Highly substituted enynes via a palladium-catalyzed tandem three carbon-carbon bonds forming reaction procedure from benzyl halides and alkynyl tributyltin reagents

Article abstract of DOI:10.1016/j.tetlet.2004.03.173

The first report of the palladium-catalyzed cross coupling reaction of benzyl halides with alkynyl tributyltin reagents is described. This unprecedented coupling, which involves in a single reaction a tandem Stille-carbopalladation-Stille sequence allows the formation of three carbon-carbon bonds chemo-, regio- and stereoselectively and provides an efficient synthesis of highly substituted enynes.

Full text of DOI:10.1016/j.tetlet.2004.03.173

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4035–4038
Highly substituted enynes via a palladium-catalyzed tandem three
carbon–carbon bonds forming reaction procedure from benzyl
halides and alkynyl tributyltin reagents
*
^
Laurent Romain Pottier, Jean-Franßcois Peyrat, Mouad Alami and Jean-Daniel Brion
Laboratoire de Chimie Thꢀerapeutique, BioCIS-CNRS (UMR 8076), Universitꢀe Paris-Sud XI, Facultꢀe de Pharmacie,
rue J.B. Clꢀement, 92296 Ch^atenay-Malabry cedex, France
Received 5 March 2004; revised 24 March 2004; accepted 26 March 2004
Abstract—The first report of the palladium-catalyzed cross coupling reaction of benzyl halides with alkynyl tributyltin reagents is
described. This unprecedented coupling, which involves in a single reaction a tandem Stille–carbopalladation–Stille sequence allows
the formation of three carbon–carbon bonds chemo-, regio- and stereoselectively and provides an efficient synthesis of highly
substituted enynes.
Ó 2004 Elsevier Ltd. All rights reserved.
The palladium-catalyzed cross-coupling of organo-
stannanes with organic electrophiles, known as the Stille
reaction, has become an extremely powerful tool for the
construction of carbon–carbon bonds.1 Moreover, the
reaction tolerates a wide range of functionality in either
or both of the coupling partners so that tedious pro-
tection-deprotection reactions of the functional groups
carried into the coupling product are not necessary.
to expectations, the major product from the reaction of
1a with 2a under standard conditions, summarized in
Scheme 1, was found to be conjugated enyne 4a, while
the Stille product 3a was only formed in small amounts
(3a/4a: 9/91). On the basis of this result, we have
explored this unprecedented tandem Stille–carbopalla-
dation–Stille sequence for the preparation of highly
substituted enynes 4 from functionalized benzyl halides
1 and alkynyltributyltin reagents 2. This new four-
component procedure allows in a single reaction the
tandem formation of three carbon–carbon bonds in a
stereo- and regioselective manner. A proposal for this
reaction mechanism is presented in this paper.
Among various organic electrophiles used, aryl, hetero-
aryl, alkenyl and allyl halides are well known to readily
participate in the cross-coupling with organostannanes.
Few studies on the palladium-catalyzed coupling with
benzyl halides have been reported because good non-
catalyzed reaction protocols exist. Benzyl bromide has
been shown to couple under palladium catalysis with
tetramethylstannane, phenyl- and alkenyltributylstann-
anes in good yields.2 Reaction with hexaalkyldistann-
anes yields benzylic stannanes in fair to good yields.3
However, to our knowledge, Pd-catalyzed alkynylation4
of benzyl halides with alkynyltin derivatives5 is not
known. We sought to utilize this Stille coupling reaction
for rapid synthesis of functionalized skipped arylalkynes
3 from various functionalized benzyl halides. Contrary
In order to determine the optimum reaction conditions,
we examined the influence of the palladium catalyst,
ligand, additive and solvent towards the reaction of
X
R1
3
R1
1
PdCl2(PPh3)2
NMP, 50°C
R
R
R
+
+
Bu3Sn
R1
2
R
4
R1
a: R = H, R1 = CH2OH
1a: R = H, X = Br
2a: R1 = CH2OH
Keywords: Stille coupling; Benzyl halides; Alkynylstannanes; Palla-
dium; Enynes; Four-component coupling.
3a/4a: 9/91
* Corresponding author. Tel.: +33-146835887; fax: +33-146835828;
e-mail: mouad.alami@cep.u-psud.fr
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.173

