Palladium(0)-catalyzed cross-coupling of potassium (z)-2-chloroalk-1-enyl trifluoroborates: A chemo- and stereoselective access to (z)-chloroolefins and trisubstituted alkenes

Article abstract of DOI:10.1002/chem.200900425

We describe the preparation of a series of new potassium trifluoroborates 1 and the study of their behaviour in a Pd⁰-catalyzed cross-coupling reaction. We found that compounds 1 are endowed with original properties as they behave as nucleophil

Full text of DOI:10.1002/chem.200900425

FULL PAPER
DOI: 10.1002/chem.200900425
Palladium(0)-Catalyzed Cross-Coupling of Potassium (Z)-2-Chloroalk-1-enyl
Trifluoroborates: A Chemo- and Stereoselective Access to (Z)-Chloroolefins
and Trisubstituted Alkenes
Xavier Guinchard, Xavier Bugaut, Cyril Cook, and Emmanuel Roulland*[a]
Abstract: We describe the preparation of a series of new potassium trifluorobo-
rates 1 and the study of their behaviour in a Pd0-catalyzed cross-coupling reaction.
We found that compounds 1 are endowed with original properties as they behave
as nucleophilic cross-coupling partners chemoselectively but also as ambivalent
synthons. The usefulness of this methodology has been successfully illustrated by
the first total synthesis of an N-acyl spermidine.
Keywords: alkenes · boron · cross-
coupling · palladium · vinyl chloride
Introduction
The (Z)-chloroolefin functionality occurs in numerous natu-
ral or synthetic biologically active or pharmaceutically rele-
vant compounds, making the development of methods for
the synthesis of this structural motif an interesting area of
investigation. Among the natural products bearing a (Z)-
chloroolefin functionality are, for instance, the biselide and
haterumalide family,[1] chagosensine,[2] spongistatin,[3] auran-
tosides,[4] halichlorine[5] and pinnaic acid.[6] Among synthetic
and biologically active products one can find, for instance,
Scheme 1. Transformations of potassium (Z)-2-chloroalk-1-enyltrifluoro-
borates 1. a) Chemoselective Pd0-catalyzed cross-coupling involving the
nucleophilic pole of 1 to yield 2. b) Substitution of the chlorine atom of 2
giving 3. c) One-pot access to trisubstituted alkenes giving 3 from 1.
pyrethroids that are widely used selective insecticides.[7]
Since the Pd0-catalyzed cross-coupling reaction of chlorinat-
ed olefins has been rendered efficient thanks to the develop-
ment of new ligands,[8] (Z)-chloroolefins 2 (Scheme 1) may
also be regarded as suitable intermediates for the still chal-
lenging stereoselective synthesis of trisubstituted olefins 3.[9]
Furthermore, the Suzuki–Miyaura cross-coupling[10] has re-
ceived an important improvement with the use of organotri-
fluoroborates chemistry as demonstrated by Genet et al.[11]
and as widely implemented by Molander et al.[12] Combining
these two considerations, we reasoned that potassium (Z)-2-
catalyzed reactions. As underlined in a recent review by Ne-
gishi et al.,[13] the chemistry of 2-halo-1-boro-1-alkene deriv-
atives remains hitherto not fully exploited in the context of
the Pd0 cross-coupling chemistry. We wish to report herein
the synthesis of compounds 1 and the study of their reactivi-
ty in Pd0-catalyzed cross-coupling reactions and its applica-
tion in the total synthesis of an N-acyl spermidine. This
study is a part of our program on the development of new
synthetic methods to access (Z)-chloroolefins 2 and their ap-
plications to natural product total synthesis. In a previous
paper,[14] we described a first efficient stereoselective access
to (Z)-chloroolefins 2 by the Suzuki–Miyaura cross-coupling
of 1,1-dichloro-1-alkenes 4 with 9-alkyl-9-BBN 5; further
transformation of compounds 2 led stereoselectively to the
corresponding trisubstituted alkenes 3 (Scheme 2). The effi-
ciency of this methodology was illustrated by our total syn-
chloroalk-1-enyltrifluoroborate derivatives
1 (Scheme 1)
would behave as ambivalent cross-coupling partners in Pd0-
[a] Dr. X. Guinchard, X. Bugaut, C. Cook, Dr. E. Roulland
CNRS-Institut de Chimie des Substances Naturelles
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
Fax : (+33)1-6907-7247
E-mail: emmanuel.roulland@icsn.cnrs-gif.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900425.
