Palladium-catalyzed addition of mono- and dicarbonyl compounds to conjugated dienes

Article abstract of DOI:10.1021/jo0490999

An inter molecular, palladium-catalyzed addition of the α-C-H bond of monocarbonyl and 1,3-dicarbonyl compounds to dienes has been developed, and an exploration of the scope of these reactions with a broad range of carbonyl compounds and nitriles was cond

Full text of DOI:10.1021/jo0490999

P a lla d iu m -Ca ta lyzed Ad d ition of Mon o- a n d Dica r bon yl
Com p ou n d s to Con ju ga ted Dien es
†
†
Andreas Leitner, J ens Larsen, Christian Steffens, and J ohn F. Hartwig*
Department of Chemistry, Yale University, Post Office Box 208107, New Haven, Connecticut 06520-8107
john.hartwig@yale.edu
Received May 28, 2004
An intermolecular, palladium-catalyzed addition of the R-C-H bond of monocarbonyl and
1
,3-dicarbonyl compounds to dienes has been developed, and an exploration of the scope of these
reactions with a broad range of carbonyl compounds and nitriles was conducted. The combination
of CpPd(allyl) and the commercially available 1,3-bis(dicyclohexylphosphino)propane (DCyPP)
catalyzed the 1:1 addition of the C-H bonds of these substrates to dienes in high yields. These
reactions included unusual additions of the C-H bonds of ketones, lactones, esters, and nitriles to
dienes, as well as the more common additions of cyanoesters, malononitrile, and R-sulfonyl esters.
Reactions of these substrates with both cyclic and acyclic dienes are reported. Reactions catalyzed
by complexes of nonracemic chiral ligands were also conducted, and the first enantioselective version
of this reaction was achieved with a J osiphos ligand with enantioselectivities up to 81%.
In tr od u ction
compounds to butadiene and methyl-substituted 1,3-
dienes, such as isoprene, in the presence of (η -butadi-
ene)[bis(dialkylphosphino)ethane]palladium as catalyst.
This catalyst simplified the system by eliminating ad-
ditional reagents, such as triethylaluminum or alkoxides.
Trost and co-workers reported intermolecular additions
of bis(phenylsulfonyl)methane and 1,3-dicarbonyl com-
2
The development of highly efficient, catalytic addition
reactions is an important synthetic goal because these
reactions occur without byproducts. During studies of
the hydroamination of dienes and vinylarenes with alkyl-
and arylamines, we became interested in the reactions
1
2
between dienes and substrates with C-H bonds that are
pounds to dienes in the presence of [(π-allyl)PdCl]
2
, dppp
3
similar in acidity to the N-H bonds of amines. Taka-
[
1,3-bis-(diphenylphosphino)propane], and NaOMe as a
hashi et al.4 described the addition of 1,3-dicarbonyl
compounds to dienes in the early 1970s; however, the
scope of carbonyl compound and diene was narrow.
Furthermore, the reactions yielded mixtures of 1,2- and
7
reducing reagent and enantioselective additions to al-
lenes catalyzed by [(π-allyl)PdCl]
2
and the ligand devel-
8
oped by their group.
More recently, Widenhoefer and co-workers9 have
1
,4-addition products and 2:1 telomerization products.
published intramolecular reactions of the R-C-H bonds
of ketones to olefins to form products of both oxidative
processes and addition reactions. These reactions were
The telomerization can be suppressed by using catalysts
with bidentate phosphine ligands instead of monodentate
ligands.4
In 1986 Moberg and co-workers5 reported a Ni(0)-
catalyzed addition of active methylene compounds, such
as diethylmalonate and acetoacetate, to 1,3-conjugated
dienes. The catalyst was prepared in situ by reduction
2 2
conducted with Pd(II) catalysts, such as (RCN) PdCl .
