Michael reaction of stabilized carbon nucleophiles catalyzed by [RuH2(PPh3)4]

Article abstract of DOI:10.1021/ja961373w

The Michael reaction of active methylene compounds lacking cyano groups such as malonates, β-ketoesters, 1,3-diketones, 1,1-disulfones, nitrocompounds, Meldrum acid, and anthrone with common acceptors proceeds in acetonitrile solution in the presence of [RuH₂(PPh₃)₄] as the catalyst. Cyano acetates, more acidic than malonates in organic solvents, are also excellent substrates for this reaction. In a number of cases, intramolecular aldol reactions catalyzed by [RuH₂(PPh₃)₄] were also observed as side reactions. Catalysis by other ruthenium and rhodium complexes has been examined. Selectivity studies performed with malonate and disulfone donors indicate that the catalyst selectively activates Michael donors that can coordinate with ruthenium(II). Additionally, it has been shown that the reaction requires the presence of free phosphine. Therefore, the Michael reaction of stabilized enolates appears to be a ruthenium- and phosphine-catalyzed reaction. From a practical point of view, the use of readily prepared [RuH₂(PPh₃)₄] as the catalyst in acetonitrile provided the best solution for the Michael reaction of active methylene compounds.

Full text of DOI:10.1021/ja961373w

J. Am. Chem. Soc. 1996, 118, 8553-8565
8553
Michael Reaction of Stabilized Carbon Nucleophiles Catalyzed
by [RuH2(PPh3)4]
Enrique Go´mez-Bengoa, Juan M. Cuerva, Cristina Mateo, and
Antonio M. Echavarren*
Contribution from the Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
ReceiVed April 26, 1996X
Abstract: The Michael reaction of active methylene compounds lacking cyano groups such as malonates, â-ketoesters,
1,3-diketones, 1,1-disulfones, nitrocompounds, Meldrum acid, and anthrone with common acceptors proceeds in
acetonitrile solution in the presence of [RuH2(PPh3)4] as the catalyst. Cyano acetates, more acidic than malonates
in organic solvents, are also excellent substrates for this reaction. In a number of cases, intramolecular aldol reactions
catalyzed by [RuH2(PPh3)4] were also observed as side reactions. Catalysis by other ruthenium and rhodium complexes
has been examined. Selectivity studies performed with malonate and disulfone donors indicate that the catalyst
selectively activates Michael donors that can coordinate with ruthenium(II). Additionally, it has been shown that
the reaction requires the presence of free phosphine. Therefore, the Michael reaction of stabilized enolates appears
to be a ruthenium- and phosphine-catalyzed reaction. From a practical point of view, the use of readily prepared
[RuH2(PPh3)4] as the catalyst in acetonitrile provided the best solution for the Michael reaction of active methylene
compounds.
Introduction
phines.7 These ruthenium- or rhodium-catalyzed conjugate
additions proceeded readily at room temperature and, more
importantly, under neutral conditions.
The Michael addition of stabilized nucleophiles to R,â-
unsaturated carbonyl compounds is one of the fundamental
processes for the formation of carbon-carbon bonds.1,2 The
reactions is quite general, although in certain cases the Michael
adducts suffer further transformations such as retrograde Michael
reactions and intramolecular condensations.1 Additionally,
polymerization of the Michael acceptor under the basic condi-
tions is frequently observed.1 Recently, Murahashi reported on
the Michael and Knoevenagel reactions of activated nitriles
catalyzed by the ruthenium complex [RuH2(PPh3)4] (1).3,4,5 The
Michael reaction also proceeds in the presence of a rhodium(I)
hydride,6 which has led to the development of efficient
asymmetric processes by using trans-chelating chiral diphos-
In all these processes, active methylene compounds lacking
cyano groups such as 1,3-diketones, â-ketoesters, dialkyl
malonates, and nitroalkanes were shown to be unreactive.3,6
A
mechanistic rationale has been advanced by Komiya and
Murahashi3b,8 to explain the selectivity observed for the
ruthenium-catalyzed Michael reaction. According to this ra-
tionale, which was based on the isolation of an intermediate
ruthenium(II) enolate,8 coordination of the substrate to Ru(II)
through the cyano group was a requirement for the conjugate
addition.3
However, in contradiction to the above findings, we have
found that ruthenium complex 1 is an excellent catalyst for the
Michael addition of non-cyano nucleophiles when the reactions
are performed in acetonitrile instead of THF. Under these
reaction conditions the ruthenium-catalyzed Michael reaction
is quite general providing the desired adducts in good yields
under mild conditions (eq 1). Apparently, we have succeeded
X Abstract published in AdVance ACS Abstracts, August 15, 1996.
(1) (a) Jung, M. E. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 1.1. (b)
Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959, 10, 179. (c)
House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park,
1972; pp 595-623. (d) Perlmutter, P. Conjugate Addition Reactions in
Organic Synthesis; Pergamon: Oxford, 1992. (e) March, J. AdVanced
Organic Chemistry, 4th ed.; Wiley: New York, 1992; pp 795-797. (f)
Stowell, J. C. Carbanions in Organic Synthesis; Wiley: New York, 1987.
(2) For recent lead references on Michael reactions of activated nucleo-
philes, see: (a) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.;
Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 104. (b) Ozaki, Y.;
Kubo, A.; Okamura, K.; Kim, S.-W. Chem. Pharm. Bull. 1995, 43, 734.
(c) Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1571.
(d) Bonadies, F.; Lattanzi, A.; Orelli, L. R.; Pesci, S.; Scettri, A. Tetrahedron
Lett. 1993, 34, 7649. (e) Lubineau, A.; Auge´, J. Tetrahedron Lett. 1992,
33, 8073. (f) Antonioletti, R.; Bonadies, F.; Monteagudo, E. S.; Scettri, A.
Tetrahedron Lett. 1991, 32, 5373. (g) Ranu, B. C.; Bhar, S.; Sarkar, D. C.
Tetrahedron Lett. 1991, 32, 2811. (h) Botteghi, C.; Schianato, A.; Rosini,
C.; Salvadori, P. J. Mol. Catal. 1990, 63, 155. (i) Koerner, M.; Rickborn,
B. J. Org. Chem. 1990, 55, 2662.
(3) (a) Naota, T.; Taki, H.; Mizuno, M.; Murahashi, S.-I. J. Am. Chem.
Soc. 1989, 111, 5954. (b) Murahashi, S.-I.; Naota, T.; Taki, H.; Mizuno,
M.; Takaya, H.; Komiya, S.; Mizuho, Y.; Oyasato, N.; Hiraoka, M.; Hirano,
M.; Fukuoka, A. J. Am. Chem. Soc. 1995, 117, 12436.
(4) (a) Knoevenagel condensation of activated nitriles catalyzed by Ir
and Ru hydrides: Lin, Y.; Zhu, X.; Xiang, M. J. Organomet. Chem. 1993,
448, 215. (b) Knoevenagel condensation of activated nitriles catalyzed by
a Re hydride: Hirano, M.; Ito, Y.; Hirai, M.; Fukuoka, A.; Komiya, S.
Chem. Lett. 1993, 2057.
(5) (a) The related reaction of activated nitriles with imine derivatives
is catalyzed by a variety of metal complexes: Yamamoto, Y.; Kubota, Y.;
Honda, Y.; Fukui, H.; Asao, N.; Nemoto, H. J. Am. Chem. Soc. 1994, 116,
3161. (b) For the reaction of activated nitriles with allenes catalyzed by
Pd(0) complexes, see: Yamamoto, Y.; Al-Masum, M.; Asao, N. J. Am.
Chem. Soc. 1994, 116, 6019.
(6) Paganelli, S.; Schionato, A.; Botteghi, C. Tetrahedron Lett. 1991,
32, 2807.
S0002-7863(96)01373-X CCC: $12.00 © 1996 American Chemical Society

8554 J. Am. Chem. Soc., Vol. 118, No. 36, 1996
Go´mez-Bengoa et al.
Chart 1
ruthenium dihydride17 as shown in the uneventful formation of
adducts 31 and 32 from donor 5 and acceptors 14 and 19. With
dibenzylideneacetone (20) as the acceptor, malonate 2 led to
the formation of cyclohexanone 4418 by a double Michael
process. The reaction of 2 with cyclohexenone (21) was slow
at room temperature in acetonitrile and was better performed
under refluxing conditions to give 45 in moderate yield.2b
Disulfones 12 and 1319 also reacted in the presence of 1 with
acrolein (15) and methyl vinyl ketone (14) to give adducts 42
and 43, respectively, in good yields.
The reaction of 2 with 2 equiv of 14 in the presence of only
0.1 mol % of 1 afforded a 1:1 mixture of dialkylated 23 and
cyclic aldol 24a, as a single stereoisomer, in almost quantitative
yield. The stereochemistry of 24a was assigned as shown with
the hydroxyl cis to the acetyl group on the basis of the
appearance in the 1H NMR spectrum of a doublet for the
chelated hydroxyl at δ 3.92 coupled with the axial H-5 at δ
1.26 with a 4J ) 2.3 Hz. When the same reaction was
performed in the presence of 3 mol % of catalyst 1, 24a was
cleanly obtained as the only product in excellent yield. It is
interesting to note that, despite the ready availability of the
starting materials, 24a has not been previously described.
Similar results were obtained in the reactions of Michael
acceptor 14 with 7, 8, and 11 as the donors. The Michael
reactions of 14 with 7 and 8 provided 34 and 37 stereoselec-
tively, while the corresponding reaction of nitroethane (11) with
14 gave 41 as a mixture of four possible stereoisomers. In
contrast with these reactions in which aldols were obtained as
the major or exclusive products, the reaction of Meldrum acid
(6) and anthrone (10) with 14 gave only 1,7-diketones 33 and
39, respectively.
in increasing substantially the reactivity of the parent ruthenium
complex 1 by substitution of one or more triphenylphosphine
ligands by acetonitrile. Herein we report the scope of this
reaction. We also address in this paper the nature of the catalytic
species and the essential role played by the phosphine in the
reaction system.9,10
Results and Discussion
Reaction Scope. The reactions of Michael donors 2-13 with
acceptors 14-21 proceeded very cleanly in the presence of
ruthenium dihydride 1 (3 mol %) in acetonitrile at 23 °C (Table
1).11 Dimethyl malonate (2) reacted smoothly with 1 equiv of
methyl vinyl ketone (14), acrolein (15), crotonaldehyde (16),12
and dimethyl fumarate (18) to give monoalkylated products 22,13
25,12 26,12,14 and 28,15 respectively, in 54-96% yields. Methyl
acrylate (17) led to dialkylated malonate 279 in quantitative
yield. Substituted malonates 3 and 4 also reacted with 14 to
give adducts 2916 and 30, respectively, in excellent yields. The
presence of a terminal alkyne does not interfere with the
The pKa values of the above donors in dimethyl sulfoxide
(DMSO) ranged from 7 for the more acidic Meldrum acid 620
to 16-20 for malonates 2-5 and nitroethane (11).21,22 Less
acidic donors reacted more sluggishly. Thus, fluorene (46) (pKa
) 23, DMSO)21 reacted with 14 in the presence of 3 mol % of
(14) Skarzewski, J. Synthesis 1990, 1125.
(15) (a) Ferappi, M.; Carotti, A.; Casini, G.; De Laurentis, N.; Giardina,
D.; Cingolani, G. M.; Gavuzzo, E.; Mazza, F. J. Heterocycl. Chem. 1983,
20, 439. (b) Ogibin, Y. N.; Elison, M. N.; Kikishin, G. I.; Kadentesev, V.
I.; Chizhov, O. S. IzV. Akad. Nauk SSSR, Ser. Khim. 1979, 3, 557; Chem.
Abstr. 1979, 91, 38882f.
(7) (a) Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992,
114, 8295. (b) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron 1994,
50, 4439. (c) Sawamura, M.; Hamashima, H.; Shinoto, H.; Ito, Y.
Tetrahedron Lett. 1995, 36, 6479. (d) Sawamura, M.; Sudoh, M.; Ito, Y. J.
Am. Chem. Soc. 1996, 118, 3309.
(8) Mizuho, Y.; Kasuga, N.; Komiya, S. Chem. Lett. 1991, 2127.
(9) White, D. A.; Baizer, M. M. Tetrahedron Lett. 1973, 3597.
(10) (a) Baraldi, P. G.; Guarneri, M.; Pollini, G. P.; Simoni, D.; Barco,
A.; Benetti, S. J. Chem. Soc., Perkin Trans. 1 1984, 2501. (b) Somei, M.;
Karasawa, Y.; Kaneko, C. Heterocycles 1981, 16, 941.
(11) We have routinely carried out the Michael reactions one order of
magnitude more diluted (0.3 M donor and acceptor and 0.01 M catalyst 1)
than those reported by Murahashi (4 M concentration of donor and acceptor
and 0.1 M of 1).3 Catalyst 1 is almost insoluble in acetonitrile although it
dissolved immediately after the addition of the acceptor alkene.
(12) R,â-Unsaturated aldehydes usually give lower yields in Michael
reactions: Yamaguchi, M.; Yokota, N.; Minami, T. J. Chem. Soc., Chem.
Commun. 1991, 1088.
(16) Tamblyn, W. H.; Waltemire, R. E. Tetrahedron Lett. 1983, 24, 2803.
(17) (a) Certain ruthenium(II) dihydrido complexes react with alkynes
to give butenynyl derivatives: Wakatsuki, Y.; Yamazaki, H.; Kumegawa,
N.; Satoh, T.; Satoh, J. Y. J. Am. Chem. Soc. 1991, 113, 9604. (b) For the
related reaction of ruthenium(II) dihydrido η2-dihydrogen complexes, see:
Jia, G.; Meek, D. W. Organometallics 1991, 10, 1444.
(18) Kohler, E. P.; Dewey, C. S. J. Am. Chem. Soc. 1924, 46, 1267.
(19) Benedetti, F.; Berti, F.; Fabrissin, S.; Gianferrara, T.; Risaliti, A. J.
Org. Chem. 1991, 56, 3530.
(20) For a discussion on the higher acidity of Meldrum acid, see:
Evanseck, J. D.; Houk, K. N.; Briggs, J. M.; Jorgensen, W. L. J. Am. Chem.
Soc. 1994, 116, 10630 and references cited therein.
(21) Equilibrium acidities in DMSO at 25 °C: Bordwell, F. G. Acc.
Chem. Res. 1988, 21, 456.
(22) (a) Although relative acidities in DMSO and acetonitrile do not to
differ greatly,21 significant differences are expected in the absolute values:
Kolthoff, I. M.; Chantooni, M. K.; Bhowmik, S. J. Am. Chem. Soc. 1968,
90, 23. (b) The acidity of carbon acids in DMSO and THF is comparable:
Fraser, R. R.; Mansour, T. S.; Savard, S. J. Org. Chem. 1985, 50, 3232.
(13) Tsuji, J.; Minato, M. Tetrahedron Lett. 1987. 28, 3683.