4036
L. R. Pottier et al. / Tetrahedron Letters 45 (2004) 4035–4038
Table 1. Optimization of the palladium-catalyzed four-component coupling of 2a with benzyl bromide 1a
Entry
PdLn
Additive Solvent
Yield (%)a
3a
4a
1
2
3
4
5
6
7
8
9
10
PdCl2 (PPh3)2
Pd(PPh3)4
––
––
NMP
NMP
4
43
17
32
68
30
41
45
75
75
53
20
9
Pd(dba)2 + AsPh3
Pd(dba)2 + TFP
Pd(dba)2 + TFP
Pd(dba)2 + TFP
Pd(dba)2 + TFP
Pd(dba)2 + TFP
Pd(dba)2 + TFP
Pd(dba)2 + TFP
––
––
NMP
NMP
––
22
––
––
<3
<3
––
CuI
––
NMP
MeCN
THF
––
––
Toluene
Dioxane
Dioxane
––
Bu4NF
a Isolated yield based on benzyl bromide 1a.
benzyl bromide 1a with 3-tributylstannyl-prop-2-yn-1-ol
2a. Table 1 summarizes the results of these studies.
(entry 3). Interestingly, replacing the triphenylarsine
ligand by tri-2-furylphosphine (TFP) gave the enyne 4a
as the only product in a 68% isolated yield (entry 4). It
should be noted that the addition of CuI as co-catalyst,
which may facilitate the rate-determining transmetalla-
tion step7 dramatically decreased both the yield and the
selectivity of the reaction (entry 5). Finally, the influence
of solvent was also examined and has a positive effect
since the yield of 4a was improved to 75% when the
coupling reaction was performed in toluene or dioxane
(entries 8 and 9). Under these optimum conditions, the
use of TBAF as nucleophilic activator of organostann-
anes8 resulted in a noticeable lowering of the yield (entry
10).
Attempted coupling of 1a with 2a in N-methyl-pyrro-
lidinone (NMP), which has been shown to be the best
solvent for Stille reaction6 in the presence of
PdCl2(PPh3)2, gave no product at room temperature.
However, heating the reaction at 50 °C for 3 h provided
the conjugated enyne 4a in 43% isolated yield together
with a small amount of the Stille coupling product 3a
(4%) (entry 1); no reaction occurs in the absence of a
palladium catalyst. It is noteworthy that the selectivity
of this reaction markedly in favour of the enyne 4a was
dependant on the palladium catalysts. Changing the
catalyst to Pd(PPh3)4 resulted in a mixture of both
product 3a/4a in a 54/46 ratio (entry 2). This selectivity
was enhanced when using Pd(dba)2 as catalyst associ-
ated with Farina ligands6 such as triphenylarsine but
side product 3a is still produced in substantial amount
In order to demonstrate the efficiency of this new four-
component procedure, a variety of functionalized benzyl
bromides or chlorides were reacted with alkynyltributy-
ltin derivatives 2 (Table 2). In most cases the reactions
Table 2. Synthesis of highly substituted enynes 4 by palladium-catalyzed coupling of alkynylstannanes with benzyl halidesa
Entry
RSnBu3
2
Benzyl halide 1
Enyne 4b
Yield (%)c
45
HO
CN
Br
HO
CN
SnBu3
1
NC
2a
1b
4b
OH
Br
Br
Br
HO
HO
SnBu3
2
33
2a
1c
4c
Br
HO
OH
HO
HO
Br
SnBu3
3
4
84
53
1a
2b
OH
4d
HO
Br
CN
CN
SnBu3
NC
2b
2b
1b
OH
4e
Br
HO
Br
Br
HO
SnBu3
5
42
1c
OH
4f
Br

