Direct synthesis of ester-containing indium homoenolate and its application in palladium-catalyzed cross-coupling with aryl halide

Article abstract of DOI:10.1039/c0cc05597b

An efficient method for the synthesis of ester-containing indium homoenolate via a direct insertion of indium into β-halo ester in the presence of CuI/LiCl was described. The synthetic utility of the indium homoenolate was demonstrated by palladium-cataly

Full text of DOI:10.1039/c0cc05597b

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COMMUNICATION
Direct synthesis of ester-containing indium homoenolate and its
application in palladium-catalyzed cross-coupling with aryl halidew
Zhi-Liang Shen, Kelvin Kau Kiat Goh, Colin Hong An Wong, Yong-Sheng Yang,
Yin-Chang Lai, Hao-Lun Cheong and Teck-Peng Loh*
Received 15th December 2010, Accepted 22nd February 2011
DOI: 10.1039/c0cc05597b
An efficient method for the synthesis of ester-containing indium
homoenolate via a direct insertion of indium into b-halo ester in
the presence of CuI/LiCl was described. The synthetic utility of
the indium homoenolate was demonstrated by palladium-
catalyzed cross-coupling with aryl halides in DMA with wide
functional group compatibility.
such as formyl and hydroxyl groups.6–8 We envisaged that if
the ester-containing indium homoenolate can be successfully
prepared, it will allow the transition metal-catalyzed cross-
coupling with aryl halide to take place with wide functional
group tolerance. In continuation of our efforts in exploring
facile methods for the synthesis of indium homoenolate as well
as its application in organic synthesis, herein we report an
efficient method for the synthesis of ester-containing indium
homoenolate via a direct insertion of indium into b-halo ester
in the presence of CuI/LiCl. The synthetic utility of the
ester-containing indium homoenolate was demonstrated
through the synthesis of b-aryl ester9 via a palladium-catalyzed
cross-coupling10,11 with aryl halide in DMA with wide
functional group compatibility.
Homoenolate1 is useful synthon for organic synthesis as it
readily allows the nucleophilic functionalization of organic
molecules with a carbonyl-containing three-carbon moiety.
The first efficient method for the preparation of synthetically
useful metal homoenolate was reported by Kuwajima and
Nakamura via siloxycyclopropane ring-opening with various
metal halides.2 Later on, Yoshida et al. described an alternative
method for the synthesis of zinc homoenolate via a direct
insertion of zinc to b-iodo ester.3 In addition, Knochel and
others also have developed other typical methods for the
preparation of metal homoenolates.4 Recently, it was found
that homoenolate intermediates also can be easily generated
from enals in the presence of a nucleophilic heterocyclic
carbene (NHC) catalysis.5
Initially, commercially available ethyl 3-bromopropionate
(1a) was chosen as a substrate to optimize the reaction
conditions for the synthesis of ester-containing indium
homoenolate 2a via a direct insertion of indium into b-halo
ester. After many trials, it was found that the insertion
proceeded efficiently in the presence of one equiv. of indium,
one equiv. of CuI, and one equiv. of LiCl8a–c in refluxing THF,
affording exclusively the ester-containing indium homoenolate
2a12 in excellent yield (>90%, Scheme 1). Both CuI and LiCl
are indispensable for the efficient transformation of 1a to 2a:
without the use of LiCl, the reaction proceeded sluggishly;
without the use of CuI, mainly two types of organoindium
reagents were generated (see ESIw for details of 1H NMR
comparison of the reaction products obtained under different
conditions). As a result, both CuI and LiCl were employed as
additives for the insertion reaction in order to exclusively
generate a single type of ester-containing indium homoenolate.
Transition metal-catalyzed cross-coupling of organoindium
reagents with various aryl halides has emerged as one
of the most powerful platforms for carbon–carbon bond
formation because of its mild reaction conditions and its
compatibility with a wide variety of functional groups.6–8,10
More recently, our group has described the synthesis of a
ketone-type indium homoenolate via oxidative addition of
indium(I) halide to enone in aqueous media, as well as its
application in the synthesis of 1,4-dicarbonyl compounds via
palladium-catalyzed cross-coupling with acid chloride.6
However, by using this method, our attempt to synthesize
the ester-containing indium homoenolate was unsuccessful
because the a,b-unsaturated ester remained intact under the
aforementioned conditions. On the other hand, to the best
of our knowledge, currently there is no report available
associated with the preparation of the ester-containing indium
homoenolate. Therefore, it is still desirable to develop an
efficient method for the synthesis of the synthetically useful
ester-containing indium homoenolate. Recent development
in organoindium chemistry has indicated that organoindium
reagents show great tolerance to important functional groups
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371. E-mail: teckpeng@ntu.edu.sg; Fax: +65-67911961
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c0cc05597b
Scheme 1 Synthesis of ester-containing indium homoenolate 2a from
ethyl 3-bromopropionate (1a).
