First nickel-catalyzed 1,4-conjugate additions to α,β-unsaturated systems using triorganoindium compounds

Full text of DOI:10.1021/jo981830m

10074
J . Org. Chem. 1998, 63, 10074-10076
Sch em e 1
F ir st Nick el-Ca ta lyzed 1,4-Con ju ga te
Ad d ition s to r,â-Un sa tu r a ted System s
Usin g Tr ior ga n oin d iu m Com p ou n d s
Ignacio Pe´rez,† J ose´ Pe´rez Sestelo,† Miguel A. Maestro,†
Antonio Mourin˜o,‡ and Luis A. Sarandeses*,†
Departamento de Quı´mica Fundamental e Industrial,
Universidade da Corun˜a, E-15071 A Corun˜a, Spain, and
Departamento de Quı´mica Orga´nica,
Ta ble 1. Effects of Nick el Com p lexes on th e Con ju ga te
Ad d ition of n -Bu 3In to 2-Cycloh exen -1-on e
Universidade de Santiago de Compostela,
E-15706 Santiago de Compostela, Spain
yield (%)a
entry no.
catalyst
no catalyst
2b
3b
1
Received September 8, 1998
1
2
3
4
5
6
7
10
80
80
60
75
95
82
Ni(PPh3)2Cl2
13
30
16
Ni(acac)2
In tr od u ction
Ni(PPh3)2Cl2/DIBALHc
Ni(acac)2/DIBALHd
e
Organometallic 1,4-conjugate addition to enones is an
important means of C-C bond formation in organic
synthesis.1 This reaction was once limited to organo-
copper chemistry, but now it has been known to be
possible with other organometallic compounds through
catalysis by metals, nickel especially.2 In continuance of
our research on new applications of organometallics to
the 1,4-conjugate addition reaction and others,3 we report
herein a novel, efficient nickel-catalyzed conjugate ad-
dition of triorganoindium compounds to R,â-unsaturated
systems.
Indium has drawn the attention of chemists for many
years due to its position in the periodic table, in the same
group as boron and aluminum and close to zinc and tin,
and to its interesting chemical properties.4 Nevertheless,
the synthetic applications of organoindium compounds
are few, are relatively recent,4 and are limited to (i) the
allylation of carbonyls and triple bonds under classical5
or Barbier conditions (mostly in aqueous media)6 and (ii)
Reformatsky-type reactions.7 Alkyl organoindium species,
Ni(PPh3)4
Ni(COD)2
15
80
f
a
b
d
Isolated yields. R ) n-Bu. c Reference 10a. Reference 10b.
e Reference 11. f Reference 12.
as far as we know, have only been used in cross-coupling
reactions with chloroalkenes.8
Resu lts a n d Discu ssion
The 1,4-conjugate addition reaction of organoindium
compounds has previously been studied by Araki et al.,
who reported that triorganoindium compounds are un-
reactive toward enones but that some tetraalkylindates
add in a 1,4-fashion in moderate yields.9 In our experi-
ments the reactivity of triorganoindium compounds with
enones was also low, giving <10% yields of the tertiary
alcohol product of the 1,2-addition (Scheme 1); the main
component of the reaction mixture was unreacted enone.
We found, however, that the reaction is promoted by
catalytic amounts of nickel complexes. Table 1 lists the
results obtained with various different nickel complexes
in the addition of tri-n-butylindium to 2-cyclohexen-1-
one (1).
† Universidade da Corun˜a.
‡ Universidade de Santiago de Compostela.
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, U.K., 1992. (b) Kozlowski, J . A. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, U.K., 1992; Vol. 4, p 169.
(2) (a) Petrier, C.; de Souza Barbosa, J . C.; Dupuy, C.; Luche, J .-L.
J . Org. Chem. 1985, 50, 5761. (b) Eshelby, J . J .; Crowley, P. J .; Parsons,
P. J . Synlett 1993, 279. (c) Schwartz, J .; Carr, D. B.; Hansen, R. T.;
Dayrit, F. M. J . Org. Chem. 1980, 45, 3053. (d) Westermann, J .;
Nickisch, K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1368. (e) Flem-
ming, S.; Kabbara, J .; Nickisch, K.; Neh, H.; Westermann, J . Tetra-
hedron Lett. 1994, 35, 6075. (f) Flemming, S.; Kabbara, J .; Nickisch,
K.; Neh, H.; Westermann, J . Synthesis 1995, 317. (g) Westermann, J .;
Imbery, U.; Nguyen, A. T.; Nickisch, K. Eur. J . Inorg. Chem. 1998,
295.
