Palladium-catalyzed cross-coupling reaction of triorganoindium reagents with propargylic esters

Article abstract of DOI:10.1021/ol060192o

Triorganoindium reagents (R₃In) react with propargylic esters under palladium catalysis via an S_N2′ rearrangement to afford allenes in good yields and with high regioselectivity. The reaction proceeds smoothly at room temperature wit

Full text of DOI:10.1021/ol060192o

ORGANIC
LETTERS
2006
Vol. 8, No. 7
1403-1406
Palladium-Catalyzed Cross-Coupling
Reaction of Triorganoindium Reagents
with Propargylic Esters
Ricardo Riveiros, David Rodr´ıguez, Jose´ Pe´rez Sestelo,* and Luis A. Sarandeses*
Departamento de Qu´ımica Fundamental, UniVersidade da Corun˜a,
E-15071 A Corun˜a, Spain
qfsarand@udc.es
Received January 23, 2006
ABSTRACT
Triorganoindium reagents (R3In) react with propargylic esters under palladium catalysis via an SN2
′
rearrangement to afford allenes in good
yields and with high regioselectivity. The reaction proceeds smoothly at room temperature with a variety of R3In (aryl, alkenyl, alkynyl, and
methyl). When chiral, nonracemic propargylic esters are employed, the reaction takes place with high anti-stereoselectivity providing allenes
with high enantiomeric excess.
Since our discovery in 1999,1 the palladium-catalyzed cross-
coupling reaction of indium(III) organometallics with organic
halides has been shown to be a useful reaction in organic
synthesis.2,3 In this reaction, triorganoindium reagents
(R3In) can efficiently couple with aryl, alkenyl, benzyl, and
acyl halides and triflates under palladium catalysis with high
atom economy. The reaction was later extended to other
indium organometallics such as tetraorganoindates or
allylindium species.4
Recently, we have shown that R3In can be regioselectively
coupled with allyl halides and esters under palladium
catalysis affording the SN2 product or, under copper catalysis,
affording the SN2′ product.5 In this communication, we report
the SN2′ palladium-catalyzed cross-coupling reaction of
triorganoindium compounds with propargylic esters and the
utility of this reaction in the synthesis of allenes.
The allene functionality is present in natural products6 and
is a versatile group in organic synthesis. It can react as either
a nucleophile or an electrophile7 and also participate in
cycloaddition reactions.8 In addition to these abilities, allenes
(1) (a) Pe´rez, I.; Pe´rez Sestelo, J.; Sarandeses, L. A. Org. Lett. 1999, 1,
1267-1269. (b) Pe´rez, I.; Pe´rez Sestelo, J.; Sarandeses, L. A. J. Am. Chem.
Soc. 2001, 123, 4155-4160.
(2) For contributions of this group, see: (a) Pena, M. A.; Pe´rez, I.; Pe´rez
Sestelo, J.; Sarandeses, L. A. Chem. Commun. 2002, 2246-2247. (b) Pena,
M. A.; Pe´rez Sestelo, J.; Sarandeses, L. A. Synthesis 2003, 780-784. (c)
Pena, M. A.; Pe´rez Sestelo, J.; Sarandeses, L. A. Synthesis 2005, 485-
492.
(3) For references from other groups, see: (a) Legros, J. Y.; Primault,
G.; Fiaud, J. C. Tetrahedron 2001, 57, 2507-2514. (b) Takami, K.;
Yorimitsu, H.; Oshima, K. Org. Lett. 2002, 4, 2993-2995. (c) Lehmann,
U.; Awasthi, S.; Minehan, T. Org. Lett. 2003, 5, 2405-2408. (d) Takami,
K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. J. Org. Chem.
2003, 68, 6627-6631. (e) Qian, M. X.; Huang, Z. H.; Negishi, E. Org.
Lett. 2004, 6, 1531-1534. (f) Gopalsamuthiram, V.; Wulff, W. D. J. Am.
Chem. Soc. 2004, 126, 13936-13937. (g) Qian, M. X.; Negishi, E. I.
Tetrahedron Lett. 2005, 46, 2927-2930. (h) Fausett, B. W.; Liebeskind,
L. S. J. Org. Chem. 2005, 70, 4851-4853.
(4) (a) Lee, K.; Lee, J.; Lee, P. H. J. Org. Chem. 2002, 67, 8265-8268.
(b) Lee, P. H.; Lee, S. W.; Seomoon, D. Org. Lett. 2003, 5, 4963-4966.
(5) (a) Rodr´ıguez, D.; Pe´rez Sestelo, J.; Sarandeses, L. A. J. Org. Chem.
2003, 68, 2518-2520. (b) Baker, L.; Minehan, T. J. Org. Chem. 2004, 69,
3957-3960. (c) Rodr´ıguez, D.; Pe´rez Sestelo, J.; Sarandeses, L. A. J. Org.
Chem. 2004, 69, 8136-8139.
(6) (a) Krause, N.; Hoffmann-Ro¨der, A. In Modern Allene Chemistry;
Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; pp 997-
1039. (b) Hoffmann-Ro¨der, A.; Krause, N. Angew. Chem., Int. Ed. 2004,
43, 1196-1216. (c) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122,
10470-10471.
(7) Ma, S. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K.,
Eds.; Wiley-VCH: Weinheim, 2004; pp 595-699.
(8) Murakami, M.; Matsuda, T. In Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; pp 727-815.
10.1021/ol060192o CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/09/2006

