Palladium-catalyzed cross-coupling of indium homoenolate with aryl halide with wide functional group compatibility

Article abstract of DOI:10.1021/ol102755q

An efficient palladium-catalyzed cross-coupling of indium homoenolate with aryl halide is described. The reactions proceeded efficiently in DMA at 100 °C to afford the desired products of β-aryl ketones in moderate to good yields. Various important functi

Full text of DOI:10.1021/ol102755q

ORGANIC
LETTERS
2011
Vol. 13, No. 3
422-425
Palladium-Catalyzed Cross-Coupling of
Indium Homoenolate with Aryl Halide
with Wide Functional Group
Compatibility
Zhi-Liang Shen, Yin-Chang Lai, Colin Hong An Wong, Kelvin Kau Kiat Goh,
Yong-Sheng Yang, Hao-Lun Cheong, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371
teckpeng@ntu.edu.sg
Received November 13, 2010
ABSTRACT
An efficient palladium-catalyzed cross-coupling of indium homoenolate with aryl halide is described. The reactions proceeded efficiently in
DMA at 100 °C to afford the desired products of ꢀ-aryl ketones in moderate to good yields. Various important functional groups including
COR, COOR, CHO, CN, OH, and NO2 can be well tolerated in the protocol.
Transition-metal-catalyzed cross-coupling of organometallic
reagents with various electrophiles constitutes one of the most
important methods for the construction of the C-C bond.1
Among the various organometallic reagents developed,
organoindium reagents, because of their wide compatibility
with various functional groups such as hydroxyl, carbonyl,
and even water,2-8 have emerged as an important alternative
to other reactive organometallic species such as organomag-
nesium and organozinc reagents. The first cross-coupling of
an organoindium reagent with an aryl halide was pioneered
by Sarandeses employing a triorganoindium reagent (R3In,
prepared via transmetalation of RLi or RMgX with InCl3)
in THF.9,10 Recently, Knochel,2,3 Minehan,4 Chupak,5 and
Yamamoto6 have reported efficient methods for the direct
syntheses of benzyl and/or aryl indium reagents from
organohalides and their applications in palladium-catalyzed
cross-coupling with aryl halides.
More recently, our group8 has reported an efficient method
for the synthesis of water-tolerant, ketone-type indium
homoenolate11-13 via oxidative addition of an indium(I)
reagent to enone in aqueous media, and the synthetic utility
of the indium homoenolate was demonstrated by the
synthesis of a 1,4-dicarbonyl compound via palladium-
catalyzed coupling with acid chloride in THF. In continuation
of our further efforts in developing the synthetic utility of
the indium homoenolate in organic synthesis, we aimed at
achieving the transition-metal-catalyzed cross-coupling of the
(1) Knochel, P. Handbook of Functionalized Organometallics; Wiley-
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(9) For pioneering works relating to the use of a triorganoindium reagent
(R3In) in palladium-catalyzed coupling reactions by Sarandeses et al., see:
(a) Perez, I.; Perez Sestelo, J.; Sarandeses, L. A. J. Am. Chem. Soc. 2001,
123, 4155. (b) Perez, I.; Perez Sestelo, J.; Sarandeses, L. A. Org. Lett. 1999,
.
.
1, 1267.
10.1021/ol102755q  2011 American Chemical Society
Published on Web 12/23/2010