Chem. Eur. J. 2009, 15, 5793 – 5798
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5793

thesis of (+)-oocydin A/haterumalide NA 6 (Scheme 2).[15]
One must notice that Negishi et al. reported an alternative
cross-coupling of 1,1-dichloro-1-alkenes 4 with alkylzinc re-
agents.[16] Nevertheless, the synthetic methods for (Z)-chloro-
olefins 2 described above suffer from some limitations: i)
they are restricted to alkyl nucleophilic coupling partners, ii)
starting material 4 is neither commercially available nor
straightforwardly accessed, iii) these cross-coupling reactions
require the use of a somewhat expensive ligands (XantPhos
or DpePhos).
fluoroborate derivatives 1 (Scheme 3) starting from the
well-known chloroboration reaction of terminal alkynes by
BCl3.[17] This reaction is stereospecific as it results from the
À
syn addition of BCl3 to the C C triple bond. Furthermore
this reaction is highly regioselective as it always delivers the
boron atom at the terminal position leading to intermediate
7 (Scheme 3).[20] The transformation of intermediates 7 into
their corresponding potassium trifluoroborate salts 1 was
performed by a treatment with an aqueous solution of
KHF2 (Scheme 3, method A). With most alkynes, yields
were nevertheless increased by synthesizing the cyclic bor-
onic ester of 2-methylpentane-2,4-diol[21] 8 as an intermedi-
ate which was subsequently transformed into 1 by treatment
with KHF2 in water (Scheme 3, method B). Thus, we ob-
tained a series of pure (Z)-potassium trifluoroborate salts 1
in poor to good yields (34 to 80%) from both aromatic or
aliphatic terminal alkynes.[22] The poor yields being mostly
due to purification problems. This inexpensive process was
easily performed on large scale (40 mmol), furnishing 1 as
stable salts that can be kept on the shelf for a long period of
time. As we were writing this article, the synthesis of a bro-
minated analogue of 1c (Scheme 3) has been reported
through a similar method, but no mention of its reactivity
was made.[23]
Scheme 2. Our previous study on the synthesis of chlorovinylic com-
pounds 2 and our target (+)-oocydin A/haterumalide NA (6).
Compounds such as 1 are new and not previously de-
scribed potassium trifluoroborate derivatives. Very few ana-
logues of 1 have been reported in the literature and even
less studied in Pd0-catalyzed chemistry. Among these, 2-
iodo- and 2-bromo-1-vinyl-9-BBN derivatives were synthe-
sized by haloboration of alkynes, while the corresponding
chlorinated olefin could not be obtained this way because 9-
chloro-9-BBN do not react with alkynes.[17] Furthermore, 2-
bromo-1-vinyl-9-BBN and their corresponding cyclic esters
of 2-bromo-1-vinyl-borane were tested as coupling partners
with no success.[17] Only the products of bromoboration of
alkynes by BBr3 were successfully engaged in Pd0-catalyzed
reactions.[17,18] Thus, with alkylzinc reagents as coupling part-
ners, the substitution of the bromine atom furnished the cor-
responding sensitive boronic halides that were directly sub-
mitted to Suzuki–Miyaura cross-coupling conditions yielding
trisubstituted alkenes. Closely related to this is the polyene
synthesis methodology developed by Burke et al. using B-
protected trans-haloalkenylboronic acid derivatives.[19]
Whilst efficient for preparation of trisubstituted alkenes,
these methods do not furnish access to halogenated alkenes.
