Preparation of ethyl 2-aryl 2,3-alkadienoates via palladium-catalyzed selective cross-coupling reactions

Article abstract of DOI:10.1021/jo1020085

Pd-catalyzed cross-coupling reactions of aryl iodides containing not only an electron-donating group but also an electron-withdrawing group on the aryl ring with organoindium reagents generated in situ from indium and ethyl 4-bromo-2-alkynoates produced s

Full text of DOI:10.1021/jo1020085

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SCHEME 1. Synthetic Methods of Alkyl 2,3-Alkadienoates
Having a Substituent at the 2-Position
Preparation of Ethyl 2-Aryl 2,3-Alkadienoates via
Palladium-Catalyzed Selective Cross-Coupling
Reactions
Phil Ho Lee,* Juntae Mo, Dongjin Kang, Dahan Eom,
Chansoo Park, Chang-Hee Lee, Young Mee Jung, and
Hyonseok Hwang
Department of Chemistry, National Research Laboratory
for Catalytic Organic Reactions and Institute for
Molecular Science and Fusion Technology,
Kangwon National University, Chuncheon 200-701,
Republic of Korea
phlee@kangwon.ac.kr
Received October 10, 2010
importance and still a very challenging problem since they
have been utilized in a variety of molecular transformations
such as Michael addition, lactonization, cyclization, and
cycloaddition reactions.3 Although several methods for pre-
paration of 2,3-alkadienoates are known,4 they seem to lack
generality as far as 2-aryl-substituted analogues are con-
cerned. Traditionally, 2,3-alkadienoates were prepared from
reaction of stabilized ylide with derivatives of benzyl bro-
mide followed by treatment of acid chloride in the presence of
triethylamine (Scheme 1, eq 1).5 Unfortunately, this method
cannot be applied to the preparation of alkyl 2-aryl-2,3-
alkadienoates because ylides do not react with aryl halide.
Gillmann reported a silver oxide-assisted Pd-catalyzed cross-
coupling reaction of methyl 2-halo-2,3-butadienoate with
arylboronic acid to produce methyl 2-aryl-2,3-butadienoates
(Scheme 1, eq 2).6 However, not only preparation of ethyl
2-halo-2,3-butadienoate but also introduction of a substitu-
ent on the γ-position is difficult.7 Moreover, the yield of
cross-coupling reaction of methyl 2-halo-2,3-butadienoate
with phenylboronic acid is variable (Br, 0-52%, I,
52-98%).6 Recently, Pd-catalyzed cross-coupling reactions
using organoindium reagents have been described.8 In addi-
tion, we reported Pd-catalyzed cross-coupling reactions
of allylindiums, allenylindiums, 1,3-butadien-2-ylindiums,
tetra(organo)indates, and indium tri(organothiolates) with
Pd-catalyzed cross-coupling reactions of aryl iodides
containing not only an electron-donating group but also
an electron-withdrawing group on the aryl ring with
organoindium reagents generated in situ from indium
and ethyl 4-bromo-2-alkynoates produced selectively
ethyl 2-aryl-2,3-alkadienoates in good yield.
Transition-metal-catalyzed cross-coupling reactions rep-
resent an extremely versatile tool in organic synthesis.1
Cross-coupling reactions leading to C-C bond formation
are often key steps in a wide range of organic processes.2
During the past decades, a variety of organometallic
reagents, such as alkyl-, allyl-, allenyl-, benzyl-, vinyl-,
and arylmetals, have been used as nucleophiles in cross-
coupling reactions.1 Recently, because allenes have been
widely used in organic reactions, development of novel
synthetic methods of allenes has been required.3 In parti-
cular, preparation of 2,3-alkadienoates is of synthetic
(4) (a) Taylor, E. C.; Robey, R. L.; Mc Killop, A. J. Org. Chem. 1972, 37,
2797. (b) Silveira, A., Jr.; Angelastro, M.; Israel, R.; Totino, F.; Williamsen,
P. J. Org. Chem. 1980, 45, 3522. (c) Myrboh, B.; Ila, H.; Junjappa, H.
Synthesis 1982, 1100. (d) Moriarty, R. M.; Vaid, R. K.; Ravikumar, V. T.;
Hopkins, T. E.; Farid, P. Tetrahedron 1989, 45, 1605. (e) Lang, R. W.;
Hansen, H.-J. Helv. Chim. Acta 1980, 63, 438. (f ) Tsuji, J.; Sugiura, T.;
Minami, I. Tetrahedron Lett. 1986, 27, 731. (g) Conrads, M.; Mattay, J.
