Highly efficient Pd-catalyzed carbonylative cross-coupling reactions with tetraorganoindates

Article abstract of DOI:10.1021/jo0495790

Tetraorganoindates, which were prepared easily from the reaction of 1 equiv of InCl₃ with 4 equiv of organometallics, could be employed as effective nucleophilic cross-coupling partners in Pd-catalyzed carbonylative cross-coupling reactions with a variety of organic electrophiles. The present method gave unsymmetrical ketones and 1,4-diacylbenzenes in good yields with highly efficient transfer of almost all the organic groups attached to the indium under a carbon monoxide atmosphere in THF at 60 °C.

Full text of DOI:10.1021/jo0495790

SCHEME 1
High ly Efficien t P d -Ca ta lyzed
Ca r bon yla tive Cr oss-Cou p lin g Rea ction s
w ith Tetr a or ga n oin d a tes
Sung Wook Lee, Kooyeon Lee, Dong Seomoon,
Sundae Kim, Hyunseok Kim, Hyun Kim,
Eunkyong Shim, Miae Lee, Seokju Lee,
Misook Kim, and Phil Ho Lee*
Department of Chemistry, Kangwon National University,
Chunchon 200-701, Republic of Korea
of organoindiums acted as nucleophilic coupling partners
in transition metal-catalyzed cross-coupling reactions.6
During the course of this study, we considered the
possibility of extending the metal-catalyzed carbonylative
cross-coupling reaction7 using organoindates to overcome
previously encountered defects associated with a high
pressure of carbon monoxide, high temperature, the
transfer of only one of the organic groups attached to the
metal, and â-hydride elimination. Although organoin-
dates could be easily prepared and their structure
elucidated,8 their application to organic synthesis had not
been reported except for 1,4-addition to R,â-unsaturated
ketones9 and cross-coupling reactions.10 As part of our
continued studies directed toward the development of
efficient indium-mediated reactions,11 we describe a
successful Pd-catalyzed carbonylative cross-coupling re-
action with organoindates (Scheme 1).
We first examined the Pd-catalyzed carbonylative
cross-coupling reaction of 4-iodotoluene with lithium
tetra-n-butylindate, which was prepared in situ from the
reaction of 1 equiv of indium trichloride with 4 equiv of
n-butyllithium (Table 1).8 Of the catalytic systems
screened, the best result was obtained with 4 mol % of
Pd(PPh3)4 at 60 °C under a balloon containing carbon
monoxide, whereupon n-butyl 4-methylphenyl ketone (2)
was produced in 84% yield together with n-butyl-4-
methylbenzene (3) in 6% yield (entry 4). THF was the
solvent of choice among several reaction media examined.
Although the desired compound 2 was obtained in 18%,
42%, and 72% yields by using 0.07, 0.14 and 0.21 mol of
phlee@kangwon.ac.kr
Received March 13, 2004
Abstr a ct: Tetraorganoindates, which were prepared easily
from the reaction of 1 equiv of InCl3 with 4 equiv of
organometallics, could be employed as effective nucleophilic
cross-coupling partners in Pd-catalyzed carbonylative cross-
coupling reactions with a variety of organic electrophiles.
The present method gave unsymmetrical ketones and 1,4-
diacylbenzenes in good yields with highly efficient transfer
of almost all the organic groups attached to the indium
under a carbon monoxide atmosphere in THF at 60 °C.
Development of efficient methods for C-C bond forma-
tion is an important ongoing research theme of organic
synthesis. Transition metal-catalyzed cross-coupling re-
actions of organometallic reagents with electrophilic
coupling partners represent one of the most powerful
methods to generate C-C bonds.1 Among these, a reac-
tion using an organoindium reagent has emerged as a
favorite due to its reactivity, efficiency, versatility, and
chemoselectivity.2 On the basis of these properties of
organoindiums, we reported Pd-catalyzed cross-coupling
reactions of allylindiums3 or allenylindiums,4 and carbon-
ylative cross-coupling reactions of triorganoindiums5 with
a variety of electrophiles. Also, it was found that a variety
* Address correspondence to this author. Phone: +82 33 250 8493.
Fax: +82 33 253 7582.
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S.; Lee, P. H.; Iwasawa, N. Org. Lett. 2003, 5, 1725. (b) Lee, P. H.;
Seomoon, D.; Lee, K.; Heo, Y. J . Org. Chem. 2003, 68, 2510. (c) Lee,
K.; Kim, H.; Miura, T.; Kiyota, K.; Kusama, H.; Kim, S.; Iwasawa, N.;
Lee, P. H. J . Am. Chem. Soc. 2003, 125, 9682. (d) Lee, P. H.; Seomoon,
D.; Kim, S. D.; Nagaiah, K.; Damle, S. V.; Lee, K. Synthesis 2003, 2189
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10.1021/jo0495790 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/02/2004
4852
J . Org. Chem. 2004, 69, 4852-4855