Intermolecular reactions between 1,3-dicarbonyl com-
pounds and ethylene and propylene have also been
achieved with similar palladium and analogous platinum
catalysts.10 Most recently, Yao and Li reported a gold-
catalyzed addition of 1,3-dicarbonyl compounds to viny-
larenes. Finally, Murahashi and co-workers have re-
ported ruthenium-catalyzed Michael additions and aldol
reactions12 of substrates with acidic C-H bonds, such as
11
of Ni(acac)
PBu
2
with trimethylaluminum in the presence of
at -50 °C. J olly and co-workers later published
6
3
an improved protocol for the addition of 1,3-dicarbonyl
†
13
These authors contributed equally to this work.
malononitrile.
(
1) (a) Trost, B. M. Science 1991, 254, 1676. (b) Hartwig, J . F. Science
002, 297, 1653-1654.
2) (a) Utsunomiya, M.; Kuwano, R.; Kawatsura, M.; Hartwig, J . F.
2
(6) (a) J olly, P. W.; Kokel, N. Synthesis 1990, 771-773. (b) Goddard,
R.; Hopp, G.; J olly, P. W.; Kruger, C.; Mynott, R.; Wirtz, C. J .
Organomet. Chem. 1995, 486, 163-170.
(7) Trost, B. M.; Zhi, L. Tetrahedron Lett. 1992, 33, 1831-1834.
(8) Trost, B. M.; J aekel, C.; Plietker, B. J . Am. Chem. Soc. 2003,
125, 4438.
(9) (a) Pei, T.; Widenhoefer, R. A. J . Am. Chem. Soc. 2001, 123,
11290-11291. (b) Pei, T.; Widenhoefer, R. A. Chem. Commun. 2002,
650-651. (c) Pei, T.; Wang, X.; Widenhoefer, R. A. J . Am. Chem. Soc.
2003, 125, 648-649.
(10) Wang, X.; Widenhoefer, R. A. Chem. Commun. 2004, 660-661.
(11) Yao, X.; Li, C.-J . J . Am. Chem. Soc. 2004, 126, 6884-6885.
(12) For an enantioselective aldol reaction, see also Kuwano, R.;
Miyazaki, H.; Ito, Y. Chem. Commun. 1998, 71-72.
(
J . Am. Chem. Soc. 2003, 125, 5608-5609. (b) Pawlas, J .; Nakao, Y.;
Kawatsura, M.; Hartwig, J . F. J . Am. Chem. Soc. 2002, 124, 3669-
3
1
2
1
679. (c) Nettekoven, U.; Hartwig, J . F. J . Am. Chem. Soc. 2002, 124,
166-1167. (d) Kawatsura, M.; Hartwig, J . F. Organometallics 2001,
0, 1960. (e) Kawatsura, M.; Harwig, J . F. J . Am. Chem. Soc. 2000,
22, 9546-9547.
(3) Murai, S.; Chatani, N.; Kakiuchi, F. Pure Appl. Chem. 1997, 69,
5
4
1
89-594.
(
4) Takahashi, K.; Miyake, A.; Hata, G. Bull. Chem. Soc. J pn. 1972,
5, 1183-1191.
(
5) Andell, O. S.; B a¨ ckvall, J . E.; Moberg, C. Acta Chem. Scand.
986, B 40, 184-189.
1
0.1021/jo0490999 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/05/2004
7
552
J . Org. Chem. 2004, 69, 7552-7557

Mono- and Dicarbonyl Addition to Conjugated Dienes
SCHEME 1
Resu lts a n d Discu ssion
In Situ Ca ta lyst P r ep a r a tion a n d Effects of Ca ta -
lyst Str u ctu r e. The most efficient previous catalyst for
2
the addition of 1,3-dicarbonyl compounds to dienes, (η -
i
i
6
1
2 2 4 2
,3-butadiene)Pd(Pr PC H Pr ), is difficult to generate
and isolate. Thus, we hoped to increase the scope of the
C-H addition process and to develop a more convenient
catalyst system. Because CpPd(allyl) is a known precur-
sor to Pd(0)18 and can be synthesized easily from com-
2
mercially available [Pd(allyl)Cl] and NaCp, we tested
combinations of this precursor and bidentate phos-
phine ligands for the reaction of pronucleophiles with
dienes.
