Synthesis and characterization of polycarbonyl compounds via their BF 2-adducts

Article abstract of DOI:10.1021/ol102083v

A cobalt-catalyzed 1,4-hydrovinylation reaction is the key step in the synthesis of 1,3-dicarbonyl and higher tri- and tetracarbonyl compounds after ozonolysis of the 1,4-diene intermediates. For the isolation and characterization of the products, the 1,3-dicarbonyl subunits were complexed with a BF₂- or a BR₂-fragment eliminating the keto-enol tautomerisation. Other 2,3-disubstituted 1,3-butadienes can be generated by a Grubbs enyne metathesis of a symmetrical internal alkyne with ethene. After hydrovinylation and ozonolysis, other 1,3-diketones are accessible.

Full text of DOI:10.1021/ol102083v

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4920-4923
Synthesis and Characterization of
Polycarbonyl Compounds via their
BF2-Adducts
Laura Kersten, Stefan Roesner, and Gerhard Hilt*
Fachbereich Chemie, Philipps-UniVersita¨t Marburg, Hans-Meerwein-Strasse,
35043 Marburg, Germany
hilt@chemie.uni-marburg.de
Received September 1, 2010
ABSTRACT
A cobalt-catalyzed 1,4-hydrovinylation reaction is the key step in the synthesis of 1,3-dicarbonyl and higher tri- and tetracarbonyl compounds
after ozonolysis of the 1,4-diene intermediates. For the isolation and characterization of the products, the 1,3-dicarbonyl subunits were complexed
with a BF2- or a BR2-fragment eliminating the keto-enol tautomerisation. Other 2,3-disubstituted 1,3-butadienes can be generated by a Grubbs
enyne metathesis of a symmetrical internal alkyne with ethene. After hydrovinylation and ozonolysis, other 1,3-diketones are accessible.
Compounds with a 1,3-dicarbonyl group have found a large
number of various applications in modern synthetic organic
Scheme 1
.
Synthesis of 1,3-Dicarbonyl Derivatives from a
1,3-Diene and a Terminal Alkene
chemistry whereas tricarbonyl, tetracarbonyl and polycar-
bonyl derivatives are far less often described in the lit-
erature.1,3e Nature, on the other hand, regularly utilizes
polycarbonyl compounds as starting materials for the syn-
thesis of phenoles and other polycyclic aromatic natural
products such as tetracyclines.2
ing 1,3-dicarbonyl derivatives 1 by ozonolysis. In this context
we recently reported the synthesis of some small natural
products.4
To investigate the synthetic approach toward unsym-
metrical 1,3-dicarbonyl compounds and then polycarbonyl
derivatives, the cobalt-catalyzed 1,4-hydrovinylation of ter-
minal alkenes was extended toward the synthesis of more
complex 1,4-dienes and polyenes (Scheme 2). The results
of these investigations are summarized in Table 1.
Our approach toward the synthesis of 1,3-dicarbonyl
derivatives starts with the synthesis of linear precursors
generated by a cobalt-catalyzed 1,4-hydrovinylation reaction
(Scheme 1).3 The 1,4-dienes (2) derived therefrom can be
easily purified and thereafter converted into the correspond-
(1) (a) Bringmann, G. Angew. Chem., Int. Ed. 1982, 21, 200. (b)
Bringmann, G. Liebigs Ann. Chem. 1985, 2105. (c) Krohn, K. Eur. J. Org.
Chem. 2002, 1351. (d) Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001,
18, 380. (e) Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34,
677. (f) Reim, S.; Michalik, D.; Weisz, K.; Xiao, Z.; Langer, P. Org. Biomol.
(3) (a) Hilt, G.; du Mesnil, F.-X.; Lu¨ers, S. Angew. Chem., Int. Ed. 2001,
40, 387. (b) Hilt, G.; Lu¨ers, S. Synthesis 2002, 609. (c) Hilt, G.; Lu¨ers, S.;
Schmidt, F. Synthesis 2003, 634. (d) Hilt, G.; Danz, M.; Treutwein, J. Org.
Lett. 2009, 11, 3322. (e) Hilt, G.; Weske, D. F. Chem. Soc. ReV. 2009, 38,
3082. (f) Hilt, G.; Treutwein, J. Chem. Commun. 2009, 1395.
Chem. 2008, 6, 3079
.
(2) Leading references: Chem. ReV. 1997, 97, issue 7 gives a compre-
hensive introduction into biochemical and biological aspects of polyketides;
see also: Sattely, E. S.; Fischbach, M. A.; Walsh, C. T. Natural Prod. Rep.
2008, 25, 757.
(4) Hilt, G.; Arndt, M.; Weske, D. F. Synthesis 2010, 1321.
10.1021/ol102083v  2010 American Chemical Society
Published on Web 10/11/2010

