Efficient synthesis of trisubstituted alkenes in an aqueous-organic system using a versatile and recyclable Rh/m-TPPTC catalyst

Article abstract of DOI:10.1016/j.tetlet.2004.03.136

We have found that the use of [Rh(cod)OH]₂ associated with the water-soluble ligand m-TPPTC was highly efficient for the Rh-catalyzed arylation of alkynes. Aryl and alkyl alkynes were transformed to alkenes using 3mol% rhodium catalyst and 2.5equiv of boronic acid at 100°C in a biphasic water/toluene system in 80-99% yield. The reaction was found to be totally regioselective for alkyl arylalkynes and alkyl silylated alkynes. The Rh/m-TPPTC system was for the first time recycled with no loss of the activity and with excellent purity of the desired alkene.

Full text of DOI:10.1016/j.tetlet.2004.03.136

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4157–4161
Efficient synthesis of trisubstituted alkenes in an aqueous–organic
system using a versatile and recyclable Rh/m-TPPTC catalyst
*
*
ꢀ
Emilie Genin, Veronique Michelet and Jean-Pierre Genet
^
Laboratoire de Synthꢁese Sꢀelective Organique et Produits Naturels, ENSCP, UMR 7573,
11 rue P. et M. Curie, F-75231 Paris Cedex 05, France
Received 25 February 2004; revised 18 March 2004; accepted 22 March 2004
Abstract—We have found that the use of [Rh(cod)OH]2 associated with the water-soluble ligand m-TPPTC was highly efficient for
the Rh-catalyzed arylation of alkynes. Aryl and alkyl alkynes were transformed to alkenes using 3 mol % rhodium catalyst and
2.5 equiv of boronic acid at 100 °C in a biphasic water/toluene system in 80–99% yield. The reaction was found to be totally regio-
selective for alkyl arylalkynes and alkyl silylated alkynes. The Rh/m-TPPTC system was for the first time recycled with no loss of the
activity and with excellent purity of the desired alkene.
Ó 2004 Elsevier Ltd. All rights reserved.
Organic synthesis in water has recently received much
attention, not only because unique reactivity and selec-
tivity are often exhibited in water but also because it is
an economical and environmentally friendly solvent.1;2
The development of water-soluble organometallic sys-
tems has also given the ability to combine the high
efficiency of the catalyst with the possible metal recy-
cling and the easy product/catalyst separation.1;2 As part
of an ongoing program devoted to metal-catalyzed
reactions in aqueous media,3 we have recently reported
the versatile preparation of the water-soluble ligand
m-TPPTC 1, a carboxylated analogue of the sulfonated
TPPTS ligand 2 (Scheme 1).4;5 As recent years witnessed
tremendous growth in Rh-catalyzed addition of organo-
boronic acids to unsaturated compounds,6 we sought to
evaluate the reactivity of the new carboxylated ligand
for C–C bond formation.
We turned our attention to the Rh-catalyzed addition of
boronic acids to alkynes described recently for the first
time by Hayashi’s group in a dioxane/water mixture.7
Despite this unique work based on a rhodium/diphenyl-
phosphane8 system in organoaqueous conditions, there
is one system described so far in water.9 This latter,
requiring basic conditions and the presence of a sur-
factant, is very specific to pyridyl-substituted alkynes as
it is inefficient with alkyl or aryl substituted ones.
Moreover, the use of the well-known sulfonated ligands
TPPTS 2 and TPPDS 3 (Scheme 1) was ineffective and
consequently led the authors to synthesize the ligand 4.9
Having in hand a novel water-soluble ligand, we wish to
report our preliminary results concerning a versatile,
highly efficient and for the first time recyclable water-
soluble system.
LiO2C
NaO3S
P
P
3
3
m-TPPTC 1
KO3S
TPPDS 3
TPPTS 2
KO3S
P
PPh
2
2
N
The addition of phenylboronic acid to oct-4-yne 5 was
chosen as a standard reaction and some results are
summarized in Table 1. We screened different rhodium
precursors to find a suitable system to promote the
reaction without base or surfactant. For example, the
use of Rh(acac)(C2H4)2 and [Rh(C2H4)Cl]2 gave disap-
pointing results as low yields were obtained (entries 1,
4
Scheme 1.
Keywords: Water-soluble ligand; Boronic acids; Alkynes; Recyclable
rhodium/m-TPPTC system; Biphasic system.