To optimize the reactions with this precatalyst, we
conducted the addition of 2,4-pentanedione to 1,3-cyclo-
hexadiene (1.5 equiv) in several solvents and with a wide
range of bidentate phosphine ligands at room tempera-
ture with 1% catalyst under concentrated conditions. In
2
contrast to reactions catalyzed by (η -1,3-butadiene)Pd-
i
i
19
(
2 2 4 2
Pr PC H Pr ) that were dependent on solvent, reac-
The additions of substrates with acidic C-H bonds to
dienes could occur by the mechanism in Scheme 1. An
electron-rich metal center could deprotonate a weakly
acidic substrate in an endo- or exothermic step, depend-
ing on acidity, to generate a hydride that would insert
diene to generate an allyl intermediate. Alternatively, the
carbonyl compound could protonate a complex between
tions catalyzed by a combination of bidentate ligands and
CpPd(allyl) occurred in similar yield and with similar
rates in tetrahydrofuran (THF), toluene, acetone, 1,2-
dimethoxyethane (DME), dichloromethane (DCM), N,N-
dimethylacetamide, dioxane, and tert-amyl alcohol. The
small solvent effect may result from the small quantity
of solvent (see Experimental Section for details). How-
ever, reactions conducted in DME were fastest and were
slightly faster than those conducted in THF and dioxane.
The effects of varying the ligand were more pro-
nounced. As shown in Table 1, the reactions catalyzed
by the combination of 1,3-bis(dicyclohexylphosphino)-
propane (DCyPP; entry 8) or 1,3-bis(diisopropylphosphi-
no)propane (entry 7) and CpPd(allyl) occurred fastest. As
shown by J olly, the hydrocarbon chain bridging the two
phosphorus atoms significantly affects the rate of reac-
2
the diene and the L Pd(0) fragment, and the resulting
complex could undergo insertion to generate the same
allyl intermediate. Subsequent attack of the enolate on
the allyl intermediate would generate the final addition
product. The step that forms the bond in the product
would be related to that of allylic substitution, but the
intermediate would be generated without the need for a
leaving group or external base.
To the best of our knowledge, no intermolecular,
enantioselective addition of C-H bonds across 1,3-dienes
has been developed. More commonly, the allylic products
6
tion. In contrast to previous findings, however, we found
that reactions conducted with ligands containing a three-
carbon bridge occurred up to twice as fast as reactions
with a two-carbon bridge. On the basis of this series of
studies, experiments to explore the reaction scope were
performed with a ratio of pronucleophile to diene between
1
4
have been prepared by substitution chemistry. Yet the
factors that control enantioselectivity of the addition
process would be related to those that control enantio-
selectivity in allylic substitution because the intermediate
that forms the C-C bond in the product by the mecha-
nism of Scheme 1 would be the same as the one that
forms the C-C bond in enantioselective allylic alkylation.
This paper delineates our progress toward developing
1
:1.5 and 1:4 in DME with a 1:1 mixture of DCyPP and
CpPd(allyl) as catalyst.
In cr ea sed Scop e of Nu cleop h iles. Because the
published additions of C-H bonds to dienes4 have been
conducted with a limited scope of pronucleophiles (see
Chart 1), we evaluated the catalyst generated from
DCyPP and CpPd(allyl) for reactions of monocarbonyl
compounds and nitriles, in addition to the more standard
reactions of the 1,3-dicarbonyl compounds.
-7
the addition of substrates with mildly acidic C-H bonds,
often termed pronucleophiles,15 to substrates with con-
jugated carbon-carbon multiple bonds. We show that the
scope of this process can be extended to the intermolecu-
lar addition16 of benzylic ketones, lactones, esters, lac-
As shown in Table 2, a variety of 1,3-dicarbonyl
compounds, R-cyanocarbonyl compounds, and malononi-
trile (entries 1-7) reacted with dienes in high yields to
form the desired addition products. In some cases, the
product from a 1:2 ratio of pronucleophile and diene was
tams, and nitriles and that the addition of 1,3-dicarbonyl
compounds17 to dienes can be conducted enantioselec-
tively.