Synthesis 1991, 11.
(1) (a) Heck, R. F. Palladium Reagents in Organic Synthesis; Academic
Press: New York, 1985. (b) Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(5) Buono, G. Tetrahedron Lett. 1972, 3257.
(6) Gillmann, T.; Weeber, T. Synlett 1994, 649.
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1983. (b) Thomson, R. H. The Chemistry of Natural Products; Blackie and
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Cesario, M.; Guenard, D.; Gueritte, F. J. Org. Chem. 2002, 67, 1199.
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312 J. Org. Chem. 2011, 76, 312–315
Published on Web 12/08/2010
DOI: 10.1021/jo1020085
r
2010 American Chemical Society

Lee et al.
JOCNote
TABLE 1. Optimization of Pd-Catalyzed Cross-Coupling Reactionsa
entry
Met
ligand
16 mol % Ph3P
16 mol % Ph3P
8 mol % Xantphos
8 mol % Xantphos
8 mol % DPEphos
16 mol % (4-CH3OC6H4)3P
16 mol % (4-CH3OC6H4)3P
16 mol % (4-CF3C6H4)3P
16 mol % (4-CF3C6H4)3P
16 mol % (4-CF3C6H4)3P
16 mol % (4-CF3C6H4)3P
16 mol % (4-CF3C6H4)3P
solvent
additive (equiv)
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
In
In
In
In
In
In
In
In
In
In
In
In
In
Mg
Zn
DMF
DMF
DMF
THF
DMF
DMF
THF
DMF
THF
THF
DMF
THF
DMF
THF
THF
LiI (3)
18
18
24
15
15
12
12
3
3
3
5
3
10
0
0
0
0
0
0
0
0
LiC1 (3)
LiI (3)
LiI (3)
LiI (3)
LiI (3)
NaI (1)
LiI (3)
NaI (1)
NaI (1.5)
NaI (1.5)
NaI (1.5)
LiI (3)
56
58
0
79c
0d
0
16 mol % (4-CF3C6H4)3P
16 mol % (4-CF3C6H4)3P
NaI (1.5)
NaI (1.5)
0
aReactions performed with In (1 equiv) and 2a (1.5 equiv). bIsolated yield. cIn (1.5 equiv) and 2a (2.3 equiv) were used. dPd(dppf )Cl2 was used as a
catalyst.
SCHEME 2. Preparation of Ethyl 2-Aryl-2,3-alkadienoates
Our initial study focused on Pd-catalyzed cross-coupling
reactions of ethyl 4-iodobenzoate (1a) with organoindium
reagent11 generated in situ from indium and ethyl 4-bromo-
2-butynoate (2a)12 (Table 1). Reaction of 1a with organoin-
dium did not proceed with 2 mol % of Pd2dba3CHCl3 and a
variety of ligands such as Ph3P, Xantphos,13 DPEphos,14 (4-
CH3OC6H4)3P, and (4-CF3C6H4)3P in the presence of MX
(M = Li and Na, X = Cl and I) as an additive in DMF or
THF (entries 1-8). However, 2 mol % of Pd2dba3CHCl3
and 16 mol % of (4-CF3C6H4)3P in the presence of NaI (1
equiv) afforded selectively ethyl 2-(4-ethoxycarbonylphenyl)-
2,3-butadienoate 3a in 56% yield in THF, indicating
that an electron-poor ligand is better than an electron-
rich ligand (entry 7 vs 9). In addition, comparison of
solvents suggests that THF is critically important for a
successful reaction (entry 11 vs 12). Of the catalytic sys-
tems examined, the best results were obtained with 2 mol %
of Pd2dba3CHCl3 and 16 mol % of (4-CF3C6H4)3P in
the presence of NaI (1.5 equiv) in THF at 70 °C for 3 h,
producing selectively 3a in 79% yield (entry 12). There is
no propargylic cross-coupling product formed. Organo-
indium generated in situ from indium (1.5 equiv) and
2a (2.3 equiv) gave the best result as a coupling partner.
