The first Negishi cross-coupling reaction of two alkyl centers utilizing a Pd-N-heterocyclic carbene (NHC) catalyst

Article abstract of DOI:10.1021/ol0514909

(Chemical Equation Presented) The development of an NHC-based system capable of cross-coupling sp³-sp³ centers in high yield has been a long-standing challenge. This communication describes the use of a Pd-NHC catalytic system that achieves room-temperature Negishi cross-couplings of unactivated, primary bromides and alkyl organozinc reagents with a variety of functionality.

Full text of DOI:10.1021/ol0514909

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3805-3807
The First Negishi Cross-Coupling
Reaction of Two Alkyl Centers Utilizing
a Pd−N-Heterocyclic Carbene (NHC)
Catalyst†
Niloufar Hadei, Eric Assen B. Kantchev, Christopher J. O’Brien, and
Michael G. Organ*
Department of Chemistry, York UniVersity, 4700 Keele Street, Toronto,
Ontario M3J 1P3, Canada
organ@yorku.ca
Received June 25, 2005
ABSTRACT
The development of an NHC-based system capable of cross-coupling sp3
communication describes the use of a Pd NHC catalytic system that achieves room-temperature Negishi cross-couplings of unactivated,
primary bromides and alkyl organozinc reagents with a variety of functionality.
−
sp3 centers in high yield has been a long-standing challenge. This
−
Palladium-catalyzed cross-coupling reactions of unsaturated
organohalides and sulfonates with organometallic reagents
are well established and powerful methods for construction
of carbon-carbon bonds.1 While coupling of alkyl organo-
metallic reagents has been known for some time, the use of
unactivated alkyl chlorides, bromides, or tosylates as coupling
partners posed a greater challenge,2 isolated early examples
notwithstanding.3 Until recently, there was no general and
efficient catalytic protocol for alkyl-alkyl cross-coupling
reactions.
catalyst for Negishi4 and Suzuki5 cross-couplings of primary
alkyl halides (Cl, Br, I) and tosylates. Kambe and co-workers
disclosed Pd-1,3-diene catalysts for Kumada couplings of
unactivated alkyl halides (Cl, Br) and tosylates.6 In addition,
(3) (a) Kochi, J. K. J. Organomet. Chem. 2002, 653, 11-19. (b) Castle,
P. L.; Widdowson, D. A. Tetrahedron Lett. 1986, 27, 6013-6016. (c)
Nunomoto, S.; Kawakami, Y.; Yamashita, J. J. Org. Chem. 1983, 48, 1912-
1914. (d) Tamura, M.; Kochi, J. K. J. Organomet. Chem. 1972, 42, 205-
228. (e) Tamura, M.; Kochi, J. J. Organomet. Chem. 1971, 31, 289-309.
(f) Tamura, M.; Kochi, J. Synthesis 1971, 303-305. (g) Kochi, J. K.;
Tamura, M. J. Am. Chem. Soc. 1971, 93, 1485-1487. (h) Kochi, J. K.;
Tamura, M. J. Am. Chem. Soc. 1971, 93, 1483-1485.
(4) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527-12530.
(5) (a) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 13662-13663. (b) Kirchhoff, J. H.; Dai, C.; Fu, G.
C. Angew. Chem., Int. Ed. 2002, 41, 1945-1947. (c) Netherton, M. R.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 3910-3912. (d) Netherton, M. R.;
Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 10099-
10100.
Previous work by Fu and co-workers demonstrated that
Pd(PR3)2 (R ) cyclohexyl, cyclopentyl) is an effective
† This study was first disclosed at the Canadian Society for Chemistry
National Meeting (Saskatoon, Saskatchewan, Canada, May 29, 2005);
Abstract #73: Multicomponent Synthesis: Metals, MicrowaVes and Mi-
crochannels.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions, 2 ed.; de Meijere,
A., Diederich, F., Eds.; John Wiley & Sons: New York, 2004. (b) Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John
Wiley & Sons: New York, 2002.
(6) (a) Terao, J.; Todo, H.; Watanabe, H.; Ikumi, A.; Kambe, N. Angew.
Chem., Int. Ed. 2004, 43, 6180-6182. (b) Terao, J.; Nii, S.; Chowdhury,
F. A.; Nakamura, A.; Kambe, N. AdV. Synth. Catal. 2004, 346, 905-908.
(c) Terao, J.; Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Lett. 2003, 32,
890-891.
(2) (a) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674-
688. (b) Ca´rdenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-387.
10.1021/ol0514909 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/22/2005