(13) (a) 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, 12436-12451. See also (b)
Takaya, H.; Murahashi, S.-I. Synlett 2001, 991-994.
(17) (a) For an enantioselective Michael addition of 1,3-dicarbonyl
compounds with enones, see Hamashima, Y.; Hotta, D.; Sodeoka, M.
J . Am. Chem. Soc. 2002, 124, 11240-11241. (b) For a recent organo-
catalytic enantioselective addition of 1,3-dicarbonyl compounds to
alkynones, see Bella, M.; J ørgensen, K. A. J . Am. Chem. Soc. 2004,
126, 5672-5673.
(18) Yoshida, T.; Otsuka, S. Inorg. Synth. 1985, 28, 113.
(19) D o¨ ring, A.; Goddard, R.; Hopp, G.; J olly, P. W.; Kokel, N.;
Kr u¨ ger, C. Inorg. Chim. Acta 1994, 222, 179-192.
(
14) Negishi, E. Handbook of Organopalladium Chemistry for
Organic Synthesis, Wiley: New York, 2002; Vol. 2, pp 1669-2289.
15) (a) Trost, B. M.; Van Franken, D. L. Chem. Rev. 1996, 96, 325-
22. (b) Trost, B. M. Chem. Eur. J . 1998, 4, 2405-2412.
16) For intramolecular additions of dialkyl ketones to alkenes, see
Wang, X.; Pei, T.; Han, X.; Widenhoefer, R. A. Org. Lett. 2003, 5, 2699-
701.
(
4
(
2
J . Org. Chem, Vol. 69, No. 22, 2004 7553

Leitner et al.
TABLE 1. Rela tive Ra tes of Rea ction w ith Ca ta lysts Gen er a ted fr om a Ser ies of Alk ylbisp h osp h in es
a
Relative conversion was measured as the ratio of the moles of product after 7.5 h at room temperature to moles of nucleophile added
at t ) 0 for reactions with the ligand shown vs reactions with dippe as ligand.
CHART 1. Su bstr a tes Th a t Un d er w en t Ad d ition s
of C-H Bon d s to Dien es in P r eviou s Wor k
temperatures. In all three cases, the monoaddition
products were obtained exclusively.
The scope of this methodology extends to acyclic
dienes. As shown in Table 3, reactions of the acyclic
2
,3-dimethylbutadiene occurred to give high yields of
the addition products. In contrast to reactions of 1,3-
cyclohexadiene that form equivalent products from 1,2-
and 1,4-additions, reactions of acyclic dienes generate
different products from 1,4- and 1,2-additions. If the
reactions occur by insertion of diene into a palladium
hydride, as shown in Scheme 1, a single allyl complex
shown below would be generated from 2,3-dimethylbuta-
diene. The enolate or nitrile anion would then add
preferentially to the less substituted terminus of the
π-allyl group.20 In this case, the more sterically crowded
substrates (entries 5 and 10) would react with higher
selectivity for the 1,4-addition products over the 1,2-
addition products.
generated when the reactions were conducted at higher
temperatures. For example, the reaction of malononitrile
with 1,3-cyclohexadiene at room temperature occurred
to form a 5:1 ratio of mono- and diaddition products and
to generate 68% isolated yield of monoaddition product,
but reaction of the same substrates at 80 °C formed the
diallyl product in 97% yield (entry 6).