2). Moreover, we observed the formation of
by-product 7a that was separated from the alkene 6a
a
* Corresponding authors. Tel.: +33-1-44-27-67-42; fax: +33-1-44-07-
10-62; e-mail addresses: genet@ext.jussieu.fr; michelet@ext.jussieu.fr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.136

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E. Genin et al. / Tetrahedron Letters 45 (2004) 4157–4161
Table 1. Rh-catalyzed addition of phenylboronic acid to oct-4-yne 5 in water and in biphasic H2O/toluene media
C3H7
Rh catalyst (1.5%)
ligand (6%)
Ph
H
Ph
C3H7
+
C3H7
C3H7
PhB(OH)2 2.5-5eq
100 °C, 3h
C3H7
C3H
7C3H7
C3H7
7a
5
6a
Entry
Rh catalyst/ligand
Conditions
Yielda (%)
6a/7a Ratio (%)b
1c
2
Rh(acac)(C2H4)2/1
[Rh(C2H4)Cl]2/1
[Rh(cod)OH]2/1
[Rh(cod)OH]2/2
[Rh(cod)OH]2/1
[Rh(cod)OH]2/1
[Rh(cod)OH]2/1
[Rh(cod)OH]2/2
[Rh(cod)OH]2/1
H2O
H2O
20
22
95
63
99
99
96
89
84
70/30
64/36
80/20
60/40
60/40
100/0
98/2
3
H2O
H2O
4
5
H2O, Na2CO3
H2O/toluene 1/1
H2O/toluene 1/1
H2O/toluene 1/1
H2O/toluene 1/1
6
7d
8d
9e
85/15
95/5
a Isolated yield.
b Measured by 1H NMR and GC.
c 3 mol % catalyst.
d 2.5 equiv of phenylboronic acid.
e 2.5 equiv of phenylboronic acid, 50 °C, 6.3 h.
and identified as a single diene by spectral 1H NMR and
NOESY effect. No traces of trimer were detected. The
formation of such diene is unique during the course of
the Rh-catalyzed hydroarylation, since 7a was only
reported with nickel catalyst, as a mixture of stereo-
isomers though.10 We prepared the [Rh(cod)OH]2 cata-
lyst according to literature procedure11 as this precursor
seems to be involved in several couplings of boronic
acids and other organometallic partners.6;9;12 We found
that under the same reaction conditions, the yield was
increased to 95% and the 6a/7a ratio was still in favor of
the desired product (entry 3). The use of the TPPTS
ligand 2 gave a 3/2 mixture of compounds 6a/7a in a
moderate 63% yield (entry 4). We also investigated the
influence of a base:4b;9 the addition of a mineral base
(Na2CO3, 2 equiv) was significant as the 6a/7a ratio
decreased from 80/20 to 60/40 (entry 5).13 Speculating
that the influence of water was also profound on the
selectivity of the reaction and more specifically on the
formation of 7a, we studied the hydroarylation under
biphasic conditions. We were pleased to find that the use
of the biphasic system toluene/water completely sup-
pressed the formation of the diene 7a. The desired
alkene was isolated in 99% yield and 100% selectivity
(entry 6). Interestingly, the quantity of boronic
acid could then be reduced from 5 to 2.5 equiv (entry 7)
with still excellent yield and selectivity.14 It has to be
noticed that the use of the TPPTS ligand 2 afforded a
significant amount of the diene 7a (entry 8) in a lower
yield. Lowering the temperature to 50 °C increased
the reaction time but still gave 6a in a good 84% yield
(entry 9).
The well-accepted catalytic cycle involves a classic
transmetallation leading to a [RhLn]-Ph intermediate6
and then an addition to the alkyne (Scheme 2).7 Sub-
sequent hydrolysis with water results in the formation of
alkene 6a and regeneration of the catalyst.15 The for-
mation of the diene 7a, that may also be related to
polymerization reactions,16 is favored in water. This
may be rationalized by the unique structure and pro-
perties of water compared to usual solvents. It is now
well-known that water has the highest cohesive energy
density, a very large surface tension, and a high heat
capacity.1;2 The principal consequence of these effects is
the entropy-driven association of apolar solutes in
water. The hydrophobic effect, in our case due to the low
water-solubility of the alkyl alkyne, may therefore pro-
mote a second addition of alkyne, as several alkynes are
close to each other. The use of a biphasic system thus
controls the concentration17 of the alkyne in the water
phase and therefore influences the selectivity of the
reaction in favor of the monoaddition of the alkyne.