Michael Reaction of Stabilized Carbon Nucleophiles
J. Am. Chem. Soc., Vol. 118, No. 36, 1996 8555
Table 1. Ruthenium-Catalyzed Michael Reaction of Activated Carbon Nucleophilesa
a Unless otherwise stated the reactions were carried out in the presence of 3 mol % ruthenium dihydride 1 in MeCN at 23 °C with 1 equiv each
of donor and acceptor. b Reaction carried out with 2 equiv of acceptor. c Reaction carried out with 0.1 mol % ruthenium dihydride 2. d 34 was
obtained as a 3:2 mixture of C-1 epimers. e 41 was obtained as a 2:1:1:1 mixture of diastereomers. f Reaction carried out at 80 °C.
1 to give dialkylated 47 in only 11% yield even after being
Since the preparation of complex 1 according to the pub-
heated under reflux in acetonitrile for 24 h (eq 2).
lished procedures uses NaBH4 as the reducing agent for

8556 J. Am. Chem. Soc., Vol. 118, No. 36, 1996
Go´mez-Bengoa et al.
Scheme 1
ruthenium(III)23 or ruthenium(II),24 it could be conceived that
traces of basic NaB(OR)4, the product of the reaction between
NaBH4 with the solvent methanol25 or ethanol, may act as the
true catalyst of the reaction. Not unexpectedly, the Michael
reaction between 2 and 14 (2.5 equiv) proceeded in the presence
of NaB(OMe)4 as the catalyst (3 mol %, acetonitrile, 23 °C, 2
h). However, the reaction was less selective with this basic
catalyst, leading to aldol 24a (62% yield) and an inseparable
mixture of its diastereomer 24b and diketone 23 (ca. 3:1, 33%).26
Michael reaction of malonate 22 with 2 equiv of acrolein (15)
(5 mol % of 1, acetonitrile, 23 °C, 16 h) afforded 48 (43%)
and cyclic aldol 49 (6%). The cyclization of ketoaldehyde 48
could be carried out with 10 mol % of 1 to give 49 as a mixture
of stereoisomers (acetonitrile, 23 °C, 2 h, 35% yield). Although
the yield of this cyclization was poor, the aldol reaction was
selective since none of the alternative aldol 50, resulting from
the condensation of the ketone enolate with the aldehyde, was
observed in the crude reaction mixture. Alternatively, aldol 50,
as a mixture of two stereoisomers, could be obtained in the
reaction of malonate 25 with 14 (3 mol % 1, acetonitrile, 23
°C, 1 h, 64%). In this example, the uncyclized ketoaldehyde
was not observed in the crude reaction mixture.
Elimination of any basic impurity from 1 was easily achieved
by washing crude ruthenium dihydride with a large volume of
water under an inert atmosphere of Ar, leading to a yellow
material which showed no sign of loss of catalytic activity in
the Michael addition.
Intramolecular Aldol Reactions. Intramolecular aldol reac-
tions occurred in the transformations leading to 24a, 34, 37,
and 41 (Table 1). These aldol reactions are also catalyzed by
complex 1. Thus, the intramolecular aldol reaction of diketone
23 was cleanly performed by using 5 mol % of complex 1 in
acetonitrile at 23 °C for 16 h to give stereoselectively 24a as
the only product (eq 3).
Catalysis with Other Ruthenium and Rhodium Com-
plexes. The results obtained with different ruthenium and
rhodium complexes in the reactions of malonates 2 and 4 with
acceptor 14 are summarized in Table 2. Ruthenium dihydride
5129 with triphenylarsine instead of triphenylphosphine catalyzed
the slow formation of aldol 24a from 2 in moderate yield (entry
1; compare Table 1, entry 3). The same reaction in THF was
considerably slower, giving monoadduct 22 in low yield (entry
2). Slow reactions were observed with ruthenium dihydride
5230 and monohydrides 5331 and 54.32 These processes may
be catalyzed by the phosphine released from the ruthenium
complexes33 since no reaction was observed with the related
cationic hydride 5534 with two tightly bound trans phosphine
ligands.35 Hydrides 56 and 5736 were active catalysts for the
Michael reaction. Noteworthy, bisacetonitrile complex 57
efficiently catalyzed the addition of 2 to 14 to give a 3:1 mixture
of mono- and dialkylated derivatives 22 and 23 in quantitative
The intramolecular reactions of ketoaldehydes proceed by
attack of the R-carbon of the ketone or the aldehyde depending
on the strain of the formed ring and the reaction conditions.27,28
The cyclizations outlined in Scheme 1 demonstrate that an
enolate is formed under the conditions of the ruthenium-
catalyzed Michael reaction, which reacts intramolecularly with
the carbonyl group to afford aldols under kinetic conditions.
(29) This complex was prepared by using a procedure similar to that
used for the preparation of 1 with AsPh3 instead of PPh3. For an alternative
preparation: Dedieu, M.; Pascal, Y.-L. J. Mol. Catal. 1980, 9, 71.
(30) (a) Knoth, W. H. J. Am. Chem. Soc. 1972, 94, 104. (b) Chaudret,
B. N.; Cole-Hamilton, D. J.; Nohr, R. S.; Wilkinson, G. J. Chem. Soc.,
Dalton Trans. 1977, 1546. (c) Cole-Hamilton, D. J.; Wilkinson, G. NouV.
J. Chim. 1977, 1, 133.
(31) Robinson, S. D.; Levison, J. J.; Ahmand, N.; Uttley, M. F. Inorg.
Synth. 1974, 15, 48.
(32) Santos, A.; Lo´pez, J.; Montoya, J.; Noheda, P.; Romero, A.;
Echavarren, A. M. Organometallics 1994, 13, 3605.
(33) Facile substitution of the equatorial triphenylphosphine ligand has
been observed in the reaction of hydride 53 with 1-alkynes: (a) Torres, M.
R.; Vegas, A.; Santos, A. J. Organomet. Chem. 1986, 209, 169. (b) Torres,
M. R.; Santos, A.; Ros, J.; Solans, X. Organometallics 1987, 6, 1091. (c)
Torres, M. R.; Vegas, A.; Santos, A.; Ros, J. J. Organomet. Chem. 1987,
326, 413.
(23) Synthesis of 1 from RuCl3‚3H2O: Levison, J. J.; Robinson, S. D.
J. Chem. Soc. A 1970, 2947.
(24) Synthesis of 1 from [Ru(PPh3)3Cl2] (60): Young, R.; Wilkinson,
G. Inorg. Synth. 1990, 28, 337.
(25) Golden, J. M.; Schreier, C.; Singaram, B.; Williamson, S. M. Inorg.
Chem. 1992, 31, 1533.
(26) Very similar results were obtained in the presence of NaBH4 (3
mol %, 23 °C, 2 h, acetonitrile). Probably the actual catalyst in this case is
the corresponding alkoxyde resulting from the reduction of the carbonyl of
14. Under these conditions, a mixture of aldol 24a (70%), its stereoisomer
24b (ca. 20%), and diketone 23 (ca. 10%) was obtained.
(27) (a) Nielsen, A. T.; Houlihan, W. J. Org. React. 1968, 16, 1. (b)
Reference 1e, p 940.
(28) Under kinetic conditions the rate-determining deprotonation of the
more acidic aldehydes usually leads to the formation of cyclic â-hydroxy
aldehydes: (a) Guthrie, J. P.; Cossar, J. Can. J. Chem. 1986, 64, 2470. (b)
Guthrie, J. P. J. Am. Chem. Soc. 1991, 113, 7249.
(34) This hydride was prepared by a procedure analogous to that used
for the synthesis of the PF6- complex by using NaBF4: Lo´pez, J.; Romero,
A.; Santos, A.; Vegas, A.; Echavarren, A. M.; Noheda, P. J. Organomet.
Chem. 1989, 373, 249.