Monocarbonyl compounds and nitriles also underwent
intermolecular additions to cyclohexadiene, as shown in
Table 2. Reaction of the lactone isochroman-3-one (entry
8
) as well as the ketone 2-tetralone (entry 9) with
cyclohexadiene occurred to give the desired addition
products in high yields. Reactions with purely aliphatic
esters and ketones did not occur, suggesting that the
acidity remains important in controlling the scope of the
reaction. Activated nitriles (entries 7 and 10) also reacted
to give the addition products in high yields at elevated
A broad range of compounds with mildly acidic C-H
bonds added to acyclic dienes. 1-Phenylbutan-2-one, the
7
554 J . Org. Chem., Vol. 69, No. 22, 2004

Mono- and Dicarbonyl Addition to Conjugated Dienes
TABLE 2. Rea ction s of Va r iou s P r on u cleop h iles w ith 1,3-Cycloh exa d ien e
a
Yields are for isolated material and are an average of two runs. RT, room temperature. b Yield of the dialkylation product.
ethyl ester of phenylacetic acid (entries 2 and 4), nitriles
such as phenylacetonitrile, benzoylacetonitrile, and
phenylsulfonylacetonitrile (entries 6-8) all added to
(pK
a
) 18.7 in DMSO).22 The reaction of the less acidic
acyclic ketone required higher catalyst loading, higher
temperature, and a longer reaction time. The same
correlation was observed for reaction of the ethyl ester
2
,3-dimethyl-1,3-butadiene in good yields and formed
the monoaddition products with high selectivities.
Even an aqueous solution of N-methyl acetoacetamide
of phenylacetic acid (pK
entry 4), and of the benzolactone (pK
a
22.7 in DMSO) (Table 3,
18.8 in DMSO)
a
(
65%) reacted in high yields after only 2 h (Table 3,
(Table 3, entry 3).23 The benzolactone isochroman-
3-one (Table 3, entry 3) reacted faster and in higher
yield. The reactions of amides followed the same trend.
The benzo-fused lactams (Table 3, entries 9 and 10)
reacted readily, whereas N-methyl-2-phenylacetamide
and N,N-diethyl-2-phenylacetamide did not react at
all.
entry 11). Clearly, the catalyst is not sensitive to mois-
ture.
In contrast, oxindole (Table 3, entry 9) and malononi-
trile (entry 15) formed a mixture of mono- and diaddition
products, even at early reaction times when the concen-
tration of reagent exceeds that of product. Interestingly,
only one of the two isomeric monoaddition products
underwent a second addition to the diene. Thus, the ratio
of 1:2 decreased to favor 2 as the reaction of oxindole
Asym m etr ic Ad d ition s. These C-H additions across
conjugated dienes can generate products with a new
stereocenter at a carbon that originated from the diene
or the pronucleophile or both. We investigated both
additions of symmetric carbon pronucleophiles to 1,3-
cyclohexadiene (Scheme 2, top) and addition of a dissym-
metric carbon pronucleophile to a terminal, acyclic diene
(Table 3, entry 9) proceeded.
The reaction of N-methyloxindole occurred more slug-
gishly, perhaps due to a less acidic C-H bond, but
occurred with selectivity that was similar to the reaction
of the parent oxindole. The product from addition of two
dienes formed well before all of the N-methyloxindole was
consumed. In contrast, 1,3-dimethyloxindole (Table 3,
entry 10) proceeded without any side reaction to provide
the addition product in 97% yield.
(Scheme 2, bottom). More examples of allylic substitu-
tions that occur with high enantioselectivities with
prochiral allylic electrophiles are known than examples
that occur with high enantioselectivities with prochiral
24
nucleophiles. Thus, the first approach was more likely
Even though factors other than the pK of the C-H
a
to uncover an enantioselective addition of acidic C-H
bonds across dienes.
bond affected the scope of pronucleophile, the reactant
with the more acidic C-H bond tended to react faster
within the same class of substrate. A comparison of the
reactions of cyclic and acylic benzylic ketones (Table 3,
entries 1 and 2) revealed this trend. In water, the cyclic
To study enantioselective additions of carbonyl com-
pounds to prochiral dienes, the addition of 2,4-pentadione
to 1,3-cyclohexadiene was conducted. Because bidentate
alkylphosphines generated more active catalysts for the
addition process than did bidentate arylphosphines, a
ketone has a pK
analogue has a pK
one in DMSO is not reported, the pK
17.0 in DMSO) is lower than that of dibenzyl ketone
a
value of 12.9, whereas the acyclic
of 15.9.21 Though the pK
of â-tetral-
of 2-indanone (pK
a
a
a
a
(
22) Acid-Base Dissociation Constants in Dipolar Aprotic Solvents;
)
Izutsu, K., Ed.; Blackwell Scientific Publications: Boston, MA, 1990.