The versatility of the catalyst system and especially the
addition of various arylboronic acids to alkyl and aryl
substituted alkynes was then examined (Table 2). Other
7a
6a
PhB(OH)2
B(OH)3
[RhLn]
O
H
[RhLn] OH
H2O
Ph
C3H7
H2O
C3H7
[RhLn]
C3H7
[LnRh]
Ph
[RhLn] Ph
C3H7
C3H7
The optimized system therefore consists of 3 mol % of
rhodium, 6 mol % of the water-soluble monophosphane
1 and only 2.5 equiv of boronic acid in an essential
biphasic water/toluene media. These conditions also
provide a facile separation of the resulting alkene from
the catalyst system.14
C3H7
C3H7
C3H7
[RhLn] Ph
L = m-TPPTC
Scheme 2.

E. Genin et al. / Tetrahedron Letters 45 (2004) 4157–4161
4159
boron partners still reacted very smoothly in the stan-
dard conditions. Either electro-withdrawing boronic
acid (entry 1) or electro-donating boronic acids (entries
2, 3) could react in short reaction time leading to 80–
99% isolated alkenes 6b–c. It has to be noted that no
reduction of the boronic acid was observed, especially in
the case of the 4-methoxyphenylboronic, on the con-
trary to the study of Hayashi et al.7 The reaction was
also chemoselective as the bromo-substituted boronic
acid (entry 4) was added with an excellent yield. The
addition of a bromoaryl group to unsaturated com-
pound was already found to be chemoselective with
different Rh systems in water and is of particular interest
for further cross-coupling reactions.4b;18 We decided to
study the difficult case of 1-phenylpropyne, for which
only a mixture of regioisomers (3:1) could be obtained
so far.7 We observed the formation of the expected
alkenes 9a–c with high yields (entries 5–7). Moreover,
the regioselectivity was found to be >95% as no trace of
another isomer was detected by NMR or GC. The
addition of the aryl groups occurs exclusively at the b-
position of the phenyl group. The ability of the catalytic
system to perform the hydroarylation in high yield and
to induce formation of a unique isomer may be a con-
sequence of the intrinsic properties (steric and elec-
tronic) of the phosphane.4b;19 The system was also
compatible with a pyridyl substituted alkyne9 and an
excellent regioselectivity was also observed. The alkene
11 was isolated in 98% yield (entry 8). The influence of a
silyl group was then investigated through the reaction of
the aryl-substituted alkyne 12. The reaction was still
highly chemoselective. Despite the total conversion of
Table 2. Rh-catalyzed arylation of alkynes in a biphasic H2O/toluene phase
[Rh(cod)OH]2 (1.5%)
Ar
H
m-TPPTC (6%)
R
R'
ArB(OH)2
2.5 eq.
+
H2O/toluene (1:1)
100 °C
R
R'
Entry
1
Alkyne
Ar
Product
t (h)
Yielda (%)
99
4-CF3C6H4
H
C3H7
C3H7
C3H7
C3H7
C3H7
5
5
5
5
8
8
8
6b
6c
6d
6e
9a
9b
9c
3
4-CF3C6H4
4-MeC6H4
C3H7
C3H7
4-MeC6H4
H
2
3
4
5
6
7
C3H7
C3H7
C3H7
3
98
80
99
95
96
95
C3H7
C3H7
H
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
C6H5
3
C3H7
C3H7
4-BrC6H4
H
3
C3H7
C3H7
C6H5
H
2.5
2.5
2.5
C6H5
3-MeOC6H4
H
C6H5
3-MeOC6H4
4-BrC6H4
4-BrC6H4
H
C6H5
C6H5
C4H9
H
N
8
10
C6H5
11
3
98
C4H9
N
C6H5
H
H
C6H5
4-BrC6H4
9
12
14
C6H5
C6H5
13
15
3
3
99b
94
+
Me3Si
Me3Si
Br
Me3Si
H
4-BrC6H4 Me3Si
C6H5
10
C4H9
Me3Si
C4H9
a Isolated yield.
b 1/1 mixture determined by 1H NMR and GC.

4160
E. Genin et al. / Tetrahedron Letters 45 (2004) 4157–4161
the alkyne, we observed the formation of two isomers
13, which were found to be regioisomers (entry 9).20 The
silyl group may therefore have the same effect as the
phenyl group and promotes the addition of the aryl
group at the b-position. This could be demonstrated by
choosing a substrate bearing an alkyl and a silyl group.