indium homoenolate with an aryl halide. However, owing
to the low reactivity of the indium homoenolate, our attempt
to carry out the palladium-catalyzed coupling of the indium
homoenolate with an aryl halide in THF failed. The reaction
Table 1. Screening of Organic Solventsa
(10) For other selected examples concerning the palladium-catalyzed
coupling of R3In or other types of organoindium reagents with various
electrophiles (such as aryl halide, acid chloride, benzyl halides, alkenyl
halides), see: (a) Caeiro, J.; Sestelo, J. P.; Sarandeses, L. A. Chem.sEur.
J. 2008, 14, 741. (b) Pena, M. A.; Perez, I.; Perez Sestelo, J.; Sarandeses,
L. A. Chem. Commun. 2002, 2246. (c) Nomura, R.; Miyazaki, S.-I.;
Matsuda, H. J. Am. Chem. Soc. 1992, 114, 2738. (d) Lee, P. H.; Sung, S.;
Lee, K. Org. Lett. 2001, 3, 3201. (e) Pena, M. A.; Perez Sestelo, J.;
Sarandeses, L. A. Synthesis 2003, 780. (f) Gotov, B.; Kaufmann, J.;
Schumann, H.; Schmalz, H. G. Synlett 2002, 361. (g) Jaber, N.; Gelman,
D.; Schumann, H.; Dechert, S.; Blum, J. Eur. J. Org. Chem. 2002, 1628.
(h) Lee, K.; Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67, 8265. (i) Lee, K.;
Seomoon, D.; Lee, P. H. Angew. Chem., Int. Ed. 2002, 41, 3901. (j) Takami,
K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2002, 4, 2993. (k) Lee, P. H.;
Lee, S. W.; Lee, K. Org. Lett. 2003, 5, 1103. (l) Takami, K.; Mikami, S.;
Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Org. Chem. 2003, 68, 6627.
(m) Lee, P. H.; Lee, S. W.; Seomoon, D. Org. Lett. 2003, 5, 4963. (n)
Pena, M. A.; Perez Sestelo, J.; Sarandeses, L. A. Synthesis 2005, 485. (o)
Pena, M. A.; Perez Sestelo, J.; Sarandeses, L. A. J. Org. Chem. 2007, 72,
1271. (p) Font-Sanchis, E.; Cespedes-Guirao, F. J.; Sastre-Santos, A.;
Fernandez-Lazaro, F. J. Org. Chem. 2007, 72, 3589. (q) Riveiros, R.; Saya,
L.; Perez Sestelo, J.; Sarandeses, L. A. Eur. J. Org. Chem. 2008, 1959. (r)
Zhao, Y.; Jin, L.; Li, P.; Lei, A. J. Am. Chem. Soc. 2008, 130, 9429. (s)
Jin, L.; Zhao, Y.; Zhu, L.; Zhang, H.; Lei, A. AdV. Synth. Catal. 2009,
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entry
solvent
THFc
1,4-dioxane
toluene
n-PrOHc
CH3NO2
H2O
yield (%)b
1
2
3
4
5
6
7
8
9
<5
<5
<5
<5
0
<10
85
87
78
93
NMP
DMSO
DMF
10
DMA
a Unless otherwise noted, the reactions were carried out at 100 °C for
24 h using indium homoenolate 1a (0.3 mmol), aryl iodide 2a (0.5 mmol),
PdCl2(PPh3)2 (0.025 mmol), LiCl (1 mmol), and solvent (3 mL). b Isolated
yield based on aryl iodide 2a as limiting reagent. c Under refluxing
conditions.
(11) For reviews concerning homoenolate chemistry, see: (a) Werstiuk,
N. H. Tetrahedron 1983, 39, 205. (b) Hoppe, D.; Hense, T. Angew. Chem.,
Int. Ed. 1997, 36, 2282. (c) Hoppe, D.; Marr, F.; Bruggemann, M. Top.
Organomet. Chem. 2003, 5, 61. (d) Kuwajima, I.; Nakamura, E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Vol. 2, p 441 and references cited therein. (e)
Kuwajima, I.; Nakamura, E. In Topics in Current Chemistry; Springer:
Berlin, 1990; Vol. 155, p 3.
proceeded sluggishly under the above conditions to furnish
the desired product in <5% yield. In order to circumvent
the problem, a more comprehensive study was carried out.
Herein, we report an efficient palladium-catalyzed cross-
coupling of the indium homoenolate with various aryl halides
in DMA. The reactions proceeded efficiently at 100 °C to
afford the desired products of ꢀ-aryl ketones in moderate to
good yields with wide functionality compatibility.14
Initially, various organic solvents were screened in order
to optimize the reaction conditions for the palladium-
catalyzed coupling of indium homoenolate 1a with 4-io-
doacetophenone (2a). As shown in Table 1, the coupling
reaction utilizing PdCl2(PPh3)2 (5 mol %) as a catalyst
(12) For selected examples associated with the synthesis and application
of metal homoenolates in organic synthesis by Kuwajima, Nakamura,
Yoshida, Knochel, and others, see: (a) Nakamura, E.; Kuwajima, I. J. Am.
Chem. Soc. 1977, 99, 7360. (b) Nakamura, E.; Kuwajima, I. J. Am. Chem.
Soc. 1984, 106, 3368. (c) Nakamura, E.; Shimada, J.-i.; Kuwajima, I.
Organometallics 1985, 4, 641. (d) Oshino, H.; Nakamura, E.; Kuwajima,
I. J. Org. Chem. 1985, 50, 2802. (e) Nakamura, E.; Oshino, H.; Kuwajima,
I. J. Am. Chem. Soc. 1986, 108, 3745. (f) Nakamura, E.; Kuwajima, I. J. Am.
Chem. Soc. 1985, 107, 2138. (g) Horiguehi, Y.; Nakamura, E.; Kuwajima,
I. J. Org. Chem. 1986, 51, 4323. (h) Nakamura, E.; Kuwajima, I. J. Am.
Chem. Soc. 1983, 105, 651. (i) Tamaru, Y.; Ochiai, H.; Nakamura, T.;
Yoshida, Z. Angew. Chem., Int. Ed. Engl. 1987, 26, 1157. (j) Tamaru, Y.;
Ochiai, H.; Nakamura, T.; Tsubaki, K.; Yoshida, Z. Tetrahedron Lett. 1985,
26, 5559. (k) Ochiai, H.; Tamaru, Y.; Tsubaki, K.; Yoshida, Z. J. Org.
Chem. 1987, 52, 4418. (l) Sidduri, A.; Rozema, M. J.; Knochel, P. J. Org.
Chem. 1993, 58, 2694. (m) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
(n) Goswami, R. J. Org. Chem. 1985, 50, 5907. (o) Cozzi, P. G.; Carofiglio,
T.; Floriani, C. Organometallics 1993, 12, 2845. For the cross-coupling
reactions of zinc homoenolates with aryl halides, see: (p) Nakamura, E.;
Aoki, S.; Sekiya, K.; Oshino, H.; Kuwajima, I. J. Am. Chem. Soc. 1987,
109, 8056. (q) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z.
Tetrahedron Lett. 1986, 27, 955.
Table 2. Screening of Palladium Catalystsa
(13) For reviews regarding the generation of homoenolate intermediates
with the use of nucleophilic heterocyclic carbene (NHC) catalysis, see: (a)
Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. ReV. 2008, 37, 2691. For
recent examples, see: (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am.
Chem. Soc. 2004, 126, 14370. (c) Burstein, C.; Glorius, F. Angew. Chem.,
Int. Ed. 2004, 43, 6205. (d) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131.
(e) Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett.
2006, 8, 507. (f) Nair, V.; Poonoth, M.; Vellalath, S.; Suresh, E.; Thirumalai,
R. J. Org. Chem. 2006, 71, 8964. (g) Nair, V.; Vellalath, S.; Poonoth, M.;
Suresh, E. J. Am. Chem. Soc. 2006, 128, 8736. (h) Phillips, E. M.;
Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
3107. (i) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc.
2007, 129, 3520. (j) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.;
Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098. (k) He, M.; Bode,
J. W. J. Am. Chem. Soc. 2008, 130, 418. (l) Nair, V.; Babu, B. P.; Vellalath,
S.; Suresh, E. Chem. Commun. 2008, 747. (m) Chan, A.; Scheidt, K. A.
J. Am. Chem. Soc. 2007, 129, 5334. (n) Phillips, E. M.; Reynolds, T. E.;
Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2416. (o) Chan, A.; Scheidt,
K. A. J. Am. Chem. Soc. 2008, 130, 2740. (p) Sohn, S. S.; Bode, J. W.
Org. Lett. 2005, 7, 3873. (q) He, M.; Struble, J. R.; Bode, J. W. J. Am.
Chem. Soc. 2006, 128, 8418.
entry
catalyst
yield (%)b
1
2
3
4
5
6
PdCl2(PPh3)2 (5 mol %)
Pd(OAc)2 (5 mol %), Me-Phos (10 mol %)
Pd(dppf)Cl2 (5 mol %)
Pd2(dba)3 (2.5 mol %), PPh3 (10 mol %)
Pd(PhCN)2Cl2 (5 mol %), PPh3 (10 mol %)
Pd(PPh3)4 (5 mol %)
93
73
76
70
76
81
a Unless otherwise noted, the reactions were carried out at 100 °C for
24 h using indium homoenolate 1a (0.3 mmol), aryl iodide 2a (0.5 mmol),
Pd cat. (0.025 mmol), phosphine ligand (0.05 mmol), LiCl (1 mmol), and
DMA (3 mL). b Isolated yield based on aryl iodide 2a as limiting reagent.
Org. Lett., Vol. 13, No. 3, 2011
423