catalysts based on Ni6,7 or other transition metals (Fe, Cu)3,8
have been used successfully in alkyl-alkyl cross-coupling
protocols.
these disappointing results, we still believed that the NHC
ligand platform should be effective for alkyl-alkyl coupling
reactions.
To this end, we submitted 4 to Negishi conditions
developed by Fu et al.,4 assuming that the alkylzinc reagent
would facilitate the formation of active catalyst (Table 1).
The main problems when attempting to couple haloalkanes
are the reluctance of saturated carbon-halogen bonds to
undergo oxidative addition2b compared to aryl, vinyl, or allyl
halides and competing â-H elimination from the oxidative
addition intermediate, which results in unwanted alkene
formation (Scheme 1). A viable process must overcome these
Table 1. Effect of Reaction Conditions on the Yield of
Alkyl-Alkyl Negishi Coupling
Scheme 1. General, Simplified Mechanism for Pd-Catalyzed
Alkyl-Alkyl Cross-Coupling Reactions
entry
change from standard conditions
yield (%)a
1
2
3
4
5
6
7
8
9
none
no ligand (4)
no Pd2(dba)3
no NMI
substituted toluene for NMP
substituted CH2Cl2 for NMP
substituted THF for NMP
substituted DME for NMP
substituted DMF for NMP
substituted DMA for NMP
substituted ligand 5 for 4
75
0.3
0.0
75
2
2
2
3
4
10
11
50
8
obstacles. Recent mechanistic studies suggest that palladium
insertion into an alkyl halide bond (oxidative addition) occurs
via an SN2-type mechanism and is enhanced by an electron-
rich palladium center.9 Effective reductive elimination is
dependent on the catalyst’s steric environment.10
a GC yield against a calibrated internal standard (undecane); reactions
were performed in duplicate, and the average yield is reported.
Although N-heterocyclic carbenes (NHCs) have received
considerable attention as an alternative to phosphines due
to their excellent σ-donor properties, ease of synthesis, and
variable steric bulk,11 there has been limited success in using
Pd-NHC catalytic protocols for alkyl-alkyl cross-coupling
reactions. Fu and co-workers reported low yields when NHC
ligands related to 5 were employed in Negishi4 or Suzuki5b
couplings. Caddick, Cloke et al. reported an alkyl-alkyl
Suzuki reaction utilizing 4 with moderate yields.12a Despite
We were delighted to find that cross-coupling occurred in
high yield (Table 1, entry 1). Further examination of the
conditions revealed that 5 was inactive (Table 1, entry 11)
and N-methylimidazole (NMI) was not a necessary additive
in these experiments (Table 1, entry 4). However, a solvent
study revealed the same dependence on 1-methyl-2-pyrroli-
dinone (NMP) to achieve high yields (Table 1, entries 5-10)
as reported by Fu et al.4
Following our initial success, we conducted a more
detailed investigation of the coupling conditions (Table 2).
Screening of the Pd:IPr (4) ratio confirmed that a 1:2 ratio
was optimal (Table 2, entries 1-4). The impressively high
yield was retained when the reaction was conducted at room
temperature (Table 2, entry 6).
Evaluation of the source of palladium demonstrated that
Pd2(dba)3 and Pd(OAc)2 were equally effective at 75 °C and
room temperature (Table 2, entries 7-8), while other Pd
precursors were less effective (Table 2, entries 9-11).
A variety of substrates were coupled in good to excellent
yields at room temperature using the optimal conditions
developed for the Negishi alkyl-alkyl coupling reaction.13
The results (Table 3) indicate that a number of functional
(7) (a) Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 126, 4594-4595.
(b) Anderson, T. J.; Jones, G. D.; Vicic, D. A. J. Am. Chem. Soc. 2004,
126, 8100-8101. (c) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004,
346, 1525-1532. (d) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
14726-14727. (e) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe,
N. J. Am. Chem. Soc. 2002, 123, 4222-4223. (f) Jensen, A. E.; Knochel,
P. J. Org. Chem. 2002, 67, 79-85. (g) Giovanini, R.; Stu¨dermann, T.;
Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544-
3553. (h) Giovanini, R.; Stu¨dermann, T.; Dussin, G.; Knochel, P. Angew.
Chem., Int. Ed. 1998, 37, 2387-2390.
(8) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc.
2004, 126, 3686-3687.
(9) Hills, I. D.; Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2003,
42, 5749-5752.
(10) Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Org.
Lett. 2005, 7, 1991-1994.
(11) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
(12) (a) Arentsen, K.; Caddick, S.; Cloke, F. G. N.; Herring, A. P.;
Hitchcock, P. B. Tetrahedron Lett. 2004, 45, 3511-3515. NHC ligands
have also been employed in Sonogashira and Kumada reactions of alkyl
bromides; see: (b) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
13642-13643. (c) Frisch, A. C.; Rataboul, F.; Zapf, A.; Beller, M. J.
Organomet. Chem. 2003, 687, 403-409.
3806
Org. Lett., Vol. 7, No. 17, 2005