are chiral compounds, so they are useful intermediates in
asymmetric synthesis.9
Table 1. Reactions of Ph3In with Propargylic Estersa
One of the most important ways to synthesize allenes is
by nucleophilic SN2′ displacement of the leaving group from
propargylic halides, esters, or sulfonates. Nevertheless, this
reaction has been much less extensively investigated than
the corresponding allylic substitution reaction.10 In the
propargylic reaction, various types of nucleophiles such as
hydrides, halides, and organometals can be employed.
Organocopper reagents react stereoselectively with propar-
gylic derivatives via SN2′ in good yields.11 Other organo-
metals such as Grignard12 or organozinc reagents13 can also
be employed for the SN2′ propargylic substitution under
transition-metal catalysis.14
entry
X
catalyst
yield (%)b
1
2
3
4
5
6
OBz (1a)
OBz (1a)
OBz (1a)
OBz (1a)
OAc (1b)
OCO2Me (1c)
Pd2dba3, PPh3
Pd2dba3, P(2-fur)3
Pd(PPh3)4
Pd(DPEphos)Cl2
Pd(DPEphos)Cl2
Pd(DPEphos)Cl2
70c (54)d
78
71
79 (56)d
96
90
To explore the reactivity of triorganoindium reagents
toward propargylic substrates, we selected as coupling
partners triphenylindium and propargylic esters (acetates,
benzoates, and carbonates), easily prepared from the corre-
sponding alcohols. In our first experiment, we tested the
reaction conditions developed for the SN2′ copper-catalyzed
reaction of R3In with allylic halides and esters.5a In this way,
the reaction of Ph3In with the benzoate 1a, using Cu(OTf)2
(15 mol %) and P(OEt)3 (30 mol %) as the catalytic system,
failed to produce the allene 2 and most of the starting
benzoate was recovered. Alternatively, the use of CuBr‚SMe2
as catalyst provided the desired allene in low yield (26%).
Under these circumstances, we turned our attention toward
palladium catalysis. In this case, we observed that the reaction
of Ph3In (1.2 equiv) with the propargylic benzoate 1a using
Pd2(dba)3 (1 mol %) and PPh3 (4 mol %) as the catalytic
system afforded, after 24 h in refluxing THF, the allene 2 in
70% yield with high regioselectivity (only the SN2′ product
was detected by NMR, Table 1, entry 1). In the reaction,
besides the allene, the formation of biphenyl by reductive
homodimerization occurred and some of the starting benzoate
1a was recovered. The nucleophilic addition of Ph3In to the
ester group was not observed. This encouraging result
prompted us to examine new reaction conditions using other
a Reactions performed using 1.2 equiv of Ph3In. b Isolated yield. c Re-
action performed at reflux for 24 h. d In parentheses, yield using 0.5 equiv
of Ph3In.
catalytic systems and propargylic esters. In subsequent
experiments, we observed that the palladium complexes
15
Pd2(dba)3‚P(2-Furyl)3, Pd(PPh3)4, or Pd(DPEphos)Cl2 al-
lowed the reaction at room temperature, in shorter reaction
times and with total consumption of the starting benzoate
(entries 2-4). In this study, we also found that other
propargylic esters such as acetate 1b or carbonate 1c gave
the allene 2 in good yield under the same reaction conditions
(entries 5 and 6). In these experiments, we also realized that
stoichiometric amounts of Ph3In are necessary to consume
totally the propargylic ester. Although the results obtained
showed the transfer of more than one phenyl group attached
to indium, using lower amounts of Ph3In, the reaction is not
complete and afforded higher quantities of biphenyl after
10 h (entries 1 and 4, yields in parentheses).
After studying the SN2′ reaction of Ph3In with various
propargylic esters, we explored the reaction of other trior-
ganoindium reagents (aryl, alkenyl, alkynyl, and alkyl) with
the propargylic benzoate 1a and the propargylic acetate 3b.16
The results of this study are shown in Table 2. We found
that substituted arylindium reagents such as tri(o-methoxy-
phenyl)indium reacted efficiently with benzoate 1a affording
aryl allene 4 in good yield (Table 2, entry 2). The reaction
of alkenylindium reagents, such as trivinylindium, with
benzoate 1a also afforded the corresponding alkenyl allene
5 in high yield (Table 2, entry 3). The alkynyl group can be
efficiently transferred from indium reagents; tri(phenylethy-
nyl)indium or tris[(trimethylsilyl)ethynyl]indium reacted with
benzoate 1a affording the corresponding allenynes 6 and 7,
as a nice complement to the copper chemistry developed for
the propargylic substitution reaction (Table 2, entries 4 and
5). Unfortunately, the reaction of n-Bu3In with benzoate 1a
(9) (a) Brummond, K. M.; Chen, H. In Modern Allene Chemistry; Krause,
N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; pp 1041-1090.
(b) Marshall, J. A. Chem. ReV. 1996, 96, 31-48. (c) Marshall, J. A. Chem.
ReV. 2000, 100, 3163-3186.
(10) Keinan, E.; Bosch, E. J. Org. Chem. 1986, 51, 4006-4016.
(11) For general references, see: (a) Tsuji, J.; Mandai, T. In Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, 2004; pp 585-618. (b) Alexakis, A. Pure
Appl. Chem. 1992, 64, 387-392. (c) Hoffmann-Ro¨der, A.; Krause, N. In
Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-
VCH: Weinheim, 2004; pp 51-92.
(12) (a) Pasto, D. J.; Hennion, G. F.; Shults, R. H.; Waterhouse, A.;
Chou, S.-K. J. Org. Chem. 1976, 41, 3496-3496. (b) Jeffery-Luong, T.;
Linstrumelle, G. Tetrahedron Lett. 1980, 21, 5019-5020.
(13) (a) Negishi, E.; Liu, F. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002; pp 551-
589. (b) Kleijn, H.; Meijer, J.; Overbeek, G. C.; Vermeer, P. Recl. TraV.
Chim. Pays-Bas 1982, 101, 97-101. (c) Darcel, C.; Bruneau, C.; Dixneuf,
P. H. J. Chem. Soc., Chem. Commun. 1994, 1845-1846. (d) Dixneuf, P.
H.; Guyot, T.; Ness, M. D.; Roberts, S. M. Chem. Commun. 1997, 2083-
2084.
(14) Other organometals have found isolated applications: Boron: (a)
Moriya, T.; Miyaura, N.; Suzuki, A. Synlett 1994, 149-151. (b) Ishikura,
M.; Matsuzaki, Y.; Agata, I.; Katagiri, N. Tetrahedron 1998, 54, 13929-
13942. Aluminum: (c) Keinan, E.; Bosh, E. J. Org. Chem. 1986, 51, 4006.
Tin: (d) Tsutsumi, K.; Ogoshi, S.; Kakiuchi, K.; Nishiguchi, S.; Kurosawa,
H. Inorg. Chim. Acta 1998, 296, 37-44.
(15) DPEphos ) bis(o-(diphenylphosphino)phenyl) ether. (a) Kranenburg,
M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081-3089. (b) Huang,
Z.; Qian, M.; Babinski, D. J.; Negishi, E. Organometallics 2005, 24, 475-
478.
(16) For a general experimental procedure for the preparation of
triorganoindium reagents as well the experimental conditions for the SN2′
propargylic reaction, see Supporting Information.
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Org. Lett., Vol. 8, No. 7, 2006