The high selectivity of the present reaction was compared
to Grignard and organozinc reagents. Under the optimum
a variety of electrophiles.9 During the course of our
research program aimed at finding new indium-mediated
organic reactions,10 we envisioned the possibility of ethyl
2,3-alkadien-2-yl cross-coupling reactions by using in-
dium and ethyl 4-bromo-2-alkynoates. Herein, we report
that cross-coupling reaction of a variety of aryl iodides
with organoindium reagents generated in situ from in-
dium and ethyl 4-bromo-2-alkynoate produced ethyl
2-aryl-2,3-alkadienoates with complete regioselectivity
and chemoselectivity (Scheme 2).
(9) (a) Lee, P. H.; Sung, S.-Y.; Lee, K. Org. Lett. 2001, 3, 3201. (b) Lee, K.;
Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67, 8265. (c) Lee, K.; Seomoon, D.;
Lee, P. H. Angew. Chem., Int. Ed. 2002, 41, 3901. (d) Lee, P. H.; Lee, S. W.;
Seomoon, D. Org. Lett. 2003, 5, 4963. (e) Lee, J.-Y.; Lee, P. H. J. Org. Chem.
2008, 73, 7413. (f ) Kim, S.; Seomoon, D.; Lee, P. H. Chem. Commun. 2009,
1873. (g) Lee, P. H.; Lee, S. W.; Lee, K. Org. Lett. 2003, 5, 1103. (h) Lee,
S. W.; Lee, K.; Seomoon, D.; Kim, S.; Kim, H.; Kim, H.; Shim, E.; Lee, M.;
Lee, S.; Kim, M.; Lee, P. H. J. Org. Chem. 2004, 69, 4852. (i) Lee, P. H.;
Seomoon, D.; Lee, K.; Kim, S.; Kim, H.; Kim, H.; Shim, E.; Lee, M.; Lee, S.;
Kim, M.; Sridhar, M. Adv. Synth. Catal. 2004, 346, 1641. (j) Lee, P. H.; Kim,
S.; Lee, K.; Seomoon, D.; Kim, H.; Lee, S.; Kim, M.; Han, M.; Noh, K.;
Livinghouse, T. Org. Lett. 2004, 6, 4825. (k) Lee, P. H.; Seomoon, D.; Lee, K.
Org. Lett. 2005, 7, 343. (l) Lee, P. H.; Lee, K. Angew. Chem. Int. Ed. 2005, 44,
3253. (m) Lee, P. H.; Lee, K.; Kang, Y. J. Am. Chem. Soc. 2006, 128, 139.
(n) Seomoon, D.; Lee, K.; Kim, H.; Lee, P. H. Chem. Eur. J. 2007, 13, 5197.
(o) Lee, P. H.; Sung, S.-Y.; Lee, K.; Chang, S. Synlett 2002, 146.
(12) (a) Crimmins, M. T.; Nantermet, P. G. J. Org. Chem. 1990, 55, 4235.
(b) Crimmins, M. T.; Nantermet, P. G.; Trotter, B. W.; Vallin, I. M.; Watson,
P. S.; McKerlie, L .A.; Reinhold, T. L.; Cheung, A. W. J. Org. Chem. 1993,
58, 1038. (c) Jordan, R. W.; Villeneuve, K.; Tam, W. J. Org. Chem. 2006, 71,
5830. (d) Trost, B. M.; Ball, Z. T.; Joge, T. J. Am. Chem. Soc. 2002, 124, 7922.
(e) Oh, C. H.; Park, S. J.; Ryu, J. H.; Gupta, A. K. Tetrahedron Lett. 2004, 45,
7039. (f ) MacInnes, I.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1987,
1077. (g) Lowe, J. T.; Youngsaye, W.; Panek, J. S. J. Org. Chem. 2006, 71,
3639. (h) Cai, G.; Zhu, W.; Ma, Dawei. Tetrahedron 2006, 62, 5697. (i) Cable,
J. R.; Tramontano, A.; Midland, M. M. J. Org. Chem. 1980, 45, 28. (j) Rao,
K. S.; Mullanti, K.; Reddy, S.; Pal, M.; Iqbal, J. Tetrahedron Lett. 2005, 46,
2287.
