Suzuki-Miyaura cross-coupling of 1,1-dichloro-1-alkenes with 9-alkyl-9-BBN

Article abstract of DOI:10.1021/jo061908w

We addressed an unexplored application of the Suzuki-Miyaura protocol to the cross-coupling of 1,1-dichloro-1-alkenes with 9-alkyl-9-BBN. The use of bisphosphine ligands with a large P-Pd-P bite angle allowed us to synthesize Z-chlorinated internal alkenes in good yields resulting from a selective monocoupling process, a recurrent challenge with 1,1-dichloro-1-alkenes. Moreover, these monochlorinated olefins could be further transformed providing stereospecifically trisubstituted olefins.

Full text of DOI:10.1021/jo061908w

Suzuki-Miyaura Cross-Coupling of
1,1-Dichloro-1-alkenes with 9-Alkyl-9-BBN
Fre´de´ric Liron,† Ce´line Fosse,‡ Alban Pernolet,§ and
Emmanuel Roulland*,†
Institut de Chimie des Substances Naturelles, CNRS, aVenue de
la Terrasse, 91198 Gif-sur-YVette, France, SerVice de
Spectrome´trie de Masse, Ecole Normale Supe´rieure, 24,
rue Lhomond, 75231 Paris, Cedex 05, and UMR 7573, Ecole
Normale Supe´rieure de Chimie de Paris, 11, rue Pierre et
Marie Curie, 75231, Paris cedex 05, France
emmanuel.roulland@icsn.cnrs-gif.fr
FIGURE 1. Some examples of natural products bearing a chlorovinyl
function.
ReceiVed September 15, 2006
acid4 or halichlorine5 (Figure 1). Starting from these Z-
chloroalkenes, we could attempt the challenging synthesis of
stereospecifically trisubstituted alkenes by making use of
recently developed palladium catalysts.6
Whereas the reactivity of 1,1-dibromo-1-alkenes has been
extensively studied,7 only a few successful metal-catalyzed
cross-couplings involving 1,1-dichloro-1-alkenes are known in
3
the literature. Thus, only a few examples of Csp nucleophilic
coupling partners have been reported (organozincs8-10 or
We addressed an unexplored application of the Suzuki-
Miyaura protocol to the cross-coupling of 1,1-dichloro-1-
alkenes with 9-alkyl-9-BBN. The use of bisphosphine ligands
with a large P-Pd-P bite angle allowed us to synthesize
Z-chlorinated internal alkenes in good yields resulting from
a selective monocoupling process, a recurrent challenge with
1,1-dichloro-1-alkenes. Moreover, these monochlorinated
olefins could be further transformed providing stereospe-
cifically trisubstituted olefins.
Grignards8,11) along with some Csp (organozincs,8,9 Grignards,11
2
organoboranes,12 organoalanes13) and Csp partners.13 However,
it is important to notice that 1,1-dibromo-1-alkenes and 1,1-
dichloro-1-alkenes do not behave the same way in palladium-
catalyzed cross-coupling reactions. Thus, whereas it is easy to
be selective of monosubstitution with 1,1-dibromo-1-alkenes,
1,1-dichloro-1-alkene electrophiles, in similar classical reaction
conditions, lead always to 2-fold substitution. As monochloro-
olefins are usually regarded as being unsuitable electrophilic
coupling partners, the involvement of the remaining chloride
appears anomalous. As an explanation, Negishi suggested10 the
Palladium-catalyzed cross-coupling reactions represent one
of the most popular and efficient chemical tools used for the
formation of C-C or C-heteroatom bonds. Many electrophilic
(2) (a) Takada, N.; Sato, H.; Suenaga, K.; Arimoto, H.; Yamada, K.;
Ueda, K.; Uemura, D. Tetrahedron Lett. 1999, 40, 6309-6312. (b) Strobel,
G.; Li, J.; Sugawara, F.; Koshino, H.; Harper, J.; Hess, W. M. Microbiology
1999, 145, 3557-3564.
2
coupling partners (typically halogenated Csp ) can react with a
wide variety of organometallic species from which alkyl,
alkenyl, aryl, or alkynyl groups are transferred.1 During the
course of our investigations on the total synthesis of the
macrolactone haterumalide NA2 (Figure 1), we planned to use
a retrosynthetic disconnection implying a yet unexplored
Suzuki-Miyaura3 cross-coupling between 1,1-dichloro-1-alk-
enes and 9-alkyl-9-BBNs leading to Z-chloroalkenes as repre-
sented in eq 1.