Scheme 3. Synthesis of potassium (Z)-2-chloroalk-1-enyltrifluoroborates
1: a) BCl3, CH2Cl2, RT, then H2O, 0 8C, KHF2. b) BCl3, CH2Cl2, RT, then
2-methylpentane-2,4-diol. c) KHF2, H2O/MeOH, RT.
Results and Discussion
Synthesis of potassium (Z)-2-chloroalk-1-enyltrifluoroborate
derivatives 1: The main goal of our study was to synthesize
(Z)-chlorovinylic derivatives 2 from (Z)-2-chloroalk-1-enyl-
trifluoro-borates 1 by Pd0 cross-coupling. Hence, we expect-
ed to establish reaction conditions allowing the nucleophilic
pole of 1 to react chemoselectively while the chlorine atom
would remain intact. Before this, we investigated reaction
conditions to access potassium (Z)-2-chloroalk-1-enyltri-
Studies of the palladium-catalyzed reaction of potassium
(Z)-2-chloroalk-1-enyltrifluoroborate derivatives 1: We then
focused on the study of the Pd0-catalyzed cross-coupling of
these new organotrifluoroborates 1. With potassium trifluoro-
borate 1a as a test compound facing methyl 4-iodobenzoate
as coupling partner, we targeted vinylic chloride 2a. The
first trials (Table 1) readily demonstrated that classical
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Chem. Eur. J. 2009, 15, 5793 – 5798

Palladium(0)-Catalyzed Cross-Coupling Reactions
FULL PAPER
Table 1. Optimization of the cross-coupling conditions on a test reaction.
Suzuki–Miyaura reaction condi-
tions were not suitable (Table 1,
entries 1,2). We shifted towards
large bite angle phosphines[24]
such as XantPhos or DpePhos,
assuming that the intermediate
stemming from the reductive
elimination step should be simi-
lar to the one formed in the
course of the cross-coupling of
1,1-dichloroalkenes 4 which we
Entry
Pd source, ligand
[PdCl2A
(dppf)][a]
[PdCl2A
(dppf)][a]
[Pd2A
(dba)3], XantPhos[e]
[Pd2A
(dba)3], XantPhos[e]
[Pd2A
(dba)3], XantPhos[e]
[Pd2A
(dba)3], XantPhos[e]
[Pd2A
(dba)3], XantPhos[f]
[Pd2A
(dba)3], DpePhos[e]
PdCl2, RuPhos[g]
[Pd2A(dba)3], P(tBu)3·HBF4
PdCl2, P(tBu)3·HBF4
[Pd2A(dba)3], P(tBu)3·HBF4
[Pd2A(dba)3], P(tBu)3·HBF4
Base[b], solvent[c]
T, reaction time
Isolated yield [%] 2a (9a)
1
2
3
4
5
6
7
8
G
G
K3PO4, THF
reflux, 48 h
reflux, 48 h
908C, 16 h[j]
908C, 90 h[j]
908C, 36 h[j]
908C, 20 h[j]
908C, 20 h[j]
908C, 16 h[j]
reflux, 60 h
908C, 20 h[j]
reflux, 60 h
reflux, 90 h
1208C, 12 h[j]
n.r.
n.r.
E
K3PO4, THF/H2O
K3PO4, THF/H2O
KOH, THF/H2O
Cs2CO3, THF/H2O
K3PO4, PhMe/H2O
Cs2CO3, THF/H2O
Cs2CO3, THF/H2O
Cs2CO3/THF/H2O
Cs2CO3, THF/H2O
Cs2CO3, THF/H2O
Cs2CO3, THF/H2O
Cs2CO3, THF/H2O[d]
E
E
50 (25)[k]
50[k]
70 (20)[k]
n.r.
R
CHTUNGTRENNUNG
R
CHTUNGTRENNUNG
E
CHTUNGTRENNUNG
previously
studied
N
N
85
n.r.