c
4778 Chem. Commun., 2011, 47, 4778–4780
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Table 1 Screening of various organic solventsa
Table 2 Screening of various palladium catalystsa
Yieldb (%)
Yieldb (%)
4a0
4a
4a0
Entry
Solvent
T/1C
4a
Entry
Pd cat. (mol%)
T/1C
c
1
2
3
4
5
6
7
8
9
10
THF
65
70
70
70
70
50
70
70
70
70
o10
o10
o10
o10
o10
30
72
48
64
83
—
—
—
—
—
0
1
2
3
4
5
6
7
8
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
Pd(OAc)2–MePhos (5/10)
Pd(dppf)Cl2 (5)
Pd2(dba)3–PPh3 (2.5/10)
Pd(PhCN)2Cl2–PPh3 (5/10)
Pd(PPh3)4 (5)
70
100
70
70
70
70
70
90
83
60
27
18
80
72
45
88
4
13
27
8
3
8
c
c
c
c
1,4-Dioxane
Toluene
n-PrOH
CH3NO2
NMP
NMP
12
9
8
0
0
DMSO
DMF
DMA
Pd(PPh3)4 (5)
a
Unless otherwise noted, the reactions were carried out at 70–100 1C
for 24 h using indium homoenolate 2a (B1.0 mmol, prepared from
1.0 mmol 1a), ArI 3a (0.7 mmol), Pd catalyst (0.05 mmol), phosphine
4
a
Unless otherwise noted, the reactions were carried out at 50–70 1C
for 24 h using indium homoenolate 2a (B1.0 mmol, prepared from
1.0 mmol 1a), ArI 3a (0.7 mmol), PdCl2(PPh3)2 (0.05 mmol), LiCl
b
ligand (0.1 mmol), LiCl (1.0 mmol), and DMA (3 mL). See footnote
b in Table 1.
b
(1.0 mmol), and solvent (3 mL). A combined isolated yield of 4a and
4a0, based on ArI 3a as limiting reagent, was obtained due to
non-separation of the mixture. The exact yields of 4a and 4a0 listed
was determined by 1H NMR analysis of the isolated mixture of 4a and
Table 3 Substrate scope studya,b
c
4a0 after silica gel column chromatography purification. Not
determined.
Thus, the cross-coupling of the ester-containing indium homo-
enolate 2a with aryl halide was subsequently investigated.
Normally, the cross-coupling of organoindium reagent with
aryl halide was carried out in the presence of a palladium
catalyst in THF. However, our attempt to perform the reaction of
indium homoenolate 2a with 4-iodoacetophenone (3a) in the
presence of PdCl2(PPh3)2 (5 mol%) in refluxing THF failed.
Poor yield (o10%) was obtained under the above reaction
conditions which might be due to the low reactivity of the
indium homoenolate generated in our protocol. Thus, we
embarked on the optimization of the cross-coupling reaction
conditions by screening various organic solvents.
As shown in Table 1, the reactions proceeded sluggishly in
some commonly used organic solvents such as THF,
1,4-dioxane, toluene, n-propanol and nitromethane (Table 1,
entries 1–5). Interestingly, it was observed that the reactions
proceeded well in relatively polar organic solvents such as
DMF, DMSO, NMP and DMA (Table 1, entries 7–10).
Among them, it was gratifying to find that the best yield of
83% was obtained when DMA was employed as reaction
solvent (Table 1, entry 10). However, the formation of a
by-product of 4a0 was also observed in the cross-coupling
reaction which made the isolation of a pure product 4a
difficult, owing to a similar polarity of 4a and 4a0 on silica
gel column chromatography purification. Thus, in order to
eliminate the formation of the undesired by-product 4a0, we
continued to optimize the reaction conditions by surveying
various palladium catalysts.
a
b
See ESIw for detailed reaction conditions. Isolated yield based on
ArX 3 as limiting reagent.
the by-product 4a0 can be completely suppressed, though only
a moderate yield (45%) of the desired product 4a was obtained
(Table 2, entry 7). Encouragingly, a good isolated yield of 4a
(88%) was obtained when the reaction was carried out at an
elevated temperature of 90 1C (Table 2, entry 8), along
with complete suppression of the by-product 4a0. The direct
comparison of PdCl2(PPh3)2 (entry 1) with Pd(PPh3)4
(entries 7–8) shows that an excess of PPh3 is necessary to
stabilize the in situ generated Pd(0) catalysis in the reaction
and thus suppress b-hydride elimination as an unwanted
side-reaction.
