Atom-efficient metal-catalyzed cross-coupling reaction of indium organometallics with organic electrophiles

Article abstract of DOI:10.1021/ja004195m

The novel metal-catalyzed cross-coupling reaction of indium organometallics with organic electrophiles is described. Triorganoindium compounds (R₃In) containing alkyl, vinyl, aryl, and alkynyl groups are efficiently prepared from the correspond

Full text of DOI:10.1021/ja004195m

J. Am. Chem. Soc. 2001, 123, 4155-4160
4155
Atom-Efficient Metal-Catalyzed Cross-Coupling Reaction of Indium
Organometallics with Organic Electrophiles
Ignacio Pe´rez, Jose´ Pe´rez Sestelo, and Luis A. Sarandeses*
Contribution from the Departamento de Qu´ımica Fundamental, UniVersidade da Corun˜a,
E-15071 A Corun˜a, Spain
ReceiVed December 7, 2000
Abstract: The novel metal-catalyzed cross-coupling reaction of indium organometallics with organic
electrophiles is described. Triorganoindium compounds (R3In) containing alkyl, vinyl, aryl, and alkynyl groups
are efficiently prepared from the corresponding lithium or magnesium organometallics by reaction with indium
trichloride. The cross-coupling reaction of R3In with aryl halides and pseudohalides (iodide 2, bromide 5, and
triflate 4), vinyl triflates, benzyl bromides, and acid chlorides proceeds under palladium catalysis in excellent
yields and with high chemoselectivity. Indium organometallics also react with aryl chlorides as under nickel
catalysis. In the cross-coupling reaction the triorganoindium compounds transfer, in a clear example of atom
economy, all three of the organic groups attached to the metal, as shown by the necessity of using only 34 mol
% of indium. The feasibility of using R3In in reactions with different electrophiles, along with the high yields
and chemoselectivities obtained, reveals indium organometallics to be useful alternatives to other organometallics
in cross-coupling reactions.
Introduction
chemo- and stereoselectivity, and the ability to form C-C bonds
between all of the different carbon types (sp3, sp2, and sp) is
still of great interest. In addition, the minimization of side-
product formation6 and the choice of processes with little or no
risk associated to humans or the environment are major
contemporary concerns.7 A number of organometallic species
used in cross-coupling reactions have shown limitations con-
cerning the use of alkyl (sp3) organometallics as coupling
partners, the toxicity associated with the metal, or undesirable
side reactions. The transfer of only one of the organic substit-
uents attached to the metal has also been a significant handicap,
this problem has sometimes been overcome by using mixed
organometallic species2,3 or catalytic amounts of the metal.8 The
discovery of an organometallic nucleophile of general use,
regardless of the nature of the organic electrophile, is a
worthwhile goal.
Transition metal-catalyzed cross-coupling reactions of orga-
nometallic compounds with organic electrophiles represent one
of the most powerful methods for the construction of C-C
bonds, especially between unsaturated carbons.1 In recent years,
the synthetic scope of this kind of reaction has been continuously
expanded by the use of new organic electrophiles, catalysts,
and organometallics. Hitherto, several organometallic nucleo-
philes have been useful in the palladium- or nickel-catalyzed
reactions, particularly tin organometallics (Stille reaction),2
organoboron compounds (Suzuki reaction),3 and zinc or zinc-
copper organometallics.4 Other organometallic species have also
been of use in synthesis.5
The development of new cross-coupling reactions with high
degrees of conversion of the organometallic species, high
As part of a project aimed at finding new organometallic
compounds that would be useful in organic synthesis, we
recently discovered the palladium-catalyzed cross-coupling
reaction of indium organometallics with vinyl and aryl triflates
or iodides.9 Here, we report in full the novel metal-catalyzed
cross-coupling reactions of a wide array of triorganoindium
compounds (R3In, R ) alkyl, alkenyl, alkynyl, aryl) with a
variety of organic electrophiles, such as aryl halides and triflates,
vinyl triflates, benzyl bromides, and acid chlorides (eq 1).
(1) (a) Diederich, F., Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998. (b) Geissler, H. In Transition
Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH:
Weinheim, 1998; Chapter 2.10, pp 158-183. (c) Tsuji, J. Transition Metal
Reagents and Catalysts; Wiley: Chichester, U.K., 2000; Chapter 3, pp 27-
108.
(2) (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771-1780. (b) Stille,
J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524. (c) Mitchell, T. N.
Synthesis 1992, 803-815. (d) Farina, V.; Krishnamurty, V.; Scott, W. J.
Org. React. 1997, 50, 1-652. (e) Mitchell, T. N. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; Chapter 4, pp 167-202.
(3) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483. (b)
Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter 2, pp 49-97.
(4) (a) Negishi, E. In Organozinc Reagents; Knochel, P., Jones, P., Eds.;
Oxford University Press: Oxford, U.K., 1999; Chapter 11, pp 213-243.
(b) Giovannini, R.; Stu¨dermann, T.; Devasagayaraj, A.; Dussin, G.; Knochel,
P. J. Org. Chem. 1999, 64, 3544-3553.
(5) For the use of magnesium, copper, aluminum, and zirconium
organometallics, see ref 1. For recent applications of silicon reagents, see:
(a) Mowery, M. E.; DeShong, P. J. Org. Chem. 1999, 64, 1684-1688. (b)
Denmark, S. E.; Choi, J. Y. J. Am. Chem. Soc. 1999, 121, 5821-5822. (c)
Denmark, S. E.; Wehrli, D. Org. Lett. 2000, 2, 565-568.