36
63
72
81
92
(Scheme 2).[14] Actually, using
one molecule of XantPhos per
palladium, we succeeded in per-
forming the desired coupling
but with the formation of the
unwanted alkyne derivative 9a
(Table 1, entries 3, 5). When
using two molecules of Xant-
Phos per palladium, the reac-
tion was cleaner (Table 1,
entry 7) but was difficult to re-
produce with other substrates.
R
E
9
[h]
10
11
12
13
G
N
G
[g]
E
[h]
[i]
R
U
R
A
N
A
[a] (5 mol%). [b] Base: 3 equiv [c] conc. 0.15m, THF/H2O or PhMe/H2O 9:1. [d] conc. 0.7m, THF/H2O 3:4.
[e] [Pd2A(dba)3] (1.5 mol%), phosphine (3 mol%). [f] [Pd2A(dba)3] (1.5 mol%), XantPhos (6 mol%). [g] PdCl2
(5 mol%), phosphine (10 mol%). [h] [Pd2A(dba)3] (2.5 mol%), (tBu)3·HBF4A(5 mol%). [i] [Pd2A(dba)3]
(1.5 mol%), P
(tBu)3·HBF4 (3 mol%). [j] Sealed tube. [k] 1H NMR estimated yield. dba=dibenzylidene ace-
C
CHTUNGTRENNUNG
C
P
A
G
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
tone, dppf=1,1’-Bis(diphenylphosphino)ferrocene, XantPhos=9,9-dimethyl-4,5-bis(diphenylphosphino)xan-
thene, DpePhos=(Oxydi-2,1-phenylene)bis(diphenylphosphine), RuPhos=2-Dicyclohexylphosphino-2’,6’-dii-
sopropoxybiphenyl.
Surprisingly, DpePhos gave no reaction (Table 1, entry 8).
The Buchwaldꢁs ligand RuPhos, known to allow the coupling
of potassium trifluoroborates,[25] was used but furnished 2a
vestigated. This experiment seems to indicate that potassium
trifluoroborates 1 are superior to their boronic ester ana-
logues 8 at least as reagents for the synthesis of (Z)-chloro-
olefins 2.
in poor yield (Table 1, entry 9). Finally, we tried the P
ligand developed by Fu.[26] Various palladium sources were
tried, and the combination of [Pd2A(dba)3] (1.5 mol%) with
(tBu)3·HBF4 (3 mol%) turned out to give the best yields
ACHTUNGERTN(NUNG tBu)3
In order to explore the scope of this reaction, we conduct-
ed cross-couplings upon 1a with various halogenated cou-
pling partners (Table 2, entries 1–10). Thus, the reactions
proceeded with moderate to good yields (46 to 91%) with a
large variety of both iodinated (Table 2, entries 1, 9, 10) or
brominated (Table 2, entries 1–6) aromatic compounds, as
iodinated (Table 2, entry 7) or brominated (Table 2, entry 8)
olefins, demonstrating that this reaction is compatible with
electron-rich (Table 2, entries 2, 4, 5, 9, 10) and electron-
poor (Table 2, entries 1, 3, 6) aromatic substrates. Interest-
ingly, the coupling of 1a with 2-iodophenol furnished 2-pen-
tylbenzofurane 2j (58%, Table 2, entry 10). This product
likely originates from a domino process in the course of
which the expected Suzuki coupling occurs followed by an
intramolecular Ullmann-type reaction. However, the cou-
pling of 1a with 2-iodoaniline only gave aniline derivative 2i
(74%, Table 2, entry 9) and not the corresponding 2-penty-
lindole.
