Double-and triple-cobalt catalysis in multicomponent reactions

Article abstract of DOI:10.1021/ol300504f

The combination of different types of cobalt-catalyzed transformations in one-pot procedures is described. One of the key building blocks, a boron-functionalized isoprene derivative (boroprene), led to the realization of four-component reaction sequences comprising the cobalt-catalyzed Diels-Alder and a 1,4-hydrovinylation reaction. Eventually, a reaction sequence including a cobalt-catalyzed Diels-Alder reaction, a cobalt-catalyzed 1,4-hydrovinylation, an allylboration, and a cobalt-catalyzed Alder-ene reaction led to a five-component one-pot reaction sequence in which five carbon-carbon bonds were formed in excellent regio-and diastereoselectivity to generate complex products in good overall yields.

Full text of DOI:10.1021/ol300504f

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1884–1887
Double- and Triple-Cobalt Catalysis
in Multicomponent Reactions
Florian Erver and Gerhard Hilt*
€
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Str., 35043
Marburg, Germany
hilt@chemie.uni-marburg.de
Received February 28, 2012
ABSTRACT
The combination of different types of cobalt-catalyzed transformations in one-pot procedures is described. One of the key building blocks, a boron-
functionalized isoprene derivative (boroprene), led to the realization of four-component reaction sequences comprising the cobalt-catalyzed
DielsꢀAlder and a 1,4-hydrovinylation reaction. Eventually, a reaction sequence including a cobalt-catalyzed DielsꢀAlder reaction, a cobalt-
catalyzed 1,4-hydrovinylation, an allylboration, and a cobalt-catalyzed Alder-ene reaction led to a five-component one-pot reaction sequence in
which five carbonꢀcarbon bonds were formed in excellent regio- and diastereoselectivity to generate complex products in good overall yields.
The generation of increasingly complex molecules in
atom- and step-economic one-pot multicomponent reac-
tions starting from readily available starting materials is
attracting many chemists. Moreover, it is of great interest
when one catalyst is able to initiate two or more different
types of reactions in a multicomponent transformation
(double catalysis).1,2
The application of a wide variety of cobalt-catalyzed
transformations3 led us to consider such reactions in multi-
component sequences. Inthis respect, we recently described
the application of the boron-functionalized isoprene deri-
vative 14 in a cobalt-catalyzed 1,4-hydrovinylation5/allyl-
boration/1,4-hydrovinylation reaction sequence for the
generation of 2. This sequence represents a benchmark
(4) Erver, F.; Hilt, G. Org. Lett. 2011, 13, 5700.
(1) For selected recent reviews, see: (a) Zhou, J. Chem.;Asian J.
2010, 5, 422. (b) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev. 2004,
248, 2365. (c) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C.
Chem. Rev. 2005, 105, 1001. (d) Mayer, S. F.; Kroutil, W.; Faber, K.
Chem. Soc. Rev. 2001, 30, 332.
ꢁ
(5) (a) Arndt, M.; Dindaroglu, M.; Schmalz, H.-G.; Hilt, G. Org.
Lett. 2011, 13, 6236. (b) Hilt, G.; Roesner, S. Synthesis 2011, 662.
(c) Arndt, M.; Reinhold, A.; Hilt, G. J. Org. Chem. 2010, 75, 5203.
(d) Hilt, G.; Arndt, M.; Weske, D. F. Synthesis 2010, 1321. (e) Kersten,
€
L.; Roesner, S.; Hilt, G. Org. Lett. 2010, 12, 4920. (f) Hilt, G.; Luers, S.;
(2) For recent reviews on transition-metal- and organo-catalyzed
ꢀ
€
Schmidt, F. Synthesis 2004, 634. (g) Hilt, G.; Luers, S. Synthesis 2002,
multicomponent reactions, see: (a) Barluenga, J.; Fernandez-Rodrıguez,
M. A.; Aguilar, E. J. Organomet. Chem. 2005, 690, 539. (b) Enders, D.;
Narine, A. A. J. Org. Chem. 2008, 73, 7857. For an example of a multi-
€
609. (h) Hilt, G.; du Mesnil, F.-X.; Luers, S. Angew. Chem., Int. Ed. 2001,
40, 387. For 1,2-hydrovinylation reactions, see: (i) Sharma, R. K.;
RajanBabu, T. V. J. Am. Chem. Soc. 2010, 132, 3295. (j) Saha, B.;
Smith, C. R.; RajanBabu, T. V. J. Am. Chem. Soc. 2008, 130, 9000.
(k) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 5410.
(l) Saha, B.; RajanBabu, T. V. J. Org. Chem. 2007, 72, 2357.
€
component reaction initiated by cobalt catalysis, see: (c) Hilt, G.; Luers, S.;
Smolko, K. I. Org. Lett. 2005, 7, 251.
(3) For recent reviews, see: (a) Hess, W.; Treutwein, J.; Hilt, G.
Synthesis 2008, 3537. (b) Omae, I. Appl. Organomet. Chem. 2007, 21,
318. (c) Laschat, S.; Becheanu, A.; Bell, T.; Baro, A. Synlett 2005, 2547.
ꢂ
(m) Lassauque, N.; Francio, G.; Leitner, W. Adv. Synth. Catal. 2009,
ꢂ
351, 3133. (n) Lassauque, N.; Francio, G.; Leitner, W. Eur. J. Org.
€
ꢀ
(d) Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787. (e) Malacria, M.;
Chem. 2009, 3199. (o) Grutters, M. M. P.; Muller, C.; Vogt, D. J. Am.
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. (f) Welker, M. E. Curr. Org. Chem. 2001, 5,
785. (g) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901. (h) Ojima,
I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev. 1996, 96
635. (i) Lautens, M.; Klute, W.; Tam, W. Chem. Rev. 1996, 96, 49.
(j) Jeganmohan, M.; Cheng, C.-H. Chem.;Eur. J. 2008, 14, 10876.
Chem. Soc. 2006, 128, 7414. See also: (p) Wei, C.-H.; Mannathan, S.;
Cheng, C.-H. J. Am. Chem. Soc. 2011, 133, 6942. (q) Chang, H.-T.;
Jayanth, T. T.; Cheng, C.-H. J. Am. Chem. Soc. 2007, 129, 4166.
(r) Chang, H.-T.; Jayanth, T. T.; Wang, C.-C.; Cheng, C.-H. J. Am.
Chem. Soc. 2007, 129, 12032. (s) Mannathan, S.; Cheng, C.-H. Chem.
Commun. 2010, 1923. (t) Wang, C.-C.; Lin, T.-S.; Cheng, C.-H. J. Am.
Chem. Soc. 2002, 124, 9696.
r
10.1021/ol300504f
Published on Web 03/20/2012
2012 American Chemical Society

