Palladium-catalyzed cross-coupling of aryl electrophiles with dimethylalkynylaluminum reagents

Article abstract of DOI:10.1021/ol048741i

(Chemical Equation Presented) Alkynyldimethylaluminum reagents are easily available from terminal akynes and trimethylaluminum via a triethylamine- catalyzed metalation. These compounds can react with various aromatic and heterocyclic halides in the presence of palladium in a fast and efficient way. This catalyzed cross-coupling reaction provides a simple entry to numerous internal alkynes, using a readily available, inexpensive, and nontoxic metalating agent.

Full text of DOI:10.1021/ol048741i

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3481-3484
Palladium-Catalyzed Cross-Coupling of
Aryl Electrophiles with
Dimethylalkynylaluminum Reagents
Baomin Wang, Martine Bonin,* and Laurent Micouin*
Laboratoire de Chimie The´rapeutique, UMR 8638 associe´e au CNRS et a` l’UniVersite´
Rene´ Descartes, Faculte´ des Sciences Pharmaceutiques et Biologiques,
4 aV de l’ObserVatoire, 75270 Paris Cedex 06, France
laurent.micouin@uniV-paris5.fr
Received July 2, 2004
ABSTRACT
Alkynyldimethylaluminum reagents are easily available from terminal akynes and trimethylaluminum via a triethylamine-catalyzed metalation.
These compounds can react with various aromatic and heterocyclic halides in the presence of palladium in a fast and efficient way. This
catalyzed cross-coupling reaction provides a simple entry to numerous internal alkynes, using a readily available, inexpensive, and nontoxic
metalating agent.
The Pd-catalyzed alkynylation1 is now one of the most
general and reliable methods for the synthesis of alkynes,
which are known to be useful building blocks for many
organic preparations. The Heck and Sonogashira couplings
can be performed with terminal alkynes and have found
numerous applications.2 In some cases, however, significant
alkyne homodimerization can be encountered, leading to
troublesome purifications and low yield of isolated cross-
coupled product. The use of preformed metalated alkynes,
especially those containing Zn (Negishi coupling),3 Sn (Stille
coupling),4 and B (Suzuki coupling)5 can generally overcome
this problem. These reactive species are usually prepared via
a deprotonation step by a strong base followed by trans-
metalation of the alkynyllithium or -sodium intermediate.
Some examples of the direct preparation of metallic acetyl-
ides from terminal alkynes with metals other than alkali have
also been reported. In these cases, the metalation generally
requires several equivalents of an organic base.6
As a part of our work on the use of mixed dialkylalky-
nylaluminum reagents in stereoselective transformations,7
we recently reported a straightforward access to these spe-
cies by a base-catalyzed alumination of terminal alkynes
(Figure 1).8
(1) For recent reviews, see: (a) Negishi, E.-I.; Anastasia, L. Chem. ReV.
2003, 103, 1979. (b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(c) Negishi, E.-I. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience: New York, 2002; p 215.
(2) (a) Sonogashira, K. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience: New York, 2002;
p 493. (b) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; p 203.
(3) Negishi, E.-I. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience: New York, 2002;
p 229. See also ref 1a.
(4) (a) Kosugi, M.; Fugami, K. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience:
New York, 2002; p 263. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J.
Org. React. 1997, 50, 1.
(5) (a) Suzuki, A. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience: New York, 2002;
p 249. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
Figure 1. Triethylamine-catalyzed alumination of terminal alkynes.
This simple procedure does not require strong bases or a
transmetalation step and uses widely available, nontoxic
trimethylaluminum as a metalating agent.
Although the palladium-catalyzed coupling of alkenyl-
alanes with various electrophiles is a classical procedure for
the synthesis of stereodefined olefins,9 the corresponding
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reaction starting from alkynylalanes has been surprisingly
less investigated. Despite one promising example of this
reaction reported by Negishi in the early 1980s, the reactivity
of aluminum acetylides in cross-coupling reactions has yet
to be delineated, as outlined by this author in a recent
review.1,10
Table 3. Electrophile Variation in the Cross-Coupling Reaction
We initially examined the cross-coupling reaction of
dimethylheptynylaluminum with phenyl iodide and THF as
a cosolvent with different precatalysts (Table 1). Best results
Table 1. Precatalyst Screen in the Cross-Coupling of
Dimethylheptynylaluminum with Phenyl Iodide
entry
Pd0, ligand
Pd(PPh3)4
Pd(PPh3)2Cl2 + 2PPh3
Pd(OAc)2 + 4PPh3
conversion (%)a
1
2
3
4
5
6
7
<10
10
13
40
<10
10
Pd2(dba)3‚CHCl3
Pd2(dba)3‚CHCl3 + 4PPh3
Pd2(dba)3‚CHCl3 + 2dppb
Pd2(dba)3‚CHCl3 + 2dppf
100
a Estimated by GC after 24 h.
were obtained with Pd0 sources and dppf as a ligand, leading
to a full conversion after 24 h (entry 7).
The introduction of a cosolvent proved to have a dramatic
influence on the rate of cross-coupling, as depicted in Table
2. Low conversion was observed in toluene, CH2Cl2, or DMF
Table 2. Cosolvent Influence in the Cross-Coupling of
Dimethylheptynylaluminum with Phenyl Iodide
entry
cosolvent
time (h)
conversion (%)a
1
2
3
4
5
toluene
CH2Cl2
DMF
THF
DME
24
24
24
8
40
40
30
100
100
4.5
a Estimated by GC.
(entries 1-3), whereas a significant rate enhancement could
be obtained with DME (entry 5) and, to a lesser extent, THF
(entry 4).
These optimized conditions were then used for a compara-
tive study of different electrophiles (Table 3). With iodinated
a Reaction conditions: ArX (1 equiv), Pent-tAlMe2 (1.5 equiv).
b Isolated yield based on ArX. c Performed with 2 equiv of alanes. d Pent-
t-t-Pent was obtained in 75% yield (based on PenttAlMe2). e Con-
version ) 75%.
(6) For a review on σ-metal alkynyl complexes, see: (a) Long, N. J.;
Williams, C. K. Angew. Chem., Int. Ed. 2003, 42, 2586. For recent examples
of Negishi coupling with in-situ-generated alkynylzinc derivatives, see: (b)
Negishi, E.-I. Qian, M.; Zeng, F.; Anastasia, L.; Babisnski, D. Org. Lett.
2003, 5, 1597. (c) Anastasia, L.; Negishi, E.-I. Org. Lett. 2001, 3, 3113.
3482
Org. Lett., Vol. 6, No. 20, 2004