(3) (a) Dupuy, C.; Petrier, C.; Sarandeses, L. A.; Luche, J .-L. Synth.
Commun. 1991, 21, 643. (b) Sarandeses, L. A.; Mourin˜o, A. Luche, J -L.
J . Chem. Soc., Chem. Commun. 1992, 798. (c) Pe´rez-Sestelo, J .;
Mascaren˜as, J . L.; Castedo, L.; Mourin˜o, A. J . Org. Chem. 1993, 58,
118.
(4) For a review of the applications of indium in organic synthesis,
see: Cintas, P. Synlett 1995, 1087.
The commercially available nickel(II) catalysts
Ni(PPh3)2Cl2 and Ni(acac)2 afforded the 1,4-addition
product 2 in yields e30%. The results obtained with
nickel(0) complexes depended on the source of the lat-
ter: when Ni(0) was generated in the reaction medium
by reduction with DIBALH10 (Table 1, entries 4 and 5),
most of the enone was recovered and the yields of the
11
1,4-addition product were lower than 20%. Ni(PPh3)4
proved no better, but a yield of 80% was obtained with
Ni(COD)2.12 The presence of additives such as trimeth-
(7) (a) Chao, L.-C.; Rieke, R. D. J . Org. Chem. 1975, 40, 2253. (b)
Araki, S.; Ito, H.; Butsugan, Y. Synth. Commun. 1988, 18, 453. (c)
Schick, H.; Ludwig, R.; Schwarz, K.-H.; Kleiner, K.; Kunath, A. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1191.
(5) (a) Araki, S.; Ito, H.; Butsugan, Y. J . Org. Chem. 1988, 53, 1831.
(b) Araki, S.; Shimizu, T.; J ohar, P. S.; J in, S.-J .; Butsugan, Y. J . Org.
Chem. 1991, 56, 2538. (c) Araki, S.; Imai, A.; Shimizu, K.; Yamada,
M.; Mori, A.; Butsugan, Y. J . Org. Chem. 1995, 60, 1841.
(6) (a) Li, C.-J .; Chan, T.-H. Tetrahedron Lett. 1991, 32, 7017. (b)
Kim, E.; Gordon, D. M.; Schmid, W.; Whitesides, G. M. J . Org. Chem.
1993, 58, 5500. (c) Chan, T.-H.; Lee, M.-C. J . Org. Chem. 1995, 60,
4228. (d) Maguire, R. J .; Mulzer, J .; Bats, J . W. J . Org. Chem. 1996,
61, 6936. (e) Paquette, L. A.; Mitzel, T. M. J . Org. Chem. 1996, 61,
8799. (f) Yi, X.-H.; Meng, Y.; Li, C.-J . Chem. Commun. 1998, 449.
(8) Nomura, R.; Miyazaki, S.-I.; Matsuda, H. J . Am. Chem. Soc.
1992, 114, 2378.
(9) Araki, S.; Shimizu, T.; J in, S.-J .; Butsugan, Y. J . Chem. Soc.,
Chem. Commun. 1991, 824.
(10) (a) Negishi, E.; Takahashi, T.; Baba, S.; Van Horn, D. E.;
Okukado, N. J . Am. Chem. Soc. 1987, 109, 2393. (b) Dayrit, F. M.;
Schwartz, J . J . Am. Chem. Soc. 1981, 103, 4466.
(11) Negishi, E.-I.; Baba, S. J . Chem. Soc., Chem. Commun. 1976,
596.
(12) Krysan, D. J .; Mackenzie, P. B. J . Org. Chem. 1990, 55, 4229.
10.1021/jo981830m CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/08/1998

Notes
J . Org. Chem., Vol. 63, No. 26, 1998 10075
Ta ble 2. Resu lts of 1,4-Ad d ition of Or ga n oin d iu m
Com p ou n d s to r,â-Un sa tu r a ted System s
afford an indium enolate that would be protonated during
workup.
entry
no.