(10) (a) Kim, H.; Lee, K.; Kim, S.; Lee, P. H. Chem. Commun. 2010, 46,
6341. (b) Mo, J.; Kim, S. H.; Lee, P. H. Org. Lett. 2010, 12, 424. (c) Kang, D.;
Eom, D.; Kim, H.; Lee, P. H. Eur. J. Org. Chem. 2010, 2330. (d) Lee, K.; Lee,
P. H. Tetrahedron Lett. 2008, 49, 4302. (e) Lee, W.; Kang, Y.; Lee, P. H.
J. Org. Chem. 2008, 73, 4326. (f ) Seomoon, D.; Lee, P. H. J. Org. Chem. 2008,
73, 1165.
(11) 1H NMR (400 MHz, DMF-d7, 25 °C) spectrum of organoindium
reagents showed two signals (δ 4.01 and 3.88) for the methylene group,
indicating that two types of propargylindium reagents (ratio = 2.62:1 for
30 min, 2.40:1 for 45 min and 1.86:1 for 60 min) were produced and the
corresponding allenylindium reagent was not formed.
(13) Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
(14) DPEphos: bis(2-diphenylphosphinophenyl)ether.
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TABLE 2. Preparation of Ethyl 2-Aryl-2,3-alkadienoates via Pd-Catalyzed Cross-Coupling Reactions with Organoindiuma
aReactions performed with 2 mol % of Pd2dba3CHCl3 and 16 mol % of (4-CF3C6H4)3P in the presence of NaI (3 equiv) in refluxing THF.
Organoindium was obtained from In (1.5 equiv) and 2 (2.3 equiv). bIsolated yields. cOrganoindium (2 equiv) was used. d2a (4.5 equiv), In (3 equiv), and
NaI (3 equiv) were used. eKBr (1.5 equiv) was used instead of NaI.
reaction conditions, reaction of 1a with 2a (1.8 equiv) and
Mg (1.5 equiv) or Zn (1.5 equiv) in refluxing THF did not
proceed (entries 14 and 15). Aromatic bromides and
chlorides did not react with organoindium reagent.
To demonstrate the efficiency and scope of the present
method, we applied this catalytic system to reactions of a
variety of aryl iodides with organoindium reagent generated in
situ from indium and ethyl 4-bromo-2-alkynoates (Table 2).
Reaction of iodobenzene (1b) with 2a and indium gave selec-
tively ethyl 2-phenyl-2,3-butadienoate (3b) in 85% yield (entry 1)
However, bromobenzene and chlorobenzene did not react with
2a. Under the optimum conditions, 1-iodonaphthalene (1c)
was converted to ethyl 2-(1-naphthyl)-2,3-butadienoate (3c) in
53% yield (entry 2). Electronic variation on the aromatic
314 J. Org. Chem. Vol. 76, No. 1, 2011

Lee et al.
JOCNote
substituents, such as methyl, n-butyl, methoxy, nitro, formyl,
acetyl, ethoxycarbonyl, and N-benzylamido group, did not
diminish the efficiency and selectivity in Pd-catalyzed cross-
coupling reactions (entries 3-15). Treatment of 1d and 1e
having an electron-donating group (n-Bu and MeO) with
organoindium produced the desired products 3d and 3e in
79% and 65% yields, respectively (entries 3 and 4). 4-Iodoace-
tophenone was subjected to cross-coupling reaction with 2a and
indium, affording 3g in 81% yield (entry 6). Organoindium
generated in situ from ethyl 4-bromo-2-pentynoate (2b) and
indium reacted with 2-iodotoluene (1h) to give selectively 3h in
85% yield (entry 8). The reaction conditions were mild enough
to tolerate a formyl group, which would be incompatible with
other organometallic reagents (entry 9). Ethyl iodobenzoate (1j
and 1a) and N-benzyl 4-iodobenzamide (1k) worked equally
well with organoindium generated in situ from 2b and indium,
producing 2-aryl-2,3-pentadienoates (3j, 3k, and 3l) in good
yields (entries 10-12). Subjecting 1b to ethyl 4-bromo-2-hep-
tynoate (2c) and indium provided 3m in 85% yield (entry 13).
