Regiocontrolled cobalt-catalyzed Diels-Alder reactions of silicon-functionalized, terminal, and internal alkynes

Article abstract of DOI:10.1021/ol802837m

(Chemical Equation Presented) The efficient control of the regiochemistry of the Diels-Alder adducts which are formed in excellent yields from 1,3-dienes and alkynylsilanes can be realized utilizing cobalt complexes with a pyridine-imine ligand or a dppe ligand, respectively. The application of 2-trimethylsilyloxy-1,3-butadiene leads to a very interesting cyclohexenone derivative suitable for further transformations.

Full text of DOI:10.1021/ol802837m

ORGANIC
LETTERS
2009
Vol. 11, No. 3
773-776
Regiocontrolled Cobalt-Catalyzed
Diels-Alder Reactions of
Silicon-Functionalized, Terminal, and
Internal Alkynes
Gerhard Hilt* and Judith Janikowski
Fachbereich Chemie, Philipps-UniVersita¨t Marburg, Hans-Meerwein-Strasse, 35043
Marburg, Germany
hilt@chemie.uni-marburg.de
Received December 9, 2008
ABSTRACT
The efficient control of the regiochemistry of the Diels-Alder adducts which are formed in excellent yields from 1,3-dienes and alkynylsilanes
can be realized utilizing cobalt complexes with a pyridine-imine ligand or a dppe ligand, respectively. The application of 2-trimethylsilyloxy-
1,3-butadiene leads to a very interesting cyclohexenone derivative suitable for further transformations.
Silicon-functionalized building blocks are finding more and
more applications in carbon-carbon bond formation pro-
Scheme 1
.
Regioselective Cobalt-Catalyzed Diels-Alder
cesses. The interest arises not only from the low toxicity,
ease of handling, and stability of the silicon-functionalized
compounds but also from the increasing number of meth-
odologies available for their synthesis and use in follow-up
reactions.1
Reactions
Consequently, simple and flexible approaches for the
synthesis of silicon-functionalized compounds are needed to
permit access to increasingly complicated structures. Among
such new techniques are hydrosilylation and metal-silicon
exchange reactions.2 The use of silicon-functionalized build-
ing blocks in cycloadditions and, in particular, in Diels-Alder
reactions is mostly limited to the use of silyloxy-function-
alized dienes. Rarely are trialkylsilyl-functionalized 1,3-
dienes and dienophiles used, mainly because of their
(1) For selected reviews, see: (a) Welker, M. E. Tetrahedron 2008, 64,
11529. (b) Denmark, S. E.; Baird, J. D. Chem.sEur. J. 2006, 12, 4954. (c)
Rendler, S.; Oestreich, M. Synthesis 2005, 1727. (d) Denmark, S. E.; Sweis,
R. F. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 16, pp 3-216. (e)
Spivey, A. C.; Gripton, C. J. G.; Hannah, J. P. Curr. Org. Synth. 2004, 1,
211. (f) Denmark, S. E.; Sweis, R. F. Chem. Pharm. Bull. 2002, 50, 1531.
(g) Hiyama, T.; Shirakawa, E. Handb. Organopalladium Chem. Org. Synth.
2002, 285–309. (h) Hiyama, T. J. Organomet. Chem. 2002, 653, 58.
(2) For representative overviews, see: (a) Trost, B. M.; Ball, Z. T. J. Am.
Chem. Soc. 2005, 127, 17644. (b) Hosomi, A.; Miura, K. Bull. Chem. Soc.
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S. Chem. ReV. 2004, 104, 5847. (d) Denmark, S. E.; Ober, M. H. Aldrichim.
Acta 2003, 36, 75.
10.1021/ol802837m CCC: $40.75
Published on Web 01/06/2009
2009 American Chemical Society