Michael Reaction of Stabilized Carbon Nucleophiles
J. Am. Chem. Soc., Vol. 118, No. 36, 1996 8557
Table 2. Reactions of Malonates 2 or 4 with 3-Buten-2-one (14)
and Complexes 51-62a
Chart 2
reaction
time (h)
yield
(%)
donor
complex
solvent
product
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
51
51
52
53
53
54
54
55
55
56
57
58
58
59
59
60
61
61
62
62
51
51
52
52
54
54
55
55
58
58
59
59
61
61
62
62
MeCN
THF
MeCN
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
MeCN
THF
24
52
24
23
26
22
52
26
26
4
24a
22
b
22
22
22
22
b
57
18
27
22
13
14
b
22
48
100
79
23
69
79
41
4
22 + 23 (3:1)
24
24
24
24
72
26
26
27
52
29
29
30
26
45
26
45
26
24
24
24
24
29
29
29
29
22 + 23 (12:1)
22
22 + 23 (16:1)
22 + 23 (10:1)
22
b
b
22
22
30
30
30
30
b
30
b
b
30
b
30
30
b
64
40
20
30
14
13
2
56
that none of the ruthenium and rhodium complexes examined
was superior to the parent ruthenium dihydride 1.
61
33
Nature of the Ruthenium Catalyst Species. Dihydride 1
reacts easily at room temperature with weak donor ligands by
substitution of a triphenylphosphine ligand.30,38,39,41 In fact, the
1H NMR spectrum of 1 in benzene-d6 showed, besides the
multiplet at δ -10.14 corresponding to 1,42,43 a small quartet
at δ -17.20 (J ) 29.4 Hz) probably corresponding to the
coordinatively unsaturated dihydride 6344 in equilibrium with
1.45 Addition of acetonitrile to 1 led to the clean formation of
the ruthenium dihydride 6446,47,48 (Scheme 2), which showed
two well differentiated signals for the hydride ligands at δ -8.90
(dtd, J ) 76.3, 31.2, 7.1 Hz) and -14.96 (tdd, J ) 28.5, 13.7,
7.0 Hz).
b
30
30
MeCN
THF
65
41
a All reactions were performed in the presence of 3 mol % of
complex at 23 °C. b No reaction was observed.
yield, although no intramolecular aldol reaction of 23 was
observed. Dihydrogen dihydride ruthenium complex 5837 and
binuclear hydride 5938 were also moderate catalysts for the
addition process. [Ru(PPh3)3Cl2] (60)39 showed some catalytic
activity, whereas no reaction was observed with [Rh(PPh3)3Cl]
(61).40a The related rhodium hydride [RhH(CO)(PPh3)2] (62)40b
is only a moderate catalyst for this reaction leading to the
formation of monoalkylated 22 from donor 2. In all cases, lower
conversions were obtained with more substituted malonate 4
as the Michael donor. The results of Table 2, with only two
exceptions, show that acetonitrile is a superior solvent to THF
for this type of Michael addition. It is important to note also
Available literature evidence suggests that dihydride 1 reacts
with an alkene by ligand substitution to form coordination
(41) (a) Ito, T.; Kitazume, S.; Yamamoto, A.; Ikeda, S. J. Am. Chem.
Soc. 1970, 92, 3011. (b) Komiya, S.; Yamamoto, A. J. Chem. Soc., Chem.
Commun. 1974, 523.
(42) A cis-dihydrido stereochemistry has been demonstrated for [RuH2-
(L)4] (L ) phosphine or phosphite): (a) Meakin, P.; Muetterties, E. L.;
Jesson, J. P. J. Am. Chem. Soc. 1973, 95, 75. (b) Dewhirst, K. C.; Keim,
W.; Reilly, C. A. Inorg. Chem. 1968, 7, 546.
(35) Cationic complexes of type 55 retain the axial triphenylphosphine
ligands in the reactions with alkynes, carbon monoxide, or isocyanides:
(a) See ref 34. (b) Montoya, J.; Santos, A.; Echavarren, A. M.; Ros, J. J.
Organomet. Chem. 1990, 390, C57. (c) Echavarren, A. M., Lo´pez, J.; Santos,
A.; Romero, A.; Hermoso, J. A.; Vegas, A. Organometallics 1991, 10, 2371.
(d) Montoya, J.; Santos, A.; Echavarren, A. M.; Ros, J.; Romero, A. J.
Organomet. Chem. 1992, 426, 383.
(36) Sanders, J. R. J. Chem. Soc., Dalton Trans. 1973, 743.
(37) (a) Harris, R. O.; Hota, N. K.; Sadavoy, L.; Yuen, J. M. C. J.
Organomet. Chem. 1973, 54, 259. (b) Ashworth, T. V.; Singleton, E. J.
Chem. Soc., Chem. Commun. 1976, 705. (c) Crabtree, R. H.; Hamilton, D.
G. J. Am. Chem. Soc. 1986, 108, 3124. (d) Hamilton, D. G.; Crabtree, R.
H. J. Am. Chem. Soc. 1988, 110, 4126.
(38) Sluys, L. S.; Kubas, G. J.; Caulton, K. G. Organometallics 1991,
10, 1033.
(39) (a) Hallman, P. S.; Stephenson, T. A.; Wilkinson, G. Inorg. Synth.
1970, 12, 238. (b) Stephenson, J. A.; Wilkinson, G. J. Inorg. Nucl. Chem.
1966, 28, 945.
(40) (a) Osborn, J. A.; Jardine, F. H.; Young, J. F.; Wilkinson, G. J.
Chem. Soc. A 1966, 1711. (b) Evans, D.; Osborn, J. A.; Wilkinson, G. Inorg.
Synth. 1968, 11, 99.
(43) Minor amounts of tetrahydride 58 were also observed in some of
the samples of crude hydride 1 prepared according to the described
procedures.23,24
(44) (a) For the related dihydride [RuH2(p-C6H5CH3PPh2)3], see: Ar-
liguie, T.; Chaudret, B.; Morris, R. H. Polyhedron 1988, 7, 2031. (b) See
also: Linn, D. E.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 2969.
(45) We have found that the elusive coordinatively unsaturated ruthenium
dihydride39 can be readily obtained from 1 in polar solvents: Mateo, C.;
Cuerva, J. M.; Echavarren, A. M. Unpublished results.
(46) [RuH2(RCN)(PPh3)3]: (a) R ) Ph: ref 30a. (b) R ) Me (64), Ph:
ref 37a.
(47) For related acetonitrile ruthenium complexes, see: (a) Cole-
Hamilton, D. J.; Wilkinson, G. J. Chem. Soc., Dalton Trans. 1979, 1283.
(b) The electrochemical reduction of [Ru(PPh3)4Cl2] in MeCN was reported
to give [Ru(PPh3)4(π-MeCN)]‚MeCN: Sherman, E. O.; Schreiner, P. R. J.
Chem. Soc., Chem. Commun. 1976, 3. This complex was later reformulated
as RuH(C6H4PPh2)(MeCN)(PPh3)2.47a
(48) The high affinity of Ru(II) complexes for acetonitrile has been
applied for the in situ generation of active catalysts: Pertici, P.; Ballantini,
V.; Salvadori, P.; Bennett, M. A. Organometallics 1995, 14, 2565 and
references cited therein.

8558 J. Am. Chem. Soc., Vol. 118, No. 36, 1996
Go´mez-Bengoa et al.
Scheme 2
intermediate ruthenium(0) complexes of type 68 may react
further with the phosphine ligand by ortho metalation or undergo
a variety of intramolecular oxidative addition reactions.41b,56
Dihydride 1 and related complexes have also been reported to
promote the polymerization of acrylonitrile, acrolein, methyl
vinyl ketone, and methyl acrylate.56c,57,58,59 The alternative
formation of a coordinatively unsaturated [Ru(PPh3)4] as an
intermediate by reductive elimination of H2 is unlikely under
the moderate conditions required for the formation of the alkene
complexes.60
In accordance with the hypothetical involvement of ruthenium-
(0) complexes in the catalytic cycle, complex 68 (R ) CO2-
Me)55 is a moderately active catalyst for the Michael reaction.
Thus, the reaction between 2 and 14 (2 equiv) proceeded readily
in acetonitrile in the presence of 3 mol % of 68 to give a 1:1.9
mixture of diketone 23 and aldol 24a in 84% yield after 6 h at
23 °C. Addition of 6 mol % of triphenylphosphine increased
slightly the reactivity of the catalyst leading to a 1:3.4 mixture
of 23 and 24a (91% yield) under otherwise identical conditions.
Scheme 3
Ruthenium Hydride or Phosphine Catalyzed Reaction?
As stated before, complex 1 is known to release easily one of
the phosphine ligands to form a coordinatively unsaturated
pentacoordinated ruthenium complex 63 which can react with
a molecule of acetonitrile to form hexacoordinated complex 64.
Since phosphines are known to catalyze the Michael addition
of certain active methylene compounds,1a,9,10,61 the possibility
exists that the Michael reactions may be simply catalyzed by
the free triphenylphosphine released upon coordination of
acetonitrile or the acceptor substrate with complex 1. In fact,
literature precedent prescribes the use of caution in proposing
mechanistic hypothesis for reactions presumably catalyzed by
transition metals62 which could also be performed in the
presence phosphines as the catalysts.63,64
(56) (a) Cole-Hamilton, D. J.; Wilkinson, G. NouV. J. Chim. 1977, 1,
141. (b) Smith, A. E. Inorg. Chem. 1972, 11, 2306. (c) Komiya, S.;
Yamamoto, A. J. Organomet. Chem. 1975, 87, 333. (d) Komiya, S.; Ito,
T.; Cowie, M.; Yamamoto, A.; Ibers, J. A. J. Am. Chem. Soc. 1976, 98,
3875. (e) Komiya, S.; Aoki, Y.; Mizuno, Y.; Oyasato, N. J. Organomet.
Chem. 1993, 463, 179.
(57) (a) Ito, T.; Kitazume, S.; Yamamoto, A.; Ikeda, S. J. Am. Chem.
Soc. 1970, 92, 3011. (b) Yamamoto, A.; Ikeda, S. J. Macromol. Sci.-Chem.
1975, A9, 931.
(58) However, these polymerizations may be just the result of a process
catalyzed by the nucleophilic phosphine released from the ruthenium
complex. Indeed, PMe3 released from [RuH2(PMe3)4] initiates the rapid
polymerization of acrylonitrile, methacrylonitrile, and methyl vinyl ke-
tone: Rappert, T.; Yamamoto, A. Organometallics 1994, 13, 4984.
(59) The polymerization of methyl acrylate (17) by 1 has not been
confirmed.55a
(60) (a) Elimination of H2 from 1 and related ruthenium dihydrides
proceeds very slowly and requires heating at a rather high temperature (140-
200 °C).41a (b) [RuH2(PMe3)4] undergoes elimination at >180 °C: Hartwig,
J. F.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1991, 113, 6492.
(c) [RuH2(dmpe)2] (dmpe ) 1,2-bis(dimethylphosphino)ethane) requires ca.
140 °C: Hsu, G. C.; Kosar, W. P.; Jones, W. D. Organometallics 1994,
13, 385. (d) No elimination was observed when [RuH2(CO)(PPh3)3] (52)
was heated at 120 °C for 1.5 h: Kakiuchi, F.; Sekine, S.; Tanaka, Y.;
Kamatani, A.; Sonoda, M.; Chatani, N.; Murai, S. Bull. Chem. Soc. Jpn.
1995, 68, 62.
(61) Some nucleophilic phosphines catalyze the Michael additions of
nitroalkanes: (a) Polystyryltributylphosphine: Kim, B.; Kodomari, M.;
Regen, S. L. J. Org. Chem. 1984, 49, 3233. (b) Tris(2,4,6-trimethoxy-
phenyl)phosphine: Masanori, W.; Aki, T.; Kumiko, N.; Tatsuo, E. Nippon
Kagaku Kaishi 1987, 1284; Chem. Abstr. 1988, 108, 149866t. (c) PBu3:
Miyakoshi, T. Yakugaku Zasshi 1988, 37, 19; Chem. Abstr. 1988, 109,
92232x.
(62) (a) Trost, B. M.; Schmidt, T. J. Am. Chem. Soc. 1988, 110, 2301.
(b) Ma, D.; Lin, Y.; Lu, X.; Yu, Y. Tetrahedron Lett. 1988, 29, 1045. (c)
Ma, D.; Yu, Y.; Lu, X. J. Org. Chem. 1989, 54, 1105. (d) Guo, C.; Lu, X.
Tetrahedron Lett. 1991, 32, 7549.
(63) (a) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933.
(b) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993, 1921. See also:
(c) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167. (d) Trost, B.
M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 10819. (e) Zhang, C.; Lu, X.
Synlett 1995, 645.
complex 65, followed by a facile insertion49 to give the
hydridoalkyl ruthenium(II) complex 66, which could suffer
reductive elimination to give intermediate Ru(0) species 67
(Scheme 3).50 Coordination of two molecules of alkene
RCHdCH2 to the ruthenium(0) intermediate then leads to stable
complex [Ru(RCHdCH2)2(PPh3)2] (68).51 This type of behavior
has been described for styrene52,53,54 and, more recently, for
methyl acrylate.55 With other alkenes the highly reactive
(49) (a) Hill, A. F. In ComprehensiVe Organometallic Chemistry II; Abel,
E. W., Stone, H. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995;
Vol. 7, Chapter 6. (b) For a recent study on the insertion of styrenes into
Ru-H bonds, see: Faller, J. W.; Chase, K. J. Organometallics 1995, 14,
1592.
(50) For a recent discussion on Ru(0) complexes, see: Ogasawara, M.;
Macgregor, S. A.; Streib, W. E.; Folting, K.; Eisenstein, O.; Caulton, K.
G. J. Am. Chem. Soc. 1995, 117, 8869.
(51) For lead references on (η2-alkene)ruthenium(0) complexes, see:
Bennett, M. A. In Comprehensive Organometallic Chemistry II; Abel, E.
W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford, 1995; Vol.
7, Chapter 7.
(52) (a) Komiya, S.; Yamamoto, A.; Ikeda, S. J. Organomet. Chem. 1972,
42, C65. (b) Komiya, S.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1976, 49,
2553. (c) Carrondo, M.; Chaudret, B. N.; Cole-Hamilton, D. J.; Skapski,
A. C.; Wilkinson, G. J. Chem. Soc., Chem. Commun. 1978, 463. (d)
Chaudret, B. N.; Cole-Hamilton, D. J.; Wilkinson, G. J. Chem. Soc., Dalton
Trans. 1978, 1739. (e) Rosete, R. O.; Cole-Hamilton, D. J.; Wilkinson, G.
J. Chem. Soc., Dalton Trans. 1984, 2067.
(53) For the reaction of [Ru(CH2dCHPh)2(PPh3)2] with other alkenes,
see: (a) Chaudret, B. N.; Cole-Hamilton, D. J.; Wilkinson, G. Acta Chem.
Scand., Ser. A 1979, 32, 763. (b) Reference 52d.
(54) However, it has been point out that the X-ray structure of the
coordinatively unsaturated styrene complex [Ru(Ph-CHdCH2)2(PPh3)2]52c
reveals that one of the styrene ligands may be η3-coordinated.50
(55) The complex with methyl acrylate was isolated as a pentacoordinated
aquo derivative [Ru(CH2dCHCO2Me)2(H2O)(PPh3)2]: (a) Sustmann, R.;
Patzke, B.; Boese, R. J. Organomet. Chem. 1994, 470, 191. (b) See also:
Patzke, B.; Sustmann, R. J. Organomet. Chem. 1994, 480, 65.