Scheme 2
.
Cobalt-Catalyzed 1,4-Hydrovinylation of Terminal
Akenes with 2,3-Dimethyl-1,3-butadiene
Table 1. Results of the Cobalt-Catalyzed 1,4-Hydrovinylation
Reactions of Terminal Alkenes with
2,3-Dimethyl-1,3-butadienea
With only very few exceptions (Table 1, entries 10 and
13), the cobalt-catalyzed 1,4-hydrovinylation of terminal
alkenes is a high-yielding process and results very often in
clean products of type 2 after simple filtration through a small
plug of silica gel to remove the inorganic components and
the catalyst system from the reaction mixture. Within this
investigation, we focus upon additional oxygen based func-
tionalities present in the starting materials. Accordingly,
unprotected alcohol (entry 9), ketone and ester functionalities
are accepted. Even if the functional groups are considered
to be good leaving groups (entries 2 and 3) the yields remain
high, indicating a reduced tendency to generate π-allyl
complexes from such intermediates in comparison to trans-
formations induced by palladium.5
The ozonolysis of these materials of type 2 obtained by
the cobalt-catalyzed 1,4-hydrovinylation reaction leads to
simple 1,3-dicarbonyl derivatives such as octane-2,4-dione
from 2a as well as a more complex hexacarbonyl derivative
generated from 2m.
However, the keto-enol tautomerisation of ketones com-
plicates the assignment of the NMR signals, even more so
when multiple carbonyl groups, such as 1,3,5-tricarbonyl
compounds, are present. In addition, such tri- or tetracarbonyl
derivatives are very hard, if not impossible, to purify by
simple column chromatography on silica gel. This is based
on their strong affinity to silica gel and other usually applied
stationary phases.6 Unfortunately, the higher carbonyl deriva-
tives are also sensitive toward acidic and basic conditions
leading to unwanted degradation or condensation reactions.
It is therefore advantageous to identify a protecting group
to allow a simple purification and characterization of the
materials generated after ozonolysis by surpressing the
keto-enol tautomerisation. Under these circumstances, sev-
eral approaches including complexation with main group
elements and transition metals7 can be found in the literature.
Inspired by conversations with Prof. Reinhard Hoffmann,
we investigated different boron-based protecting groups for
1,3-dicarbonyl compounds.
For this purpose, the commercially available compound
1-phenylbuta-1,3-dione 3 was used as the prototype substrate
(5) Materials similar to 2c have been used in palladium-catalyzed
Tsuji-Trost reactions: Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999,
121, 10727.
a E ) CO2Me.
(6) Personal communication with Prof. K. Krohn, Paderborn University,
Germany as well as with Prof. M. Albrecht RWTH Aachen, Germany.
(7) Leading references: (a) Mehrotra, R. C.; Bohra, R.; Gaur, D. P. In
Metal ꢀ-Diketonates and Allied DeriVatiVes; Academic Press, New York,
1978. See also: . (b) Macedo, F. P.; Gwengo, C.; Lindeman, S. V.; Smith,
M. D.; Gardinier, J. R. Eur. J. Inorg. Chem. 2008, 3200. (c) Ono, K.;
Yoshikawa, K.; Tsuji, Y.; Yamaguchi, H.; Uozumi, R.; Tomura, M.; Taga,
K.; Saito, K. Tetrahedron 2007, 63, 9354.
and converted into different boron derivatives 4 in order to
identify a suitable protecting group to minimize the men-
tioned disadvantages when dealing with polycarbonyl deriva-
tives (Scheme 3).
Org. Lett., Vol. 12, No. 21, 2010
4921