R,â-unsaturated
R in R3In
and product
yield
(%)a
In conclusion, we have developed a novel, efficient,
nickel-catalyzed 1,4-conjugate addition of triorgano-
indium compounds to R,â-unsaturated systems. This
method can be used as an alternative to the use of other
organometallics to add both alkyl and aryl groups to a
variety of R,â-unsaturated systems in good yields. The
catalyst of choice is Ni(COD)2. Studies of other applica-
tions of organoindium compounds in 1,4-conjugate addi-
tion and carbon-carbon bond-forming reactions are in
progress.
syst
product
1
2
3
4
5
6
7
8
9
1
4
5
6
1
4
5
1
4
5
n-Bu
n-Bu
n-Bu
n-Bu
t-Bu
t-Bu
t-Bu
Ph
2
7
8
9
2
7
8
2
7
8
80
81
88
72
81
70
50
89
71
61
Ph
Ph
10
a
Isolated yields.
Exp er im en ta l Section
Sch em e 2
Gen er a l Con sid er a tion s. All reactions were conducted in
flame-dried glassware under
a positive pressure of argon.
Tetrahydrofuran (THF) was dried by distillation from the sodium
ketyl of benzophenone. Thin-layer chromatography was effected
on silica gel 60 F254 (layer thickness 0.2 mm), and components
were located by observation under UV light and/or by treatment
of the plates with a phosphomolybdic acid reagent followed by
heating. Flash chromatography was performed on silica gel 60
(230-400 mesh) by Still’s method.15 2-Cyclohexen-1-one, methyl
vinyl ketone, ethyl acrylate, acrylonitrile, and 1,5-cyclooctadiene
were purified, immediately before use, by distillation at room
temperature in a high-vacuum line and were trapped at -78
°C in a dry ice-acetone bath. Organolithium reagents and
DIBALH were used after titration by known procedures.16
Nick el Com p lexes. Ni(PPh3)4 was prepared following the
procedure of Negishi and Baba:11 a 25 mL round-bottomed flask
charged with a stir bar and Ni(acac)2 (30 mg, 0.1 mmol) was
dried under high vacuum with a heat gun. After the mixture
was cooled and a positive argon pressure was established, dry
THF (4 mL) and PPh3 (110 mg, 0.4 mmol) were successively
added. To the resulting light green solution was added a solution
of DIBALH in toluene (0.070 mL, 0.1 mmol, 1.5 M) over a 10
min period, yielding a dark brown solution which was stirred
for 1 h at room temperature and directly used.
Ni(COD)2 was prepared according to the method of Krysan
and Mackenzie:12 a 10 mL round-bottomed flask with a stir bar
charged with Ni(acac)2 (26 mg, 0.1 mmol) was dried under high
vacuum with a heat gun. After the mixture was cooled and a
positive argon pressure was established, dry THF (2 mL) and
1,5-cyclooctadiene (0.050 mL, 0.4 mmol) were successively added.
The resulting mixture was cooled to -78 °C, and a solution of
DIBALH in toluene (0.170 mL, 0.25 mmol, 1.5 M) was slowly
added over a 15 min period. The resulting reddish brown solution
was stirred for 1 h at the same temperature and then stirred
for 1 h at 0 °C and used immediately.
ylsilyl chloride13 as well as the nickel catalyst did not
improve the 1,4-addition in any case, the corresponding
silyl enol ether being obtained without modification of
the yield of 1,4-addition product.
To explore the scope of the reaction, we applied it to
the addition of a variety of alkyl and aryl groups to
various R,â-unsaturated systems. Since organocopper
compounds have important limitations for the addition
of tertiary and aryl groups to enones,1b these were the
first reactions investigated. The organoindium com-
pounds were prepared from commercially available or-
ganolithium compounds by transmetalation with InCl3.
We found that tri-tert-butylindium reacts efficiently with
enones (Table 2, entries 5 and 6) under Ni(COD)2
catalysis, affording the desired conjugate addition prod-
ucts in yields similar to these obtained with tri-n-
butylindium. Triphenylindium (Table 2, entries 8 and 9)
also reacted efficiently, under these conditions, affording
the 1,4-addition products in good yields (71-89%).
