Kumada-Corriu reactions of alkyl halides with alkynyl nucleophiles

Article abstract of DOI:10.1021/ol049686g

Pd₂(dba)₃-Ph₃P-catalyzed Kumada-Corriu coupling reactions of unactivated alkyl bromides or iodides with an alkynyl nucleophile furnish C_sp-C_sp3 bond formation. Alkynyl nucleophiles can be alkynyllithiums or the corresponding Grignard reagents. The superior performance of Ph₃P ligand over the trialkylphosphine ligands indicates that this cross-coupling reaction may be a reductive-elimination-controlled process.

Full text of DOI:10.1021/ol049686g

ORGANIC
LETTERS
2004
Vol. 6, No. 9
1461-1463
Kumada−Corriu Reactions of Alkyl
Halides with Alkynyl Nucleophiles
,†,‡,§
Lian-Ming Yang,† Li-Fu Huang,†,‡ and Tien-Yau Luh*
Department of Chemistry and Institute of Polymer Science and Engineering,
National Taiwan UniVersity, Taipei, Taiwan 106, and Institute of Chemistry,
Academia Sinica, Nangang, Taipei, Taiwan 115
tyluh@chem.sinica.edu.tw
Received February 23, 2004
ABSTRACT
Pd2(dba)3−Ph3P-catalyzed Kumada−Corriu coupling reactions of unactivated alkyl bromides or iodides with an alkynyl nucleophile furnish
C −C 3 bond formation. Alkynyl nucleophiles can be alkynyllithiums or the corresponding Grignard reagents. The superior performance of
sp
sp
Ph3P ligand over the trialkylphosphine ligands indicates that this cross-coupling reaction may be a reductive-elimination-controlled process.
Transition metal-catalyzed cross couplings have provided a
very powerful arsenal for carbon-carbon bond formation.1
The mechanism for these important reactions, in general,
involves (i) oxidative addition of an organic electrophile to
a low-valent metal center and (ii) transmetalation to give a
diorganometallic derivative, followed by (iii) a reductive
elimination process to yield the coupling product with
concomitant regeneration of the low-valent active metallic
species for further catalytic cycling.1,2 The nature of the
ligand(s) apparently plays a pivotal role on the activity of
the catalyst.3-9 Trialkylphosphine ligands have recently been
demonstrated to be particularly useful to facilitate coupling
reactions of aliphatic electrophiles.4 Presumably, the oxida-
tive addition across the C-X bond may become more facile
when an electron-rich metal catalyst is used. However, the
electron demand for reductive elimination would be opposite
to that for oxidative addition. In other words, electron-
donating ligands may slow the catalytic process of cross-
coupling reactions because the reductive elimination step may
be decelerated. When the intermediate with the metal center
in a higher oxidation state contains ligands that are vulnerable
to oxidation, oxidative coupling of such ligands may lead to
(4) (a) Netherton, M. R.; Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 10099-10100. (b) Kirchhoff, J. H.; Netherton, M. R.; Hills,
I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 13662-13663. (c) Kirchhoff,
J. H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 1945-1947. (d)
Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910-3912.
(e) Frisch, A. C.; Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
2002, 41, 4056-4059. (f) Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003,
125, 3718-3719. (g) Lee, J. Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
5616-5617. (h) Huang, L.-F.; Huang, C.-H.; Stulgies, B.; de Meijere, A.;
Luh, T.-Y. Org. Lett. 2003, 5, 4489-4491.
(5) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341.
(b) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527-12530. (c)
Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
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Int. Ed. Engl. 1995, 34, 2723-2725. (b) Giovannini, R.; Stu¨demann, T.;
Dussin, G.; Knochel, P. Angew. Chem., Int. Ed. 1998, 37, 2387-2390. (c)
Giovannini, R.; Stu¨demann, T.; Devasagayaraj, A.; Dussin, G.; Knochel,
P. J. Org. Chem. 1999, 64, 3544-3553. (d) Piber, M.; Jensen, A. E.;
Knochel, P. Org. Lett. 1999, 1, 1323-1326. (e) Jensen, A. E.; Knochel, P.
J. Org. Chem. 2002, 67, 79-85.
† Academia Sinica.
‡ Department of Chemistry, National Taiwan University.
§ Institute of Polymer Science and Engineering, National Taiwan
University.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: New York, 1998. (b) Cross-Coupling Reactions:
A Practical Guide; Miyaura, N., Ed.; Topics in Current Chemistry Series
219; Springer-Verlag: New York, 2002.
(2) Collman, P.; Hegedus, S.; Norton, R.; Finke, G. Principles and
Applications of Organotransition Metal Chemistry; University Science
Books: Mill Valley, CA, 1987; Chapters 4-6.
(3) For reviews see: (a) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem.
ReV. 2000, 100, 3187-3204. (b) Ca´rdenas, D. J. Angew. Chem., Int. Ed.
2003, 42, 384-387.
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10.1021/ol049686g CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/03/2004