R3In + 3 R′-X Pd or Ni catalyst8 3 R′-R
(1)
THF
(6) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281.
(7) Anastas, P. T.; Warner, J. C. Green Chemistry; Oxford University
Press: Oxford, 1998; pp 29-55.
(8) (a) Maleczka, R. E., Jr.; Terstiege, I. J. Org. Chem. 1998, 63, 9622-
9623. (b) Maleczka, R. E., Jr.; Gallagher, W. P.; Terstiege, I. J. Am. Chem.
Soc. 2000, 122, 384-385.
(9) For a preliminary communication, see: Pe´rez, I.; Pe´rez Sestelo, J.;
Sarandeses, L. A. Org. Lett. 1999, 1, 1267-1269.
10.1021/ja004195m CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/12/2001

4156 J. Am. Chem. Soc., Vol. 123, No. 18, 2001
Pe´rez et al.
Results and Discussion
available organolithium or Grignard reagents.20 By following
this method, we were able to access a wide range of triorga-
noindium compounds including aryl, vinyl, alkynyl and alkyl,
derivatives (1a-h, eq 2). With the indium organometallics in
hand, we proceeded to explore their reactivity in metal-catalyzed
cross-coupling reactions toward organic electrophiles.
Indium Organometallics. Group 13 organometallics have
in boron the most representative element, although aluminum
also has useful synthetic applications. Indium has also warranted
the attention of organic chemists in recent years. The apparent
low toxicity10 associated with indium as well as other interesting
chemical properties, such as low nucleophilicity and hetero-
philicity or similarities with magnesium, zinc, and tin, makes
indium organometallics attractive reagents for organic synthe-
sis.11
During the past decade, indium has been extensively applied
in allylation and related reactions under Barbier conditions in
aqueous media12 or in organic solvents.13 On the other hand,
the use of triorganoindium species (R3In) has been limited thus
far to the uncatalyzed cross-coupling reaction with electron-
deficient alkenyl chlorides14 and to our recently developed
nickel-catalyzed 1,4-conjugate addition to electron-deficient
olefins.15
Indium organometallics are readily accessible by different
methods: (a) reaction between an organic halide and indium
metal,16 preferably using Rieke indium,17 (b) transmetalation
between an organomercury compound and indium metal,18 and
(c) metathesis reaction of lithium, magnesium, sodium, alumi-
num, or zinc organometallics with indium halides.19
In this study, triorganoindium compounds (R3In) were
prepared as solutions in THF by reaction of InCl3 with readily
Cross-Coupling Reaction of Indium Organometallics with
Aryl Electrophiles. Aryl halides and pseudohalides (such as
triflates) are among the most common electrophiles in metal-
catalyzed cross-coupling reactions.1,2 For our initial studies on
the participation of triorganoindium compounds in this kind of
reaction, we chose as coupling partner 4-iodotoluene (2, Table
1). We found that reaction of triorganoindium reagents (R3In)
with 4-iodotoluene (1:1 ratio) in THF at reflux in the presence
of catalytic amounts of Pd(PPh3)2Cl2, afforded the corresponding
cross-coupling products in quantitative yields after short reaction
times (1-4 h). Further experimental research showed that the
amount of R3In could be reduced to a 3:1 ratio of 2/R3In,
keeping the yields still near to quantitative, a result that suggests
that all three of the organic groups attached to indium are
transferred. Moreover, the reaction proceeds in similar yields
when other palladium(II) or palladium(0) complexes [Pd(CH3-
CN)2Cl2, Pd(PPh3)4, Pd2(dba)3, Pd(dppp)Cl2] are used, and with
just 1 mol % loading.
On using 4-iodotoluene as the electrophile, all of the
triorganoindium compounds (1a-h) afforded the coupling
products in excellent yields (82-96%, Table 1) with just 34
mol % of R3In and 1 mol % of Pd(PPh3)2Cl2. The cross-coupling
reaction efficiently transfers alkyl, both primary and secondary,
vinyl, and alkynyl groups. Interestingly, the reaction with
triphenylindium provides biphenyl 3a in high yield (96%). In
all of these reactions we also proved that, in contrast with all
other metals employed in cross-coupling reactions, the triorga-
noindium compounds transfer to the electrophile all three groups
attached to indium.
(10) (a) Wade, K.; Banister, A. J. In ComprehensiVe Inorganic Chemistry;
Bailar, J. C., Jr., Emele´us, H. J., Nyholm, R., Trotman-Dikenson, A. E.,
Eds.; Pergamon: Oxford, U.K., 1973; Vol. 1, Chapter 12, p 1072. (b)
Worrall, I. J.; Smith, J. D. In Organometallic Compounds of Aluminum,
Gallium, Indium and Thallium; McKillop, A., Smith, J. D., Worrall, I. J.,
Eds.; Chapman and Hall: London, U.K., 1985; p 137.
(11) (a) Cintas, P. Synlett 1995, 1087-1096. (b) Marshall, J. A.
Chemtracts: Org. Chem. 1997, 10, 481-496. (c) Li, C.-J.; Chan, T.-H.