CTHUNGTRENNUNG
P
ACHTUNGTRENNUNG
particularly at 1208C in a sealed tube with more concentrat-
ed conditions (0.7 molLÀ1) offering then a markedly short-
ened reaction time (Table 1, entry 13). The Z configuration
of 2a was confirmed by comparison with the NMR data of
known analogues with very closely related structures.[14]
Lower palladium loads led to lower yields. Other solvents
(DMF, dioxane, toluene, EtOH) and other bases (K3PO4,
CsF, CsOH, KOH, TMSOK) were also tried but with no sat-
isfactory results. It is important to note that the reaction
conditions that we have established here are unexpectedly
chemoselective. Despite the use of the strongly activating P-
ACHTUNGTRENNUNG(tBu)3 ligand, we actually observed that 1a is neither reac-
tive enough to cross-couple with itself, nor with any chlori-
nated electrophilic coupling partner. We assume that for
both steric and electronic reasons, each pole of the ambiva-
lent synthon 1 deactivate the other: i) the double bond that
The cross-coupling of potassium (Z)-2-chloroalk-1-enyltri-
fluoroborates 1b to 1g also proceeded successfully using
methyl 4-iodobenzoate as coupling partner (Table 2, en-
tries 11, 14–18) giving mostly satisfactory yields (36 to
81%). Interestingly, the coupling of chlorinated electro-
is electron-enriched by the trifluoroborate group, might
0
À
render oxidative insertion of Pd into the C Cl bond more
difficult. ii) the nucleophilicity of the trifluoroborate func-
tion might also be diminished probably because of the chlor-
ine atomꢁs electron-withdrawing effect, leading to a more
difficult transmetallation step.
philes failed despite the use of PACHTNUTRGNEUNG(tBu)3 as ligand (Table 2,
entries 1, 6) correlatively, potassium (Z)-2-chloroalk-1-enyl-
trifluoroborate 1e yielded the dichlorinated compound 2p
in 81% (Table 2, entry 16). In all these above described
cross-couplings, the geometry of the double bond remained
intact.[28]
We obviously also explored the behaviour of cyclic boron-
ic ester 8a[27] (Scheme 3) and obtained coupling product 2a,
unfortunately always accompanied by an important propor-
tion of the side product 9a despite numerous conditions in-
Chem. Eur. J. 2009, 15, 5793 – 5798
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5795

E. Roulland et al.
Table 2. Synthesis of (Z)-chloroalkenes 2 by coupling of potassium (Z)-
2-chloroalk-1-enyltrifluoroborates 1.
Table 2. (Continued)
Entry
1
Halide
Product
Yield
[%][a]
17
18
1 f
1g
2q, 79
Entry
1
1
Halide
Product
Yield
[%][a]
2r, 50[g]
2a, X=I,
91
[a] Isolated yields. [b] Reaction time: 48 h. [c] Reaction time: 36 h.
[d] Reaction time: 72 h in a sealed tube with 2.5 mol% of [Pd(P(tBu)3)2]
1a
X=Br,
63[b]
ACHTUNGTRENNUNG
catalyst at 808C. [e] Due to its high volatility 2 equiv of 1-bromo-2-meth-
ylprop-1-ene were used. [f] The corresponding alkyne derivative 9b was
formed in 16% yield. [g] Obtained as a Z/E 62:38 separable mixture.
X=Cl, 0
2
3
1a
1a
2b, 70
2c, 46
Synthesis of trisubstituted alkenes 3: We investigated condi-
tions in order to obtain trisubstituted alkenes 3 by substitu-
tion of the chlorine atom of chloroalkenes 2 by coupling
with commercially available potassium trifluoroborates
(Table 3). Various studies[25,29] described the coupling of aryl
or vinyl potassium trifluoroborates with arylchlorides but, to
the best of our knowledge, no cross-coupling of vinylic chlo-
ride was reported. Inspired by these, we found out that
using RuPhos as palladium ligand with Cs2CO3 as base, in a
mixture of THF and water at 808C, provided trisubstituted
alkenes 3 in good yield (69 to 99%) and importantly with
full conservation of the double-bond geometry.[30] We also
demonstrated that we could efficiently substitute the chlor-
ine atom by a methyl group using trimethylboroxine as dem-
onstrated by the synthesis of olefin 3e from chloroalkene 2a
(Table 3, entry 5). The few precedents involved activated ar-
omatic electrophilic coupling partners[31] and, to the best of
our knowledge, only one cross-coupling methodology was
described which involved non-activated aryl chlorides.[32]
This useful transformation offers an interesting stereoselec-
tive access to the 1,2-disubstituted (E)-prop-1-enylidene
motif and thus to the class of polyenes natural products
which is a important and large family.[33]
4
5
1a
1a
2d, 77[c]
2e, 56[c]
2 f, X=Br,
25[f]
X=Cl,
deg.