Table 2. Reactions of Triorganoindium Reagents with 1a and 3b
a Isolated yield. b Reaction performed at reflux. c Pd2dba3‚P(2-furyl)3 (1:4, 2 mol %) as catalyst. d Compound 8 was obtained in 70% yield.
afforded only allene 8, the product of a â-hydride elimination
reaction prior to the formation of the carbon-carbon bond
by reductive elimination, in 70% yield (Table 2, entry 6).
Only the reaction of alkylindium reagents without â-hydro-
gens such as trimethylindium afforded the desired allene 9
in modest yield (Table 2, entry 7).17
alcohol of cyclohexanone, the corresponding allenes 10-
14 were obtained in good yields (Table 2, entries 8-12).
Finally, we also studied the asymmetric synthesis of
allenes by reaction of R3In with chiral, nonracemic pro-
pargylic esters. As mentioned before, the axial chirality
of allenes makes them particularly amenable to organic
synthesis.9a Additionally, these reactions can be used to
test the general mechanism proposed in the palladium-
catalyzed propargylic reaction with organometallic nucleo-
philes.18
In an analogous way, when the reactions were performed
using the propargylic acetate 3b, derived from the propargylic
(17) In the reaction, compound 8 (Table 2, entry 6) was also obtained
as a major byproduct.
Org. Lett., Vol. 8, No. 7, 2006
1405