Organic Reactions in Aqueous Media; Wiley: New York, 1997; Chapter
4, pp 64-114. (d) Paquette, L. A. In Green Chemistry: Frontiers in Benign
Chemical Synthesis and Processing; Anastas, P. T., Williamson, T. C., Eds.;
Oxford University Press: Oxford, U.K., 1998; Chapter 15, pp 250-264.
(e) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149-11176. (f) Ranu,
B. C. Eur. J. Org. Chem. 2000, 2347-2356.
(12) (a) Allylation of carbonyls: Chan, T. H.; Yang, Y. J. Am. Chem.
Soc. 1999, 121, 3228-3229. (b) Allenylations of carbonyls: Yi, X.-H.;
Meng, Y.; Hua, X.-G.; Li, C.-J. J. Org. Chem. 1998, 63, 7472-7480. (c)
Reductive dimerization of aldimines: Kalyanam, N.; Rao, G. V. Tetrahedron
Lett. 1993, 34, 1647-1648.
(13) (a) Allylation of carbonyls: Lloyd-Jones, G. C.; Russell, T. Synlett
1998, 903-905. (b) Allylation and alkylation of enones: Araki, S.; Horie,
T.; Kato, M.; Hirashita, T.; Yamamura, H.; Kawai, M. Tetrahedron Lett.
1999, 40, 2331-2334. (c) Allylation of imines: Choudhury, P. K.; Foubelo,
F.; Yus, M. J. Org. Chem. 1999, 64, 3376-3378. (c) Allylation of
enamines: Bossard, F.; Dambrin, V.; Lintanf, V.; Beuchet, P.; Mosset, P.
Tetrahedron Lett. 1995, 36, 6055-6058. (d) Allylation of triple bonds: (i)
Fujiwara, N.; Yamamoto, Y. J. Org. Chem. 1999, 64, 4095-4101. (ii) Klaps,
E.; Schmid, W. J. Org. Chem. 1999, 64, 7537-7546. (e) Reformatsky-
type reactions: Schick, H.; Ludwig, R.; Schwarz, K.-H.; Kleiner, K.; Kunath,
A. Angew. Chem., Int. Ed. Engl. 1993, 32, 1191-1193. (f) Allylation of
cyclopropenes: Araki, S.; Nakano, H.; Subburaj, K.; Hirashita, T.; Shibutani,
K.; Yamamura, H.; Kawaki, M.; Butsugan, Y. Tetrahedron Lett. 1998, 39,
6327-6330. (g) Friedel-Crafts reactions: Lim, H. J.; Keum, G.; Kang, S.
B.; Kim, Y.; Chung, B. Y. Tetrahedron Lett. 1999, 40, 1547-1550.
(14) Nomura, R.; Miyazaki, S.-I.; Matsuda, H. J. Am. Chem. Soc. 1992,
114, 2738-2740.
(15) Pe´rez, I.; Pe´rez Sestelo, J.; Maestro, M. A.; Mourin˜o, A.; Sarandeses,
L. A. J. Org. Chem. 1998, 63, 10074-10076.
(16) (a) Deacon, G. B.; Parrot, J. C. Aust. J. Chem. 1971, 24, 1771-
1779. (b) Gynane, M. J. S.; Waterworth, L. G.; Worrall, I. J. J. Organomet.
Chem. 1972, 40, C9-C10.
(17) (a) Chao, L. I.; Rieke, R. D. J. Organomet. Chem. 1974, 67, C64-
C66. (b) Chao, L. I.; Rieke, R. D. J. Org. Chem. 1975, 40, 2253-2255. (c)
Rieke, R. D.; Sell, M. S.; Klein, W. R.; Chen, T.; Brown, J. D.; Hanson,
M. V. In ActiVe Metals; Fu¨rstner, A., Ed.; VCH: Weinheim, 1996; Chapter
1, pp 1-59.
(18) (a) Dennis, L. M.; Work, R. W.; Rochow, E. G. J. Am. Chem. Soc.
1934, 56, 1047-1049. (b) Dolzine, T. W.; Oliver, J. P. J. Organomet. Chem.
1974, 78, 165-176.
These initial results reveal indium organometallics to be
powerful reagents in metal-catalyzed cross-coupling reactions.
Boron or aluminum, which are in the same group as indium,
can only transfer one group, as other metals used in cross-
coupling reactions such as tin or zinc do. This extraordinary
efficiency has only previously been observed by Nomura,14 some
years ago, for the addition of trialkylindium reagents to
chloroalkenes and, more recently, in cross-coupling reactions
of some boron compounds.21
After the first series of reactions using aryl iodide 2, we
studied the reactivity of indium organometallics with aryl triflate
4 (Table 2). Aryl triflates are an important family of electrophiles
(19) (a) Tuck, D. G. In ComprehensiVe Organometallic Chemistry;
Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon: Oxford, U.K.,
1982; Vol. 1, Chapter 7, pp 683-723. (b) Auner, N. In Synthetic Methods
of Organometallic and Inorganic Chemistry; Herrmann, W. A., Ed.;
Thieme: Stuttgart, 1996; Vol. 2, pp 118-127.
(20) Clark, H. C.; Pickard, A. L. J. Organomet. Chem. 1967, 8, 427-
434.
(21) (a) Bumagin, N. A.; Bykov, V. V. Tetrahedron 1997, 53, 14437-
14450. (b) Bumagin, N. A.; Tsarev, D. A. Tetrahedron Lett. 1998, 39,
8155-8158.