6
1a
7
8
1a
1a
2g, 81[d]
2h, 70[e]
9
1a
1a
1b
2i, 74
2j, 58
2k, 36
10
11
We also investigated the conditions of a one-pot–two-
steps sequence targeting a rapid elaboration of trisubstituted
alkenes by assembling our ambivalent synthon 1 with two
other components (Table 3, method B). We have already es-
tablished above that the RuPhos ligand is not suitable for
the first step involving the nucleophilic pole of 1. We found
12
13
14
1c
1c
1c
2l, 70
2m, 46
2n, 80
that palladium with PACTHNUTRGNEUNG(tBu)3 as ligand, allowed the two steps
to proceed. Thus, once the first coupling step achieved, the
introduction in the reaction medium of a third component
such as an aryl or a vinyl potassium trifluoroborate along
with more [Pd2ACHTNUGRTENNUG(dba)3] and PCAHTUNGTRNEN(UGN tBu)3, led to the substitution of
the chlorine atom furnishing the desired trisubstituted al-
kenes 3 in a range of 26 to 56% yield.
15
16
1d
1e
2o, 52
2p, 81
Application of the methodology in total synthesis: In order
to illustrate the usefulness of our methodology, we per-
formed a short and efficient total synthesis of the N-acyl
spermidine 11 (Scheme 4). This natural product isolated
from the soft coral Sinularia sp.[34] bears a (E,Z)-dienic
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Palladium(0)-Catalyzed Cross-Coupling Reactions
FULL PAPER
Table 3. Synthesis of trisubstituted alkenes from 1 or 2.[a]
tion activity.[35] Using our methodology, we straightforwardly
obtained intermediate 3j in four steps (50% overall yield)
from undecyne with full control of the conjugated diene
configuration. The coupling with amine 10[36] supplied the
targeted N-acyl spermidine derivative 11, the characteriza-
tion data of which were similar to those of the naturally oc-
curring compound.
Entry Product
Method A: Method B:
Yield [%]
Yield [%]
1
3a
87
26[c]
Conclusions
2
3b 89
38
We have prepared and described a series of new potassium
trifluoroborates 1, and studied their behaviour in the con-
text of a Pd0-catalyzed cross-coupling. We found out that
those compounds 1 are endowed with original and versatile
properties as they behave as nucleophilic cross-coupling
partners in a chemoselective manner and also as ambivalent
synthons. Thus, the nucleophilic pole of 1 has reacted che-
moselectively furnishing a series of chloroalkenes 2 with
pure Z geometry. A one-pot–two-steps rapid elaboration of
valuable trisubstituted alkenes 3 has been performed involv-
ing both poles of the synthon 1 successively. The usefulness
of this methodology has been successfully illustrated by the
first total synthesis of the N-acyl spermidine 11.
3
4
5
3c
87
42
56[d]
–
3d 69[b]
3e
3 f
67[e]
84
6
7
44
43
3g
97
Experimental Section
General procedure for the synthesis of potassium trifluoroborates 1: To a
solution of BCl3 (4 mmol, 1m in hexane) in CH2Cl2 (6 mL) under argon
at room temperature was slowly added a solution of the alkyne (1 equiv)
in CH2Cl2 (4 mL). The resulting solution was stirred for 1 h and then
cooled to 08C. Anhydrous Et2O was added (4 mL), followed by a solu-
tion of 2-methylpentan-2,4-diol (1.2 equiv) in Et2O (4 mL). The resulting
solution was allowed to stir at room temperature for 30 min and trans-
ferred to a separating funnel. The organic phase was washed twice by
water, then dried over anhydrous MgSO4, filtered and concentrated
under vacuum. The resulting crude boronic ester was dissolved in MeOH
(4 mL) under argon, and solid KHF2 (3 equiv) was added. H2O (4 mL)
was added dropwise to this mixture over 5 min. The resulting mixture
was stirred at room temperature for 2 h and then fully evaporated under
vacuum. The solids were washed three times by refluxing acetone and
the combined acetone phases were evaporated. The resulting solid was
washed washed by Et2O and dried under vacuum to yield potassium tri-
fuoroborate 1.