(
23) (a) Bordwell, F. G.; Fried, H. E. J . Org. Chem. 1981, 46, 4327-
(
20) Acemoglu, L.; Williams, M. J . In Handbook of Organopalladium
4331. (b) Zhang, X. M.; Bordwell, F. G. J . Org. Chem. 1994, 59, 6456-
6458.
(24) For early examples, see (a) Trost, B. M.; Ariza, X. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2635-2637. (b) Kuwano, R.; Ito, Y. J . Am.
Chem. Soc. 1999, 121, 3236-3237.
Chemistry for Organic Synthesis; Negishi, E., de Meijere, A., Eds.;
Wiley: New York, 2002; Vol. 2, pp 1689-1705.
(21) Ross, A. M.; Whalen, D. L.; Eldin, S.; Pollack, R. M. J . Am.
Chem. Soc. 1988, 110, 1981-1982.
J . Org. Chem, Vol. 69, No. 22, 2004 7555

Leitner et al.
TABLE 3. Ad d ition of Su bstr a tes w ith Acid ic C-H Bon d s a cr oss 2,3- Dim eth ylbu ta d ien e
a
Yields are for isolated material and are an average of two runs. b The diaddition product was also isolated. c The yield is estimated
from 1H NMR spectroscopy because the mono- and diaddition products could not be separated.
SCHEME 2
93% yield. Similar yields and ee values were obtained
with 1,3-cyclohexadiene and dimethyl malonate (91%
yield, 72% ee) as well as with diethyl-2-fluoromalonate
(
97% yield, 71% ee). Because the malonates were less
reactive than the â-diketones, a higher catalyst loading
of 5% was used. After optimization of solvent, reaction
temperature, and catalyst loading, the reaction of 2,4-
pentadione with 1,3-cyclohexadiene occurred in THF
at 0 °C with 5 mol % catalyst over 48 h to give the
addition product in a good yield of 71% and in 81% ee
series of chiral, nonracemic, bidentate di- and trialkyl-
phosphines were tested as ligands. A series of experi-
ments conducted at room temperature with 1% catalyst
in THF for 24 h showed that (R)-(-)-1-[(S)-2-diphen-
ylphosphinoferrocenyl]ethyl-di-tert-butylphosphine25 gen-
erated the product in 72% enantiomeric excess (ee) and
(Scheme 3).
(25) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J . Am. Chem. Soc. 1994, 116, 4062-4066.
7
556 J . Org. Chem., Vol. 69, No. 22, 2004

Mono- and Dicarbonyl Addition to Conjugated Dienes
SCHEME 3
0.0400 mmol) as a solution in 0.1 mL of DME, and CpPd(allyl)
8.5 mg, 0.040 mmol) as a solution in 0.05 mL of DME. The
(
vial was sealed with a cap containing a PTFE septum and
removed from the drybox. After being stirred at room temper-
ature for 8 h, the reaction mixture was dissolved in CH Cl ,
2 2
and the volatile materials were evaporated under reduced
pressure. Automated column chromatography (diethyl ether/
pentane gradient from 2/98 to 4/96) gave the title compound
as a mixture of regioisomers 1:2 in a ratio of 96:4 as slightly
1
yellow oil (309.5 mg, 68% yield). H NMR (400.13 MHz, CDCl
3
)
δ 7.22-7.13 (m, 3H), 6.89 (d, J ) 7.3 Hz, 1H), 3.46 (dd, J )
9
6
2
.6 and 6.1 Hz, 1H), 3.31-3.23 (m, 1H), 2.99 (ddd, J ) 15.7,
.4, and 3.4 Hz, 1H), 2.76 (ddd, J ) 17.7, 5.4, and 3.4 Hz, 1H),
The reactions of prochiral pronucleophiles occurred
with lower enantioselectivities. To date, the reaction of
1
3
.56-2.42 (m, 3H), 1.63 (s, 3H), 1.58 (s, 3H), 1.19 (s, 3H);
C
NMR (100.5 MHz, CDCl
28.9 (1C), 128.3 (1C), 127.6 (1C), 126.7 (1C), 126.4 (1C), 123.3
1C), 53.3 (1C), 38.3 (1C), 37.7 (1C), 27.6 (1C), 20.6 (1C), 19.8
1C), 18.6 (1C). Anal. Calcd for C16 20O: C, 84.16; H, 8.83.