DMA was employed as the reaction solvent, affording the
desired product 3a in 93% yield (Table 1, entry 10).
Next, various palladium catalysts were employed to
investigate their efficiency in the cross-coupling reactions.
As shown in Table 2, all the palladium catalysts screened in
the reactions could efficiently catalyze the cross-coupling to
furnish the desired product 3a in good to excellent yields.
Among them, the use of PdCl2(PPh3)2 (5 mol %) as the
catalyst afforded the product 3a with an excellent yield of
93% (Table 2, entry 1). Thus, the following cross-coupling
reactions were chosen to be carried out at 100 °C for 24 h
using PdCl2(PPh3)2 as the catalyst, LiCl as an additive, and
DMA as the solvent.
Table 3. Substrate Scope Studya
With the optimized reaction conditions in hand, we
continued our task on the exploration of the reaction substrate
scope. As shown in Table 3, the cross-coupling of indium
homoenolate with various aryl halides proceeded efficiently
under optimized conditions to furnish the ꢀ-aryl ketones in
moderate to good yields. A range of important functional
groups which were sensitive to organomagnesium and/or
organozinc reagents can be well tolerated in the cross-
coupling reactions. For instance, functional groups including
COR, NO2, CN, COOR, and CHO were compatible to the
reaction conditions. Especially noteworthy, the reactions
using substrates 2e and 2k bearing a free hydroxyl group
occurred smoothly without any protection, generating the
cross-coupling products 3e and 3k in acceptable yields of
62 and 60%, respectively (Table 3, entries 5 and 11). In
addition, heterocyclic halides such as 2g, 2h, and 2l can be
employed in the reactions as well (Table 3, entries 7, 8, and
12). Furthermore, less reactive aryl chloride 2n was also
proven as a good candidate for the coupling reaction leading
to the expected product 3j in 60% yield (Table 3, entry 14).
Next, we turned our attention to the cross-coupling of aryl
iodide 2a with a range of indium homoenolates. As shown
in Table 4, both aliphatic substituted indium homoenolates
(entries 1 and 2) and aromatic substituted indium homoeno-
Table 4. Substrate Scope Studya
a The reactions were carried out at 100 °C for 24 h using indium
homoenolate 1a (0.3 mmol), ArX 2 (0.5 mmol), PdCl2(PPh3)2 (0.025 mmol),
LiCl (1 mmol), and DMA (3 mL). b Isolated yield based on ArX 2 as limiting
reagent.
entry
R
R’
product 3
yield (%)b
1
2
3
4
5
6
Et
H
H
H
H
H
Me
3a
3m
3n
3o
3p
3q
93
77
82
85
70
69
n-pentyl
Ph
4-ClC6H4
2-thienyl
Ph
proceeded sluggishly in commonly used organic solvents
such as THF, 1,4-dioxane, toluene, n-propanol, nitromethane,
and water (Table 1, entries 1-6). In sharp contrast, the cross-
coupling was dramatically enhanced by employing polar
organic solvent such as NMP, DMSO, DMF, and DMA
(Table 1, entries 7-10). Optimal results were obtained when
a The reactions were carried out at 100 °C for 24 h using indium
homoenolate 1 (0.3 mmol), ArI 2a (0.5 mmol), PdCl2(PPh3)2 (0.025 mmol),
LiCl (1 mmol), and DMA (3 mL). b Isolated yield based on ArI 2a as
limiting reagent.
424
Org. Lett., Vol. 13, No. 3, 2011