In the presence of 10% of Ni(COD)2, the reactions of
tri-n-butylindium with ethyl acrylate (5) and acrylonitrile
(6) in THF at room temperature also afforded the
corresponding conjugate addition products in good yields
(88% and 72% respectively; Scheme 2). Other organoin-
dium compounds (t-Bu3In and Ph3In) afforded lower
yields when reacted with ethyl acrylate (50% and 61%,
respectively) but were nevertheless still more reactive
than other organometallics toward these non-enone R,â-
unsaturated systems.1
Other nickel complexes are available commercially and were
used after drying over P2O5 overnight.
Gen er a l P r oced u r e for th e Con ju ga te Ad d ition Rea c-
tion . A 25 mL round-bottomed flask with a stir bar was charged
with InCl3 (1.3 mmol) and dried under vacuum with a heat gun.
After the mixture was cooled and a positive argon pressure was
established, dry THF (7 mL) was added. The resulting solution
was cooled to -78 °C, and a solution of RLi (3.6 mmol, 1.0-2.5
M in hexanes or Et2O) was slowly added (15-30 min). After the
mixture was stirred for 30 min, the cooling bath was removed,
the reaction mixture was warmed to room temperature, and a
solution of the olefin (1 mmol) and Ni(COD)2 (0.1 mmol) in dry
THF (5 mL) was added. The resulting brown-black mixture was
stirred for 2-4 h and the reaction quenched by addition of drops
The mechanism of the reaction remains unclear. It has
been suggested14 that oxidative addition of a low-valent
nickel species to an enone affords a π-allyl complex.
Transfer of the group to be added from indium to nickel,
followed by reductive elimination of the catalyst, would
(14) (a) J ohnson, J . R.; Tully, P. S.; Mackenzie, P. B.; Sabat, M. J .
Am. Chem. Soc. 1991, 113, 6172. (b) Grisso, B. A.; J ohnson, J . R.;
Mackenzie, P. B. J . Am. Chem. Soc. 1992, 114, 5160. (c) Montgomery,
J .; Savchenko, A. V. J . Am. Chem. Soc. 1996, 118, 2099. (d) Savchenko,
A. V.; Montgomery, J . J . Org. Chem. 1996, 61, 1562. A single electron-
transfer mechanism involving a catalytic Ni(I) species has also been
proposed.10b
(15) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(16) Brown, H. C. Organic Synthesis via Boranes; Wiley: New York,
1975; p 191.
(13) Lipschutz, B. H.; Dimock, S. H.; J ames, B. J . Am. Chem. Soc.
1993, 115, 9283 and references therein.

10076 J . Org. Chem., Vol. 63, No. 26, 1998
Notes
of MeOH. The mixture was concentrated in vacuo, and aqueous
HCl (5%, 10 mL) was added. Extraction with Et2O (2 × 15 mL)
gave an organic phase which was washed with saturated
aqueous NaHCO3 (15 mL) and brine (15 mL), dried over
anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography to afford, after
concentration and high-vacuum drying, the conjugate addition
product in 50-89% yield as a colorless liquid.
Com p ou n d s P r ep a r ed . The products prepared are already
known: 3-n-butylcyclohexanone (2, R ) n-Bu),17 3-tert-butylcy-
clohexanone (2, R ) t-Bu),17 5,5-dimethyl-2-hexanone (7, R )
t-Bu),18 ethyl 4,4-dimethylpentanoate (8, R ) t-Bu),19 3-phenyl-
cyclohexanone (2, R ) Ph),20 ethyl 3-phenylpropanoate (8, R )
Ph).21 2-Octanone (7, R ) n-Bu), ethyl heptanoate (8, R ) n-Bu),
heptanenitrile (9, R ) n-Bu), and 4-phenyl-2-butanone (7, R )
Ph) are commercially available.
Ack n ow led gm en t. This work was supported by the
University of A Corun˜a.
Su p p or tin g In for m a tion Ava ila ble: Text giving NMR
data and figures giving NMR spectra for the compounds
prepared (20 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(17) Posner, G. H.; Whitten, C. E.; Sterling, J . J . J . Am. Chem. Soc.
1973, 95, 7788.
(18) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988,
29, 1041.
J O981830M
(19) Gendreau, Y.; Normant, J . F. Bull. Soc. Chim. Fr. 1979, 305.
(20) Bertz, S. H.; Dabbagh, G. Tetrahedron 1989, 45, 425.
(21) Boldrini, G. P.; Savoia, D.; Tagliavini, E.; Trombini, C.; Umani
Ronchi, A. J . Organomet. Chem. 1986, 301, C62.