Atom-Efficient Metal-Catalyzed Cross-Coupling Reaction
J. Am. Chem. Soc., Vol. 123, No. 18, 2001 4157
Table 1. Results of the Palladium-Catalyzed Cross-Coupling
Reaction of Triorganoindium Compounds (1a-h) with
4-Iodotoluene (2)a
Table 2. Results of the Palladium-Catalyzed Cross-Coupling
Reaction of Triorganoindium Compounds (1a-h) with
4′-Substituted Acetophenones 4 and 5a
entry no.
R
t (h)
product
yield (%)b
1
2
3
4
5
6
7
8
Ph (1a)
1
3a
3b
3c
3d
3e
3f
96
89
90
93
82
85
92
93
entry no.
R
electrophile t (h) product yield (%)b
CH2dCH (1b)
PhCtC (1c)
TMSCtC (1d)
n-Bu (1e)
Me (1f)
c-C3H5 (1g)
TMSCH2 (1h)
0.5
0.5
1
4
1
3
2
1
2c
Ph (1a)
4
3
3
6a
6b
6c
6d
6e
6f
95
89
94
93
91
91
89
96
91
94
94
91
91
94
92
94
CH2dCH (1b)
PhCtC (1c)
TMSCtC (1d)
n-Bu (1e)
3c
1
1
4c
5
6
7
8
1.5
4.5
3
3g
3h
Me (1f)
c-C3H5 (1g)
TMSCH2 (1h)
Ph (1a)
CH2dCH (1b)
PhCtC (1c)
TMSCtC (1d)
n-Bu (1e)
Me (1f)
c-C3H5 (1g)
TMSCH2 (1h)
6g
6h
6a
6b
6c
6d
6e
6f
a Reactions were conducted in THF at reflux using 34 mol % of
R3In and 1 mol % of Pd(PPh3)2Cl2. b Isolated yield based on the
electrophile added.
1
9
5
1.5
2.5
1.5
1
1.5
1
10c
11c
12c
13
14
15c
16
in palladium-catalyzed cross-coupling reactions22 due to their
ease of preparation from readily available phenols and to the
possibility of transforming the C-O bond into a C-C bond.
The reaction of indium organometallics (1a-h) with aryl triflate
4, in the presence of catalytic amounts of Pd(PPh3)2Cl2 (1 mol
%), afforded the cross-coupled products in excellent yields
(Table 2, entries 1-8). The reaction with triphenylindium (1a),
trimethylindium (1f), tri-n-butylindium (1e), or tricyclopropyl-
indium (1g) afforded the corresponding products in 89-96%
yields. The use of other palladium catalysts, such as Pd(PPh3)4,
led to similar yields. The reactions of vinyl and alkynyl indium
reagents in the presence of Pd(PPh3)2Cl2 as a catalyst gave lower
yields (35-60%), with the starting triflate 4 being recovered.
In these cases the use of a more reactive palladium catalyst,
such as Pd(dppf)Cl223 (1 mol %), improved the yields markedly
(89-93%). In all cases, the reactions were carried out using
just 34 mol % of the triorganoindium reagent, and the results
are consistent with the transfer of all three groups attached to
the indium. Furthermore, the reaction is chemoselective since
nucleophilic addition to the carbonyl group was not detected.
Following the studies of the reactivity of indium organome-
tallics in cross-coupling reactions with aryl halides and pseudo-
halides, the next electrophile to be assessed was 4′-bromoace-
tophenone (5). Aryl bromides are commonly used in cross-
coupling reactions due to their ease of preparation and high
stability. Aryl bromides usually have lower reactivity than the
analogous iodides, with the choice of catalyst being particularly
important in this case.1,2 The metal-catalyzed cross-coupling of
triorganoindium reagents (1a-h) with 5 (3:1 ratio Ar-Br/
R3In), using Pd(PPh3)2Cl2 as the catalyst (1 mol %), afforded
the corresponding coupled products in high yields (91-94%)
and short reaction times (1-3.5 h, Table 2, entries 9-16). With
vinyl-, alkynyl-, or cyclopropylindium reagents the yields were
lower than in the corresponding cases in which Pd(PPh3)2Cl2
was used as the catalyst, a situation similar to that occurring in
the case of triflate 4. However, when Pd(dppf)Cl2 was employed,
the yields were improved (Table 2, entries 10-12 and 15). As
in the reaction with aryl triflate 4, the reaction proceeds with
high chemoselectivity since the products from nucleophilic
3.5
1
6g
6h
a Reactions were conducted in THF at reflux using 34 mol % of
R3In and 1 mol % of Pd(PPh3)2Cl2, except for entries 2-4, 10-12,
and 15. b Isolated yield based on the electrophile added. c Pd(dppf)Cl2
(1 mol %) as catalyst.
The reactivity study on triorganoindium compounds in cross-
coupling reactions was continued using aryl chlorides as
electrophiles, that is, 4-chlorotoluene (7, eq 3). Chloroarenes
have generally been seen as unreactive halides in metal-
catalyzed cross-coupling reactions, but the recent development
of new catalysts has allowed their participation under mild
conditions and with low catalyst loading.24 Indeed, these systems
have been used in Stille25 or Suzuki reactions under palladium
catalysis24,26 and in cross-coupling reactions with Grignard27
or organozinc organometallics under nickel catalysis.28 In our
case, indium organometallics showed low reactivity toward aryl
chloride 7 under palladium catalysis, even using Buchwald or
Fu catalysts.24 However, the use of Ni(0) catalysts (5 mol %)29
provided satisfactory yields of the cross-coupling products 3a
and 3e (74 and 83%, respectively). As in previous palladium-
catalyzed reactions, the transfer of all three groups attached to
(24) (a) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J.