TABLE 1. Op tim iza tion of th e P d -Ca ta lyzed
Ca r bon yla tive Cr oss-Cou p lin g Rea ction
8, 9, and 11). Heterocyclic aryl ketones were also obtained
under the standard reaction conditions (entries 16 and
17). Treatment of â-bromostyrene with 0.28 equiv of
tetra-sec-butylindate gave the R,â-enone 19 in 63% yield
(entry 18). Next, we examined the reactivity of benzyl
bromide to expand the utility of organoindates in Pd-
catalyzed carbonylative cross-coupling reactions. Al-
though tetraorganoindates seem to be more reactive than
triorganoindiums, the Pd-catalyzed carbonylative cross-
coupling product 20 is obtained in 75% yield without
nucleophilic substitution (entry 19). Treatment of 0.28
mol of tetraphenylindate with benzoyl chloride in the
presence of Pd(0) led to the formation of benzil (21) in
73% yield (entry 20). Results in Table 2 suggest that
organoindates react faster than organoindiums, by com-
parison with data using organoindiums.5a The present
method was also successfully tested in reactions leading
to di-p-acylbenzenes. Reactions of 0.84 mol of organoin-
date with 1,4-diiodobenzene under these optimum condi-
tions afforded good yields of the desired products (entries
13 and 14). Dimerized compounds of aryl halide and
cross-coupling products were produced as byproducts in
Pd-catalyzed carbonylative cross-coupling reactions.
In summary, we have shown that tetraorganoindates
can be directly employed in Pd-catalyzed carbonylative
cross-coupling reactions with a variety of organic elec-
trophiles such as aryl and vinyl halide, aryl triflate,
benzyl bromide, and benzoyl chloride. In these reactions,
tetraorganoindates containing methyl and primary and
secondary alkyl and aryl groups transferred the four
organic groups to electrophiles producing unsymmetrical
ketones and 1,4-diacylbenzenes in good yields. Although
Sn and other metals were used as nucleophilic coupling
partners in Pd-catalyzed carbonylative cross-coupling
reactions, the present method complements the existing
synthetic methods owing to some advantageous proper-
ties such as availability, ease of preparation and han-
dling, high reactivity, operational simplicity of organoin-
date reagents, and mild reaction conditions.
GC ratio
theoretical
isolated
entry N (mol) time (h) yield (%)a
1
2
3
yield (%)a,b
1
2
3
4
5
6
0.07
0.14
0.21
0.28
0.28
0.37f
1
1
1
1
16
3
28
56
83
82 18
58 42
20 72
0
0
3
7
100
0
91
84 (6)c
69d (12,c 12e)
89 (2)e
a
Theoretical yield and isolated yield were based on 4-iodotolu-
b
ene. Reaction performed in the presence of 4 mol % of Pd(PPh3)4
and N mol of n-Bu4InLi under a balloon containing CO, unless
d
otherwise noted. c 1-n-Butyl-4-methylbenzene (3). 10 atm of CO.
e n-Butyl-4-methylbenzoate. f 0.37 mol of n-Bu3In was used instead
of n-Bu4InLi.5a
tetra-n-butylindate, respectively (entries 1-3), the best
results were obtained with 0.28 mol of tetra-n-butylindate
(entry 4). This result shows that all of the n-butyl groups
attached to the indium were involved in product forma-
tion. Under 10 atm pressure of CO, the carbonylative
cross-coupling product was formed in 69% yield together
with 12% of n-butyl-4-methylbenzene (3) and 12% of
n-butyl-4-methylbenzoate, respectively (entry 5). Because
4-methylphenyl n-butyl ketone (2) was obtained in 89%
yield with tri-n-butylindium in THF at 66 °C for 3 h,5
tetra-n-butylindate seems to be a more reactive nucleo-
philic coupling partner than tri-n-butylindium in Pd-
catalyzed carbonylative cross-coupling reactions (entries
4 and 6).
The scope of the carbonylative cross-coupling reaction
with respect to the ligand on tetraorganoindates was
examined (Table 2). A variety of alkyl groups such as
methyl, butyl, isopropyl, isobutyl, sec-butyl, and phenyl
exhibited little effect, either on the reaction rates or on
product yields for the tetraorganoindates as nucleophilic
coupling partners. Under the optimized conditions, sub-
jecting 4-iodotoluene to 0.28 mol of tetraisopropylindate
and tetraisobutylindate afforded 4-methylphenyl isopro-
pyl ketone (5) and 4-methylphenyl isobutyl ketone (6) in
80% and 70% yields, respectively (entries 2 and 3).
Although tetra-tert-butylindate did not react with 4-iodo-
toluene, tetra-sec-butylindate gave the desired product
in 68% yield (entries 4 and 5). In the case of tetravinylin-
date, 4-vinyltoluene, which was the cross-coupling prod-
uct, was obtained in 92% yield (entry 6). Reaction of
4-iodotoluene with tetraphenylindate afforded 4-meth-
ylphenyl phenyl ketone (9) in 72% yield (entry 8). All of
the reactions proceeded cleanly with just 0.28 mol of
organoindates under a balloon containing CO. On the
basis of these results, the substituent effect on the
electrophilic coupling partners was investigated. Aryl
iodides having electron-withdrawing groups such as
ethoxycarbonyl and halogen and triflate of 2-naphthol
underwent the carbonylative cross-coupling reaction
(entries 10, 12, and 15). Also, electron-donating groups
such as methyl, methoxy, and hydroxy substituents
produced the desired product in good yields (entries 1-4,
Exp er im en ta l Section
Typ ica l Exp er im en ta l P r oced u r e. To a solution of InCl3
(30.5 mg, 0.138 mmol) in THF (1 mL) at -78 °C was added
n-BuLi (0.55 mmol, 1.55 M in hexane) under the nitrogen
atmosphere. After the mixture was stirred for 30 min, the cooling
bath was removed, and the reaction mixture was warmed to
room temperature over 30 min. A solution of n-Bu4InLi (0.138
mmol, ∼0.l38 M in dry THF) was subsequently added to a
mixture of Pd(PPh3)4 (23.1 mg, 4 mol %) and 4-iodotoluene (109.0
mg, 0.5 mmol) in THF (1 mL) under the nitrogen atmosphere.
The resulting mixture was bubbled with CO gas for 5 min at
room temperature to flush out nitrogen, then a positive CO
pressure with balloon was established. The reaction mixture was
warmed to 60 °C over 40 min and refluxed under atmospheric
pressure of CO gas for 0.5 h at 60 °C. After being cooled to room
temperature, the reaction mixture was quenched with NaHCO3
(saturated aqueous). The aqueous layer was extracted with ether
(3 × 20 mL), and the combined organic phases were washed with
water and brine, dried with MgSO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (EtOAc:hexane ) 1:50) to give n-butyl
1
4-methylphenyl ketone (2) (74.0 mg, 84%). H NMR (400 MHz,
CDCl3) δ 7.86 (d, J ) 8.11 Hz, 2H), 7.25 (d, J ) 7.79 Hz, 2H),
2.94 (t, J ) 7.45 Hz, 2H), 2.41 (s, 3H), 1.67-1.75 (m, 2H), 1.38-
1.43 (m, 2H), 0.93-0.97 (m, 3H); 13C NMR (100 MHz, CDCl3) δ
J . Org. Chem, Vol. 69, No. 14, 2004 4853