L. R. Pottier et al. / Tetrahedron Letters 45 (2004) 4035–4038
4037
Table 2 (continued)
Entry
RSnBu3
2
Benzyl halide 1
Enyne 4b
Yield (%)c
30
HO
Br
HO
SnBu3
6
7
1a
2c
4g
OH
24
CN
Br
SnBu3
CN
NC
2d
1b
4h
HO
HO
Cl
SnBu3
8
9
70d;e;f
1d
2a
4a
OH
HO
Cl
Cl
Cl
HO
HO
HO
Cl
36d
SnBu3
Cl
2a
1e
4i
OH
HO
Cl
Cl
SnBu3
10
11
30d
Cl
2b
2b
1e
OH
4j
HO
F
Cl
29d
SnBu3
F
F
1f
OH
4k
a For a general procedure see Ref. 9.
b The structures of enynes 4 were established by HMBC, NOESY and HSQC 2D NMR spectroscopy. All new compounds exhibited satisfactory
spectral properties and isomeric purity (>95%).
c All reactions were carried out under unoptimized conditions. Isolated yield based on benzyl halide.
d Performed in the presence of a 1 M THF solution of TBAF (1 equiv).
e A 25% yield of skipped arylalkyne 3a were isolated.
f Without TBAF, 13% yield of enyne 4a and 43% yield of skipped arylalkyne 3a were obtained.
R
produced the corresponding highly substituted enynes 4
in fair to good yields starting from benzyl bromides
bearing different substituents in ortho or para position.
The selectivity of this tandem Stille–carbopalladation–
Stille sequence from the ortho bromobenzyl bromide 1c
must be especially underlined since no product arising
from the coupling at the Csp2–Br bond could be isolated
(entries 2 and 5). On the other hand, this process is also
effective from benzyl chlorides; the reaction required the
use of TBAF as activator to promote the reactivity of 2
and afforded the enyne products in fair yields (entries 8–
11). While the overall yield of this process is in some
cases lower, it represents in a single reaction the for-
mation of three carbon–carbon bonds.
X
Ar
Ar
Ar
R
Pd
II
Pd
3
I
R
Ar
R
Pd (0)
SnBu3
Pd
Ar
III
X
X
Pd
SnBu3
Ar
Ar
R
R
I
Pd
Ar
R
Ar
X
IV
Ar
R
1
Ar
4
R
Scheme 2. Proposed mechanism for the Pd-catalyzed enyne synthesis
(ligands on the scheme are omitted).
On the basis of the known palladium chemistry, we
propose a plausible reaction mechanism as shown in
Scheme 2 to account for the present tandem Stille–
carbopalladation–Stille sequence. The catalytic reaction
is initiated by oxidative addition of benzyl halide 1 to
palladium(0) followed by transmetallation of the
resulting electrophilic Pd(II) complex I with alkynyltin
and reductive elimination of II regenerate the palla-
dium(0) complex and provide the Stille cross coupling