Am. Chem. Soc. 1999, 121, 9550-9561. (b) Littke, A. F.; Dai, C.; Fu, G.
C. J. Am. Chem. Soc. 2000, 122, 4020-4028.
(25) (a) Shirakawa, E.; Yamasaki, K.; Hiyama, T. J. Chem. Soc., Perkin
Trans. 1 1997, 2449-2450. (b) Shirakawa, E.; Yamasaki, K.; Hiyama, T.
Synthesis 1998, 1544-1549. (c) Littke, A. F.; Fu, G. C. Angew. Chem.,
Int. Ed. 1999, 38, 2411-2413.
(26) (a) Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37,
2993-2996. (b) Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997,
62, 8024-8030. (c) Indolese, A. F. Tetrahedron Lett. 1997, 38, 3513-
3516. (d) Shen, W. Tetrahedron Lett. 1997, 38, 5575-5578. (e) Old, D.
W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722-
9723. (f) Firooznia, F.; Gude, C.; Chan, K.; Satoh, Y. Tetrahedron Lett.
1998, 39, 3985-3988. (g) Galland, J.-C.; Savignac, M.; Geneˆt, J.-P.
Tetrahedron Lett. 1999, 40, 2323-2326. (h) Bei, X.; Crevier, T.; Guram,
A. S.; Jandeleit, B.; Powers, T. S.; Turner, H. W.; Uno, T.; Weinberg, W.
H. Tetrahedron Lett. 1999, 40, 3855-3858. (i) Zhang, C.; Huang, J.; Trudell,
M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804-3805.
(27) (a) Ikoma, Y.; Taya, F.; Ozaki, E.; Higuchi, S.; Naoi, Y.; Fuji-i, K.
Synthesis 1990, 147-148. (b) Wang, J.; Pomerantz, M. Tetrahedron Lett.
1995, 36, 2571-2574. (c) Bo¨hm, V. P. W.; Weskamp, T.; Gsto¨ttmayr, C.
W. K.; Herrmann, W. A. Angew. Chem., Int. Ed. 2000, 39, 1602-1604.
(28) (a) Miller, J. A.; Farrell, R. P. Tetrahedron Lett. 1998, 39, 6441-
6444. (b) Lipshutz, B. H.; Blomgren, P. A.; Kim, S.-K. Tetrahedron Lett.
1999, 40, 197-200.
1
addition to the carbonyl group were not detected by H NMR
spectroscopy.
(22) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478-
5486.
(23) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158-163.

4158 J. Am. Chem. Soc., Vol. 123, No. 18, 2001
Pe´rez et al.
Table 3. Results of the Palladium-Catalyzed Cross-Coupling
indium is also observed in nickel-catalyzed cross-coupling
reactions.
Reaction of Triorganoindium Compounds (1a-h) with Vinyl
Triflate 11a
entry no.
R
t (h)
product
yield (%)b
To explore the relative reactivities of triorganoindium reagents
with aryl halides and triflates in palladium-catalyzed cross-
coupling reactions, we carried out a number of competitive
experiments. We performed the reaction of n-Bu3In (34 mol
%) with a 1:1 mixture of 4-iodotoluene (2, 100 mol %) and
4-bromotoluene (8, 100 mol %) in the presence of Pd(PPh3)2-
Cl2 (1 mol %). We found that, after 5 h at reflux, the cross-
coupling product 3e was isolated in 80% yield, and all of the
4-bromotoluene was recovered (eq 4). When n-Bu3In (34 mol
%) was mixed with a 1:1 mixture of aryl triflate 4 (100 mol %)
and bromide 5 (100 mol %), under the same reaction conditions
as before, the coupling product 6e was obtained in good yield,
and equal quantities of the starting compounds were recovered.
These results suggest that aryl iodides are more reactive than
bromides and that bromides have a similar reactivity to triflates.
This order of reactivity is similar to that observed with other
organometallic species, and that led us to believe that the rate-
limiting step in cross-coupling reactions with triorganoindium
reagents is also the oxidative addition.
To study the possibility of performing a selective function-
alization of polyhalogenated aryl derivatives with indium
organometallics, we carried out the reactions of Ph3In (1a) and
n-Bu3In (1e) with 4-bromoiodobenzene (9, eq 5). On using Ph3In
the cross-coupling product, 4-bromobiphenyl (10a), was ob-
tained in 90% yield after 2 h refluxing, and with n-Bu3In,
1-bromo-4-n-butylbenzene (10e) was obtained in 80% yield after
4 h at reflux. In both cases, reaction at the C-Br bond was not
observed, suggesting that indium organometallics can be used
to perform selective functionalization of polyhalogenated aryl
compounds.