the dimerization product(s). Indeed, palladium catalysts are
known to mediate dimerization of terminal alkynes.10,11
Although the palladium-catalyzed coupling reactions of
alkynyl Grignard reagents with Csp2 electrophiles are well
documented,12,13 the corresponding Kumada-Corriu reaction
with alkyl substrates is not known. Modified Sonogashira
reaction using imidazolinylidene ligands appears to be the
only known example of cross-coupling reaction of an
aliphatic halide with an alkyne.8 We envisaged that a balance
of the reactivity of oxidative addition and reductive elimina-
tion steps would be necessary to promote the cross-coupling
reaction of alkyl halides and alkynyl Grignard reagents, and
we now describe the first such palladium-catalyzed such
coupling reaction.
Table 1. Palladium-Catalyzed Cross Coupling of
Phenylmagnesium Iodide with Octyl Bromide under Various
Conditions
catalyst
(mol %)
ligand
% yield % yield % yield
entry
(mol %)
of 2b
of 3b
of 4b
1
2
3
4
5
6
7
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (5)
MeBut2P (10) 26
8
10
12
40
83c
20
30
42
14c
0
But3P (10)
18
23
13
9
Ph3P (10)
In the beginning of this research, a mixture of phenyl-
ethynyl Grignard reagent 1 and 1 equiv of 1-bromooctane
in the presence of a palladium catalyst and a phosphine ligand
in THF was refluxed for 8 h (eq 1). A range of different
catalysts and ligands were screened, and the product distribu-
tions are summarized in Table 1.
Pd2(dba)3 (2.5) Ph3P (10)
Pd2(dba)3 (2.5) Ph3P (10)
Pd2(dba)3 (2.5) Cy3P (10)
Pd2(dba)3 (2.5) MeBut2P (10)
trace
6
45
21
0
8
9
8d Pd2(dba)3 (2.5) MeBut2P (10) 28
9
10
11
12
13
Pd2(dba)3 (2.5) MeBut2P (10) 11
Pd2(dba)3 (2.5) dppb (10)
Pd(PPh3)4 (2.5)
Pd2(dba)3 (2.5)
trace
25
10
trace
trace
As can be seen in Table 1, palladium acetate in the
presence of a phosphine ligand apparently was not an
effective catalyst for this coupling reaction (entries 1-3).
Instead, zero-valent palladium catalyst appears to be essential
for this purpose. To our surprise, trialkylphosphine ligands
were not as efficient as triphenylphosphine ligand in this
coupling reaction. Indeed, the use of triphenylphosphine
ligand has been known in the Suzuki coupling of alkyl
halides.14 Although electron-donating trialkylphosphine ligands
may accelerate the oxidative addition of low-valent palladium
across aliphatic carbon-halogen bonds, our results, together
with the literature data,9,12 suggested that such a step can
occur even in the presence of less reactive triarylphosphine
ligands.
51c
trace
0
0
0
a Typical reaction conditions: A mixture of octyl bromide, phenylethy-
nylmagnesium iodide, palladium catalyst, and ligand in THF was refluxed
for 8 h, unless otherwise mentioned. b Isolated yields. c Phenylethynylmag-
nesium iodide was added dropwise to the reaction mixture containing octyl
bromide, palladium catalyst, and ligand at refluxing temperature. d Reaction
temperature: 45-50 °C.
tory (entry 11). It is noteworthy that both Pd2(dba)3 and Ph3P
are essential for this catalytic process (entries 12 and 13).
Table 2 summarizes the representative examples of the
cross-coupling reactions of phenyl- or silyl-substituted alky-
nyl Grignard reagents with a range of alkyl halides (eq 2).
Either bromide or iodide gave satisfactory yields of the
coupling products. It is interesting to note that one of the
two carbon-bromine bonds in dibromide can be selectively
replaced when 1 equiv of the Grignard reagent was employed
(entry 17). Bis-alkynylation was obtained in the presence of
3 equiv of the Grignard reagent under similar conditions (eq
3).
It is known that Cl2Pd(PPh3)2 reacts with 2 equiv of
alkynyllithium to form dimeric diyne and with excess
alkynyllithium to afford Li2Pd(CtCR)4, which is not an
active catalyst for promoting cross-coupling reactions.12,13
As shown in Table 1, cross-coupling reaction of octyl
bromide with PhCtCMgX appeared to be sluggish (entry
4). To avoid the side reaction and increase the yield of 4, it
was envisaged that a slow addition of the Grignard reagent
to the reaction mixture would slow the dimerization process.
Indeed, the yield of the cross-coupling reaction increased to
83% (entry 5). Ph3P was essential for avoiding the oxidative
dimerization of alkyne (entry 5), a much lower yield being
observed when tBu2MeP was used (entries 7-9). Bidentate
ligand, dppb, was not effective at all for the transformation
shown in eq 1 (entry 10). When Pd(PPh3)4 was employed
under slow addition conditions, the yield of 4 was unsatisfac-
Unexpectedly, alkyl-substituted alkynyl Grignard reagents
did not undergo coupling reactions with alkyl halides under
Table 2. Pd2(dba)3-Ph3P-catalyzed Cross-Coupling Reaction
of Alkyl Halide and Pheny- or Trimethylsilyl-Substituted
Alkynyl Grignard Reagen
(10) (a) Wang, S.; Thomas, S. A. Org. Lett. 2000, 2, 2857-2860. (b)
Negishi, E.-i.; Hata, M.; Xu, C. D. Org. Lett. 2000, 2, 3687-3689. (c)
Abele, E.; Rubina, K.; Fleisher, M.; Popelis, J.; Arsenyan, P.; Lukevics, E.
Appl. Organomet. Chem. 2002, 16, 141-147. (d) Damle, S. V.; Seomoon,
D.; Lee, P. H. J. Org. Chem. 2003, 68, 7085-7087.
(11) Yang, C. L.; Nolan, S. P. J. Org. Chem. 2002, 67, 591-593.
(12) Negishi, E.-i.; Anastasia, L. Chem. ReV. 2003, 103, 1979-2017.
(13) Negishi, E.-i.; Akiyoshi, K.; Takahashi, T. J. Chem. Soc., Chem.
Commun. 1987, 477-478.
entry
R
X
R′
Y
% yield
nC8H17
Br
I
Br
Br
83
86
65
77
-
-
14
15
16
17
Ph
Ph
TMS
TMS
I
I
I
Br
nC4H9
-
nC8H17
-
Br(CH2)6
1462
Org. Lett., Vol. 6, No. 9, 2004