4038
L. R. Pottier et al. / Tetrahedron Letters 45 (2004) 4035–4038
2195; (f) Crawforth, C. M.; Fairlamb, I. J. S.; Taylor, R. J.
K. Tetrahedron Lett. 2004, 45, 461–465.
3. Azizian, H.; Eaborn, C.; Pidcock, A. J. Organomet. Chem.
1981, 215, 49–58.
4. An excellent overview of palladium catalyzed alkynylation
of organic halides appeared recently, see: Negishi, E.;
Anastasia, L. Chem. Rev. 2003, 103, 1979–2017.
5. For a recent report of palladium-catalyzed benzylation of
tris(alkynyl)indiums, see: (a) Perez, I.; Perez Sestelo, J.;
Sarandeses, L. J. Am. Chem. Soc. 2001, 123, 4155–4160;
For noncatalyzed benzylation of alkynyllithium see: (b)
Sun, H.; Mahadevan, A.; Razdan, R. K. Tetrahedron Lett.
2004, 45, 615–617.
product 3. This latter, undergoes then regio- and stereo-
selective benzylpalladation reaction of benzylpalla-
dium intermediate I to give the vinylpalladium adduct
III. Subsequent transmetallation of III with a second
molecule of alkynyltin and reductive elimination of
palladium from IV gives raise to the enyne derivative
and regenerates the palladium(0) catalyst.
In conclusion, the tandem Stille–carbopalladation–Stille
process developed here for the synthesis of enynes 4
allows in a single reaction to construct three carbon–
carbon bonds chemo-, regio- and stereoselectively under
mild conditions. This reaction represents the first
examples of Pd-catalyzed cross coupling of benzyl
halides with alkynylstannanes. Extension of this process
to other alkynyl metal including alkynyl copper (Sono-
gashira–Linstrumelle reaction) is currently under inves-
tigations.
6. Farina, V.; Krishman, B. J. Am. Chem. Soc. 1991, 113,
9585–9595.
7. Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebes-
kind, L. S. J. Org. Chem. 1994, 59, 5905–5911.
8. Fouquet, E.; Rodriguez, A. L. Synlett 1998, 1323–1324.
9. To a solution of Pd(dba)2 (5 mol %), TFP (10 mol %) and
benzyl bromide (1 equiv) in dioxane (c ¼ 0:2 M) was added
under N2 freshly prepared alkynyltin derivative (2 equiv).
The reaction mixture was warmed at 50 °C, monitored by
TLC until complete consumption of the benzyl halide (3–
5 h) before to be treated at room temperature by potassium
fluoride aqueous solution. After stirring for 2 h, the
resulting white precipitate of tributyltin fluoride was
removed by filtration and the filtrate was extracted with
ether. The combined organic layer was washed with brine,
dried over Na2SO4 and concentrated. Silica gel chroma-
tography of the residue afforded pure enyne 4.
Acknowledgements
The CNRS is gratefully thanked for support of this
research and the Ministere de l’Enseignement Superieur
et de la Recherche for a doctoral fellowship (PL).
(E) 3,4-Dibenzyloct-3-en-5-yne-1,8-diol 4d: 1H NMR
(400 MHz, DMSO-d-6, d ppm) 7.29–7.16 (m, 10H), 4.72
(t, 1HOH, J ¼ 5:1 Hz), 4.56 (t, 1HOH, J ¼ 5:1 Hz), 3.69 (s,
2H), 3.52 (s, 2H), 3.41 (q, 2H, J ¼ 6:3 Hz), 3.35 (q, 2H,
J ¼ 6:7 Hz), 2.33 (t, 2H, J ¼ 7:0 Hz), 2.23 (t, 2H,
J ¼ 7:1 Hz). 13C NMR (50 MHz, DMSO-d-6, d ppm)
142.4, 139.7, 139.6, 128.5, 128.4, 128.2, 126.2, 120.5, 89.7,
83.1, 61.0, 60.8, 41.2, 38.1, 34.3, 23.7.
References and notes
1. For an excellent review see: (a) Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. 1997, 50, 1–652; (b) Stille, J. K.
Angew. Chem. Int. Ed. Engl. 1986, 25, 508–524.
2. (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101,
4992–4998; (b) Crisp, G. T.; Glink, P. T. Tetrahedron 1994,
50, 3213–3234; (c) Kamlage, S.; Sefkow, M.; Peter, M. G. J.
Org. Chem. 1999, 64, 2938–2940; (d) Rayner, C. M.; Astles,
P. C.; Paquette, L. J. Am. Chem. Soc. 1992, 114, 3926–3936;
(e) Crawforth, C. M.; Burling, S.; Fairlamb, I. J. S.; Taylor,
R. J. K.; Whitwood, A. C. Chem. Commun. 2003, 2194–
(E) 2,3-bis(4-cyanobenzyl)hex-2-en-4-yne-1,6-diol 4b: 1H
NMR (400 MHz, DMSO-d-6,
d ppm) 7.74 (d, 2H,
J ¼ 8:0 Hz), 7.73 (d, 2H, J ¼ 8:0 Hz), 7.43 (d, 2H,
J ¼ 8:0 Hz), 7.39 (d, 2H, J ¼ 8:0 Hz), 4.13 (s, 2H), 4.01 (s,
2H), 3.81 (s, 2H), 3.64 (s, 2H). 13C NMR (50 MHz, DMSO-
d-6, d ppm) 146.3, 145.7, 145.2, 132.2, 129.6, 129.5, 119.0,
118.9, 118.5, 109.1, 108.9, 93.3, 83.8, 58.2, 49.4, 38.0, 37.2.