1
2
3
4
5
6
7
8
Ph (1a)
1
12a
12b
12c
12d
12e
12f
93
97
95
93
90
92
90
89
CH2dCH (1b)
PhCtC (1c)
TMSCtC (1d)
n-Bu (1e)
Me (1f)
c-C3H5 (1g)
TMSCH2 (1h)
0.5
0.5
0.5
1
7
4
12g
12h
0.5
a Reactions were conducted in THF at reflux using 34 mol % of
R3In and 1 mol % of Pd(PPh3)2Cl2. b Isolated yield based on the
electrophile added.
electrophiles in cross-coupling reactions.30 These compounds
have been commonly used in natural product synthesis31 and
exhibit a similar reactivity to aryl iodides. As shown in Table
3, the cross-coupling reaction of triorganoindium compounds
with vinyl triflate 11 (3:1 ratio 11/R3In), catalyzed by 1 mol %
of Pd(PPh3)2Cl2, afforded the corresponding products in excel-
lent yields (89-97%) and with short reaction times (0.5-7 h).
As in previous examples, the ratio of the reagents used and the
yields obtained are consistent with the transfer of all three groups
attached to indium.
The cross-coupling reactions of organometallics with benzyl
halides is usually an uncatalyzed process due to the high
reactivity of the halides. Nevertheless, low nucleophilic orga-
nometallics (B, Al, Sn, Zn) require palladium or nickel
catalysis.29c,32 Generally, the reactions afford high yields with
unsaturated organometallics. We explored the reactivity of
triorganoindium compounds with benzyl bromide (13 Table 4).
The reaction of aryl, alkenyl, and alkynyl indium organome-
tallics with 13, with a 3:1 ratio of 13/R3In in the presence of 1
mol % of Pd(dppf)Cl2, afforded the cross-coupling products with
short reactions times (1-2.5 h) in almost quantitative yields
(94-96%). When the corresponding reactions were carried out
with trialkylindium compounds (Me3In, n-Bu3In) the yields were
lower (10-20%), and the use of more reactive catalysts, higher
temperatures, or different solvents did not improve the yields.
Another important group of electrophiles in cross-coupling
reactions are the acid halides. Their reactions with organome-
tallic compounds is a useful method for the synthesis of ketones,
although sometimes nucleophilic addition to the resulting ketone
takes place. The addition of low nucleophilic organometallics
can be promoted using suitable catalysts, generally palladium
complexes.33 The low nucleophilicity of triorganoindium com-
Cross-Coupling Reaction of Indium Organometallics with
Other Electrophiles. To enlarge the scope of indium organo-
metallics in metal-catalyzed cross-coupling reactions, we studied
the reactivity toward other electrophiles, such as vinyl triflates,
benzyl halides, and acid chlorides. As a representative example
of a vinyl triflate we used 11 (Table 3). Vinyl triflates, which
are readily available from suitable ketones, are useful organic
(30) (a) Scott, W. J.; McMurry, J. E. Acc. Chem. Res. 1988, 2, 47-54.
(b) Ritter, K. Synthesis 1993, 735-762. (c) Oh-e, T.; Miyaura, N.; Suzuki,
A. J. Org. Chem. 1993, 58, 2201-2208.
(31) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis; VCH:
Weinheim, 1996; pp 591-598.
(32) (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4981-
4991 (b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992-
4998. (c) Zhang, S.; Marshall, D.; Liebeskind, L. S. J. Org. Chem. 1999,
64, 2796-2804. (d) Kamlage, S.; Sefkow, M.; Peter, M. G. J. Org. Chem.
1999, 64, 2938-2940. (e) Chowdhury, S.; Georghiou, P. E. Tetrahedron
Lett. 1999, 40, 7599-7603.
(33) (a) O’Neill, B. T. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, U.K., 1992; Vol. 1, Chapter 1.13,
pp 397-458. For recent examples, see: (b) Bumagin, N. A.; Korolev, D.
N. Tetrahedron Lett. 1999, 40, 3057-3060. (c) Kabalka, G. W.; Malladi,
R. R.; Tejedor, D.; Kelley, S. Tetrahedron Lett. 2000, 41, 999-1001.
(29) Ni(0) catalysts were obtained by reduction of Ni(PPh3)2Cl2 with
DIBALH or n-BuLi in the presence of PPh3 as a ligand, see: (a) Lipshutz,
B. H.; Bulow, G.; Lowe, R. F.; Stevens, K. L. J. Am. Chem. Soc. 1996,
118, 5512-5513. (b) Lipshutz, B. H.; Blomgren, P. A.; Kim, S.-K.
Tetrahedron Lett. 1999, 40, 197-200. (c) Lipshutz, B. H.; Bulow, G.;
Fernandez-Lazaro, F.; Kim, S.-K.; Lowe, R.; Mollard, P.; Stevens, K. L. J.
Am. Chem. Soc. 1999, 121, 11664-11673.

Atom-Efficient Metal-Catalyzed Cross-Coupling Reaction
J. Am. Chem. Soc., Vol. 123, No. 18, 2001 4159
Table 4. Results of the Palladium-Catalyzed Cross-Coupling
Reaction of Triorganoindium Compounds (1a-d) with Benzyl
Bromide (13)a
in terms of the low bond strengths in the triorganoindium
reagents and the large difference between the heats of formation
of indium trialkyls and indium halides.14,36
Nevertheless, an alternative mechanism based on the high
Lewis acid character of the indium reagents could modify the
classical mechanism with the formation of a transient Pd-In
complex as the step prior to the transmetalation.37 Bimetallic
complexes have been proposed by Marshall38 in allenylindium
additions to aldehydes and in cross-coupling reaction of
arylboronic acids.39
entry no.