transformation of our ongoing project for efficient carbonꢀ
carbon bond formation processes (Scheme 1).
After we succeededinthe synthesisofthepinacol-boron-
functionalized isoprene derivative 1 (boroprene), the gen-
eration of a complex product such as 2 was the first step to
evaluate the potential embedded in the boroprene building
block 1.
Table 1. Results for the Cobalt-Catalyzed Four-Component
Reaction Sequencea
Scheme 1. Multicomponent One-Pot Reaction via Two Cobalt-
Catalyzed 1,4-Hydrovinylations and an Allylboration
In a first set of experiments, boroprene 1 was used as a
diene component in a regioselective cobalt-catalyzed Dielsꢀ
Alder reaction6 with nonconjugated enynes 3 which were
prepared adopting known procedures.7
As we experienced from previous investigations, cobalt
catalysts with pyridyl-imine ligands8 are highly regiose-
lective in cobalt-catalyzed DielsꢀAlder reactions and are
unable to perform 1,4-hydrovinylation reactions.
Accordingly, the alkyne subunit in 3 was chemo- and
regioselectively transformed in a DielsꢀAlder reaction to
the dihydroaromatic compound 4 (Scheme 2).
Scheme 2. Double-Cobalt-Catalyzed Four-Component
DielsꢀAlder/1,4-Hydrovinylation/Allylboration Sequence
(6) (a) Danz, M.; Hilt, G. Adv. Synth. Catal. 2011, 353, 303.
(b) Auvinet, A.-L.; Harrity, J. P. A; Hilt, G. J. Org. Chem. 2010, 75, 3893.
€
(c) Hilt, G.; Janikowski, J. Org. Lett. 2009, 11, 773. (d) Morschel, P.;
a CoBr2(py-imine) (10 mol %), iron powder (20 mol %), zinc powder
(20 mol %), zinc iodide (20 mol %), boroprene 1 (1.0 equiv) and enyne 3
(1.0 equiv), CH2Cl2, 16 h, rt, then CoBr2(ligand) (10 mol %), zinc
powder (20 mol %), zinc iodide (20 mol %) and 1,3-diene 5 (1.2 equiv),
16 h, rt, then 0 °C, aldehyde (1.0 equiv), 1 h, then triethanolamine (1.1
equiv), 1 h, rt. b Only one enantiomer is shown.
Janikowski, J.; Hilt, G.; Frenking, G. J. Am. Chem. Soc. 2008, 130, 8952.
(e) Hilt, G.; Danz, M. Synthesis 2008, 2257. (f) Hilt, G.; Hengst, C.
J. Org. Chem. 2007, 72, 7337. (g) Hilt, G.; Hengst, C. Synlett 2006, 3247.
(h) Hilt, G.; Janikowski, J.; Hess, W. Angew. Chem., Int. Ed. 2006, 45,
5204. (i) Hess, W.; Treutwein, J.; Hilt, G. Synthesis 2008, 3537.
(7) For the synthesis of nonconjugated enynes, see SI.
(8) py-imine = 2,4,6-trimethylphenyl-N-(pyridin-2-ylmethylene)aniline.
Org. Lett., Vol. 14, No. 7, 2012
1885

