Benzo[cd]azulene Skeleton: Azulene. heptafulvene, and tropone derivatives

Article abstract of DOI:10.1021/ol902283q

"Chemical Equation Presented" Due to our interest in protein kinase modulating compounds, we developed syntheses for benzo[cd]azulenes. By using very common catalysts and reagents, such as t-BuOK, HCl, and mCPBA, the commercially available gualazulene Is

Full text of DOI:10.1021/ol902283q

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5363-5365
Benzo[cd]azulene Skeleton: Azulene,
Heptafulvene, and Tropone Derivatives
Ingo B. Aumu¨ller and Jari Yli-Kauhaluoma*
DiVision of Pharmaceutical Chemistry, Faculty of Pharmacy, P.O. Box 56 (Viikinkaari
5 E), FI-00014 UniVersity of Helsinki, Finland
jari.yli-kauhaluoma@helsinki.fi
Received October 2, 2009
ABSTRACT
Due to our interest in protein kinase modulating compounds, we developed syntheses for benzo[cd]azulenes. By using very common catalysts
and reagents, such as t-BuOK, HCl, and mCPBA, the commercially available guaiazulene is converted in three steps into tricyclic tropone
derivatives. Electrophilic aromatic substitution reactions of guaiazulene proceed without a catalyst. Complex one-pot reactions convert 1′-
hydroxyalkyl azulenes into tricyclic heptafulvenes, and finally, the mild oxidant mCPBA cleaves the semicyclic CdC double bonds to furnish
tropones.
Azulene is a hydrocarbon consisting of a five- and a seven-
membered ring fused to form an unsaturated bicyclic system.
Besides their intensive colors, a typical property of azulene
derivatives is the ability to undergo redox processes easily.
Another important aspect is their polar character, resulting
from contributions of charged aromatic partial structures,
such as a cyclopentadienyl anion and a tropylium cation.
These physicochemical features explain many of their
synthetic utilities and have led to the development of
interesting modern applications, such as their use as elec-
trochromic materials,1 near-infrared quenchers,2 color-tags
for the chromophore-supported purification technique,3 or
radical spin-trapping therapeutic agents.4
efficient de novo syntheses have been reported,6 and interest-
ing synthetic modifications are published frequently. Our
recent synthetic efforts resulted in three-step transformations
of simple azulene precursors into complex tricyclic ben-
zo[cd]azulenes,7,8 which are illustrative with respect to the
understanding of azulene chemistry. Benzo[cd]azulenes have
attracted interest mainly due to their unique theoretical
properties as odd nonalternant analogues of phenalene.7,9 In
contrast, the derivatives presented herein are chemically best
classified as heptafulvenes or tropones and were prepared
with the aim to investigate their properties as inhibitors of
protein kinases.10
(6) (a) Carret, S.; Blanc, A.; Coquerel, Y.; Berthod, M.; Greene, A. E.;
Depre´s, J.-P. Angew. Chem., Int. Ed. 2005, 44, 5130. (b) Kane, J. L., Jr.;
Shea, K. M.; Crombie, A. L.; Danheiser, R. L. Org. Lett. 2001, 3, 1081.
(7) Synthesis and properties: (a) Neidlein, R.; Kramer, W. HelV. Chim.
Acta 1982, 65, 280. (b) Abe, N.; Fujii, H.; Takase, K.; Morita, T. J. Chem.
Soc., Perkin Trans. 1 2001, 12, 1353. (c) Boekelheide, V.; Smith, C. D.
J. Am. Chem. Soc. 1966, 88, 3950. (d) Balduzzi, S.; Mueller-Bunz, H.;
McGlinchey, M. J. Chem.sEur. J. 2004, 10, 5398. (e) Morita, T.; Abe, N.;
In addition, pure synthetic aspects of these compounds are
being studied intensively, more than 70 years after the first
synthesis of the parent azulene.5 It is only recently that new
(1) Ito, S.; Morita, N. Eur. J. Org. Chem. 2009, 4567.
(2) Pham, W.; Weissleder, R.; Tung, C.-H. Angew. Chem., Int. Ed. 2002,
41, 3659.
Takase, K. Formosan Sci. 1996, 49, 25
.
(3) (a) Aumu¨ller, I. B. Ph.D. Dissertation, University of Kiel, Kiel,
Germany, 2002. (b) Aumu¨ller, I. B.; Lindhorst, T. K. Eur. J. Org. Chem.
2006, 1103. (c) Aumu¨ller, I. B.; Lindhorst, T. K. J. Carbohydr. Chem. 2009,
28, 330.
(8) Further syntheses: (a) Hafner, K.; Schaum, H. Angew. Chem., Int.
Ed. 1963, 2, 95. (b) Hafner, K.; Rieper, W. Angew. Chem., Int. Ed. 1970,
9, 248. (c) Neidlein, R.; Kramer, W.; Krotz, R. Arch. Pharm. (Weinheim)
1984, 317, 984. (d) Nakadate, T.; Morita, T.; Takase, K. Chem. Lett. 1977,
591. (e) Gibson, W. K.; Leaver, D.; Roff, J. E.; Cumming, C. W. J. Chem.
(4) Becker, D. A.; Ley, J. J.; Echegoyen, L.; Alvarado, R. J. Am. Chem.
Soc. 2002, 124, 4678.
Soc., Chem. Commun. 1967, 214
.
(5) Plattner, P. A.; Pfau, A. S. HelV. Chim. Acta 1937, 20, 224.
(9) Zahradn´ık, R. Angew. Chem., Int. Ed. 1965, 4, 1039
.
10.1021/ol902283q CCC: $xxxx
Published on Web 11/11/2009
 2009 American Chemical Society