R
t (h)
product
yield (%)b
1
2
3
4
Ph (1a)
CH2dCH (1b)
PhCtC (1c)
1
1
2.5
2.5
14a
14b
14c
14d
96
94
94
94
TMSCtC (1d)
Conclusions
a Reactions were conducted in THF at reflux using 34 mol % of
R3In and 1 mol % of Pd(dppf)Cl2. b Isolated yield based on the
electrophile added.
In conclusion, we have developed a new and generally high-
yielding metal-catalyzed cross-coupling reaction involving tri-
organoindium compounds. In this novel reaction triorganoin-
dium reagents containing alkyl, vinyl, alkynyl, and aryl groups
transfer, with high atom efficiency, the three organic groups to
aryl, vinyl, benzylic, and acyl electrophiles in the presence of
easily accessible palladium or nickel catalysts. The cross-
coupling reaction proceeds in short reaction times and low
catalyst loading with excellent yields and with high chemose-
lectivity, to provide an interesting range of compounds. These
novel features make indium organometallics useful alternatives
to other organometallics used in cross-coupling reactions and
also mark them out as promising reagents for organic synthesis.
Table 5. Results of the Palladium-Catalyzed Cross-Coupling
Reaction of Triorganoindium Compounds (1) with Acid Chorides 15
and 16a
entry no.
R
electrophile t (h) product yield (%)b
1
2
3
4
5
6
Ph (1a)
15
2
1
18
1
2
3
17a
17c
17f
18a
18c
18d
89
94
97
87
90
90
PhCtC (1c)
Me (1f)
Ph (1a)
16
Experimental Section
PhCtC (1c)
TMSCtC (1d)
General Methods. All reactions were conducted in flame-dried
glassware under a positive pressure of argon. Reaction temperatures
refer to external bath temperatures. All dry solvents were distilled under
argon immediately prior to use. Tetrahydrofuran (THF) and diethyl
ether (Et2O) were dried by distillation from the sodium ketyl of
benzophenone. Liquid reagents or reagent solutions were added by
syringe or cannula. The total volume of solvent is given for these
additions. Usually the compound was dissolved in 80% of the stated
volume, and the flask was then rinsed with the remaining 20% of fresh
solvent. Organic extracts were dried over anhydrous MgSO4, filtered,
and concentrated using a rotary evaporator at aspirator pressure (20-
30 mmHg). Thin-layer chromatography was effected on silica gel 60
F254 (layer thickness 0.2 mm), and components were located by
observation under UV light or by treating the plates with a phospho-
molybdic acid or p-anisaldehyde reagent followed by heating. Flash
chromatography was performed on silica gel 60 (230-400 mesh) by
Still’s method.40
a Reactions were conducted in THF at reflux using 34 mol % of
R3In and 1 mol % of Pd(PPh3)4. b Isolated yield based on the
electrophile added.
pounds led us to explore their reactivity with acid chlorides (15
and 16, Table 5) under palladium catalyst. Ketones were
obtained in good yields (87-97%) using Pd(PPh3)4 (1 mol %)
as catalyst and a ratio of acid chloride/R3In of 3:1. The results
are summarized in Table 4, showing that all types of carbon
groups can be accommodated. In these reactions, the tertiary
alcohol resulting from double addition was not detected, and
in the reaction with the R,â-unsaturated acid chloride 16, we
observed that the reaction is highly regioselective since the
competitive conjugate addition was not observed (entries 4-6).
Mechanistic Insights. The mechanism for the palladium-
catalyzed cross-coupling reaction of triorganoindium reagents
with organic electrophiles can be explained in terms of the
generally accepted mechanism for this type of reaction.34 In
accordance with our results, the rate-limiting step should be the
oxidative addition. In this mechanism we must accept that both
R2InX and RInX2 are leaving species in a catalytic cycle and
both can re-enter in a new catalytic cycle and effectively transfer
their organic groups. We tested this possibility by preparing
n-Bu2InCl and n-BuInCl2 and using them in the palladium-
catalyzed cross-coupling reaction with aryl triflate 4.20,35 The
cross-coupling product 6e was obtained in satisfactory yields
(60-70%). The reason that indium is so efficient in the rapid
transfer of the three organic groups attached can be explained
(35) R2InCl and RInCl2 can be prepared by addition of RLi (2 equiv or
1 equiv, respectively) to InCl3, and stirring at room temperature. For
experimental details, see: (a) Beachley, O. T., Jr.; Rusinko, R. N. Inorg.
Chem. 1979, 18, 1966-1968. (b) Schumann, H.; Hartmann, U.; Wasser-
mann, W. Polyhedron 1990, 9, 353-360. (c) Crittendon, R. C.; Beck, B.
C.; Su, J.; Li, X.-W.; Robinson, G. H. Organometallics 1999, 18, 156-
160.
(36) (a) Pilcher, G.; Skinner, H. A. In The Chemistry of the Metal-
Carbon Bond; Hartley, F. R., Patai, S., Eds.; Wiley: Chichester, U.K., 1982;
Vol. 1; Chapter 2; p 68. (b) O’Neill, M. E.; Wade, K. In ComprehensiVe
Organometallic Chemistry; Wilkinson, G., Stone, F. G. A., Abel, E. W.,
Eds.; Pergamon: Oxford, U.K., 1982; Vol. 1, Chapter 1, p 8.