Michael Reaction of Stabilized Carbon Nucleophiles
J. Am. Chem. Soc., Vol. 118, No. 36, 1996 8559
Table 3. Phosphine-Catalyzed Michael Reactions with
3-Buten-2-one (14)a
Scheme 4
equiv
donor of 14
reaction
yield
catalyst
PPh3
PPh3
PPh3
solvent time (h) product (%)
2
2
2
2
2
2
MeCN
MeCN
MeCN
2c
4c
48
22
22
22
24a
e
21
39
20
6
2
2
2
2
2
2
2
4
4
5
6
9
9
9
1
1
2
2
2
2
2
1
1
1
2
1
1
1
PPh3 + HOAcd MeCN
26
26
0.1
0.1
1
8
HOAcf
PBu3
PCy3
PCy3
dppf
MeCN
MeCN
MeCN
THF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
e
24a
24a
22
22
e
30
e
31
33
38
38
38
95
82
26
84
g
AsPh3
PPh3
24
f
24
26
12
24
48
48
48
4
HOAcf
PPh3
95
47
6
24
55
PPh3
PBu3
PCy3
PCy3
h
i
i
a Unless otherwise stated reactions were performed in the presence
of 3 mol % phosphine or arsine at 25 °C. b dppf ) 1,1′-bis(diphe-
nylphosphino)ferrocene. c Reaction temperature ) 40 °C. d 16 mol %
each was added. e No reaction was observed. f 16 mol % of additive
(triphenylphosphine or HOAc was used). g An identical result was
obtained with 12 mol % triphenylarsine. h 10 mol % of phosphine was
used. i 20 mol % of phosphine was used.
The phosphine released from complex 1 could promote the
Michael reaction by means of a conjugate addition to the
acceptor to form a zwitterionic intermediate 69,65 which could
then deprotonate the active methylene compound to afford a
phosphonium enolate 70 as the key intermediate (Scheme
4).9,10,66 Michael addition of 70 to the acceptor alkene would
give a new phosphonium enolate 71, which would finally lead
to the Michael adduct and intermediate 70 by reaction with the
starting donor.67
Triphenylphosphine indeed catalyzes the addition of some
Michael donors to 14 (Table 3). However, the reactions of
donor 2 with triphenylphosphine as the catalyst were slower
than those carried out with 1 leading to lower yields of
monoalkylated derivative 22 (entries 1 and 2). Furthermore,
aldol 24a was obtained in only 6% yield after 48 h at 25 °C
(entry 3). As expected, no reaction was observed in the presence
of acetic acid (entries 4 and 5). Similarly, more acidic donor
6 led to the dialkylated derivative in lower yield (47%, 24 h)
than that obtained by using 1 as the catalyst (80%, 8 h). Other
phosphines were also shown to catalyze the reaction, while
triphenylarsine was ineffective. For the reaction between 2 and
14, tributylphosphine9 or tricyclohexylphosphine in acetonitrile
were shown to be efficient catalysts leading to the formation
of 24a in very good yields (Table 3, entries 6 and 7). A
substantially slower reaction was observed in THF (compare
entries 7 and 8). Although the additions of 5 and 6 to 14 could
be catalyzed by triphenylphosphine, the phosphine-catalyzed
Michael addition is less general than the process catalyzed by
ruthenium complex 1. Thus, the reaction with diketone 9 as
the donor was very slow even in the presence of the more
nucleophilic tributylphosphine. Acceptors 16, 17, 20, and 21
failed to react with alkylated malonates 3 or 5 in the presence
of phosphine as the catalyst under the usual reaction conditions68
and acrolein (15) was polymerized under the reaction conditions.
The phosphine-catalyzed reaction is not a simple base-catalyzed
process,9,69 since neither NEt3 nor i-Pr2NEt led to significant
(>5%) transformations under the usual reaction conditions.
These results are in agreement with previous observations.9,70
Figures 1 and 2 summarize the results obtained in the
reactions of donors 2 and 4 with 1 equiv of acceptor 14 catalyzed
by ruthenium dihydride 1 or triphenylphosphine (acetonitrile-
d3, 25 °C). Data for reactions carried out with rhodium complex
6240 as the catalyst are also included. The reactions catalyzed
by 3 mol % of 1 were very rapid, giving rise to quantitative
conversions into 22 and 30. Considerably slower reactions were
observed with 62 as the catalyst, which apparently suffered
decomposition after 1-2 h. Similar experiments (not shown)
with arsine complex 51 showed considerable induction periods
(1-2 h), indicating that the slow formation of an active species
derived from 51 was necessary in this case. On the other hand,
the reactions catalyzed by triphenylphosphine (10 mol %) were
slow, leading to less than 10% conversions into the Michael
adducts after 3 h.
(64) Formation of the Michael adduct between methanol and acrylonitrile
in a cobalt carbonyl-catalyzed hydrocarbonylation reaction has also been
explained as a phosphine-catalyzed process: Dubois, R. A.; Garrou, P. E.
J. Organomet. Chem. 1984, 241, 69.
(65) The zwitterionic intermediate has been trapped with several
electrophiles: (a) Ohmori, H.; Takanami, T.; Shimada, H.; Masui, M. Chem.
Pharm. Bull. 1987, 35, 2558. (b) Cristau, H. J.; Torreilles, E.; Barois-
Gacherieu, C. Synth. Commun. 1988, 18, 185. (c) Viala, J.; Santelli, M.
Synthesis 1988, 370.
(66) Nucleophilic phosphines catalyze the addition of electrophilic
alkenes to aldehydes (Baylis-Hillman reaction). For lead references, see:
(a) Roth, F.; Gygax, P.; Fra´ter, G. Tetrahedron Lett. 1992, 33, 1045. (b)
Amri, H.; Rambaud, M.; Villieras, J. Tetrahedron Lett. 1989, 30, 7381. (c)
Miyakoshi, T.; Saito, S. Nippon Kagaku Kaishi 1983, 1623; Chem. Abstr.
1984, 100, 156191g. (d) For a rhodium(I)- or ruthenium(II)-catalyzed
process, see: Sato, S.; Matsuda, I.; Shibata, M. J. J. Organomet. Chem.
1989, 377, 347.
(67) Alternatively, 71 may react with the acceptor to furnish oligomers:
(a) Horner, L.; Jugeleit, W.; Klupfel, K. Liebigs Ann. Chem. 1955, 591,
108. (b) Kukhtin, V. A.; Kamai, G.; Sinchenko, L. A. Dokl. Akad. Nauk.
S.S.S.R. 1958, 118, 505; Chem. Abstr. 1958, 52, 10956.
Triphenylphosphine was also a poor catalyst in the reaction
of malonate 2 with methyl acrylate (17). Thus, reaction between
2 and 17 (3 equiv) in the presence of 3 mol % of triphenylphos-
phine proceeded in acetonitrile at 23 °C to give triester 72 (17%)
(68) However, it has been reported that less substituted dimethyl malonate
(2) and methyl acrylate gave a mixture of mono- (16%) and bisadduct (66%)
with tributylphosphine as the catalyst.9
(69) For the pKa of common phosphines, see: Rahman, M. M.; Liu,
H.-Y.; Eriks, K.; Prock, A.; Giering, W. P. Organometallics 1989, 8, 1 and
references cited therein.
(70) For a recent example that stresses the different catalytic abilities of
phosphines and amines, see: Vedejs, E.; Diver, S. T. J. Am. Chem. Soc.
1993, 115, 3358.

