e) Trifonov, L. S.; Orahovats, A. S. Helv. Chim. Acta 1989,
72, 59–64.
(8) For a review describing synthetic equivalents to “cyclohexa-
triene” for DielsÀAlder cycloadditions, see: Cossu, S.; Fabris, F.; De
Lucchi, O. Synlett 1997, 1327–1334.
(14) Vanderwal, C. D. J. Org. Chem. 2011, 76, 9555–9567.
(15) For the first example of the merger of DielsÀAlder cycloaddi-
tions with metathesis processes in the context of complex molecule
synthesis, see: Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1986,
108, 855–856.
(16) For some recent outstanding examples of cycloaddition/metath-
esis rearrangement strategies applied to complex natural product synth-
esis, see: (a) Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005,
127, 5334–5335. (b) Hart, A. C.; Phillips, A. J. J. Am. Chem. Soc. 2006,
128, 1094–1095. (c) Henderson, J. A.; Phillips, A. J. Angew. Chem., Int.
Ed. 2008, 47, 8499–8501.
(9) Himbert, G.; Henn, L. Angew. Chem., Int. Ed. 1982, 21, 620.
(10) Of course, there are special features of this substrate that
presumably aid in the success of the reaction. The high energy of allenes
relative to normal alkenes and the likely diminished entropy of activa-
tion from the near perfect alignment of the sp-hybridized allene carbon
with the ipso-carbon of the arene, when the tether is oriented appro-
priately, are probable contributors to the high reactivity.
(11) Selected, particularly relevant references: (a) Himbert, G.;
Diehl, K.; Maas, G. J. Chem. Soc., Chem. Commun. 1984, 900–901.
(b) Himbert, G.; Fink, D. Tetrahedron Lett. 1985, 26, 4363–4366. (c)
Henn, L.; Himbert, G.; Diehl, K.; Kaftory, M. Chem. Ber. 1986, 119,
1953–1963. (d) Himbert, G.; Diehl, K.; Schlindwein, H.-J. Chem. Ber.
1986, 119, 3227–3235. (e) Himbert, G.; Fink, D.; Diehl, K. Chem. Ber.
1988, 121, 431–441. (f) Himbert, G.; Fink, D. Z. Naturforsch., B: Chem.
Sci. 1994, 49, 542–550. (g) Himbert, G.; Fink, D. J. Prakt. Chem. 1996,
(17) (a) Eglington, G.; Jones, E. R. H.; Mansfield, G. H.; Whiting,
M. C. J. Chem. Soc. 1954, 3197–3200. (b) Hashmi, A. S. K. In Modern
Allene Chemistry, Vol. 1; Krause, N., Hashmi, A. S. K., Eds.; Wiley-
VCH: 2004; pp 3À50.
€
338, 355–362. (h) Himbert, G.; Ruppmich, M.; Knoringer, H. J. Chin.
(18) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs,
R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592.
Chem. Soc. 2003, 50, 143–151.
Org. Lett., Vol. 14, No. 21, 2012
5567

Figure 1. Cycloadditions of in situ generated allenecarboxanilides and subsequent alkene metathesis-based rearrangements to generate
complex polycyclic lactams (for specific reaction temperatures and times, as well as the X-ray structure of 8m; please see the Supporting
Information).
The two-stage sequence depicted in Scheme 1 proved to
be very general, with an additional dozen examples shown
in Figure 1. We note the similarity of these architectures to
members of the Erythrina alkaloids,19 a large family of
natural products, many of which demonstrate interesting
biological activities. The two-step sequence generates a
variety of ring sizes (see 8aÀc), accommodates a broad
range of substitution patterns on the arene and allene
(see 8eÀi), and tolerates a significant range of functional
groups (halides, trifluoromethyl, methoxy, and nitro
groups; see 8jÀm), permitting access to a large collection
of complex polycyclic lactams. This diversity of output is
readily available from simple starting materials, and an
even greater range of product scaffolds can be contem-
plated when different tethers for both the cycloaddition
and the metathesis events are studied. Confirmation of
structural identity rests on supportive NMR and mass
spectrometric data, as well as X-ray crystallographic ana-
lysis of 8m.20
complex products21 that result are available in only two
steps from simple starting materials and hold promise for
applications in natural product synthesis and medicinal
chemistry. The structural similarity of these compounds to
members of the Erythrina family of alkaloids, many of
which exhibitinteresting neurobiological activities, suggest
the possibility that our products might provide useful lead
compounds in this area. This two-step sequence is remark-
ably general with respect to substitution patterns and is
tolerant of a variety of functional groups.
This study constitutes our first foray into the strain-
driven rearrangement chemistry of Himbert cycloadducts;
given the success of the metathesis reactions, we anticipate
access to myriad structures via anion-, cation-, radical-,
or transition-metal-mediated rearrangements. In ongoing
studies, we are evaluating other tether systems and are
also engaged in mechanistic studies of both the cycloaddi-
tion and the metathesis rearrangement steps. That work,
and applications of the chemistry described herein, will be
the subject of future disclosures.
We have used the arene/allene cycloaddition discovered
by Himbert to access strained polycyclic lactams that
undergo rearrangement by alkene metathesis processes.
A key advance put forth herein involves the in situ genera-
tion of the allene dienophiles from deconjugated alkynes
under the conditions for cycloaddition. The topologically
Acknowledgment. We thank Dr. Joe Ziller (UCI) for
X-ray crystallographic analysis of 8m. We acknowledge
the NSERC of Canada for a graduate fellowship (J.K.L.)
(21) For a recent example of a complexity building strategy that
converts arenes via oxidative dearomatization into products similar to
ours, see: Leon, R.; Jawalekar, A.; Redert, T.; Gaunt, M. J. Chem. Sci.
2011, 2, 1487–1490.
(19) Parsons, A. F.; Palframan, M. J. Alkaloids 2010, 68, 39–81.
(20) The crystal structure of compound 8m has been deposited at
CCDC under number 897822.
5568
Org. Lett., Vol. 14, No. 21, 2012

and the Humboldt Foundation for a Feodor Lynen post-
doctoral fellowship (Y.S.). This work was supported by
UC Irvine, and C.D.V. is grateful for additional funding
from an AstraZeneca Excellence in Chemistry Award, an
Eli Lilly Grantee Award, and an A. P. Sloan Foundation
Fellowship. We thank Materia for a generous donation of
metathesis catalysts.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
new compounds, and CIF data for compound 8m. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
5569