As can be seen from Table 2, when the palladium-catalyzed
cross-coupling reaction was performed at 70 1C in DMA, most
of the palladium catalysts examined in the reaction produced
the undesired by-product of 4a0 (Table 2, entries 1, 3–6). Only
with the use of Pd(PPh3)4 (5 mol%) as catalyst, formation of
With the success of the above reactions, we continued to
explore the substrate scope of the reaction by using various
aryl halides with embedded functional groups. As shown in
Table 3, the palladium-catalyzed cross-coupling of the indium
c
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Table 4 Substrate scope study using various carbonyl-containing
organohalidesa,b
Notes and references
1 For reviews concerning homoenolate chemistry, see:
(a) N. H. Werstiuk, Tetrahedron, 1983, 39, 205; (b) D. Hoppe
and T. Hense, Angew. Chem., Int. Ed. Engl., 1997, 36, 2282;
(c) D. Hoppe, F. Marr and M. Bruggemann, Top. Organomet.
Chem., 2003, 5, 61; (d) I. Kuwajima and E. Nakamura, in
Comprehensive Organic Synthesis, ed. B. M. Trost and
I. Fleming, Pergamon, New York, 1991, vol. 2, p. 441;
(e) I. Kuwajima and E. Nakamura, Top. Curr. Chem., 1990,
115, 3.
2 (a) E. Nakamura and I. Kuwajima, J. Am. Chem. Soc., 1977, 99,
7360; (b) E. Nakamura and I. Kuwajima, J. Am. Chem. Soc., 1984,
106, 3368; (c) E. Nakamura, J.-i. Shimada and I. Kuwajima,
Organometallics, 1985, 4, 641; (d) H. Oshino, E. Nakamura and
I. Kuwajima, J. Org. Chem., 1985, 50, 2802; (e) E. Nakamura,
H. Oshino and I. Kuwajima, J. Am. Chem. Soc., 1986, 108, 3745;
(f) E. Nakamura, S. Aoki, K. Sekiya, H. Oshino and I. Kuwajima,
J. Am. Chem. Soc., 1987, 109, 8056; (g) E. Nakamura and
I. Kuwajima, J. Am. Chem. Soc., 1985, 107, 2138;
(h) Y. Horiguehi, E. Nakamura and I. Kuwajima, J. Org. Chem.,
1986, 51, 4323; (i) E. Nakamura and I. Kuwajima, J. Am. Chem.
Soc., 1983, 105, 651.
3 (a) Y. Tamaru, H. Ochiai, T. Nakamura and Z. Yoshida, Angew.
Chem., Int. Ed. Engl., 1987, 26, 1157; (b) Y. Tamaru, H. Ochiai,
T. Nakamura and Z. Yoshida, Tetrahedron Lett., 1986, 27, 955;
(c) Y. Tamaru, H. Ochiai, T. Nakamura, K. Tsubaki and
Z. Yoshida, Tetrahedron Lett., 1985, 26, 5559; (d) H. Ochiai,
Y. Tamaru, K. Tsubaki and Z. Yoshida, J. Org. Chem., 1987,
52, 4418.
4 For other typical methods for the synthesis of metal homoenolates,
see: (a) A. Sidduri, M. J. Rozema and P. Knochel, J. Org. Chem.,
1993, 58, 2694; (b) W. C. Still, J. Am. Chem. Soc., 1978, 100, 1481;
(c) R. Goswami, J. Org. Chem., 1985, 50, 5907.
5 For typical review, see: V. Nair, S. Vellalath and B. P. Babu, Chem.
Soc. Rev., 2008, 37, 2691, and references therein.