1′-Hydroxyalkyl azulenes are well-known to be acid-
sensitive, and this is why such compounds are usually not
prepared via electrophilic substitution reactions (SE) of
azulenes with ketones.11a,12,13 In fact, such structures are
primarily formed in these reactions, but the acidic catalyst
of SE reactions typically promotes further reaction steps.11,12
The subsequent transformations of the azulenes 1a-c into
the benzo[cd]azulenes 4a-e (Scheme 2) are best realized
Scheme 2. One-Pot Reactions for the Synthesis of the
Heptafulvenes 4a-e via Elimination Across the Respective
Azulene Moieties
Scheme 1. SE of Guaiazulene (2) to 1a-c, Using the Activated
1,2-Dicarbonyl Electrophiles 3a-c, Which Does Not Require a
Catalyst
We found, however, that the specific 1′-hydroxyalkyl azu-
lenes 1a-c are accessible by a SE, starting from guaiazulene
2 (Scheme 1). Crucial are the structures of the 1,2-dicarbonyl
electrophiles 3a-c, which are additionally activated by a
second electron-withdrawing substituent (CF3 (3a, 3c); CO2Et
(3b)). The high electrophilicity of the central carbon atom
compensates for the need for a catalyst, and the typical SE
side reactions are prevented. Additionally, the particular
substituents in 1a-c reduce the electron density on the
resulting carbinol carbons, so that these derivatives can be
conveniently isolated.
as one-pot procedures because the reaction intermediates
5a-e (also 1′-hydroxyalkyl azulenes) are, in particular, prone
to elimination of their hydroxy group, due to the concurrent
aromatization of the six-membered ring. For this reason,
5a-e were generated in situ from 1a-c, via a reaction path
initiated by deprotonation of the methyl group in 1a-c, a
common strategy in azulene chemistry.7d,8c,e,3,14 The inter-
mediate methylene carbanions of 1a-c instantly attack the
neighboring carbonyl group to form the benzo[cd]azulene
skeleton. Accordingly, the ester groups in 1a,b account for
the formation of hemiacetals in 6a,b.
The subsequent elimination of the corresponding alcohol
gives the enolates 7a,b, which are stabilized by an aromatic
cyclopentadienyl anion in the presented resonance forms.
When the base catalyst (t-BuOK) is used in stoichiometric
amounts, 7a,b are reasonably stable in solution, so that
modifications of the substitution pattern become possible.
Alkylation, silylation, and protonation led to 5a-d, respec-
(10) Some of the benzo[cd]azulenes synthesized were preliminarily tested
against a panel of 70 kinases, screening for residual kinase activity less
than 50%. The most significant inhibitions detected concern serine/threonine
kinases, which belong to the CAMK (calcium/calmodulin-regulated kinases)
family of kinases. Further work to characterize these bioactivities is now
in progress in our and in our collaborators laboratories. An example of our
previous work on protein kinase C: Boije af Gennäs, G.; Talman, V.; Aitio,
O.; Ekokoski, E.; Finel, M.; Tuominen, R. K.; Yli-Kauhaluoma, J. J. Med.
Chem. 2009, 52, 3969.
(11) (a) Hafner, K.; Pelster, H.; Schneider, J. Liebigs Ann. Chem. 1961,
650, 62. (b) Reid, D. H.; Stafford, W. H.; Stafford, W. L.; McLennas, G.;
Voigt, A. J. Chem. Soc. 1958, 1110. (c) Kirby, E. C.; Reid, D. H. J. Chem.
Soc. 1961, 3579.
(12) Hafner, K.; Bernhard, C. Liebigs Ann. Chem. 1959, 625, 108
.
(13) (a) Hafner, K.; Pelster, H. Angew. Chem. 1960, 72, 781. (b) Treibs,
W. Chem. Ber. 1959, 92, 2153. (c) Reid, D. H.; Stafford, W. H.; Stafford,
(14) Anderson, A. G.; Anderson, R. G.; Hollander, G. T. J. Org. Chem.
1965, 30, 131.
W. L. J. Chem. Soc. 1958, 1118
.
5364
Org. Lett., Vol. 11, No. 23, 2009