electrophiles, the expected coupling products were obtained
in a few hours at room temperature in almost quantitative
yields, with only traces of homocoupling product. A lower
rate was observed with ortho-substituted iodides (entries 4
and 6), but this problem was overcome by performing the
reaction at a higher temperature. Electron-donating (entries
2-4) as well as electron-withdrawing (entry 7) groups were
well tolerated, and unprotected p-iodophenol could also be
coupled if 2 equiv of alkynylalane were used (entry 5).
Surprisingly, p-nitro iodobenzene did not lead to the expected
product but cocatalyzed the alkyne homodimerization.11
Bromo-derivatives could also react when performing the
reaction at 85 °C and led to the corresponding cross-coupling
products in a few hours and fairly good yields (entries
10-12).
Since the reactivity of aromatic alkynes could differ from
the behavior of alkynes bearing aliphatic groups, the coupling
reaction was then investigated with dimethylphenylacetyl-
idealuminum (Table 4).
Table 4. Electrophile Variation in the Cross-Coupling Reaction
with Dimethylphenylacetylidealuminum
2-Substituted pyridine proved to be more reactive than its
3-substituted counterpart (entries 13 and 14), but 2,5-di-
bromopyridine could be quantitatively fully alkynylated using
2 equiv of alanes. Once again, steric hindrance led to lower
reaction rates (entry 16), and no conversion could be ob-
served when using aromatic chlorides (entry 18), except for
the more reactive 2-chloropyridine (entry 17). Triflate seems
to be a less efficient leaving group than bromide (entries 19
and 20).
a Reaction conditions: ArX (1 equiv), Pent-tAlMe2 (1.5 equiv).
b Isolated yield based on ArX. c Ph-t-t-Ph was obtained in 70% yield
(based on PhtAlMe2).
Interestingly, despite the known Lewis acidity of alumi-
num, the presence of various basic sites (S, N, O, CO group)
on the electrophiles did not significantly influence the scope
of the coupling process.
Although slightly less reactive, this alkynylalane led to
the corresponding alkyne in excellent yields (entries 1-3),
except with p-nitro iodobenzene, which cocatalyzed the
alkyne homodimerization.
Finally, the selective mono-cross-coupling of a terminal
diyne was attempted. Thus, the metalation of 1,9-decadiyne
1 in the presence of 1.1 equiv of trimethylaluminum, fol-
lowed by Pd-catalyzed coupling with aromatic halides, led
to the terminal alkynes 2 and 3 in 92 and 90% yields,
respectively (Scheme 1).
(7) (a) Blanchet, J.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.;
Husson, H.-P. Tetrahedron Lett. 1999, 40, 2935. (b) Blanchet, J.; Bonin,
M.; Micouin, L.; Husson, H.-P. J. Org. Chem. 2000, 65, 6423. (c) Blanchet,
J.; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett. 2001, 42, 3171.
(d) Blanchet, J.; Bonin, M.; Micouin, L.; Husson, H.-P. Eur. J. Org. Chem.
2002, 2598.
(8) Feuvrie, C.; Blanchet, J.; Bonin, M.; Micouin, L. Org. Lett. 2004, 6,
2333.
(9) Huo, S.; Negishi, E.-I. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-I., Ed.; Wiley-Interscience: New York,
2002; p 335.
(10) (a) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340. (b) Negishi, E.-I.
J. Organomet. Chem. 2002, 653, 34. For the use of tetraalkynylaluminates