Scheme 3
.
Protection of a 1,3-Dicarbonyl Compound as
Scheme 4. Protection of a 1,3-Dicarbonyl Compound as
Dioxaborinine Derivative 4
Difluorodioxaborinine Derivative
reaction were subjected to ozonolysis followed by reductive
workup with dimethyl sulfide and in situ complexation of
the 1,3-dicarbonyl compounds with BF3·OEt2 (Scheme 4).
The results of these investigations are summarized in Table
2. The best results were obtained for the BF2-subunit
Table 2. Results of the Complexation of a 1,3-Dicarbonyl
Functionality by Boron Derivatives
Table 3. Results of the One-Pot Procedure for the Generation of
Difluorodioxaborinine Derivatives
generated from simple BF3·OEt2 and the BPh2-subunit
obtained from conversion with BPh3, whereas the latter is
much more expensive. Unfortunately, the much less expen-
sive BPh3·NaOH complex did not result in the desired
compound in high yield. However, yield is not the only factor
that must be considered: stability toward decomposition is
also of crucial importance. Unfortunately, we identified
several boron-based protecting groups R ) alkyl (entry 5
and 7c, 7d) which showed considerable degrees of decom-
position in solution (CDCl3) after 12-24 h (see Supporting
Information).
On the basis of these results, we focused our attention upon
the development of a process to generate, protect, isolate
and characterize the desired BF2-complexed products without
isolation of the intermediates. Accordingly, the materials of
type 2 generated in the cobalt-catalyzed 1,4-hydrovinylation
4922
Org. Lett., Vol. 12, No. 21, 2010

The results of this three step, one-pot procedure for the
synthesis of protected 1,3-dicarbonyl derivatives of type 4
are summarized in Table 3.
Scheme 5. Reaction Sequence for the Flexible Generation of
Various 1,3-Dicarbonyl Compounds and Protection as
Difluorodioxaborinine Derivatives
Although the isolated yields of materials such as 4j are
relatively low, this is the first time that polycarbonyl
derivatives have been isolated by column chromatography
and characterized as a single compound by NMR as shown
in the Supporting Information. In earlier reports, similar
compounds are far less well characterized.8 For those
products of type 4 bearing additional ester functionalities,
acceptable to good yields (entries 4 and 5) can be reported.
Accordingly, we believe that the protection as a difluo-
rodioxaborinine derivative of type 4 represents a significant
improvement. Although high yields are not universally
achieved at the present time, the protocol is a considerable
improvement because the intermediately formed 1,3-dicar-
bonyl derivatives can be easily isolated and well character-
ized as a BF2 adduct proving the nature of the intermediate
indirectly.
tive 7d and the BF2-adduct 7a, the latter proved to be superior
The hydrovinylation utilizing the symmetrical 2,3-dimeth-
yl-1,3-butadiene implies the limitation that one side of the
1,3-dicarbonyl product is always methyl substituted. To
overcome this limitation other symmetrical 2,3-disubstituted
1,3-dienes must be used in a 1,4-hydrovinylation reaction
(Scheme 5).9
based on its higher stability.
Acknowledgment. This work was partly supported by the
German Science Foundation.
Supporting Information Available: Experimental pro-
cedures and full characterization of the compounds obtained
in pure form. This material is available free of charge via
the Internet at http://pubs.acs.org.
Accordingly, we utilized a ruthenium-catalyzed enyne
metathesis reaction of 4-octyne to generate the desired
symmetrical 2,3-disubstituted 1,3-diene 5. Then a cobalt-
catalyzed 1,4-hydrovinylation with allyl-phthalimide as the
alkene component was used to obtain the desired 1,4-dienes
of type 6. At this stage the ozonolysis/reductive workup/
protection sequence was utilized to generate different BR2-
protected 1,3-diene derivatives (7). Although the best results
for products of type 7 (R1 ) CH2-phthalimide) in terms of
isolated yields10 were obtained for the bis-isopropyl deriva-
OL102083V
(8) Very often melting points, IR, UV or mass spectra were reported
for the characterisation of polycarbonyl derivatives; see: Kirkemo, C. L.;
White, J. D. J. Org. Chem. 1985, 50, 1316.
(9) The cobalt complexes investigated thus far in the 1,4-hydrovinylation
reaction of unsymmetrical 1,3-dienes gave the regioisomer as major product
so that the ozonolysis produces a 3-keto-aldehyde.
(10) The reported yields correspond to the yield obtained starting from
6 (R1 ) CH2-phthalimide).
Org. Lett., Vol. 12, No. 21, 2010
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