The addition of phenylboronic acid to alkyne 14 indeed
gave exclusively the isomer 15 in 94% yield (entry 10).
Acknowledgements
ꢀ
E. Genin is grateful to the Ecole Normale Superieure de
Paris for a grant (2003–2004).
References and notes
Having found a suitable biphasic system for the aryla-
tion of alkynes bearing various groups in water, we then
explored the recycling possibility of the catalyst Rh(I)/
m-TPPTC, which has never been disclosed to our
knowledge for this reaction. We have conducted the
addition of phenylboronic acid to oct-4-yne 5 using
1.5 mol % [Rh(cod)OH]2, 6 mol % m-TPPTC 1 under
biphasic conditions. As shown in Table 3, we were
pleased to find that the water-soluble ligand 1 preserves
successfully the expensive rhodium in water, and allows
a catalyst recycling. Indeed, after completion of the
reaction, the toluene phase was separated and the water
phase was extracted two times with toluene and
reloaded with substrates in solution. The reaction time
was still very short for each of the four cycles. The
alkene 6a was isolated in 93–98 % yield and with excel-
lent purity (98–99%). It is noteworthy that during the
continuous recycle experiments, no deposition of rho-
dium metal on the glass was observed.
1. For selected books, see: (a) Organic Synthesis in Water;
Grieco, P. A., Ed.; Blacky Academic and Professional:
London, 1998; (b) Organic Reactions in Aqueous Media; Li,
C.-J., Chan, T.-H., Eds.; Wiley & Sons: New York, 1997;
(c) Aqueous-Phase Organometallic Catalysis; Cornils, B.,
Herrmann, W. A., Eds.; Wiley-VCH: New York, 1998.
2. For recent reviews, see: (a) Pinault, N.; Bruce, D. W.
Coord. Chem. Rev. 2003, 241, 1; (b) Li, C.-J. Acc. Chem.
Res. 2002, 35, 533; (c) Li, C.-J.; Chan, T. H. Tetrahedron
ꢀ
1999, 55, 11149; (d) Lubineau, A.; Auge, J. In Modern
Solvent in Organic Synthesis,Topics in Current Chemistry;
Knochel, P., Ed.; Springer: Berlin, 1999; 206, p 1; (e)
Sinou, D. In Modern Solvent in Organic Synthesis, Topics
in Current Chemistry; Knochel, P., Ed.; Springer: Berlin,
ꢀ
1999; 206, p 41; (f) Lubineau, A.; Auge, J.; Queneau, Y.
Synthesis 1994, 741; (g) Herrmann, W. A.; Kohlpaintner,
C. W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1524.
^
3. (a) Michelet, V.; Savignac, M.; Genet, J. P. Electronic
Encyclopedia of Reagents for Organic Synthesis, in press;
^
(b) Genet, J. P.; Savignac, M. J. Organomet. Chem. 1999,
576, 305; (c) Genet, J. P.; Savignac, M.; Lemaire-Audoire,
^
S. IUPAC Monographs ‘Chemistry for the 21st Century’
In Transition Metal Catalyzed Reactions; Murahashi, S.-I.,
Davies, S. G., Eds.; 1999; p 55.
In conclusion, the use of [Rh(cod)OH]2 associated with
the water-soluble ligand m-TPPTC was found to be
highly efficient for the Rh-catalyzed arylation of alky-
nes. The biphasic water/toluene system was found to be
crucial for the selectivity of the reaction. Selected alky-
nes, which were established to be unreactive in water or,
which gave mixtures in organoaqueous media, were
transformed to alkenes with a total stereo- and regio-
selectivity. Furthermore, we could perform for the first
time the recycling of the catalyst system for this reac-
tion. Other applications of this system implying various
organometallic partners are currently studied and will be
reported in due course.
4. (a) Amengual, R.; Genin, E.; Michelet, V.; Savignac, M.;
Genet, J. P. Adv. Synth. Catal. 2002, 344, 393; (b)
^
Amengual, R.; Michelet, V.; Genet, J. P. Tetrahedron
Lett. 2002, 43, 5905.
5. Abbreviations: TPPTS ¼ trisodium salt of 3,30,300-phos-
phanetriylbenzenesulfonic
acid,
TPPTC ¼ trilithium
salt of 3,30,300-phosphanetriylbenzenecarboxylic acid,
TPPDS ¼ dipotassium salt of 3,30-phosphanediylbenzene-
sulfonic acid.