This intermediate was then treated with another 1,3-diene
(5) applying the cobalt catalyst precursor CoBr2(dppe)9
which is able to catalyze a 1,4-hydrovinylation of the re-
maining terminal alkene subunit in 4 to generate intermedi-
ate 6. Treatment of 6 with an aldehyde in an allylboration
reaction and liberation of the boronic ester upon reaction
with triethanolamine led to the formation of anti-products
of type 7.
Scheme 3. Triple-Cobalt-Catalyzed Five-Component Dielsꢀ
Alder/1,4-Hydrovinylation/Allylboration/1,4-Hydrovinylation
Sequence
The double-catalysis reaction sequence was performed
in a one-pot protocol, and the products of type 7 were
isolated after single column chromatography in good to
excellent overall yields. Based on the higher C1/C4 regio-
selectivity in the 1,4-hydrovinylation of unsymmetrical
1,3-dienes, the cobalt catalyst precursor CoBr2(dppp)10
was applied in the sequences involving isoprene and myr-
cene (Table 1).
The regioselectivity of the cobalt-catalyzed DielsꢀAlder
reaction is strongly dependent on the substituents of the
alkyne subunit. The catalyst efficiently differentiates steri-
cally demanding aryl groups from less bulky alkyl substi-
tuents. In the case where the aryl group is replaced by a
hydrogen atom, the alkyl chain becomes the sterically more
demanding substituent (entry 4). The excellent overall yields
range between 54% and 88%, which appear to depend on
neither the electronic nature of the aryl group nor the chain
length of the enynes or the substituent of the aldehydes.
Furthermore, this outcome indicates that the pyridyl-imine
catalyst system used for the DielsꢀAlder reaction does not
interfere with the bisphosphine catalyst used in the 1,4-
hydrovinylation reaction. This sequence also demonstrates
the power of the allylboration reaction, as complex inter-
mediates could be transformed even when sterically more
demanding aldehydes were used (entries 8 and 13).
Table 2. Synthesis of Products 9 by the Triple-Cobalt-Catalyzed
Five-Component Reaction Sequencea
After we succeded in the parent reaction sequence, we
directed our attention toward a five-component triple-
catalysis reaction sequence comprising a cobalt-catalyzed
DielsꢀAlder reaction utilizing boroprene 1 as a central
building block, a cobalt-catalyzed 1,4-hydrovinylation re-
action, an allylboration, and another 1,4-hydrovinylation
for the synthesis of increasingly complex products. The
outline of this alternative five-component one-pot reaction
sequence is shown in Scheme 3. Compared to the reaction
sequence in Scheme 2, the parent sequence involves the
introduction of an additional terminal double bond in the
allylboration step. Utilizing 4-pentenal generates the inter-
mediate 70, but in this sequence another cobalt-catalyzed
1,4-hydrovinylation was enabled with 1,3-diene 8 to obtain
products of type 9. As known from preliminary investiga-
tions, the cobalt catalysts suffer deactivation after a pro-
longed reaction time which made it beneficial to use
additional cobalt catalyst in the last transformation. The
results of this five-component one-pot reaction sequence
with triple-cobalt catalysis are summarized in Table 2 for a
selected number of combinations.
a CoBr2(py-imine) (10 mol %), iron powder (20 mol %), zinc powder
(20 mol %), zinc iodide (20 mol %), boroprene 1 (1.0 equiv) and enyne 3
(1.0 equiv), CH2Cl2, 16 h, rt, then CoBr2(dppp) (10 mol %), zinc powder
(20 mol %), zinc iodide (20 mol %) and 1,3-diene 5 (1.0 equiv), 16 h, rt,
then 0 °C, 4-pentenal (1.0 equiv), 1 h, then CoBr2(dppp) (10 mol %), zinc
powder (20 mol %), zinc iodide (20 mol %) and 1,3-diene 8(1.2equiv), 16h,
rt, then triethanolamine (1.1 equiv), 1 h, rt. b Only one enantiomer is shown.
isomers after single column chromatography. Due to im-
perfect conversions of the intermediates, side reactions
took place which afforded rather nonpolar and therefore
separable byproducts, which explain the diminished yields.
The main products were accompanied by other side prod-
ucts (regioisomers/diastereomers). The identification of
these byproducts has been difficult, as the amounts were
The five-component reaction sequence led to good
results, and complex products could be isolated as main
(9) dppe = 1,2-bis(diphenylphosphino)ethane.
(10) dppp = 1,3-bis(diphenylphosphino)propane.
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Org. Lett., Vol. 14, No. 7, 2012