8560 J. Am. Chem. Soc., Vol. 118, No. 36, 1996
Go´mez-Bengoa et al.
Figure 2. Reaction profile for the Michael reaction between donor 4
and acceptor 14 to give 30 (Table 1, entry 9) in acetonitrile-d3 at 25
°C.
Figure 1. Reaction profile for the Michael reaction between donor 2
and acceptor 14 to give 22 (Table 1, entry 1) in acetonitrile-d3 at 25
°C.
Parallel experiments (acetonitrile, 23 °C) demonstrated that the
reaction between 73 and 17 catalyzed by 3 mol % of 1 was
much faster (>10:1) than that carried out with 6 mol % of
triphenylphosphine.
and tetraester 27 (13%) after 24 h (eq 4). In contrast, the
reaction catalyzed by 1 led to 27 in almost quantitative yield
under otherwise identical conditions (Table 1, entry 6).
Cyanoacetates are three orders of magnitude more acidic than
malonates in DMSO solution.72,73 Since a similar difference is
also expected in nonprotic polar solvents such as THF and
acetonitrile, the different reactivity observed between malonates
and cyanoacetates can be simply explained by the easier
deprotonation of the more acidic substrates. In fact, the selective
reaction of cyanoacetates was also observed in the phosphine
catalyzed reaction. A competitive experiment carried out with
1 equiv each of malonate 2, cyanoacetate 73, and acceptor 14
with triphenylphosphine as the catalyst (acetonitrile, 23 °C) gave
exclusively adduct 77. Cyano triester 78 has been shown by
Murahashi to react regio- and stereoselectively with 14 in the
presence of 1 (THF, -78 °C) to give a 97:3 mixture of 79 and
80 (73%) (eq 7).3 A mechanistic rationale has been offered
for this selectivity based on the coordination of both the nitrile
and the ester carbonyl group to Ru(II).3b In our hands, the same
regioselectivity was obtained with triphenylphosphine as the
catalyst (6 mol %, THF, 2 equiv of 14), with only slightly lower
stereoselectivity (95:5; 67% yield) at the temperature required
for the Michael addition (23 °C).74 Therefore the selectivity
found by Murahashi for the enolates derived from substrates
In contrast with the above results obtained using malonates
as the donors, the reaction of ethyl cyanoacetate (73) with
acceptor 14 proceeded very rapidly in the presence of triph-
enylphosphine as the catalyst (3 mol %) to yield the double
Michael adduct 743 in quantitative yield (acetonitrile, 23 °C, 8
min) (eq 5). The reaction catalyzed by triphenylphosphine was
slower in THF, while ruthenium hydride 1 (3%) promotes the
almost instantaneous conversion into the Michael adduct 74 (ca.
1 min in acetonitrile). Similarly, prenylated cyanoacetate 7571
gave 76 under the conditions developed by Murahashi (3 mol
% 1, THF, 25 °C, 6 h)3 in 84% yield, while the same reaction
catalyzed by 3 mol % of tricyclohexylphosphine (acetonitrile,
25 °C, 18 h) provided 76 in 91% yield. The reaction of 73
with methyl acrylate (17) in the presence of 1 (THF, 25 °C, 24
h) has been reported by Murahashi to give the double adduct
77 in 95% yield.3 We have obtained 77 in a similar yield (90%)
when the reaction was catalyzed by 6 mol % of triphenylphos-
phine under otherwise identical conditions. By using 1 in
acetonitrile, 77 was obtained in quantitative yield (24 h, 23 °C).
(72) (a) The pKa of ethyl cyanoacetate (56) in DMSO (25 °C) is 13.1:
Bordwell, F. G.; Branca, J. C.; Bares, J. E.; Filler, R. J. Org. Chem. 1988,
53, 780. (b) The pKa of diethyl malonate in DMSO (25 °C) is 16.4.22
(73) (a) Reference 1d, p 210. (b) Cope, A. C.; Holmes, H. L.; House, H.
O. Org. React. 1957, 9, 107.
(74) In our hands, the Michael addition of 78 to 14 was too slow at -78
°C leading to irreproducible yields of 79 and 80. Control experiments
demonstrated that these additions took place during the workup at room
temperature.
(71) Cuvigny, T.; Julia, M.; Rolando, C. J. Organomet. Chem. 1985,
285, 395.

Michael Reaction of Stabilized Carbon Nucleophiles
J. Am. Chem. Soc., Vol. 118, No. 36, 1996 8561
Scheme 5
like 78 is not exceptional since it is also reproduced by using
triphenylphosphine as the catalyst. The regioselectivity ob-
served with the phosphine catalyst is identical to that obtained
with 1 as the catalyst,3 and follows that expected from the
relative acidities of cyanoacetates and malonates in organic
solvents. A similar selectivity (95:5 mixture of 79/80) was
observed with 1 in acetonitrile.75
The reaction of methyl cyanoacetate with 1 or [Ru(C2H4)-
(PPh3)4] has been shown to give complex 81, in which the
cyanoester enolate coordinates with the ruthenium center through
the nitrile group.3b,8,4b Complex 81 acts also as a catalyst for
by using as an additive [Pd(COD)Cl2] (84),79 a complex which
traps irreversibly triphenylphosphine leading to the formation
of [Pd(PPh3)2Cl2] (85).80 Thus, the addition of a catalytic
amount of 84 (1 equiv per Ru complex) almost completely
inhibited the Michael additions. Reaction between 2 and 14
with 1 as the catalyst in acetonitrile in the presence of 1 equiv
of 84 gave only a 21% yield of monoalkylated 22 (compare
Table 1, entry 1). Addition of a second equivalent of 84
completely suppressed the Michael process. Similar results were
obtained by using the Pd(0) complex [Pd2(dba)3‚dba ] (86)81 as
the trapping reagent for the released triphenylphosphine.82
Control experiments demonstrated that neither 85 nor 1,5-
cyclooctadiene83 interfered with the Michael additions.84 Simi-
larly, no reaction was observed between cyanoacetate 73 and 2
equiv of 17 or 19 as the acceptors when the reactions were
carried out with 1 as the catalyst (6 mol %) and 84 (12 mol %)
in THF at 23 °C. The same inhibition was again observed with
86. It is important to note that the Knoevenagel reaction of
cyano nucleophiles catalyzed by 1 described also by Murahashi3
the Murahashi reactions and undergoes stoichiometric Knoev-
enagel and Michael reactions with aldehydes and acrylonitrile,
respectively.3b,8 Based on these experiments, a mechanistic
rationale has been proposed by Komiya and Murahashi for the
chemoselective ruthenium-catalyzed reaction of activated nitriles
which involves the activation of a C-H bond of the substrate
by an in situ formed ruthenium(0) complex (67) to give the
key intermediate 8276 followed by a conjugate addition to give
83, which would give rise to the observed Michael adduct by
an unusual reductive elimination (Scheme 5).3b
In our case, a similar activation of the Michael donor should
lead to the corresponding ruthenium(II) enolates.77 However,
no reaction was observed between complex 1 and malonate 2
at 23 °C (CDCl3 or benzene-d6 solutions). Addition of acceptor
14 to these solutions led to the formation of Michael adduct 22
with the simultaneous disappearance of the hydride resonance
corresponding to 1. Small amounts of aldol 24a were also
observed under these conditions. We have not been able to
detect any high-field hydride resonance under these stoichio-
metric conditions.78
(78) The addition of dideuterated malonate (2-d2) to 14 in the presence
of ruthenium dihydride 1 afforded adduct 22-d2. This deuteration pattern is
consistent with either a ruthenium (Scheme 5) or phosphine (Scheme 2)
catalyzed reaction.
(79) Chatt, J.; Vallarino, L. M.; Venanzi, L. M. J. Chem. Soc. 1957,
3413.
(80) Palladium complex 84 behaves as a phosphine sponge toward
phosphine-coordinated palladium(II) complexes: (a) Mateo, C.; Ca´rdenas,
D. J.; Ferna´ndez-Rivas, C.; Echavarren, A. M. Chem. Eur. J. In press. (b)
For a similar observation, see: Gretz, E.; Sen, A. J. Am. Chem. Soc. 1986,
108, 6038.
(81) (a) Takahashi, Y.; Ito, T.; Sakai, S.; Ishii, Y. J. Chem. Soc., Chem.
Commun. 1970, 1065. (b) Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnet, J. J.;
Ibers, J. A. J. Organomet. Chem. 1974, 65, 253.
(82) For the reaction between 86 and triphenylphosphine, see: Amatore,
C.; Jutand, A.; Khalil, F.; M’Barki, M. A.; Mottier, L. Organometallics
1993, 12, 3168.
On the other hand, only complexes which can easily lose a
phosphine ligand are satisfactory catalysts for the reaction (Table
3). In fact, the reactions catalyzed by 1 appear to require the
presence of free triphenylphosphine. This was demonstrated
(75) Because of the higher reactivity of malonates with 1 in acetonitrile,
the reaction was carried out with 1 equiv of 14 for 2 h at 23 °C (36% yield,
72% based on recovered starting material).
(76) For ruthenium(II) C-enolates derived from nitriles, see: (a) Ittel,
S. D.; Tolman, C. A.; English, A. D.; Jesson, J. P. J. Am. Chem. Soc. 1978,
100, 7577. (b) Hiraki, K.; Ochi, N.; Kitamura, T.; Sasada, Y.; Shinoda, S.
Bull. Chem. Soc. Jpn. 1982, 55, 2356.
(77) (a) Formation of a rhodium(I) malonate complex, in which the
malonate anion was not bound to the metal center, has been recently
reported: Grushin, V. V.; Kuznetsov, V. F.; Bensimon, C.; Alper, H.
Organometallics 1995, 14, 3927. (b) For the formation of a cationic
platinum(II) complex with disulfone anion by oxidative addition of a 1,1-
disulfone to [Pt(C2H4)(PPh3)2], see: Siedle, A. R.; Newmark, R. A.; Gleason,
W. B. J. Am. Chem. Soc. 1986, 108, 767.
(83) 1,5-Cyclooctadiene did not interfere with the reaction between 73
and 17 in THF catalyzed by 1 (3 mol %, 23 °C) to give 77 (eq 6).30c
Similarly, palladium complex 85 did not interfere in this Michael reaction
catalyzed by 1 (6 mol %, 23 °C).
(84) Complex 1 is stable for several minutes in the presence of 84 at 23
°C in benzene-d6. After ca. 30 min no hydride resonance was observed by
1H NMR.