Table 1. Results of the Cobalt-Catalyzed Diels-Alder Reaction
Scheme 3. Application of the Two Cobalt-Catalyst Systems A
and B for Regioselective Diels-Alder Reactions
with Terminal Silyl-Functionalized Alkynesa
knowledge, only cobalt-catalyzed Diels-Alder reactions lead
to the generation of both possible regioisomers from an
alkyne and a 1,3-diene by simply altering the ligands of the
cobalt complex (Scheme 1).5
The expansion of the substrate compatibility of the cobalt
catalyst systems toward terminal as well as internal alkynes
bearing silicon functionalities would greatly enhance the
usefulness of the methodology for the generation of highly
enriched regioisomers from simple starting materials. There-
fore, terminal alkynes bearing different silyl functionalities
were applied in the cobalt catalyzed Diels-Alder reaction
to generate products 1 or 2 in a regiocontrolled fashion from
identical starting materials. In the catalyst system A mesi-
tylpyridin-2-ylmethyleneamine (abbreviated as py-imin) was
utilized as the ligand in order to generate the 1,3-substituted
products (1) predominantly, whereas in case B 1,2-bis(diphe-
nylphosphino)ethane was used as the ligand (dppe) to
generate the regioisomeric “para”-product (2) with a 1,4-
substitution pattern of the methyl and the silyl group,
respectively (Scheme 2). The results of this investigation are
summarized in Table 1.
For easier determination of the regioselectivities the
primary 1,4-cyclohexadiene products of the Diels-Alder
reactions were oxidized with DDQ to the corresponding
silyl-substituted benzene derivatives. The isolation of the
a Catalysts system A: CoBr2(mesityl-pyridin-2-yl-methyleneamine) 10
mol %; iron powder 20 mol %; zinc dust 20 mol %; zinc iodide 20 mol %.
Catalyst system B: CoBr2(1,2-bis-diphenylphosphinoethane) 10 mol %; zinc
dust 20 mol %; zinc iodide 20 mol %. b The ratio of the regioisomers (1:2)
is given in parentheses.
(3) For reviews for the application of silicon-functionalized building
blocks, see: (a) Lin, L.; Liu, X.; Feng, X. Synlett 2007, 2147. (b) Gandon,
V.; Aubert, C.; Malacria, M. Curr. Org. Chem. 2005, 9, 1699. (c) Herczegh,
P.; Kovacs, I.; Erdo¨si, G.; Varga, T.; Agocs, A.; Szilagyi, L.; Sztaricskai,
F.; Berecibar, A.; Lukacs, G.; Olesker, A. Pure Appl. Chem. 1997, 69, 519.
(d) Finguelli, F.; Taticchi, A. Dienes in Diels-Alder Reactions; Wiley: New
York, 1990. (e) Petrizilka, M.; Graison, J. I. Synthesis 1981, 753. (f) Carter,
M. J.; Fleming, I.; Percival, A. J. Chem. Soc., Perkin Trans. 1 1981, 2415.
(g) Batt, D. G.; Ganem, B. Tetrahedron Lett. 1978, 18, 3323. Gonzalez-
Nogal, A. M.; Calle, M.; Cuadrado, P.; Valero, R. Tetrahedron 2006, 63,
224. (h) Coats, S. J.; Link, J. S.; Gauthier, D.; Hlasta, D. J. Org. Lett. 2005,
7, 1469. (i) Danheiser, R. L.; Sard, H. Tetrahedron Lett. 1983, 24, 23. (j)
Sauer, J.; Heldmann, D. K.; Hetzenegger, J.; Krauthan, J.; Sichert, H.;
Schuster, J. Eur. J. Org. Chem. 1998, 2855. (k) Constable, E. C.; Housecroft,
C. E.; Neuburger, M.; Reymann, S.; Schaffner, S. Eur. J. Org. Chem. 2008,
1597.
moderate activation toward thermal Diels-Alder reactions
with normal or inverse electron demand.3 Accordingly,
additional electron-withdrawing substituents are needed for
the successful application in Diels-Alder reactions with
normal electron demand. Cycloadditions can be efficiently
catalyzed by transition-metal complexes even in the absence
of such activating groups.4 Nevertheless, to the best of our
(4) For reviews on cobalt-catalyzed cycloaddition processes, see: (a)
Hilt, G. Synthesis 2008, 3537. (b) Omae, I. Appl. Organomet. Chem. 2007,
21, 318. (c) Malacria, M.; Aubert, C.; Renaud, J. L. In Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations; Lautens, M., Trost,
B. M., Eds.; Thieme: Stuttgart, 2001; Vol. 1, p 439. (d) Saito, S.; Yamamoto,
Y. Chem. ReV. 2000, 100, 2901. (e) Ojima, I.; Tzamarioudaki, M.; Li, Z.;
Donovan, R. J. Chem. ReV. 1996, 96, 635. (f) Lautens, M.; Klute, W.; Tam,
W. Chem. ReV. 1996, 96, 49.
Scheme 2. Application of the Two Cobalt-Catalyst Systems A
and B for Regioselective Diels-Alder Reactions
(5) For selected examples see: (a) Hilt, G.; Janikowski, J.; Hess, W.
Angew. Chem., Int. Ed. 2006, 45, 5204. (b) Hilt, G.; Hess, W.; Harms, K.
Org. Lett. 2006, 8, 3287. (c) Hilt, G.; Smolko, K. I. Angew. Chem., Int.
Ed. 2003, 42, 2795. (d) Hilt, G.; du Mesnil, F.-X. Tetrahedron Lett. 2000,
41, 6757.
774
Org. Lett., Vol. 11, No. 3, 2009