(37) Bimetallic complexes of metals of groups 10 and 13 are already
known: Fischer, R. A.; Weiss, J. Angew. Chem., Int. Ed. 1999, 38, 2831-
2850, and references therein.
(38) (a) Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 696-
697. (b) Marshall, J. A. Chem ReV. 2000, 100, 3163-3185. (c) See also:
Araki, S.; Kamei, T.; Hirashita, T.; Yamamura, H.; Kawai, M. Org. Lett.
2000, 2, 847-849.
(39) (a) Moreno-Man˜as, M.; Pe´rez, M.; Pleixats, R. J. Org. Chem. 1996,
61, 2346-2351. (b) Aramend´ıa, M. A.; Lafont, F.; Moreno-Man˜as, M.;
Pleixats, R.; Roglans, A. J. Org. Chem. 1999, 64, 3592-3594.
(40) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-
2925.
(34) (a) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-
3040. (b) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585-
9595. (c) Farina, V.; Krishnan, B.; Marshall, D. R.; Roth, G. P. J. Org.
Chem. 1993, 58, 5434-5444. (d) Farina, V. In ComprehensiVe Organo-
metallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Oxford, U.K., 1995; Vol. 12, Chapter 3.4, pp 161-340. (e)
Casado, A. L.; Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978-8985. (f)
Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314-321.

4160 J. Am. Chem. Soc., Vol. 123, No. 18, 2001
Pe´rez et al.
Phenyllithium, n-butyllithium, methyllithium, (trimethylsilylmethyl)-
magnesium chloride, vinylmagnesium bromide, and DIBALH were
purchased from Aldrich and used after titration by known procedures.41
(2-Phenyl)ethynyllithium and 2-(trimethylsilyl)ethynyllithium were
prepared from phenylacetylene and trimethylsilylacetylene by treatment
with n-BuLi at -78 °C and warming to room temperature. These
compounds were used immediately for the preparation of the corre-
sponding triorganoindium compound. Cyclopropyllithium was prepared
from cyclopropyl bromide by a halogen-metal exchange reaction with
t-BuLi at -78 °C. The reaction mixture was warmed to room
temperature and used immediately for the preparation of the tricyclo-
propylindium.
General Procedure for the Preparation of Indium Organome-
tallics. A 25 mL round-bottomed flask furnished with a stirrer bar was
charged with InCl3 (0.37 mmol) and dried under vacuum with a heat
gun. The mixture was cooled, a positive argon pressure was established,
and dry THF (4 mL) was added. The resulting solution was cooled to
-78 °C, and a solution of RLi or RMgBr (1.1 mmol, 1.0-1.8 M in
hexanes, THF, or Et2O) was slowly added (15-30 min). The mixture
was stirred for 30 min, the cooling bath was removed, and the reaction
mixture was warmed to room temperature.
General Procedure for the Palladium-Catalyzed Cross-Coupling
Reaction. A solution of R3In (0.34 mmol, ∼0.1 M in dry THF) was
added to a refluxing mixture of the electrophile (1 mmol) and Pd catalyst
(0.01 mmol) in dry THF (4 mL). The resulting mixture was refluxed
under argon until the starting material had been consumed (TLC or
GC), and the reaction was then quenched by the addition of few drops
of MeOH. The mixture was concentrated in vacuo and Et2O (30 mL)
was added. The organic phase was washed with aqueous HCl (5%, 10
mL), saturated aqueous NaHCO3 (15 mL), and saturated aqueous NaCl
(15 mL), dried, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography to afford, after concentration and high-
vacuum-drying, the cross-coupling product.
General Procedure for the Nickel-Catalyzed Cross-Coupling
Reaction of Aryl Chlorides. To a solution of Ni(PPh3)2Cl2 (0.05 mmol)
and PPh3 (0.10 mmol) in dry THF (5 mL) was added slowly a solution
of n-BuLi in hexanes (55 µL, 0.08 mmol, 1.5 M) [or DIBALH in
toluene (55 µL, 0.08 mmol, 1.5 M)] at room temperature. After 10
min, 4-chlorotoluene (1.00 mmol) was added, the resulting mixture
was refluxed and a solution of R3In (0.40 mmol, ∼0.1 M in dry THF)
was added. The mixture was refluxed, until the starting material had
been consumed (TLC or GC). The reaction was quenched by the
addition of few drops of MeOH. The mixture was concentrated in vacuo,
and Et2O (30 mL) was added. The organic phase was washed with
aqueous HCl (5%, 10 mL), saturated aqueous NaHCO3 (15 mL), and
saturated aqueous NaCl (15 mL), dried, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography to afford,
after concentration and high-vacuum-drying, the cross-coupling product.
Acknowledgment. We are grateful to the Xunta de Galicia
(XUGA 10305A98) and University of A Corun˜a for financial
support. I.P. acknowledges a predoctoral fellowship from the
Xunta de Galicia. We also thank Professor Dolores Pe´rez
(Universidade de Santiago de Compostela, Spain) for critical
reading of the manuscript.
Supporting Information Available: Relevant spectral data
for compounds prepared (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
(41) Brown, H. C. Organic Synthesis Via Boranes; Wiley: New York,
1975; pp 248-249.
JA004195M