6 Z. L. Shen, K. K. K. Goh, H. L. Cheong, C. H. A. Wong,
Y. C. Lai, Y. S. Yang and T. P. Loh, J. Am. Chem. Soc., 2010,
132, 15852.
a
b
See ESIw for detailed reaction conditions. Isolated yield based on
ArI 3a as limiting reagent.
homoenolate 2a with a broad range of aryl halides proceeded
smoothly under the optimized conditions, leading to the target
products of b-aryl esters in moderate to good yields. Various
important functional groups, including ketone, nitro group,
nitrile, ester and formyl group can be well tolerated in the
protocol. In addition, heterocyclic halides containing pyridine
and furan moieties also can be well employed as coupling
partners (substrates 3f, 3g and 3k). Moreover, the aryl chloride
4-chlorobenzaldehyde 3l also underwent the coupling reaction,
albeit in a moderate yield of 46%.
7 K. Takami, H. Yorimitsu, H. Shinokubo, S. Matsubara and
K. Oshima, Org. Lett., 2001, 3, 1997.
8 For recent development of aryl, benzyl and alkyl indium reagents
via direct insertion of indium into organohalides which were
pioneered by Knochel and others, see: (a) Y. H. Chen and
P. Knochel, Angew. Chem., Int. Ed., 2008, 47, 7648;
(b) Y. H. Chen, M. Sun and P. Knochel, Angew. Chem., Int. Ed.,
2009, 48, 2236; (c) V. Papoian and T. Minehan, J. Org. Chem.,
2008, 73, 7376; (d) L. S. Chupak, J. P. Wolkowski and
Y. A. Chantigny, J. Org. Chem., 2009, 74, 1388; (e) N. Fujiwara
and Y. Yamamoto, J. Org. Chem., 1999, 64, 4095; (f) Z. L. Shen,
K. K. K. Goh, Y. S. Yang, Y. C. Lai, C. H. A. Wong,
H. L. Cheong and T. P. Loh, Angew. Chem., Int. Ed., 2011, 50,
511.
In addition, a range of carbonyl-containing organohalides
were employed as substrates in the synthesis of various indium
homoenolates (and their higher homologues) followed by
palladium-mediated cross-coupling with 4-iodoacetophenone
(3a). As shown in Table 4, the cross-coupling of various b-, g-,
d-, e- and z-indium esters with 3a occurred efficiently under
optimal conditions to give the cross-coupled products in
moderate to good yields. In addition, various b-, g-, d-halo
ketones (1h, 1i, 1j, 1k and 1l) can be well converted into their
corresponding organoindium reagents as well, and effectively
underwent the subsequent cross-coupling reactions.
9 For recent example in the synthesis of b-aryl ester, see:
A. Renaudat, L. Jean-Gerard, R. Jazzar, C. E. Kefalidis, E. Clot
´
and O. Baudoin, Angew. Chem., Int. Ed., 2010, 49, 7261, and
references therein.
In summary, a facile method for the synthesis of ester-
containing indium homoenolate via a direct insertion of
indium into b-halo ester in the presence of CuI/LiCl was
described. The synthetic utility of the indium homoenolate
was demonstrated by palladium-catalyzed coupling with aryl
halides in DMA. The cross-coupling reaction proceeded
efficiently with a great tolerance to functional groups such as
formyl and hydroxyl groups which renders the method more
synthetically useful, and will serve as a complement to their
organomagnesium and organozinc counterparts.
10 For pioneering works with the use of R3In in palladium-catalyzed
coupling by Sarandeses and co-workers, see: (a) I. Perez, J. Perez
Sestelo and L. A. Sarandeses, Org. Lett., 1999, 1, 1267; (b) I. Perez,
J. Perez Sestelo and L. A. Sarandeses, J. Am. Chem. Soc., 2001,
123, 4155; also see ref. 6 for other cited works in this area.
11 For selected recent examples of palladium-catalyzed couplings, see:
(a) D. Maiti, B. P. Fors, J. L. Henderson, Y. Nakamura and
S. L. Buchwald, Chem. Sci., 2011, 2, 57; (b) D. S. Surry and
S. L. Buchwald, Chem. Sci., 2011, 2, 27.
12 Currently, we propose the structure of the ester-containing indium
homoenolate 2a as shown in Scheme 1. In addition, chelation of
the carbonyl group to indium was observed (in 13C NMR, the
chemical shift of the carbonyl group moved downfield from 170.5
to 180.4 ppm). Moreover, the coordination of THF to the indium
center was also observed and it might help to stabilize the
generated indium homoenolate by forming a five-coordinated
indium center.
We gratefully acknowledge Nanyang Technological
University (NTU), Ministry of Education (No. M45110000),
and A*STAR SERC Grant (No. 0721010024) for the funding
of this research.
c
4780 Chem. Commun., 2011, 47, 4778–4780
This journal is The Royal Society of Chemistry 2011