6. (a) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829;
(b) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169.
7. Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M.
J. Am. Chem. Soc. 2001, 123, 9918.
8. The use of triphenylphosphane led to the desired product
in low yield.7
9. (a) Lautens, M.; Yoshida, M. Org. Lett. 2002, 4, 123; (b)
Lautens, M.; Yoshida, M. J. Org. Chem. 2003, 68, 762.
10. (a) Shirakawa, E.; Takahashi, G.; Tsuschimoto, T.;
Kawakami, Y. Chem. Commun. 2001, 2688; For the
formation of dimeric compound with titane catalyst, see:
(b) Launey, V.; Beaudet, I.; Quintard, J.-P. Synlett 1997,
821.
Table 3. Recycling of the [Rh(cod)OH]2/m-TPPTC system in a H2O/
toluene mixture
[Rh(cod)OH]2 (1.5%)
11. Uson, R.; Oro, L. A.; Cabeza, J. Inorg. Synth. 1985, 23,
126.
m-TPPTC (6%)
Ph
H
C3H7
C3H7
12. (a) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara,
M. J. Am. Chem. Soc. 2002, 124, 5052; (b) Fujii, T.; Koike,
T.; Mori, A.; Osakada, K. Synlett 2002, 295; (c) Itooka,
T.; Miyaura, N. J. Org. Chem. 2003, 68, 6000, and
references cited therein; (d) Mori, A.; Danda, Y.; Fujii, T.;
Hirabayashi, K.; Osakada, K. J. Am. Chem. Soc. 2001,
123, 10774.
13. No reaction was observed under basic conditions without
rhodium catalyst.
14. Typical procedure: To a mixture of degassed [Rh(cod)OH]2
(3.4mg, 1.5mol %) and m-TPPTC (12.3mg, 6 mol %) at
PhB(OH)2 2.5 eq.
C3H7
C3H7
toluene/H2O 1/1, 100 °C
5
6a
Cycle
t (h)
Yield (%)a
Purity (%)b
1
2
3
4
1.5
1.5
1.5
1.5
96
93
97
98
98
99
98
99
a Isolated yield.
b Measured by GC.

E. Genin et al. / Tetrahedron Letters 45 (2004) 4157–4161
4161
room temperature was successively added a water (0.5 mL)/
toluene (0.5mL), phenylboronic acid (152 mg, 1.25mmol),
and oct-4-yne (74 lL, 0.5 mmol). The mixture was heated at
100 °C until completion of the reaction and then cooled to
room temperature. The alkene was isolated either through
separation and extraction with toluene (2 times) or direct
filtration on a short pad of silica gel and evaporation under
reduced pressure. 90mg (96%) of 6a were obtained as a pale
yellow oil. No further purification was necessary. The purity
(>95%) was checked by NMR and GC–MS analyses.
15. The involvement of an arylrhodium complex7 was not
considered as 90% of the deuterated alkene was observed
in a 1/1 toluene/D2O mixture.
17. For some recent successful reactions based on concentra-
tion controls in water or fluorous systems, see: (a) Ryu, I.;
Matsubara, H.; Yasuda, S.; Nakamura, H.; Curran, D. P.
J. Am. Chem. Soc. 2002, 124, 12946; (b) Xiang, J.; Orita,
A.; Otera, J. Angew. Chem., Int. Ed. 2002, 41, 4117; (c)
Kinoshita, H.; Shinokubo, H.; Oshima, K. J. Am. Chem.
Soc. 2003, 125, 7784.
18. Lautens, M.; Roy, A.; Fukuoka, F.; Fagnou, K.; Martin-
Matute, B. J. Am. Chem. Soc. 2001, 123, 5358.
19. The m-TPPTC ligand displays a higher basicity than the
TPPTS phosphane. This study will be published elsewhere.
20. We have conducted a desilylation reaction of the mixture
under standard conditions using n-Bu4NF in THF leading
to a mixture of gem-disubstituted and trans-disubstituted
alkenes (selected 1H NMR 400 MHz d ¼ 5:48, 5.46 ppm
J ¼ 1:1 Hz and 7.11, 7.04 ppm J ¼ 16:5 Hz).
16. (a) Misumi, Y.; Masuda, T. Macromolecules 1998, 31,
7572; (b) Yamamoto, M.; Onitsuka, K.; Takahashi, S.
Organometallics 2000, 19, 4669.