3-Iodoanisole (1e) turned out to be compatible with the
employed reaction conditions, producing 3n in 64% yield
(entry 14). We were pleased to obtain ethyl 2-(4-ethoxycar-
bonylphenyl)-2,3-heptadienoate 3o in 77% yield from the reac-
tion of 1a with organoindium under the optimum reaction
conditions (entry 15). Reaction of 1,4-diiodobenzene with 2a
(4.5 equiv), indium (3.0 equiv), and NaI (3.0 equiv) proceeded
smoothly to produce bis(allenyl)benzene 3p in 65% yield (entry
16). Treatment of vinyl triflate 1m and 1n with 1a and indium in
the presence of KBr (1.5 equiv) instead of NaI provided
selectively the corresponding products 3q and 3r in 63% and
54% yields, respectively (entries 17 and 18).
Experimental Section
Ethyl 2-(4-Ethoxycarbonylphenyl)-2,3-butadienoate (3a). To
a suspension of Pd2dba3CHCl3 (6.2 mg, 0.6 ꢀ 10-2 mmol) and
(p-CF3C6H4)3P (22.0 mg, 4.8 ꢀ 10-2 mmol) in THF (0.5 mL)
was added ethyl 4-iodobenzoate (1a) (50.5 μL, 0.3 mmol) at
room temperature under nitrogen atmosphere. After being
stirred for 30 min, organoindium reagent generated in situ
from indium (52.0 mg, 0.45 mmol), sodium iodide (67.5 mg,
0.45 mmol), and 2a (129.0 mg, 0.68 mmol) in THF (1.0 mL)
was added, and the mixture was stirred at 70 °C for 2 h. The
reaction mixture was quenched with saturated NaHCO3. The
aqueous layer was extracted with CH2Cl2 (3 ꢀ 20 mL), and
the combined organic layers were washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by silica gel column chro-
matography (EtOAc/hexane =1:30) to give 3a (62.0 mg,
0.24 mmol, 79%): 1H NMR (400 MHz, CDCl3) δ 8.02 (d,
J = 8.44 Hz, 2H), 7.60 (d, J = 8.44 Hz, 2H), 5.48 (s, 2H), 4.38
(q, J = 7.09 Hz, 2H), 4.30 (q, J = 7.12 Hz, 2H), 1.39 (t, J =
7.09 Hz, 3H), 1.33 (t, J = 7.12 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 216.2, 166.7, 165.9, 137.1, 129.90, 129.86, 128.7,
103.0, 81.1, 61.9, 61.4, 14.7, 14.6; IR (film) 2982, 1953, 1716,
1607, 1447, 1366, 1275, 1104, 1021, 704 cm-1; HRMS (EI)
calcd for C15H16O4 Mþ 260.1049, found 260.1046.
Acknowledgment. This work was supported by the NRL
Program funded by the Ministry of Education, Science &
Technology (MEST) and by a National Research Foun-
dation of Korea (NRF) grant funded by the Korea gov-
ernment (MEST) (2009-0087013). This work was sup-
ported by the second phase of the Brain Korea 21 Program
in 2009. Some results are from a study of the “Human
Resource Development Center for Economic Region Leading
Industry” Project, supported by MEST and NRF. Dr.
Sung Hong Kim at the KBSI (Daegu) is thanked for
obtaining the MS data. The NMR data were obtained
from the central instrumental facility in Kangwon Na-
tional University.
In conclusion, we demonstrated an efficient synthetic
method for the preparation of ethyl 2-aryl-2,3-alkadienoates
through Pd-catalyzed selective allenyl cross-coupling reac-
tions of aryl iodides with organoindiums generated in situ
from indium and ethyl 4-bromo-2-alkynoate. Because intro-
duction of aryl group to C2-position of 2,3-alkadienoate is
difficult, this method would pave a new way to synthetically
valuable processes of a wide range of functionalized 2-aryl-
2,3-alkadienoates.
Supporting Information Available: Experimental procedure
and spectral data. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 1, 2011 315