Angewandte
Communications
Chemie
increase the yields (4b, 4 f–j), albeit with a few exceptions (4d
and 4l).
To further exploit the versatility of this method, aliphatic
Conflict of interest
The authors declare no conflict of interest.
aldehydes bearing different substituents (arylmethyl, cyclo-
hexyl, and ethyl) were examined in conjugate additions to
diethyl vinylphosphonate 2g (Scheme 2, 3o–q). Unfortu-
nately, performing these reactions under standard conditions
only afforded trace amounts of the corresponding 1,4-
addition products. Enlightened by our previous study on
carbonyl and imine additions,[9] we found two critical factors
that enhance the reactivity of aliphatic aldehydes: basicity
and choice of ligand. Combination of the stronger base KOt-
Bu and the more potent phosphine ligand L4 delivered
modest yields of the desired alkyl phosphonates in all cases.
Although preliminary, success in coupling aliphatic aldehydes
with electron-deficient olefins through conjugate addition is
exciting because the majority of natural carbonyl compounds
belong to this class.
In summary, we have developed carbonyls as latent alkyl
carbanions for conjugate additions through ruthenium(II)-
catalyzed reductive coupling, with hydrazine as the key
reductant. Such carbon nucleophiles can react with various
electron-deficient olefins in a manner that is complementary
to the “soft” metal-based carbanions in the classical conjugate
additions. This reaction proceeds under mild conditions and
tolerates a variety of functional groups on both coupling
partners. Efforts to elucidate the mechanism, expand the
range nucleophilic carbonyl partners, and develop an asym-
metric variant are ongoing in our laboratory.
Keywords: carbonyls · conjugate addition ·
homogeneous catalysis · hydrazine · ruthenium
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[1] Selected books or chapters on the C C bond formation in
organic synthesis via conjugate addition reactions: a) P. Perl-
mutter, in Conjugate Addition Reactions in Organic Synthesis,
Elsevier, Amsterdam, 2013; b) H.-G. Schmalz, in Comprehen-
sive Organic Synthesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming),
Pergamon, Oxford, 1991, Chapter 1.5; c) M. E. Jung, in Com-
prehensive Organic Synthesis, Vol. 4 (Eds.: B. M. Trost, I.
Fleming), Pergamon, Oxford, 1991, Chapter 1; d) L. Kurti, B.
Czakꢀ, in Strategic Applications of Named Reactions in Organic
Synthesis, Elsevier, Amsterdam, 2005; e) J. J. Li, in Name
Reactions: A Collection of Detailed Mechanisms and Synthetic
Applications. 5th ed., Springer, Berlin, 2014.
[2] An excellent review on organocopper-mediated regioselective
references therein. Selected classical examples of the prepara-
tion and application of “lower order” organocopper reagents in
1972, 19, 1 – 113; e) G. H. Posner, in An Introduction to Synthesis
Using Organocopper Reagents. Wiley, New York, 1980. Selected
reviews on the preparation and application of “higher order”
organocopper reagents in 1,4-addition: f) B. H. Lipshutz, R. S.
Sengupta, Org. React. 1992, 41, 135 – 631. Selected reviews on
copper-catalyzed or -mediated enantioselective conjugate addi-
tion reactions: i) A. Alexakis, J. E. Bꢁckvall, N. Krause, O.
[3] An excellent review on rhodium-catalyzed enantioselective
conjugate addition reactions: a) T. Hayashi, K. Yamasaki,
conjugate addition catalyzed by a chiral rhodium complex: b) M.
[4] Selected reviews on enantioselective conjugate additions cata-
lyzed by other soft metals: a) M. P. Sibi, S. Manyem, Tetrahedron
2000, 56, 8033 – 8061; b) N. Krause, A. Hoffmann-Rçder, Syn-
Experimental Section
Representative procedure (gram-scale synthesis): A flame-dried
flask (50 cm3) equipped with a magnetic stir bar was charged with
[Ru(p-cymene)Cl2]2 (46 mg, 0.075 mmol, 0.75 mol%) and K3PO4
(0.53 g, 2.5 mmol, 25 mol%). The flask was transferred into the
glove box and charged with dmpe (25 mL, 0.15 mmol, 1.5 mol%) and
CsF (1.52 g, 10 mmol, 100 mol%) before being sealed with a rubber
septum. The flask was then moved out of the glove box and
sequentially charged with tert-butyl acrylate (2a; 1.46 mL, 10 mmol,
1.0 equiv) and “hydrazone solution” (ca. 6.8 mL, see below) under N2
atmosphere. The reaction mixture was then heated to 508C in an oil
bath. Upon stirring for 5 h, the reaction mixture was filtered through
a plug of silica gel with EtOAc (50 mL) as the eluent, concentrated,
and purified by flash chromatography (hexane/ethyl acetate 90:10 as
the eluent) to give the corresponding product 3a as a colorless oil
(1.94 g, 88% yield). Hydrazone solution: A mixture of benzaldehyde
(1a; 1.22 mL, 12 mmol, 1.2 equiv) and hydrazine monohydrate
(630 mL, 13 mmol, 64–65 wt%, 1.3 equiv) in THF (5 mL) was stirred
at room temperature for 30 min. Prior to injection of this hydrazone
solution into the reaction mixture, a small amount of anhydrous
Na2SO4 was added.
[5] An excellent review on different types of carbon nucleophiles
for conjugate additions: A. G. Csꢄkꢅ, G. D. L. Herrꢄn, M. C.
[6] a) C. Bruneau, P. H. Dixneuf, in Ruthenium Catalysts and Fine
Chemistry, Springer, Berlin, 2004. An early example on
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ruthenium(II)-catalyzed Michael addition through C H activa-
Acknowledgements
tion: b) S.-I. Murahashi, T. Naota, H. Taki, M. Mizuno, H.
Takaya, S. Komiya, Y. Mizuno, N. Oyasato, M. Hiraoka, M.
[7] Selected conceptual papers on umpolung chemistry: a) R.
reactivity: c) R. Brehme, D. Enders, R. Fernandez, J. M.
The authors acknowledge the Canada Research Chair
Foundation (to C.-J.L.), the CFI, FQRNT Center for Green
Chemistry and Catalysis, NSERC, and McGill University for
financial support. X.-J.D. thanks the chemistry department for
the Pall Dissertation Award.
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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