Table 3. Synthesis of Products 11 by the Triple-Cobalt-
Catalyzed Five-Component Reaction Sequencea
Scheme 4. Triple-Cobalt-Catalyzed Five-Component
DielsꢀAlder/1,4-Hydrovinylation/Allylboration/Alderꢀene
Sequence
a CoBr2(py-imine) (10 mol %), iron powder (20 mol %), zinc powder
(20 mol %), zinc iodide (20 mol %), boroprene 1 (1.0 equiv) and enyne 3
(1.0 equiv), CH2Cl2, 16 h, rt, then CoBr2(dppp) (10 mol %), zinc powder
(20 mol %), zinc iodide (20 mol %) and 1,3-diene 5 (1.0 equiv), 16 h, rt,
then 0 °C, 4-pentenal (1.0 equiv), 1 h, then CoBr2(dppp) (10 mol %), zinc
powder (20 mol %), zinc iodide (20 mol %) and alkyne 10 (1.5 equiv), 16 h,
rt, then triethanolamine (1.1 equiv), 1 h, rt. b Only one enantiomer is shown.
rather small and the polarities were very similar. Accord-
ingly, we are not able to quantify the regio- or diastereo-
selectivities.
catalyzed cyclotrimerization,12 and only small amounts of
products of type 11 could be isolated. However, the ten-
dency for the cyclotrimerization reaction decreases consid-
erably for the internal alkynes used, so that good yields of
11aꢀc could be obtained.
The five-component reaction sequence utilized the cobalt-
catalyzed 1,4-hydrovinylation reaction twice, with one sym-
metrical as well as one unsymmetrical 1,3-diene. Besides the
1,3-dienes, the sequence has additional flexibility as demon-
strated by the use of different functional groups on the arene
substituent of the enyne. Noteworthy, arylhalides are
well accepted in the cobalt-catalyzed DielsꢀAlder reac-
tion allowing further modifications. Also, the chain
length between alkyne and alkene in the enyne was
altered, or as another possibility, the chain length
within the enal component could have been modified
as well.
To further evaluate the compatibility of cobalt catalysts
with complex materials we decided to use the terminal
double bond introduced by the allylboration step in 7 to
facilitate a cobalt-catalyzed Alderꢀene reaction11 with an
internal alkyne (10) (Scheme 4). Thereby, a triple catalysis
utilizing three different cobalt-catalyzed reactions was rea-
lized and the products of type 11 were obtained in a one-pot
sequence. The results of this investigation applying a se-
lected number of combinations are summarized in Table 3.
The Alderꢀene reaction worked best with unsymmetri-
cal internal aryl-substituted alkynes 10. Terminal alkynes
as well as propiolates are primarily transformed in a cobalt-
In conclusion we were able to demonstrate that double-
and triple-cobalt catalyses utilizing different types of co-
balt-catalyzed reactions with four or five components are
possible to generate desired products in good yields. The
cobalt-catalyzed reactions proved that they are capable of
producing complex molecules from rather simple starting
materials. The flexibility (e.g., additional substituents,
chain length) and functional group tolerance of the cobalt-
catalyzed transformations are essential to push such multi-
component reactions to the hilt.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for a fellowship (F.E.) and the Deutsche
Forschungsgemeinschaft for financial support.
Supporting Information Available. Experimental pro-
cedures and full characterization of the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Hilt, G.; Hengst, C.; Hess, W. Eur. J. Org. Chem. 2008, 2293. (b)
Hilt,G.;Hess,W.;Vogler,T.;Hengst,C.J. Organomet. Chem. 2005,690, 5170.
(c) Hilt, G.; Vogler, T.; Hess, W.; Galbiati, F. Chem. Commun. 2005, 1474.
(11) (a) Hilt, G.; Erver, F.; Harms, K. Org. Lett. 2011, 13, 304.
(b) Hilt, G.; Paul, A.; Treutwein, J. Org. Lett. 2010, 12, 1536. (c) Hilt, G.;
Treutwein, J. Angew. Chem., Int. Ed. 2007, 46, 8500.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 7, 2012
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