8
3h 99
33
[a] Reaction conditions: a) R3BF3K, 2.5 mol% [Pd
RuPhos, 3 equiv Cs2CO3, THF/H2O 9:1, 808C, 12 to 36 h; b) R2X,
1.5 mol% [Pd2A(dba)3], 3 mol% P(tBu)3·HBF4, 3 equiv Cs2CO3, THF/H2O
4:3, 1208C, 12 h, then, R3BF3K, 2.5 mol% [Pd2A(dba)3], 10 mol% P-
ACHTUNGTRENNUNG(tBu)3·HBF4, THF/H2O 9:1, 1008C, 48 h. [b] Obtained as a Z/E mixture
85:15. [c] Contaminated by methyl biphenyl-4-carboxylate. [d] Obtained
as a Z/E mixture 60:40. [e] Using general reaction conditions but without
H2O.
2ACHTUNGTRENUN(NG dba)3], 10 mol%
G
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
motif and is endowed with cytotoxicity against various
human tumour cells[34] and an H+-pyrophosphatase inhibi-
General procedure for the palladium catalysed cross-coupling of potassi-
um trifluoroborates:
(0.5 mmol), halide (0.5 mmol), [Pd
(tBu)3·HBF4 (4.3 mg, 0.015 mmol), Cs2CO3 (489 mg, 1.5 mmol) was
A
mixture of the potassium trifluoroborate
1
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
placed in a Schlenk tube equipped with a magnetic bar. The tube was
purged by three vacuum–argon flush cycles. Freshly distilled THF
(0.4 mL) and degassed H2O (0.3 mL) were added and the Schlenk tube
was sealed and heated at 1208C for 12 h (unless otherwise noted). The
reaction mixture was cooled and filtered through a short pad of silica gel
(elution by EtOAc). The solvents were removed under vacuum and the
residue 2 was purified by chromatography on silica gel.
Representative procedure for the synthesis of trisubstituted alkenes from
vinyl chlorides—Synthesis of 3b from 2a: A mixture of the vinyl chloride
2a (87 mg, 0.327 mmol), potassium 4-methoxyphenyltrifluoroborate
(84 mg, 0.39 mmol), [Pd2ACTHNUTRGNEUNG(dba)3] (4.4 mg, 8.2 mmol), RuPhos (15 mg,
33 mmol), Cs2CO3 (320 mg, 0.98 mmol) was placed in a Schlenk tube
Scheme 4. Total synthesis of N-acyl spermidine 11.
equipped with a magnetic bar. The tube was purged by three vacuum–
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E. Roulland et al.
argon flush cycles. Freshly distilled THF (3 mL) and degassed H2O
(0.3 mL) were added and the Schlenk tube was sealed and heated at
808C for 12 h. The reaction mixture was then cooled and filtered through
a short pad of silica gel (elution by EtOAc). The solvents were removed
under vacuum and the residue was purified by chromatography on silica
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gel (EtOAc/heptane 1:19) to afford 3b as
a colourless oil (98 mg,
0.29 mmol, 89%). Rf =0.18 (EtOAc/heptane 1:9). 1H NMR (300 MHz,
CDCl3): d=0.87 (t, J=7.2 Hz, 3H), 1.25–1.46 (m, 6H), 2.48 (t, J=7.3 Hz,
2H), 3.80 (s, 3H), 3.84 (s, 3H), 6.42 (s, 1H), 6.81 (d, J=8.7 Hz, 2H), 6.99
(d, J=8.4 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.76 ppm (d, J=8.4 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=14.2, 22.6, 27.7, 31.5, 40.8, 52.0, 55.3,
114.1, 125.1, 127.3, 129.0, 129.3, 129.7, 133.0, 142.9, 146.1, 158.9,
167.1 ppm; IR (neat): n˜ =1107, 1177, 1246, 1276, 1510, 1604, 1719, 2856,
2929 cmÀ1; LRMS (ESI): m/z: 361 [M+Na]+; HRMS (ESI): m/z: calcd
for C22H26NaO3: 361.1780; found: 361.1716 [M+Na]+.