Table 3. Pd2(dba)3-Ph3P-Catalyzed Cross-Coupling Reaction
of Alkyl Bromide and Substituted Alkynyllithium
these conditions. Alkynyllithiums have been shown to be at
least as reactive as the corresponding alkynylzincs. Cross-
coupling reactions using these nucleophiles, however, were
generally unsatisfactory, in particular when Cl2Pd(PPh3)2 was
used as the catalyst.12,13 It is well documented that alkynyl-
lithiums react with primary halides in the presence of
diamines or HMPA to give the corresponding coupling
products.15 In the absence of such an additive, reaction of
phenylethynyllithium with octyl bromide in refluxing THF,
for example, afforded 4 in less than 30% yield. As shown
in Table 1, the nature of the palladium catalyst appeared to
be important in dictating the selectivity of the reaction. Since
Pd2(dba)3 is an active catalyst for alkynylation of alkyl
bromides and iodides, we examined a similar reaction using
alkynyllithiums and found that the cross-coupling products
were obtained in satisfactory yields (eq 4). Apparently, Pd2-
(dba)3 plays an important role in promoting such coupling
reactions. The results are summarized in Table 3. Different
substituents ranging from phenyl and TMS to simple alkyl
groups at the alkynyllithiums can be used. Selective monoalky-
nylation of dibromoalkanes was achieved in good yields.
In conclusion, we have demonstrated useful Pd2(dba)3-
Ph3P-catalyzed Kumada-Corriu coupling conditions for
unactivated alkyl bromides or iodides with an alkynyl
nucleophile. Under these conditions, alkynyllithiums were
active alkynylation reagents in facilitating Csp-Csp3 bond
formation. The better performance of Ph3P ligand than that
of trialkylphosphine ligands indicates that this cross-coupling
entry
R
R′
% yield
nC4H9
88
91
84
86
80
81
79
73
69
84
82
83
67
72
76
69
-
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Ph
Ph
TMS
Ph
Ph
Ph
Ph
Ph
Ph
TMS
TMS
nHex
nBu
nHex
nHex
nBu
nC8H17
nC8H17
-
-
-
-
-
-
Br(CH2)4
Br(CH2)7
Br(CH2)8
Br(CH2)9
Br(CH2)10
Br(CH2)12
-
-
-
Br(CH2)3
Br(CH2)6
-
-
PhCtC(CH2)4
PhCtC(CH2)10
-
-
BnO(CH2)8
-
-
(2,6-Me2C6H3)O(CH2)4
(3,5-Me2C6H3)O(CH2)8
reaction may be a reductive elimination-controlled process.
This study may provide an impetus for further investigations
on the nature of ligands toward the development of new
catalytic systems.
Acknowledgment. We thank the National Science Coun-
cil and the Ministry of Education of the Republic of China
for financial support.
Supporting Information Available: Experimental details
of the Pd2(dba)3/PPh3-catalyzed reactions of alkyl halides
with alkynyl nucleophiles and H NMR spectra of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Ishiyama, T.; Abe, S.; Miyamura, N.; Suzuki, A. Chem. Lett. 1992,
691-694.
(15) (a) Brandsma, L. PreparatiVe Acetylenic Chemistry, 2nd ed.;
Elsevier: Amsterdam, 1988. (b) Sankaranarayanan, S.; Chattopadhyay, S.
Tetrahedron: Asymmetry 1998, 9, 2627-2633. (c) Tyman, J.; Ghorbanian,
S.; Muir, M.; Tychopoulous, V.; Bruce, I.; Fisher, I. Synth. Commun. 1989,
19, 179-188.
1
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