(3) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(4) Chou, T.; Kuramoto, M.; Otani, Y. Shikano, M.; Yazawa, K.; Uemura,
D. Tetrahedron Lett. 1996, 37, 3871-3874.
(5) Kuramoto, M.; Tong, C.; Yamada, K.; Chiba, T.; Hayashi, Y.;
Uemura, D. Tetrahedron Lett. 1996, 37, 3867-3870.
(6) For a review, see: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176-4211.
(7) (a) Molander, G. A.; Yokoyama, Y. J. Org. Chem. 2006, 71, 2493-
2498. (b) Uenishi, J.’i.; Matsui, K.; Ohmiya, H. J. Organomet. Chem. 2002,
653, 141-149. (c) Ogasawara, M.; Ikeda, H.; Hayashi, T. Angew. Chem.,
Int. Ed. 2000, 39, 1042-1044. (d) Xu, C.; Negishi, E.-i. Tetrahedron Lett.
1999, 40, 431-434. (e) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873-
8879. (f) Roush, W. R.; Koyama, K.; Curtin, M. L.; Moriarty, K. J. J. Am.
Chem. Soc. 1996, 118, 7502-7512.
(8) (a) Minato, A.; Suzuki, K.; Tamao, K. J. Am. Chem. Soc. 1987, 109,
1257-1258. (b) Minato, A. J. Org. Chem. 1991, 56, 4052-4056.
(9) Andrei, D.; Wnuk, S. F. J. Org. Chem. 2006, 71, 405-408.
(10) Tan, Z.; Negishi, E.-i. Angew. Chem., Int. Ed. 2006, 45, 762-765.
(11) Dos Santos, M.; Franck, X.; Hocquemiller, R.; Figade`re, B.; Peyrat,
J.-F; Provot, O.; Brion, J.-D.; Alami, M. Synlett 2004, 2697-2700.
(12) Barluenga, J.; Moriel, P.; Aznar, F.; Valde´s, C. AdV. Synth. Catal.
2006, 348, 347-353.
Such a new cross-coupling process would provide a straight-
forward access to molecules bearing a Z-chloroalkene function,
which also occurs in some other natural products such as pinnaic
† ICSN.
‡ ENSCP.
§ ENS.
(1) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-i., Ed.; Wiley-Interscience: New York, 2002; Vol. 1.
(13) Ratovelomanana, V.; Hammoud, A.; Linstrumelle, G. Tetrahedron
Lett. 1987, 28, 1649-1650.
10.1021/jo061908w CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/21/2007
2220
J. Org. Chem. 2007, 72, 2220-2223

SCHEME 1. 1,1-Dichloro-olefins
FIGURE 2. Phosphine ligands used for our investigations.
TABLE 1. Influence of the Solventa
entry
solvent
T [°C]
conversion [%]b
11 [%]b
12 [%]b
1
2
3
4
5
Et2O
Et2O
benzene
THF
DMF
20
36
80
20
66
nd
35
85
nd
64
28
18
14
27
2
9
5
9
1
31
b
c
a Method A. Method B. Commercially available.
SCHEME 2. Cross-Coupling Test Reaction
a Reactions conducted with PdCl2(dppf) (2 mol %), 10 (1 equiv), K3PO4,
and KF (3 equiv). b Isolated yield.
reaction, we chose the coupling of 1,1-dichloro-1-alkene 2 with
1 equiv of 9-(3-phenylpropyl)-9-BBN 10 (Scheme 2). The
PdCl2(dppb) catalyst was reported to give double substitution
with alkylzinc nucleophiles.8 In our case, this catalyst led to
decomposition along with the formation of only a small amount
of the 2-fold substituted product 12.
persistence of the usually transitory palladium(0)-olefin com-
plex generated at the reductive elimination step. Within this
complex, a subsequent second oxidative insertion in the C-Cl
bond would be facilitated. With 9-alkyl-9-BBN nucleophiles,
as in the case of alkylzinc nucleophiles,8 we observed that dppf
or dppp bisphosphines mainly promoted biscoupling. TLC
monitoring showed only traces of the monocoupled product
during the course of the reaction suggesting a one-step process
that matches well the Negishi’s mechanistic suggestion. On the
other hand, we also observed that the dppp ligand can promote
cross-coupling reactions with monochloro-olefins (Table 3),
showing that a concurrent pathway can also yield biscoupled
products starting from 1,1-dichloro-olefins. Thus, as we started
our investigations, it appeared that the recurrent challenge with
1,1-dichloro-1-alkene electrophiles was to achieve monocoupling
selectively.