Table 2. Optimization of Catalyst Composition and
Temperature
Table 3. Room-Temperature Negishi Cross-Coupling
Reactions of Unactivated Alkyl Bromides with Alkyl Zinc
Reagentsa
entry
change from standard conditions
yield (%)a
1
2
3
4
5
6
7
8
9
Pd:IPr (4) ) 1:1
none (Pd:IPr (4) ) 1:2)
Pd:IPr (4) ) 1:2.5
Pd:IPr (4) ) 1:3
55 °C
60
75
70
50
70
77
75
75
40
19
6
rt
Pd(OAc)2
Pd(OAc)2, rt
Pd(OCOCF3)2, rt
PdCl2, rt
10
11
[(π-allyl)PdCl]2, rt
a GC yield against a calibrated internal standard (undecane); reactions
were performed in duplicate, and the average yield is reported.
groups (esters, nitriles, amides, alkynes, and acetals) were
tolerated. The addition of a small amount (12 mol %) of
n-butylzinc bromide appeared to be necessary in order to
achieve reproducible catalyst formation.14 That said, we have
one example that demonstrates that excellent yields may be
obtained when n-butylzinc bromide activation is not em-
ployed.15 It is noteworthy that the yields at room temperature
were generally higher when compared to reactions performed
at 75 °C (Table 3, entries 1-5).
In conclusion, we have demonstrated the first high-yielding
Negishi cross-coupling reaction utilizing NHC ligands.
Further, this is also the first reported room-temperature
palladium-catalyzed Negishi alkyl-alkyl coupling reaction.
a Pd2(dba)3 (2 mol %), IPr‚HCl (8 mol %), n-butylzinc bromide (0.5 M
in THF, 12 mol %), stirred for 1 h, alkyl bromide (0.5 mmol), alkylzinc
reagent (0.5 M in THF, 0.65 mmol) in THF-NMP (2:1), rt, 24 h. b Isolated
yield at room temperature; isolated yield at 75 °C in parentheses. Reactions
were performed in duplicate, and the average yield is reported.
We are currently expanding the scope of the Pd-NHC
Negishi protocol to aryl and vinyl halides, pseudo-halides,
and more elaborate zinc reagents
(13) Coupling of the chloride and tosylate analogues of 1 with n-butylzinc
bromide led to unsatisfactory yields (e30%) of 3. However, coupling of
tosylates can be achieved if the organozinc halide is prepared from Rieke
zinc made from ZnBr2. See: Rieke, R. D.; Hanson, M. V.; Brown, J. D.;
Niu, Q. J. J. Org. Chem. 1996, 61, 2726-2730. Zhu, L.; Wehmeyer, R.
M.; Rieke, R. D. J. Org. Chem. 1991, 56, 1445-1453. We believe this is
due to the bromide ion from LiBr (produced as a byproduct in Rieke zinc
fromation) displacing the tosylate group (GC/MS). Indeed, when we used
commercially available organozinc reagent (Rieke Metals, Inc., which
contains LiCl), we observed significant formation of the alkyl chloride (GC/
MS).
(14) Steric nature of the organozinc reagent could affect the formation
of the active catalyst. We observed significant variation in yield when the
organozinc reagent participating in the cross-coupling reaction was used
alone.
(15) Reaction depicted in Table 3, entry 4, yielded 87% of the cross-
coupled product when n-butylzinc bromide catalyst activation was not
employed.
Acknowledgment. We would like to thank the ORDCF
and NSERC (Canada) for financially supporting our program
and Varian Canada for their collaborative in-kind donation
(in part) of the GC/MS/MS 4000 to conduct the analyses in
this report.
Supporting Information Available: Experimental pro-
cedures for Tables 2 and 3 and characterization data for the
cross-coupling products (Table 3). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0514909
Org. Lett., Vol. 7, No. 17, 2005
3807