Hitherto, the synthesis of chiral, nonracemic allenes by
palladium propargylation has been limited to few examples
using organozinc and organoboron reagents as nucleophiles
and is shown to proceed with anti-stereoselectivity.13,18 To
investigate the behavior of R3In, and with the aim of
comparing results, we carried out the reaction of Ph3In with
the enantiopure propargylic benzoate 15a (Scheme 1).19 In
this reaction, we observed the formation of (R)-1,3-diphe-
nylallene (16) in 70% yield and 86% ee. The enantiomeric
Scheme 1. Reactions of Ph3In with Enantiopure Propargylic
Esters
1
excess was determined by H NMR using as chiral shift
reagents the complexes (+)-Yb(hfbc)3 and Ag(fod).20 This
result shows that the propargylic reaction using Ph3In is
enantioselective and proceeds with anti-stereoselectivity. To
measure the influence of the leaving group, we also carried
out the reaction of Ph3In with the enantiopure acetate 15b.
As in the case of benzoate 15a, the (R)-1,3-diphenylallene
(16) was obtained with high anti-stereoselectivity, good yield,
and similar enantioselectivity (84% ee). Under the same
reaction conditions, the reaction of Ph3In with the enantiopure
benzoate 17 afforded the (R)-1-phenyl-3-methylallene (18)
place among various propargylic esters and triaryl-, trialk-
enyl-, trialkynyl-, and trimethylindium reagents. The reaction
proceeds smoothly at room temperature, and the scope of
the propargylic substitution is comparable with that of
organozinc and organocopper reagents. The reaction with
chiral, nonracemic propargylic esters proceeds with anti-
stereoselectivity, providing chiral allenes with high enan-
tiomeric excess. Further studies and applications of this
reaction in the asymmetric synthesis of allenes are in
progress.
1
in good yield as the only enantiomer detected by H NMR.
The anti-stereoselectivity observed in these reactions can be
explained by assuming that the formation of a σ-allenylpal-
ladium species takes place with inversion of configuration,
whereas the transmetalation and the ensuing reductive
elimination proceed with retention of configuration.
In summary, triorganoindium reagents react with propargyl
esters under palladium catalysis to afford allenes in good
yields and in high regioselectivity. The reaction can take
Acknowledgment. We are grateful to the Ministerio de
Ciencia y Tecnolog´ıa (Spain, BQU2003-00301), Xunta de
Galicia (PGIDIT04PXIC10308PN), and FEDER for financial
support. R.R. thanks Xunta de Galicia for a “Isidro Parga
Pondal” contract.
(18) (a) Elsevier, C. J.; Stehouwer, P. M.; Westmijze, H.; Vermeer, P.
J. Org. Chem. 1983, 48, 1103-1105. (b) Konno, T.; Tanikawa, M.; Ishihara,
T.; Yamanaka, H. Chem. Lett. 2000, 1360-1361. (c) Yoshida, M.; Gotou,
T.; Ihara, M. Tetrahedron Lett. 2004, 45, 5573-5575. (d) Yoshida, M.;
Ueda, H.; Ihara, M. Tetrahedron Lett. 2005, 46, 6705-6708.
(19) Prepared from the corresponding commercially available alcohol.
For further experimental details, see Supporting Information.
(20) Mannschreck, A.; Munninger, W.; Burgemeister, T.; Gore, J.; Cazes,
B. Tetrahedron 1986, 42, 399-408.
Supporting Information Available: A general experi-
mental procedure and relevant spectral data for compounds
prepared. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL060192O
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Org. Lett., Vol. 8, No. 7, 2006