In a first stage, we prepared a set of 1,1-dichloro-1-alkenes
from various aldehydes by adapting known procedures (Scheme
1). From nonenolizable aldehydes, the reaction with chloroform
in DBU led to 1,1,1-trichloroalkan-2-ols that were subjected to
a subsequent one-pot acetylation followed by an elimination
promoted by zinc in acetic acid (method A).14 From all other
aldehydes, the 1,1,1-trichloroalkan-2-ol key intermediates were
obtained under milder conditions utilizing the reaction of CCl4
in the presence of aluminum and a catalytic amount of lead(II)
salt in DMF (method B).15 Subsequent acetylation and elimina-
tion steps gave 1,1-dichloro-olefins.
With PdCl2(dppf) in solvents of low polarity such as THF,
Et2O, or benzene (Table 1), more satisfactory results were
obtained as the monochlorinated product 11 was the major
product formed (11/12 ratio between 14:9 and 27:1), whereas
in DMF (Table 1, entry 5), the bissubstituted product 12 was
formed almost exclusively. At this point, nonpolar solvents thus
appeared instrumental in providing monoalkylated products.
Moreover, when using PdCl2(dppf) as the catalyst, the nature
of the 1,1-dichloro-1-alkene strongly influenced the mono/
biscoupling selectivity. Indeed, the coupling of electron-rich 1,1-
dichloro-1-alkenes such as 2 or 5 with alkyl-9-BBN 10 in THF
led to larger amounts of biscoupled products (12 and 28),
whereas under the same conditions, electron-poor substrates such
as 3 or 4 led to the exclusive formation of monocoupled
products. This observation seems in opposition with the as-
sumption that electron-rich electrophilic coupling partners are
less reactive, but it makes sense if the persistent palladium(0)/
monochloro-olefin complex is more stable when the olefin is
electron rich.
Accordingly,8 monodentate ligands such as PPh3 or 2-(dicy-
clohexylphosphino)biphenyl (Figure 2, L4)16 only led to product
12 with poor yields (Table 2, entries 1 and 2). This demonstrated
that selective monosubstitution requires bidentate bisphosphine
ligands. Moreover, the use of bisphosphines with a small
P-Pd-P bite angle θ and with a less rigid skeleton such as
dppp also led mainly to product 12 (Table 2, entry 4) and, even
worse, to decomposition in the case of dppb (entry 5).
We then focused on bidentate ligands with larger P-Pd-P
bite angles θ.17 Indeed, Negishi recently demonstrated by using
To establish the best Suzuki-Miyaura cross-coupling condi-
tions, we evaluated a broad range of phosphine ligands,
palladium catalyst precursors, bases, and solvents. As a model
(14) Aggarwal, V. K.; Mereu, A. J. Org. Chem. 2000, 65, 7211-7212.
(15) Tanaka, H.; Yamashita, S.; Yamanoue, M.; Torii, S. J. Org. Chem.
1989, 54, 444-450.
(16) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722-9723.
J. Org. Chem, Vol. 72, No. 6, 2007 2221

TABLE 2. Influence of the Catalysta
TABLE 3. Cross-Coupling of Various 1,1-Dichloro-olefins with
Various 9-Alkyl-9-BBNs
entry
palladium catalyst
conversion [%]b
11 [%]b
12 [%]b
1
2
3
4
5
6
7
PdCl2(PPh3)2
Pd(OAc)2, L4
PdCl2(dppf)
PdCl2(dppp)
PdCl2(dppb)
60
78
64
5
0
2
6
30
19
31
45
trace
<1
<1
92
100
100
100
0
Pd2(dba)3-DpePhos
Pd2(dba)3-XantPhos
58-65
72
a Reactions conducted in refluxing THF, with 2 mol % of Pd and with
KF and K3PO4 (3 equiv). b Isolated yield.