8562 J. Am. Chem. Soc., Vol. 118, No. 36, 1996
Go´mez-Bengoa et al.
Figure 4. Reaction profile for the Michael reactions of donors 2 and
12 with acceptors 14 and 87 (eqs 8-10) catalyzed by 1 in acetonitrile-
d3 at 25 °C.
Figure 3. Reaction profile for the Michael reaction between donor 12
and acceptor 87 to give 88 (eq 8) in acetonitrile-d3 at 25 °C.
is not inhibited in the presence of 84,85 which demonstrates that
the catalytically active ruthenium species in this reaction is stable
in the presence of this palladium complex.
Therefore, the puzzling obtainment of the same products in
the processes catalyzed by 1 or triphenylphosphine and the
observation of considerable rate differences in both processes
can be reconciled if the Michael reaction is catalyzed by both
the triphenylphosphine released from 1 and a ruthenium species
derived from 1. Particularly enlightening was the observation
of identical regio- and stereoselectivities in the addition of 78
to 14 catalyzed by 1 or triphenylphosphine (eq 7).
1 (3 mol %) as the catalyst in acetonitrile at 23°C to furnish
adduct 88 in 87% yield after 85 h (eq 8 and Figure 3). The
reactions between 12 and 87 with 3-18 mol % of phosphine
as the catalyst were slower than that catalyzed by 1 (Figure 3),
although the differences were not as marked as with the
malonates.
The ruthenium catalyst in the Michael addition may be acting
as a highly efficient Lewis acid86,87 complexing the carbonyl
or the cyano group of the acceptor and thus favoring the
conjugate addition of intermediates like 70 (Scheme 4). In order
to ascertain this point, we carried out the Michael addition with
a sulfone as the acceptor, since the sulfonyl functional group
does not coordinate tightly to Lewis acids.88 If the ruthenium
catalytic species acts only as a Lewis acid, similar rates are
expected in the Michael addition reactions catalyzed by 1 or
triphenylphosphine. On the other hand, a faster reaction is
expected with 1,1-disulfones because of their relatively high
acidity (the pKa of 12 is 12.25 in DMSO22). However, this
Michael reaction was considerably slower than that of malonates
2 or 4 (see Figures 1 and 2). Thus, the Michael addition of
disulfone 12 to phenyl vinyl sulfone (87) was performed with
The relatively slow reaction of donor 12 with acceptor 87
appears to be in accord with the proposed role of ruthenium
catalyst acting as a Lewis acid. However, the reaction between
12 and R,â-unsaturated acceptor 14 to give adduct 8989
proceeded with a similar rate (eq 9 and Figure 4). Additionally
the reaction of malonate 2 with vinyl sulfone 87 proceeded very
rapidly under the usual conditions affording bisadduct 90 in
97% yield after 1 h (eq 10 and Figure 4).
(85) The reaction of ethyl cyanoacetate (73) with benzaldehyde (1 equiv
each) with 1 (3 mol %) and 84 (6 mol %) in THF at 23 °C for 24 h afforded
ethyl (E)-2-cyano-3-phenyl-2-propenoate3 (75% yield).
(86) For lead references of Michael additions of 1,3-dicarbonyl catalyzed
by Lewis acids, see: (a) Bonadies, F.; Lattanzi, A.; Orelli, L. R.; Scettri,
A. Tetrahedron Lett. 1993, 34, 7649. (b) Keller, E.; Feringa, B. L.
Tetrahedron Lett. 1996, 37, 1879.
(87) No Michael reactions were observed by using RuCl3 and triph-
enylphosphine (g4 equiv per Ru) as the promoting agents.
(88) (a) For example, the dienophilic reactivity of phenyl vinyl sulfone
(87) is not enhanced by the addition of Lewis acids: Carr, R. V. C.; Paquette,
L. A. J. Am. Chem. Soc. 1980, 102, 853. (b) For a review of sulfone
chemistry, see: Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon:
Oxford, 1993.
Although 2 reacts faster than 12 with Michael acceptor 14,
an in situ competition between 2 and 12 with acceptor 14 (1
equiv each; 3 mol % of 1, acetonitrile, 23 °C) led to the selective
formation of Michael adduct 89 (ca. 4.3:1 mixture of 89 and
22 after 43 h). This apparent contradiction could be explained
if the more acidic donor 12 interferes with the catalytic
ruthenium species derived from malonate 2 leading to the
(89) de Lucchi, O.; Pasquato, L.; Modena, G. Tetrahedron Lett. 1984,
25, 3647.

Michael Reaction of Stabilized Carbon Nucleophiles
J. Am. Chem. Soc., Vol. 118, No. 36, 1996 8563
selective formation of the anion of 12. Indeed, 2-d2 suffered
deuterium scrambling with 12 (1 equiv) in acetonitrile-d3 at 23
°C in the presence of ruthenium dihydride 1 (10 mol %) and
14. In the absence of 1 and/or 14, the deuterium label scramble
between 2-d2 and 12 was slower under these conditions.
acetonitrile provided the best general solution from a practical
point of view for the Michael addition of activated nucleophiles.
Experimental Section
NMR spectra were recorded on a Bruker AC-200 (200 MHz for 1H
1
and 50 MHz for 13C NMR) or a Bruker AMX-300 (300 MHz for H,
75 MHz for 13C NMR, and 121.5 MHz for 31P). Mass spectra (electron
impact ionization, 70 eV) were obtained on a VG AutoSpec apparatus.
Only the most significant molecular ions and/or base peaks in the MS
are given. IR spectra were recorded on a Pye-Unicam SP 3-300-S
apparatus. Microanalysis were recorded at the SIdI (UAM) with a
Perkin Elmer 2400 apparatus. Chromatography was performed with
flash grade silica gel. All reactions were carried out under an
atmosphere of Ar. Dry THF was obtained by distillation under Ar
from sodium-benzophenone ketyl. Dry acetonitrile was obtained by
distillation from CaH2 and was stored over activated 4 Å molecular
sieves under Ar.
The following known compounds showed NMR identical with the
reported data: 13,19 22,13 25,14 26,14 27,9 28,15 29,16 38,91 40,92 44,17
45,2c 72,9 74,3 75,71 77,3 78,3 79,3 80,3 and 89.90b Methyl vinyl ketone
(14), acroleine (15), and methyl acrylate (17) were purified by
distillation. All other commercial compounds were used without further
purification. The following complexes were prepared according to
known procedures: 52,30 53,31 54,32 55,34 56,36 57,36 58,37 59,38 60,39
62,4b 84,81 85,93 and 86.81 Complex 61 was commercially available.
NaB(OMe)4 was prepared as a white solid by heating NaBH4 with a
large amount of methanol.25
Conclusions
The above results indicate that the Michael reaction of the
examined donors is catalyzed by ruthenium complex 1. Al-
though triphenylphosphine is also a catalyst for some of the
reactions examined, very significant rate differences were found
in the reactions of donors 2 or 4 with acceptor 14 catalyzed by
hydride 1 or triphenylphosphine. Slight, but significant, ac-
celeration was also observed in the reaction between R,â-
unsaturated carbonyl compound 14 and vinyl sulfone 87
catalyzed by 1 as compared with the same reaction in the
presence of triphenylphosphine. The reaction only proceeds
satisfactorily in the presence of free phosphine. Accordingly,
the Michael reaction of stabilized enolates appears to be a
ruthenium and phosphine catalyzed reaction. On the other hand,
the observation of identical chemo-, regio-, and/or stereoselec-
tivities in the reactions catalyzed by phosphines or ruthenium
complexes suggests that similar pathways are followed in both
processes.
The similar rates found for reaction of 12 with 14 or 87 and
the rapid reaction between 2 and 87 indicates that the ruthenium
catalyst does not behave as a simple Lewis acid that coordinates
with the Michael acceptor. Although the available data do not
allow us to unequivocally determine the precise role of the
ruthenium complex, scientific economy principles (Occam’s
razor) suggest that a similar pathway is followed for the Michael
addition of cyano and non-cyano substituted donors. The
ruthenium catalyst may activate the Michael donor by coordina-
tion through the basic functional groups facilitating their
deprotonation by zwitterionic 69. Additionally, the ruthenium
catalytic species may facilitate the Michael addition by coor-
dinating with the alkene acceptor and the anion derived from
the donor. This is supported by the ready reaction of substrates
like 290 toward a wide variety of donors and the relatively slow
reactions of disulfone 14, whose anion is not expected to
coordinate tightly with an intermediate ruthenium(II) species.88
Additionally, the interference of disulfone 12 with the Michael
reaction between malonate 2 and acceptor 14 also points to the
required activation of donor 2 by ruthenium. Another piece of
evidence supporting the activation of the donors bearing
carbonyl groups by ruthenium is the formation of intramolecular
aldol products in some of the reactions examined. The effect
of acetonitrile on the acidity of the Michael donors appears to
be, at most, secondary, since acetonitrile is actually expected
to decrease the relative acidity of carbon acids in comparison
with THF.22
Preparation of [RuH2(PPh3)4] (1). This complex was prepared
according to the described procedures from RuCl3‚3H2O23 or [Ru(PPh3)3-
Cl2] (60)24 and PPh3 using NaBH4 as the reductant (90-97% yields).
This complex could be further purified by washing with a large amount
of degasified water at room temperature under Ar to furnish 1 as a
yellow powder. 1: 1H NMR (300 MHz, benzene-d6) δ 7.40-6.74 (m,
60H), -10.14 (m, 2H); 31P{1H} NMR (121.5 MHz, benzene-d6) δ 49.80
(t, J ) 13.9 Hz, 2P), 41.65 (t, J ) 13.9 Hz, 2P). In some of the
preparations a high-field signal corresponding to tetrahydride 58 was
also observed at δ -7.10 (br s). In benzene-d6 solution (23 °C)
dihydride 1 slowly leads to coordinatively unsaturated complex 63:
1H NMR (200 MHz, benzene-d6) δ -17.52 (q, J ) 25.9 Hz, 2H).
Preparation of [RuH2(AsPh3)4] (51). This complex was prepared
by following a procedure analogous to that used in the synthesis of 1:
To a solution of AsPh3 (1.868 g, 6.1 mmol) in ethanol (40 mL) under
reflux was added a hot solution of RuCl3.3H2O (271 mg, 1.2 mmol) in
ethanol (7 mL). The resulting mixture was heated under refluxing
conditions for 10 min and a hot suspension of NaBH4 (200 mg, 5.1
mmol) in ethanol (7 mL) was added in 2-3 portions. After being
heated under reflux conditions for 10 min, the mixture was cooled to
room temperature. The resulting solid was filtered off and washed
with ethanol to give 51 as a reddish solid (1.275 g, 80%): 1H NMR
(200 MHz, CDCl3) δ 7.80-6.55 (m, 60H), -12.45 (s, 2H).29
Preparation of [RuH2(MeCN)(PPh3)3] (64). This complex was
prepared from 1 in benzene-d6 solution in an NMR tube with excess
MeCN:37a 1H NMR (300 MHz, benzene-d6) δ 7.78-6.83 (m, 45H),
0.59 (s, 3H), -8.90 (dtd, J ) 76.3, 31.2, 7.1 Hz, 1H), -14.99 (tdd, J
) 28.5, 13.7, 7.0 Hz, 1H); 31P{1H} NMR (121.5 MHz, benzene-d6) δ
61.72 (d, J ) 16.7 Hz, 2P), 49.38 (t, J ) 16.7 Hz, 1P).
Ruthenium-Catalyzed Michael Addition: General Procedure.
To a mixture of Michael donor (1.0 mmol) and ruthenium dihydride 1
(35 mg, 0.03 mmol, 3 mol %) in MeCN (3 mL) at 23 °C was added
the Michael acceptor (1 or 2 equiv, see Table 1).11 The resulting
solution was stirred at 23 °C (see Table 1 for reaction times). The
solvent was evaporated and the residue was chromatographed (hexane-
EtOAc mixtures) to give the adducts in the stated yields.
In summary, we have uncovered that the ruthenium-catalyzed
Michael addition is a more general process than originally
described.3 The reaction proceeds well in acetonitrile under
mild and neutral conditions with malonates, â-ketoesters, 1,3-
diketones, 1,1-disulfones, nitro compounds, Meldrum acid, and
anthrone as the Michael donors. In a number of cases,
intramolecular aldol reactions catalyzed by 1 were also observed
as side reactions. Cyano acetates, more acidic than malonates
in organic solvents, are excellent substrates for this reaction.
Although some of the reactions that we have studied can also
be catalyzed by nucleophilic tertiary phosphines, the use of
readily prepared ruthenium dihydride 1 as the catalyst in
Dimethyl 2,2-Bis(3-oxobutyl)malonate (23). White solid: mp 76-
1
77 °C; H NMR (200 MHz, CDCl3) δ 3.71 (s, 6H), 2.46 (t, J ) 7.1
Hz, 4H), 2.13 (s, 6H), 2.12 (t, J ) 7.1 Hz, 4H); 13C{1H} NMR (50
(91) Kagechika, K.; Shibasaki, M. J. Org. Chem. 1991, 56, 4093.
(92) (a) Bergbreiter, D. E.; Lalonde, J. J. J. Org. Chem. 1987, 52, 1601.
(b) Sasson, Y.; Arrd, O. J. Org. Chem. 1989, 54, 4993. (c) Ballini, R.;
Petrini, M. Tetrahedron Lett. 1989, 30, 5329. (d) Turner, M. J.; Luckenbach,
L. A.; Turner, E.-L. Synth. Commun. 1986, 16, 1377.
(90) Coordination of ruthenium(II) with carbonyl groups has been
frequently observed.49a
(93) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic:
Orlando, FL, 1985; p 18.