3
) δ 213.3 (1C), 137.1 (1C), 135.9 (1C),
2
,3-dimethylbutadiene with the â-diketone in Scheme 4
1
(
(
SCHEME 4
H
1
Found: C, 84.22; H, 9.10. Selected H NMR of minor isomer:
7
1
.01 (d, J ) 8.1 Hz, 1H), 4.82 (s, 1H), 4.60 (s, 1H), 1.85 (s,
H), 1.12 (s, 1H), 1.09 (s, 1H).
Rep r esen ta tive Rea ction of 1,3-Cycloh exa d ien e: 3-Cy-
cloh ex-2-en yl-3-oxo-3-p h en ylp r op ion it r ile. The reaction
was performed according to the representative procedure with
3
-oxo-3-phenylpropionitrile (144.2 mg, 0.99 mmol), 1,3-cyclo-
hexadiene (0.3 mL, 3.10 mmol), DCyPP (23.0 mg, 0.052 mmol),
and CpPd(allyl) (11.3 mg, 0.052 mmol) in 1.0 mL of DME at
8
0 °C for 7 h. Column chromatography (hexane/diethyl ether
7/1) gave the title compound as a colorless oil (204 mg, 91%
yield). 1H NMR (500.13 MHz, CDCl
occurred with the best enantioselectivity. The addition
product was isolated in an excellent yield of 97%, but the
enantiomeric excess of the product was a modest 57%.
3
) δ 7.98-7.94 (m, 4H),
.63-7.68 (m, 2H), 7.55-7.54 (m, 4H), 5.75-5.69 (m, 1H),
.50-5.45 (m, 1H), 4.40 (d, J ) 6.6 Hz, 1H), 4.30 (d, J ) 6.5
7
5
Hz, 1H), 2.97 (m, 2H), 2.03 (m, 4H), 1.92-1.75 (m, 5H), 1.68-
Con clu sion
13
1
1
1
2
7
3
.43 (m, 5H); C NMR (125.7 MHz, CDCl ) δ 190.7, 190.6,
34.6, 134.5, 134.40, 134,38, 131.7, 131.5, 129.1, 129.0, 128.69,
28.67, 126.0, 125.1, 116.4, 116.3, 45.7, 45.2, 36.4, 36.3, 27.8,
New catalysts for the palladium-catalyzed addition of
compounds with mildly acidic C-H bonds to conjugated
dienes were developed, and these catalysts significantly
expanded the scope of substrates that added to dienes.
The scope of this reaction now includes benzylic ketones,
amides, nitriles, and lactones as well as activated esters,
nitriles, and sulfones. The reactions were conducted
under conditions without base and with a catalyst
generated in situ from CpPd(allyl) and commercially
available DCyPP. The products from monoalkylation
were obtained with higher regioselectivity than those in
prior reports on related addition processes. Further, an
enantioselective version of this addition reaction was
developed; the reaction between 2,4-pentadione and 1,3-
cyclohexadiene occurred with 81% ee in the presence of
a catalyst generated from CpPd(allyl) and a J osiphos
ligand with one di-tert-butylphosphino group and one
diphenylphosphino group.