TABLE 2. P d -Ca ta lyzed Ca r bon yla tive Cr oss-Cou p lin g Rea ction s of R 4In Met w ith Electr op h iles
a
Reaction performed in the presence of 4 mol % of Pd(PPh3)4 and 0.28 mol of R4InMet under a balloon containing CO, unless otherwise
noted. Isolated yield was based on electrophiles. 1,4-Dimethylbenzene. c 4-Isopropyltoluene. 4-Methylstyrene. e 4-(Methylphenyl)phen-
b
d
ylacetylene. f 4,4′-Dimethylbiphenyl. 4-Phenylphenol. 4,4-Dichlorobiphenyl. 0.84 mol of Indate gave the best result. 2-Isopropyl-
g
h
i
j
k
naphthalene. Biphenyl.
4854 J . Org. Chem., Vol. 69, No. 14, 2004

200.3, 143.6, 134.6, 129.2, 128.2, 38.3, 26.6, 22.5, 21.6, 14.0; IR
(film) 1676, 1607 cm-1; HRMS (EI) for C12H16O [M+] calcd
176.1201, found 176.1202.
Livinghouse of Montana State University for helpful
discussions and proof reading of the manuscript.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. This work was supported by
Grant No. R02-2003-000-10023-0 of the Basic Research
Program of the Korea Science & Engineering Founda-
tion and the CMDS at KAIST. We thank Professor T.
J O0495790
J . Org. Chem, Vol. 69, No. 14, 2004 4855