Table 2. Results of the Cobalt-Catalyzed Diels-Alder Reaction with Terminal Silyl-Functionalized Alkynes
a Catalysts system A: CoBr2(mesityl-pyridin-2-yl-methyleneamine) 10 mol %; iron powder 20 mol %; zinc dust 20 mol %; zinc iodide 20 mol %.
Catalyst system B: CoBr2(1,2-bis-diphenylphosphinoethane) 10 mol %; zinc dust 20 mol %; zinc iodide 20 mol %. The ratio of the regioisomers (3:4) is
given in parentheses. b cHex ) cyclohexyl.
1,4-cyclohexadiene products can be accomplished as
demonstrated on several occasions before under exclusion
of air, and their follow-up chemistry has also been
demonstrated.6
The application of internal alkynes was then investigated
in a series of experiments (Scheme 3) for the production of
the two regioisomers 3 and 4. The results are summarized
in Table 2.
In most investigated reactions the yields for both cobalt-
catalyst systems are good to excellent over the two steps. In
terms of regioselectivity some very interesting results were
obtained. Most important, the two catalyst systems were able
to convert the terminal silyl-functionalized alkynes in very
good yields and with high complementary regioselectivity
to the desired meta-substituted products of type 1 (catalyst
A) and to the para-substituted product of type 2 (catalyst
B) respectively (entries 1-10).
It was anticipated that the regioselectivity would be
reduced if internal alkyl alkynyl silanes were applied. To
our surprise in these cases the two catalyst systems A and B
still gave good regioselectivities for both desired products.
When further functionalized internal alkynyl silanes were
used (entries 4-10) the ratios of regioisomers formed by
both catalyst A and B were also high. Only when the steric
bulk of the substituent was enlarged to an aryl substituent
the behavior changed (entries 11 and 12). While the results
for catalyst system B were still good in terms of yield and
with regioselectivity in favor of the para-substituted product,
the results for catalyst system A changed dramatically.
Although the yield of the Diels-Alder adduct is very high,
(6) (a) Hilt, G.; Hess, W.; Harms, K. Synthesis 2008, 75. (b) Hilt, G.;
Galbiati, F. Synthesis 2006, 3589. (c) Hilt, G.; Hess, W.; Schmidt, F. Eur.
J. Org. Chem. 2005, 2526. (d) Hilt, G.; Lu¨ers, S.; Smolko, K. I. Org. Lett.
2005, 7, 251.
Org. Lett., Vol. 11, No. 3, 2009
775

the product consists mainly of the para-substituted product
4f. The effect of electronic factors was investigated by
introduction of both electron-donating as well as electron-
accepting substituents (entries 13-16). In these cases the
major products were also para-substituted Diels-Alder
adducts 4g and 4h. The electronic nature of the aryl-
substituent had very little effect on the regioselectivities.
Nevertheless, there seems to be a tendency for catalyst
system B to favor the formation of the meta-substituted
products of type 3 in the latter cases as well. The conclusion
at this point in the investigation was that steric hindrance is
mainly responsible for the observed regioselectivity in the
cycloaddition for both catalyst systems A and B. The
application of 1,4-bis-trimethylsilylbutadiyne as the dieno-
phile led to very interesting results (entries 17 and 18). First,
only one of the triple bonds was chemoselectively incorpo-
rated in the cycloaddition process which can be rationalized
by the greater steric hindrance of the primary cycloaddition
product compared to the starting materials used earlier
(entries 11-16). Second, the yields for both catalyst systems
A and B are very good. Third, although the ethynyl
trimethylsilyl substituent can not be considered a very bulky
substituent the results for both catalyst systems showed the
preferential formation of the para-substituted product 4i.
The determination of factors responsible for the regiose-
lectivities observed with two such simple catalyst systems
proved to be a challenging task for theoretical chemists.7
The application of 2-trimethylsilyloxy-1,3-butadiene as
reactant with alkynyl silane 5 led to very interesting results.
While the yields and regioselectivities for the reactions with
catalyst system A and B are excellent in both cases, the
surprise came when the DDQ oxidation of the intermediates
was attempted (Scheme 4). The conversion of product 6
generated from catalyst B led to decomposition.
Scheme 4
.
2-Trimethylsilyloxy-1,3-butadiene in Regioselective
Cobalt-Catalyzed Diels-Alder Reactions
product gave the unexpected unsaturated, silicon-function-
alized ketone 9 in 80% yield as a single regioisomer.8 Most
importantly, the products 7 and 9 are generated from rather
simple starting materials in an atom economic and highly
regioselective cobalt-catalyzed Diels-Alder reaction (air
oxidation for the formation of 7) and are promising poly-
functionalized building blocks for further manipulation.
In conclusion, we have demonstrated that the regiochem-
istry of the Diels-Alder reaction of alkynylsilanes can be
efficiently controlled by complementary cobalt catalysts for
the preferential formation of the meta-substituted product
by application of a cobalt-pyridine-imine complex and of
the para-substituted product utilizing a cobalt-bis(diphenyl-
phospino)ethane complex. The cycloaddition products have
a high functional density and could be valuable intermediates
in the synthesis of complex molecules.
Acknowledgment. This work is dedicated to Prof. Ryoji
Noyori on the occasion of his 70th birthday. Financial
support by the German Science Foundation is gratefully
acknowledged.
Alternatively, air was applied as oxidizing agent and the
deprotected phenol derivative 7 was obtained after column
chromatography on silica gel in good yield (81%). On the
other hand, the attempted DDQ oxidation of intermediate 8
generated by catalyst A, and consequent workup of the
Supporting Information Available: Experimental pro-
cedures and full characterization of the compounds 1-7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL802837M
(7) Mo¨rschel, P.; Janikowski, J.; Hilt, G.; Frenking, G. J. Am. Chem.
Soc. 2008, 130, 8952.
(8) Oku, A.; Kinugasa, M.; Kamada, T. Chem. Lett. 1993, 22, 165.
776
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