8564 J. Am. Chem. Soc., Vol. 118, No. 36, 1996
Go´mez-Bengoa et al.
MHz, CDCl3) δ 206.7, 171.2, 55.8, 52.2, 38.3, 29.7, 27.0. Anal. Calcd
for C13H20O6: C, 57.34; H, 7.40. Found: C, 57.34; H, 7.47.
Dimethyl 4-Hydroxy-4-methyl-3-(1-oxoethyl)cyclohexane-1,1-di-
carboxylate (24a). (a) Colorless oil: 1H NMR (300 MHz, CDCl3) δ
3.80 (d, J ) 2.3 Hz, OH), 3.71 (s, OMe), 3.63 (s, OMe), 2.66 (dd, J
) 13.1, 3.4 Hz, H-3), 2.25 (ddd, J ) 13.1, 3.4, 2.2 Hz, H-2eq), 2.17
(s, Me), 2.16 (td, J ) 13.5, 4.0, H-6ax), 2.09-2.02 (m, H-6eq), 1.96
(t, J ) 13.1 Hz, H-2ax), 1.60 (ddd, J ) 14.3, 3.8, 3.1 Hz, H-5eq), 1.18
(td, J ) 13.6, 4.2 Hz, H-5ax), 1.09 (s, Me) (the assignments were based
on a COSY experiment); 13C{1H} NMR (50 MHz, CDCl3; DEPT) δ
214.6 (C), 171.5 (C), 171.1 (C), 68.4 (C), 54.0 (C), 52.9 (CH3), 52.7
(CH), 52.6 (CH3), 35.2 (CH2), 30.9 (CH3), 29.3 (CH2), 28.5 (CH3),
25.8 (CH2). Anal. Calcd for C13H20O6: C, 57.34; H, 7.40. Found:
C, 57.26; H, 7.40. (b) This compound could also be obtained from 23
(eq 3): A mixture of 22 (27 mg, 0.1 mmol) and 1 (5 mg, 0.005 mmol,
5 mol %) in MeCN (1 mL) was stirred at 23 °C for 16 h. The solvent
was evaporated and the residue was filtered through flash grade silica
gel (EtOAc) to give 24a (22 mg, 81%). Its diastereomer 24b was
obtained as an inseparable mixture with diketone 23 in the addition
reaction catalyzed by NaB(OMe)4 and showed the following NMR
data: 1H NMR (200 MHz, CDCl3) δ 3.75 (s, 3H), 3.68 (s, 3H), 2.84
(s, OH), 2.70 (dd, J ) 13.1, 3.7 Hz, 1H), 2.50 (ddd, J ) 11.8, 3.7, 2.6
Hz, 1H), 2.37-2.28 (m, 1H), 2.23 (s, 3H), 1.88 (t, J ) 13.1 Hz, 1H),
1.51 (td, J ) 13.5, 3.8 Hz, 1H), 1.18 (s, 3H); 13C{1H} NMR (50 MHz,
CDCl3) δ 211.31, 171.66, 170.76, 71.17, 55.34, 54.21, 52.64, 52.35,
41.51, 31.46, 29.78, 28.19, 21.43.
(CH2). Anal. Calcd for C13H20O6: C, 60.92; H, 7.86. Found: C,
60.92; H, 7.85.
5,5-Bis(1-oxoethyl)-2,8-nonadione (36). White solid: mp 57-58
1
°C; H NMR (200 MHz, CDCl3) δ 2.27 (t, J ) 7.0 Hz, 4 H), 2.12 (s,
12 H), 2.09 (t, J ) 7.0 Hz, 4 H); 13C{1H} NMR (50 MHz, CDCl3) δ
207.0, 206.8, 68.2, 37.8, 30.0, 27.0, 24.7. Anal. Calcd for C13H20O4:
C, 64.98; H, 8.39. Found: C, 64.81; H, 8.43.
1-[1,3-Bis(1-oxoethyl)-4-hydroxy-4-methylcyclohexyl]ethanone
(37). White solid: mp 80-81 °C; 1H NMR (200 MHz, CDCl3) δ 3.91
(d, J ) 2.3 Hz, 1H, OH), 2.64 (dd, J ) 13.0, 3.4 Hz, 1H), 2.38 (dd, J
) 13.2, 3.6 Hz, 1H), 2.30 (s, 3H), 2.30-2.15 (m, 2H), 2.16 (s, 3H),
2.14 (s, 3H), 1.82 (t, J ) 12.4 Hz, 1H), 1.72 (dt, J ) 14.4, 3.4 Hz,
1H), 1.15 (s, 3H), 1.20-1.10 (m, 1H); 13C{1H} NMR (50 MHz, CDCl3;
DEPT) δ 206.5 (C), 68.4 (C), 67.2 (C), 52.5 (CH), 35.0 (CH2), 31.0
(CH3), 28.4 (CH3), 27.8 (CH2), 26.3 (CH3), 25.7 (CH3), 24.7 (CH2).
Anal. Calcd for C13H20O4: C, 64.98; H, 8.39. Found: C, 65.81; H,
8.48.
10,10-Bis(3-oxobutyl)-9-anthracenone (39). White solid: mp
159-160 °C; 1H NMR (200 MHz, CDCl3) δ 8.40 (d, J ) 7.8 Hz, 2H),
7.68 (dd, J ) 6.8, 1.5 Hz, 2H), 7.62 (dt, J ) 8.2, 1.5 Hz, 2H), 7.49 (dt,
J ) 7.9, 1.4 Hz, 2H), 2.53 (m, 4H), 1.79 (s, 6H), 1.65 (m, 4H); 13C-
{1H} NMR (50 MHz, CDCl3; DEPT) δ 208.1 (C), 207.6 (C), 145.5
(C), 134.3 (CH), 132.4 (C), 127.6 (CH), 127.4 (CH), 125.9 (CH), 44.3
(C), 38.5 (CH2), 38.3 (CH2), 29.8 (CH3). MS m/z 334 (M+, 3), 263
(100), 245 (34), 220 (40).
1-(2,5-Dimethyl-2-hydroxy-5-nitrocyclohexyl)ethanone (41). White
solid: mp 52-54 °C. Major diastereomer: 1H NMR (200 MHz,
CDCl3) δ 3.90 (d, J ) 2.6 Hz, 1H, OH), 2.65 (m, 1H), 2.55 (m, 1H),
2.45 (m, 1H), 2.29 (s, 3H), 2.08 (m, 1H), 1.96 (t, J ) 13.0 Hz, 1H),
1.64 (dt, J ) 14.5, 3.8 Hz, 1H), 1.59 (s, 3H), 1.26 (m, 1H), 1.19 (s,
3H); 13C{1H} NMR (50 MHz, CDCl3; DEPT) δ 206.5 (C), 87.76 (C),
68.3 (C), 52.5 (CH), 34.6 (CH2), 33.3 (CH2), 31.2 (CH3), 30.4 (CH2),
28.6 (CH3), 28.2 (CH3). Anal. Calcd for C10H17NO4: C, 55.80; H,
7.96; N, 6.51. Found: C, 55.66; H, 7.63; N, 6.41.
Dimethyl 2-(3-Oxobutyl)-2-(phenylmethyl)malonate (30). White
1
solid: mp 72-73 °C; H NMR (200 MHz, CDCl3) δ 7.25-7.19 (m,
6H), 7.07-7.02 (m, 2H), 3.71 (s, 6H), 3.24 (s, 2H), 2.50 (t, J ) 7.1
Hz, 2H), 2.12 (s, 3H), 2.07 (t, J ) 7.1 Hz, 2H); 13C{1H} NMR (50
MHz, CDCl3) δ 207.0, 171.3, 137.52, 129.8, 128.3, 127.1, 58.2, 52.3,
39.7, 38.8, 29.8, 26.5. Anal. Calcd for C16H20O5: C, 65.73; H, 6.89.
Found: C, 65.47; H, 7.00.
Dimethyl 2-(3-Oxobutyl)-2-(2-propynyl)malonate (31). Colorless
oil: 1H NMR (200 MHz, CDCl3) δ 3.71 (s, 6H), 2.78 (d, J ) 2.7 Hz,
2H), 2.49 (t, J ) 7.4 Hz, 2H), 2.31 (t, J ) 7.2 Hz, 2H), 2.13 (s, 3H),
2.07 (t, J ) 2.7 Hz, 1H); 13C{1H} NMR (50 MHz, CDCl3; DEPT) δ
206.6 (C), 170.0 (C), 78.1 (CH), 71.6 (C), 55.6 (C), 52.5 (CH3), 38.1
(CH2), 29.5 (CH3), 26.0 (CH2), 23.4 (CH2). Anal. Calcd for
C12H16O5: C, 59.99; H, 6.71. Found: C, 59.55; H, 6.75.
Dimethyl 2-(2-Cyanoethyl)-2-(2-propynyl)malonate (32). Pale
yellow oil: 1H NMR (200 MHz, CDCl3) δ 3.79 (s, 6H), 2.86 (d, J )
2.7 Hz, 2H), 2.47 (t, J ) 5.2 Hz, 2H), 2.46 (t, J ) 5.3 Hz, 2H), 2.09
(t, J ) 2.7 Hz, 1H); 13C{1H} NMR (50 MHz, CDCl3; DEPT) δ 169.3
(C), 118.7 (C), 77.48 (CH), 72.5 (C), 55.5 (C), 53.1 (CH3), 28.4 (CH2),
23.4 (CH2), 12.8 (CH2). Anal. Calcd for C11H13NO4: C, 59.18; H,
5.87; N, 6.27. Found: C, 59.06; H, 5.90; N, 6.23.
4,4-Bis(phenylsulfonyl)butanal (42). Colorless solid: mp 82-83
1
°C; H NMR (200 MHz, CDCl3) δ 9.71 (s, 1H), 8.00-7.90 (m, 4H),
7.70-7.50 (m, 6H), 4.77 (t, J ) 6.1 Hz, 1H), 3.01 (t, J ) 7.0 Hz, 2H),
2.46 (q, J ) 6.5 Hz, 2H); 13C{1H} NMR (50 MHz, CDCl3; DEPT) δ
199.9 (CH), 137.5 (C), 134.6 (CH), 129.3 (CH, 2C), 129.1 (CH, 2C),
81.3 (CH), 40.4 (CH2), 18.4 (CH2). Anal. Calcd for C14H16O5S2: C,
54.53; H, 4.58. Found: C, 54.30; H, 4.78.
5,5-Bis(phenylsulfonyl)-8-methyl-7-nonen-2-one (43). White
1
solid: mp 96-97 °C; H NMR (200 MHz, CDCl3) δ 8.06-7.97 (m,
4H), 7.67-7.59 (m, 6H), 5.08 (tqq, J ) 6.4, 1.5, 1.4 Hz, 1H), 2.98 (t,
J ) 7.5 Hz, 2H), 2.81 (d, J ) 6.4 Hz, 2H), 2.49 (t, J ) 7.6 Hz, 2H),
2.14 (s, 3H), 1.64 (d, J ) 1.3 Hz, 3H), 1.48 (t, J ) 1.2 Hz, 3H); 13C-
{1H} NMR (50 MHz, CDCl3) δ 206.3, 137.1, 136.9, 134.6, 131.3 (2C),
128.6 (2C), 115.1, 90.1, 34.0, 30.0, 29.3, 25.9, 23.5, 18.0. Anal. Calcd
for C22H26O5S2: C, 60.81; H, 6.03. Found: C, 60.58; H, 6.30.
5,5-Bis(3-oxobutyl)-2,2-dimethyl-1,3-dioxan-4,6-dione (33). White
1
solid: mp 100-101 °C; H NMR (200 MHz, CDCl3) δ 2.55 (t, J )
7.7 Hz, 4H), 2.27 (t, J ) 7.4 Hz, 4H), 2.14 (s, 6H), 1.84 (s, 6H); 13C-
{1H} NMR (50 MHz, CDCl3; DEPT) δ 205.9 (C), 168.9 (C), 105.5
(C), 50.7 (C), 37.8 (CH2), 30.7 (CH2), 29.6 (CH3), 28.9 (CH3). Anal.
Calcd for C14H20O6: C, 59.14; H, 7.09. Found: C, 59.10; H, 6.92.
Methyl 1,3-Bis(1-oxoethyl)-4-hydroxy-4-methylcyclohexanecar-
boxylate (34). Colorless oil. Major diastereomer: 1H NMR (200 MHz,
CDCl3) δ 3.91 (d, J ) 2.4 Hz, 1H, OH), 3.80 (s, 3H), 2.69 (dd, J )
12.7, 3.3 Hz, 1H), 2.27 (s, 3H), 2.40-2.10 (m, 3H), 2.19 (s, 3H), 1.90
(m, 1H), 1.71 (m, 1H), 1.40-1.20 (m, 1H), 1.18 (s, 3H); 13C{1H} NMR
(50 MHz, CDCl3; DEPT) δ 206.2 (C), 204.9 (C), 172.8 (C), 68.4 (C),
60.8 (C), 53.0 (CH3), 52.3 (CH), 35.5 (CH2), 31.0 (CH3), 28.4 (CH3),
28.2 (CH2), 26.0 (CH3), 25.4 (CH2). Minor diastereomer: 1H NMR
(200 MHz, CDCl3) δ 3.96 (d, J ) 2.3 Hz, 1H, OH), 3.72 (s, 3H), 2.75
(dd, J ) 12.8, 3.5 Hz, 1H), 2.28 (s, 3H), 2.40-2.10 (m, 3H), 2.22 (s,
3H), 1.90 (m, 1H), 1.71 (m, 1H), 1.40-1.20 (m, 1H), 1.15 (s, 3H);
13C{1H} NMR (50 MHz, CDCl3; DEPT) δ 206.1 (C), 204.4 (C), 172.1
(C), 68.41 (C), 59.1 (C), 52.6 (CH3), 52.5 (CH), 34.9 (CH2), 31.0 (CH3),
28.4 (CH3), 28.2 (CH2), 25.5 (CH3), 25.4 (CH2). Anal. Calcd for
C13H20O5: C, 60.92; H, 7.86. Found: C, 60.86; H, 7.94.
9,9-Bis(3-oxobutyl)fluorene (47) (Eq 2). White solid: mp 90-91
°C; 1H NMR (200 MHz, CDCl3) δ 7.74-7.72 (m, 2H), 7.41-7.29 (m,
6H), 2.34 (t, J ) 7.7 Hz, 4H), 1.75 (s, 6H), 1.62 (t, J ) 7.7 Hz, 4H);
13C{1H} NMR (50 MHz, CDCl3) δ 208.5, 148.1, 141.1, 127.6, 127.5,
123.1, 119.9, 53.3, 38.1, 33.4, 29.8; MS m/z 306 (M+, 71), 235 (100),
217 (54), 178 (73).
Dimethyl 2-(3-Oxobutyl)-2-(3-oxopropyl)malonate (48) and Di-
methyl 4-Hydroxy-4-methyl-3-formylcyclohexane-1,1-dicarboxylate
(49) (Scheme 1). (a) A mixture of 22 (400 mg, 1.98 mmol), 15 (221
mg, 3.96 mmol), and 1 (24 mg, 0.023 mmol, 1 mol %) was stirred in
MeCN (3 mL) at 23 °C for 24 h. The solvent was evaporated and the
residue was chromatographed (7:3 hexane-EtOAc) to give 48 (220
mg, 43%) and 49 (30 mg, 6%) as colorless oils. 48: 1H NMR (200
MHz, CDCl3) δ 9.74 (t, J ) 0.2 Hz, 1H), 3.73 (s, 6H), 2.51 (td, J )
6.8, 0.2 Hz, 2H), 2.47 (t, J ) 6.8 Hz, 2H), 2.18 (t, J ) 6.8 Hz, 2H),
2.14 (s, 3H), 2.14 (t, J ) 7.9 Hz, 2H); 13C{1H} NMR (50 MHz, CDCl3)
δ 207.1, 200.5, 171.1, 55.9, 52.5, 38.4, 29.78, 27.2, 25.6. (b) A mixture
of 48 (20 mg, 0.078 mmol) and 1 (14 mg, 0.012 mmol, 16 mol %) in
MeCN (3 mL) was stirred at 23 °C for 24 h. The solvent was
evaporated and the residue was chromatographed (7:3 hexane-EtOAc)
to give 49 (7 mg, 35%) as a colorless oil: 1H NMR (200 MHz, CDCl3)
δ 9.80 (d, J ) 1.7 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 2.89-2.54 (m,
1H), 2.35-2.50 (m, 1H), 2.20-2.00 (m, 3H), 1.77-1.60 (m, 1H), 1.55-
Methyl 5-Oxo-2-(3-oxobutyl)-2-(1-oxoethyl)hexanoate (35). White
1
solid: mp 77-78 °C; H NMR (200 MHz, CDCl3) δ 3.74 (s, 3H),
2.45-2.30 (m, 4H), 2.17 (s, 3H), 2.14 (s, 6H), 2.20-2.00 (m, 4H);
13C{1H} NMR (50 MHz, CDCl3; DEPT) δ 206.9 (C), 204.72 (C), 172.1
(C), 61.3 (C), 52.3 (CH3), 37.8 (CH2), 29.7 (CH3), 26.6 (CH3), 25.2