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Representative one-pot procedure for the synthesis of trisubstituted al-
kenes 3 from (Z)-2-chloroalk-1-enyltrifluoroborate derivatives 1—Syn-
thesis of 3a from 1a: A mixture of the potassium trifluoroborate 1a
(119 mg, 0.5 mmol), methyl 4-iodobenzoate (130 mg, 0.5 mmol), [Pd2-
ACHTUNGTRENNUNG(dba)3] (6.8 mg, 0.0075 mmol), PACHTNUGRTEG(NNNU tBu)3·HBF4 (4.3 mg, 0.015 mmol),
Cs2CO3 (489 mg, 1.5 mmol) was placed in a Schlenk tube equipped with
a magnetic bar. The tube was purged by three vacuum–argon flush
cycles. Freshly distilled THF (0.4 mL) and degassed H2O (0.3 mL) were
added and the Schlenk tube was sealed and heated to 1208C for 14 h.
The reaction mixture was then cooled and potassium phenyltrifluorobo-
rate (110 mg, 0.6 mmol) was added to the reaction mixture, [Pd
2ACHTUNGTNER(NUNG dba)3]
(6.8 mg, 0.0075 mmol), P(tBu)3·HBF4 (4.3 mg, 0.015 mmol) and additional
ACHTUNGTRENNUNG
THF (2.6 mL). The Schlenk tube was sealed and heated at 1008C for
36 h. The reaction mixture was then cooled and filtered through a short
pad of silica gel (elution by EtOAc). The solvents were removed under
vacuum and the residue was purified by chromatography on silica gel
(EtOAc/heptane 1:19) to afford 3a as a yellow oil (40 mg, 0.13 mmol,
26%). Rf =0.30 (EtOAc/heptane 1:19). 1H NMR (300 MHz, CDCl3): d=
0.87 (t, J=7.2 Hz, 3H), 1.25–1.48 (m, 6H), 2.50 (t, J=7.2 Hz, 2H), 3.84
(s, 3H), 6.45 (s, 1H), 6.95 (d, J=8.5 Hz, 2H), 7.08–7.14 (m, 2H), 7.24–
7.30 (m, 3H), 7.74 ppm (d, J=8.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=14.2, 22.6, 27.7, 31.6, 40.9, 52.0, 125.5, 127.3, 127.5, 128.5, 128.7, 129.0,
129.3, 141.0, 142.5, 146.6, 167.1 ppm; IR (neat): n˜ =1108, 1180, 1276,
1434, 1605, 1720, 2928 cmÀ1; LRMS (EI): m/z: 308 [M]+; HRMS (EI): m/
z: calcd for C21H24O2: 308.1776; found: 308.1777 [M]+.
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geometry
con-
firmed by X-ray diffraction on compound 1c (see Supporting Infor-
mation).
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through the bromoboration of heptyne (see Supporting Information
for full description of 12). Nevertheless, under our standard cross-
coupling conditions, we only observed degradation of 12.
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Acknowledgements
We are grateful to Prof. Jean-Yves Lallemand (ICSN-CNRS) for his per-
manent interest and support. We want to thank Dr. Pascal Retailleau
(ICSN-CNRS) for crystallographic analysis and Prof. David Aitken
(ICMMO, Universitꢂ Paris Sud) for fruitful scientific discussions. This
study was financially supported by the CNRS.
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Received: February 16, 2009
Published online: April 25, 2009
5798
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Chem. Eur. J. 2009, 15, 5793 – 5798