DpePhos that a larger θ provides a good selectivity of mono-
coupling of alkylzinc with 1,1-dichloro-1-alkenes.10
In our case, the use of DpePhos in the cross-coupling of
9-alkyl-9-BBN with 1,1-dichloro-1-alkenes had a dramatic
effect: not only the yield increased but also the second coupling
was suppressed (Table 2, entry 6). We also performed experi-
ments with XantPhos, which has an even larger bite angle θ,
and we selectively obtained monocoupled Z-chloro-olefin18 with
a significantly better yield (Table 2, entry 7, Z/E 96:4). However,
with DMF as solvent, the mono-/biscoupling ratio fell.
The effect of the base is significant. Using the KF-K3PO4
combination turned out to be a good solution in most cases.
Replacement of KF by NaF led to lower cross-coupling yields.
With KF or K3PO4 alone in THF, no reaction took place, and
the addition of water led, in both cases, to a slow and incomplete
coupling reaction, thus establishing the need of a concomitant
use of a fluoride anion source along with a higher pH. In some
cases, the Cs2CO3-CsF couple appears to be a good alternative
to K3PO4-KF as it allows significantly better yields (Table 3,
entries 1, 9, 10, and 12) and E/Z selectivities (entries 1, 4, and
12) and/or higher reaction rates (entries 3, 11, and 12). The
reaction rate being already quite slow, the use of lower palladium
loads was not studied.
As demonstrated by the cross-couplings of various 9-alkyl-
9-BBNs with various 1,1-dichloro-1-alkenes (Table 3), the
conditions we established (Pd2(dba)3, (2.5 mol %), couple
F--base and XantPhos (5 mol %) in refluxing THF) are general.
The observed yields are generally good, and the selectivity of
monocoupling is almost total in every case. The Z/E ratio is
generally excellent, being in most cases superior to 95:5. As it
could be expected, the nature of the 1,1-dichloro-1-alkene has
some effects. The higher reaction rate is observed with electron-
poor styrene substrates (Table 3, entries 1 and 6). Electron-rich
styrene 1,1-dichloro-1-alkenes such as compounds 2 and 5 gave
negligible amounts of 2-fold coupled compounds 12 and 28
(entries 2, 3, and 8). This correlates with the observation
previously made with the dppf ligand. With vinylidene chloride
8, we failed to give any coupling product, but trichloroethylene
9 reacted when using our conditions. Previous investigations
demonstrated the capricious nature of trichloroethylene 9 as an
electrophile in cross-coupling reactions. Depending on the
reaction conditions, coupling took place at the bischlorinated
extremity19 or at the monochlorinated extremity.20 Under our
conditions (Scheme 3), with KF-K3PO4 as the bases couple,
(17) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes,
P. Chem. ReV. 2000, 100, 2741-2769.
1
(18) Configuration determined by H NMR NOESY experiments.
(19) Okamoto, Y.; Yoshikawa, Y.; Hayashi, T. J. Organomet. Chem.
1989, 359, 143-149.
(20) Ratovelomanana, V.; Linstrumelle, G.; Normant, J.-F. Tetrahedron
Lett. 1985, 26, 2575-2576.
1
a Isolated yield. b Determined by H NMR spectroscopy. c KF-K3PO4
couple. d CsF-Cs2CO3 couple. e 1% of biscoupling adduct 12 was isolated.
f 2% of biscoupling adduct 28 was isolated.
2222 J. Org. Chem., Vol. 72, No. 6, 2007

SCHEME 3. Coupling with Trichloroethylene 9
TABLE 4. Synthesis of Trisubstituted Olefins
bisphosphine ligand to obtain an efficient preparation of
chlorinated internal alkenes of Z-configuration along with
suppression of the 2-fold substitution side reaction. This could
result from a faster decomposition rate of the unusually
persistent palladium(0)-chloro-olefin complex due to the geo-
metrical constraints imposed by a large bite angle and rigid
bisphosphine ligand. Moreover, this approach leads to an
efficient synthesis of trisubstituted alkenes with control of the
geometry.