in palladium-catalyzed cross-coupling with aryl bromides, see: (c) Gelman,
D.; Tsvelikhovsky, D.; Molander, G. A.; Blum, J. J. Org. Chem. 2002, 67,
6287. For the use of mixed alkynylaluminum reagents in palladium-catalyzed
cross-coupling with acyl chlorides, see: (d) Wakamatsu, K.; Okuda, Y.;
Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn. 1985, 58, 2425.
(11) In this case, p-nitro iodobenzene probably behaves as an oxidant in
a palladium-catalyzed Glaser-type homocoupling. This coupling does not
occur without palladium catalyst. For a recent review on acetylenic homo-
and cross-coupling reactions, see: Siemsen, P.; Livingston, R. C.; Diederich,
F. Angew. Chem., Int. Ed. 2003, 39, 2632.
Scheme 1. Selective Mono-Cross-Coupling of Terminal Diyne
1
(12) Typical Procedure. The preparation of hept-1-ynyl-benzene (entry
1) is representative. Alane solution preparation: A dry and argon-flushed
flask equipped with a magnetic stirrer and condenser was charged with
a commercial trimethylaluminum solution (10 mL, 2 M in heptane)
(CAUTION: trimethylaluminum is flammable), and triethylamine (0.28 mL,
2 mmol) was then added dropwise via a syringe. 1-Heptyne (2.36 mL, 18
mmol) was dropwise added 5 min later, and the reaction mixture was stirred
at 60 °C for 6 h, until the gas evolution ceased. The prepared alane solution
can be stored under argon in the dark for several days. Coupling reaction:
Pd2(dba)3‚CHCl3 (11.9 mg, 0.0115 mmol), dppf (12.8 mg, 0.023 mmol),
and the alane solution (0.5 mL, 0.70 mmol) were added sequentially to a
dry Schlenk tube charged with PhI (51 µL, 0.46 mmol) and freshly distilled
dry DME (3 mL). The reaction mixture was stirred at room temperature
and monitored by GC. After completion, Et2O (3 mL) and a 2 M aqueous
solution of Rochelle’s salt (3 mL) were added. After the solution was stirred
for 10 min, the organic phase was separated, washed with water and brine,
and dried over anhydrous magnesium sulfate, and the solvent was
evaporated. Chromatographic purification on silica gel (eluent: cyclohexane)
afforded 79.1 mg of hept-1-ynyl-benzene.
In conclusion, the scope of the Pd-catalyzed alkynylation
of aromatic and heteroaromatic electrophiles with mixed
dimethylalkynylaluminum reagents appears to be broad. The
preparation of reactive acetylides, using inexpensive, widely
available, and nontoxic trimethylaluminum as a metal source
via a triethylamine-catalyzed terminal metalation can provide
a valuable alternative route to reactive acetylides in metal-
catalyzed cross-coupling reactions. Efforts are currently being
made to explore the scope of this reaction with functional
alkynes as well as the exact mechanism of this palladium
cross-coupling reaction.12
Org. Lett., Vol. 6, No. 20, 2004
3483

Acknowledgment. B.W. thanks Paris 5 University and
the MRT for a postdoctoral grant. We thank the CNRS for
financial support and Prof. H.-P. Husson for fruitful discus-
sions and encouragement.
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Received Date (will be automatically inserted after manu-
script is accepted)
Supporting Information Available: Analytical data for
all new compounds and NMR spectra of all synthesized
OL048741I
3484
Org. Lett., Vol. 6, No. 20, 2004