lates (entries 3-5) worked well in our protocol, leading to
good isolated yields of the corresponding products. Ad-
ditionally, an indium homoenolate possessing a methyl group
at R-position to the carbonyl group also can be effectively
converted to give the desired product 3q in 69% yield (Table
4, entry 6).
COOR, CHO, CN, OH, and NO2 can be well tolerated in
the protocol which renders the method synthetically useful
in organic synthesis. Further studies pertaining to the
synthetic utility of the indium homoenolate in organic
synthesis are currently underway.
Acknowledgment. We gratefully acknowledge Nanyang
Technological University (NTU), Ministry of Education (No.
M45110000), and an A*STAR SERC grant (No. 0721010024)
for the funding of this research.
In summary, an efficient palladium-catalyzed cross-
coupling of indium homoenolates with various aryl halides
in DMA was described. The reactions proceeded efficiently
to afford the desired products of ꢀ-aryl ketones in moderate
to good yields. Various functional groups including COR,
Supporting Information Available: Experimental pro-
cedures, characterization data of products, and copies of 1H
and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) For selected recent examples associated with the development of
transition-metal-catalyzed cross-coupling reactions with wide functional
group compatibility, see: (a) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am.
Chem. Soc. 2010, 132, 920. (b) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H.
J. Am. Chem. Soc. 2009, 131, 15592.
OL102755Q
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