6.0, 24.62, 24.60, 20.96, 20.7. Anal. Calcd for C15H15NO: C,
9.97; H, 6.71; N, 6.22; O, 7.10. Found: C, 79.72; H, 6.74.
Rep r esen ta tive En a n tioselective Rea ction : 3-Cyclo-
h ex-2-en ylp en ta n e-2,4-d ion e.28 In a drybox, a screw-capped
vial containing a small stir bar was charged with (R)-(-)-1-
[
(S)-2-diphenylphosphino)ferrocenyl]ethyl-di-tert-butylphos-
phine (54.2 mg, 0.0999 mmol), 1,3-cyclohexadiene (163 mg,
.04 mmol), acetylacetone (200 mg, 2.00 mmol), CpPd(allyl)
21.3 mg, 0.100 mmol), and 50 µL of THF. The vial was sealed
with a cap containing a PTFE septum and removed from the
drybox. After being stirred at 0 °C for 48 h, the reaction
mixture was dissolved in diethyl ether, and the resulting
solution was evaporated under reduced pressure. Column
chromatography (hexane/diethyl ether 10/1) afforded 3-cyclo-
2
(
hex-2-enylpentane-2,4-dione as a colorless oil (243.0 mg, 81%
1
ee, 71% yield). H NMR (400.13 MHz, CDCl
3
) δ 5.79 (m, 1H),
5
(
1
2
.38 (ddm, J ) 10 and 2 Hz, 1H), 3.63 (d, J ) 10 Hz, 1H), 3.04
m, 1H), 2.21 (s, 3H), 2.20 (s, 3H), 2.01 (m, 2H), 1.73 (m, 2H),
.60 (m, 1H), 1.22 (m, 1H); C NMR (100.5 MHz, CDCl ) δ
3
04.0, 203.8, 130.0, 127.0, 74.8, 35.6, 30.1, 29.6, 26.6, 24.9, 20.6.
13
Exp er im en ta l Section
Ackn owledgm en t. We thank the NSF (CHE0301907
Gen er a l Meth od s. Reactions were loaded in a drybox and
were conducted in 4 mL vials sealed with a cap containing a
poly(tetrafluoroethylene) (PTFE) septum. Yields refer to an
average over two runs of isolated yields of compounds.
Reagents and ligands were purchased from commercial sup-
pliers. 1,3-Dimethyl oxindole and CpPd(allyl) were prepared
by literature procedures.
for support of this work). A.L. thanks the FWF Austria
for an Erwin Schr o¨ dinger fellowship, J .L. thanks the
University of Aarhus and The Danish Natural Science
Research Council for partial support, and C.S. thanks
the DAAD for a fellowship. We thank Nancy J . Wine-
miller for assistance in preparing the manuscript.
2
6
27
Rea ction s w ith 2,3-Dim eth ylbu ta d ien e. Rep r esen ta -
tive P r oced u r e: 1-(2,3-Dim eth ylbu t-2-en yl)-2-tetr a lon e.
In a drybox, a screw-capped vial containing a small stir bar
was charged with â-tetralone (292 mg, 2.00 mmol), 2,3-
dimethylbutadiene (246 mg, 3.00 mmol), DCyPP (17.5 mg,
Su p p or tin g In for m a tion Ava ila ble: Procedures for iso-
lation and data on characterization of reaction products (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0490999
(
26) Nakazawa, N.; Tagami, K.; Iimori, H.; Sano, S.; Ishikawa, T.;
Nagao, Y. Heterocycles 2001, 55, 2157-2170.
27) Shaw, B. L. Proc. Chem. Soc. 1960, 247.
(28) Moreno-Manas, M.; Gonzalez, A.; J aime, C.; Lloris, M. E.;
Marquet, J . Tetrahedron 1991, 47, 6511-6520.
(
J . Org. Chem, Vol. 69, No. 22, 2004 7557