Michael Reaction of Stabilized Carbon Nucleophiles
J. Am. Chem. Soc., Vol. 118, No. 36, 1996 8565
1.44 (m, 1H), 1.35 (s, 3H); 13C{1H} NMR (50 MHz, CDCl3) δ 204.5,
171.8, 171.0, 68.9, 53.8, 53.5, 52.84 (2C), 36.2, 28.7, 26.7, 26.1.
Dimethyl 4-Hydroxy-3-(1-oxoethyl)cyclohexane-1,1-dicarboxylate
(50) (Scheme 1). A mixture of 25 (181 mg, 0.96 mmol), 14 (135 mg,
1.9 mmol), and 1 (7 mg, 0.006 mmol, 0.5 mol %) in MeCN (5 mL)
was stirred at 23 °C for 24 h. the solvent was evaporated and the
residue was chromatographed (7:3 EtOAc-hexane) to give 50 (160
mg, 64%) as a colorless oil. NMR showed a 2:1 mixture of isomers.
Major diastereomer: 1H NMR (300 MHz, CDCl3) δ 4.20 (m, 1H), 3.72
(s, 3H), 3.67 (s, 3H), 3.06 (br, 1H), 2.65 (ddd, J ) 13.0, 3.6, 2.2 Hz,
1H), 2.35 (m, 2H), 2.17 (s, 3H), 2.10 (m, 2H), 1.84 (dq, J ) 14.5, 6.9
Hz, 1H), 1.43 (m, 1H); 13C{1H} NMR (75 MHz, CDCl3) δ 211.9, 171.8,
171.1, 64.3, 54.3, 52.9, 52.7, 50.3, 38.5, 28.8, 26.7, 24.2. Minor
diastereomer (only distinctive 13C{1H} NMR signals): δ 207.1, 69.7,
28.50, 27.11. Anal. Calcd for C12H18O6: C, 55.81; H, 7.02. Found:
C, 55.65; H, 7.05.
Ethyl 2-Cyano-2-(3-methyl-2-butenyl)-5-oxohexanoate (76) (Eq
5). Colorless oil: 1H NMR (200 MHz, CDCl3) δ 5.18 (tsept, J ) 6.9,
1.2 Hz, 1H), 4.25 (q, J ) 7.1 Hz, 2H), 2.75-2.55 (m, 4H), 2.18 (s,
3H), 2.20-2.00 (m, 2H), 1.74 (d, J ) 0.9 Hz, 3H), 1.65 (d, J ) 0.8
Hz, 3H), 1.32 (t, J ) 7.1 Hz, 3H); 13C{1H} NMR (50 MHz, CDCl3) δ
205.7, 168.2, 137.8, 118.7, 116.0, 62.5, 61.2, 48.8, 39.0, 35.8, 29.7,
25.7, 17.9, 13.8; IR (neat) 2980, 2920, 2240, 1710, 1430 cm-1; MS
m/z 251 (M+, 2), 206 (4), 183 (17), 136 (33), 69 (100).
was carried out in THF at 23 °C.3,11 The similar transformation with
1 (3 mol %) in acetonitrile was performed under the conditions
described before for the general procedure. Diastereoselectivities were
determined by integration at 300 MHz of the well-separated doublet
signals for the C-2 hydrogen of 79 and 80.
1,1,3-Triphenylsulfonylpropane (88) (Eq 8). White solid: mp
122-124 °C; 1H NMR (200 MHz, CDCl3) δ 7.91-7.86 (m, 4H), 7.75-
7.52 (m, 6H), 3.65 (s, 6H), 3.11-3-03 (m, 4H); 13C{1H} NMR (50
MHz, CDCl3) δ 169.6, 138.5, 134.0, 129.5 (3C), 128.0 (3C), 55.1, 53.1,
51.5, 26.5. Anal. Calcd for C21H20O6S: C, 54.29; H, 4.34. Found:
C, 54.26; H, 4.41.
Dimethyl 2,2-Bis(2-phenylsulfonyl)malonate (90) (Eq 10). White
1
solid: mp 54-56 °C; H NMR (200 MHz, CDCl3) δ 7.95-7.82 (m,
6H), 7.75-7.64 (m, 3H), 7.61-7.44 (m, 6H), 5.09 (t, J ) 6.0 Hz, 1H),
3.58 (t, J ) 6.9 Hz, 2H), 2.58 (q, J ) 6.6 Hz, 2H); 13C{1H} NMR (50
MHz, CDCl3) δ 137.5, 134.8, 134.1, 129.5 (2C), 129.2 (2C), 128.2,
79.7, 52.2, 19.6. Anal. Calcd for C21H24O8S2: C, 53.83; H, 5.16; S,
13.68. Found: C, 53.64; H, 4.99; S, 13.84.
Acknowledgment. We are grateful to the DGICYT (Project
PB-94-0163) for support of this work. E.G.B., J.M.C., and C.M.
acknowledge the receipt of predoctoral fellowships by the
Gobierno Vasco, Comunidad Auto´noma de Madrid, and Min-
isterio de Educacio´n y Ciencia, respectively. We also thank
Prof. J. M. Saa´ (Universitat de les Illes Balears) for helpful
suggestions.
Reactions of Donors 2, 4, or 12 with Acceptors 14 or 87 (Tables
2 and 3 and Figures 1-4). The general procedure outlined above
was followed for the reactions summarized in Tables 2 and 3. Yields
correspond to isolated products purified by chromatography. The
reactions over time outlined in Figures 1-4 were carried out at 25 °C
in acetonitrile-d3 with accurately determined amounts of donors and
acceptors (0.9-1.4 M) and the corresponding catalyst. Progress of
the reactions was monitored by integration against the rest of undeu-
terated acetonitrile (0.2%) or t-BuOMe as internal standard.
Supporting Information Available: Selected NMR spectra
for 24a, 24b, 39, 47-49, and 76 (11 pages). See any current
masthead page for ordering and Internet access instructions.
Reaction of Donor 78 with Acceptor 14 (Eq 7). The reaction
between 78 and 14 in the presence of triphenylphosphine (6 mol %)
JA961373W