Experimental Section
Typical Procedure for Stereoselective Monocoupling. A
terminal alkene (1.2 mmol) was added to a solution of 9-BBN (0.5
M in THF, 2.4 mL, 1.2 mmol). The solution was stirred at room
temperature for 1 h under an argon atmosphere. A solution of the
1,1-dichloro-1-alkene (1.0 mmol) in THF (2 mL) was added
followed by Pd2(dba)3 (23.1 mg, 2.5 mol %), XantPhos (28.5 mg,
5 mol %), KF (180 mg, 3.0 mmol), and K3PO4 (635 mg, 3.0 mmol)
(method A). Alternatively, CsF (454.4 mg, 3.0 mmol) and Cs2CO3
(979.6 mg, 3.0 mmol) were used instead of KF and K3PO4 (method
B). The solution was refluxed under argon until completion (see
Table 3 for reaction times). After cooling to room temperature, the
reaction mixture was quenched with water and extracted with CH2-
Cl2. The combined organic layers were dried over Na2SO4 and
concentrated under vacuum. The residue was purified by column
chromatography affording the monocoupled product.
(Z)-2-Chloro-1-(4-methoxyphenyl)-5-phenylpent-1-ene (11):
prepared according to typical procedures from allylbenzene (495
µL, 4.17 mmol) and 1,1-dichloro-1-alkene 2 (609 mg, 3.00 mmol).
Purification by column chromatography (heptane/CH2Cl2, 85:15)
afforded 1 as a colorless solid (741 mg, 86%, method A; 758 mg,
88%, method B). Mp 95-96 °C; IR (solid) 2931, 2360, 1605, 1508,
1247, 1176, 1032 cm-1; 1H NMR (CDCl3, 300 MHz) δH 2.00 (m,
2H), 2.49 (t, J ) 7.2 Hz, 2H), 2.67 (t, J ) 7.5 Hz, 2H), 3.81 (s,
3H), 6.39 (s, 1H), 6.88 (dd, J ) 2.1, 6.6 Hz, 2H), 7.20 (d, J ) 6.9
Hz, 2H), 7.25-7.32 (m, 3H), 7.57 (dd, J ) 2.1, 6.9 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δC 29.1, 34.6, 40.5, 55.2, 113.5, 124.1,
125.9, 127.7, 128.3, 128.5, 130.3, 132.5, 141.8, 158.8; MS (EI)
m/z 288 (M+, 37Cl), 286 (M+, 35Cl), 181, 159, 147, 145, 131, 121,
115. Anal. calcd. for C18H19ClO: C, 75.38; H, 6.68. Found: C,
75.32; H, 6.86.
a Conditions A: PdCl2(dppp), (7 mol %), borane, KF and K3PO4 (3
equiv), THF, reflux. b Conditions B: Pd2(dba)3, (2.5 mol %), 2-(dicyclo-
hexylphosphino)biphenyl (5 mol %), borane, KF, K3PO4 (3 equiv), THF,
reflux. c 26% of 11 was recovered.
we observed the formation of two products of Z-configuration:
1,2-dichloro-1-alkene 29 resulting from the coupling of one
borane unit at C-1 and monochloro-olefin 30 in which one
borane unit was coupled at both the C-1 and C-2 positions.18
Having established efficient and selective Suzuki-Miyaura
conditions affording monochlorinated olefins, we briefly studied
the preparation of stereospecifically trisubstituted alkenes. The
2-(dicyclohexylphosphino)-biphenyl ligand (Figure 2), well-
known to promote coupling with chlorinated electrophilic
coupling partners,16 allowed cross-couplings of some of our
Z-chloroalkenes with various boron nucleophiles as shown in
Table 4. Surprisingly, PdCl2(dppp) also proved to be a suitable
catalyst for this reaction. The coupling of monochlorinated
olefins 17 and 11 with phenylboronic acid 34 yielded com-
pounds 3521 and 36 which are analogues of the antiangiogenic
agent combretastatin.
Acknowledgment. We wish to thank Dr. Robert H. Dodd
(Institut de Chimie des Substances Naturelles) and Dr. Yves
Janin (Institut Pasteur) for fruitful discussions and the CNRS
for its financial support.
Supporting Information Available: Experimental procedures
and spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Conclusion
JO061908W
We have developed a new application of the Suzuki-Miyaura
cross-coupling reaction between 9-alkyl-9-BBNs and 1,1-
dichloro-1-alkenes. This required the use of a large bite angle
(21) For a closely related homologue of compound 35: Yamanoi, S.;
Seki, K.; Matsumoto, T.; Suzuki, K. J. Organomet. Chem. 2001, 624, 143-
150.
J. Org. Chem, Vol. 72, No. 6, 2007 2223