tively. The ketone function in 1c accounts for a different
route to 5e. In contrast to 6a,b, the cyclized intermediate 6c
is an alkoxide that cannot be converted into an enolate similar
to 7a,b. By eliminating water, 6c directly forms 5e, a process
that accounts for the reprotonation of 6c. Consequently, the
milder base DBU should be used in catalytic amounts only.
Finally, the addition of HCl to the solutions of 5a-e
readily initiates an interesting type of acid-catalyzed elimina-
tion reaction leading to 4a-e. This reaction starts with the
protonation of the hydroxyl oxygens and proceeds via
isomerizations of π-bonds across the azulene moieties of
5a-e. Hydroxy eliminations of structurally related 1′-
hydroxyalkyl azulenes11,12 and benzo[cd]azulenes7a-c,15 are
known and lead usually to cationic species, in which the
positive charge is delocalized predominantly within the
seven-membered ring. The unique step in the synthesis of
4a-e is the release of a proton from the alkyl substituents
at the 8 position leading to the formation of semicyclic CdC
double bonds, which characterize the tricyclic products 4a-e
as heptafulvenes.
Scheme 3
.
Oxidations of Heptafulvenes 4a-e to the
Corresponding Tropones 8a-ea
All in all, these reactions deprive the azulene moieties in
5 of aromaticity by generating the heptafulvenes 4,16
containing an aromatic benzene unit. Analogous processes
have not been reported previously, but a few azulene-derived
heptafulvenes have been characterized as specific oxidation
products.7d,17
a The suggested reaction mechanism consumes 2 equiv of mCPBA
(mC(P)BA: meta-chloro(peroxy)benzoic acid).
Further, we examined oxidations of the heptafulvenes 4
(Scheme 3). Syntheses of tropones via heptafulvenes are not
well documented,18 but this pathway was quite profitable
for the preparation of the tricyclic tropones 8a-e, partly due
to the mildness of the oxidant. Although the cleavage of
CdC double bonds is unusual for mCPBA (m-chloroper-
oxybenzoic acid), this reagent was sufficiently strong for all
oxidations. Our hypothetical reaction mechanism suggests
that first the epoxide 9 is formed by 1 equiv of mCPBA.19
Presumably, 9 is prone to ring-opening reactions, due to the
effective stabilization of the positive charge by the conjugated
π-system (especially the seven-membered ring) in the
resulting cations 10. Therefore, even the weak acidity of
mCPBA or mCBA enables catalysis of this step. Subse-
quently, the acyl peroxides 11 are formed by nucleophilic
attack of another equivalent of mCPBA. Finally, the exit of
the leaving group mCBA initiates the fragmentation of 11,
yielding the tropones 8a-e and acetone.
In conclusion, we synthesized the tricyclic tropones 8a-e,
via three steps from the commercially available guaiazulene.
All of the three reactions comprise interesting synthetic
aspects. Uncatalyzed SE reactions of guaiazulene, complex
eliminations across azulene moieties, and CdC bond cleav-
ages with the mild mCPBA have been uncovered. All the
reaction conditions are mild; reaction times are short; and
the reagents are easily available, so that broad applicability
of these reaction types for similar structures is indicated.
Acknowledgment. We thank Walter och Lisi Wahls
Stiftelse fo¨r Naturvetenskaplig Forskning, the European
Commission (Contract No LSHB-CT-2004-503467), and the
Academy of Finland (Grant 108376) for financial support.
(15) Neidlein, R.; Kramer, W.; Scheutzow, D. HelV. Chim. Acta 1982,
65, 1804
.
(16) Heptafulvene reviews: (a) Bergmann, E. D. Chem. ReV. 1968, 68,
Supporting Information Available: Experimental pro-
41. (b) Pietra, C. F. Chem. ReV. 1973, 73, 293.
1
cedures, compound characterization data, and H and 13C
(17) Takekuma, S; Jyoujima, S.; Sasaki, M.; Matsumoto, T.; Fukunaga,
H.; Takekuma, H.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2002, 75, 151,
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
and references cited therein
.
(18) Erden, I.; Kaufmann, D. Tetrahedron Lett. 1981, 22, 215.
(19) Compare oxidations by DMSO: Antoniotti, S.; Golebiowski, J.;
Carbol-Bass, D.; Dun˜ach, E J. Mol. Struct. (Theochem) 2006, 763, 155.
OL902283Q
Org. Lett., Vol. 11, No. 23, 2009
5365