Cobalt-mediated cross-coupling reactions of primary and secondary alkyl halides with 1-(trimethylsilyl)ethenyl- and 2-trimethylsilylethynylmagnesium reagents

Article abstract of DOI:10.1021/ol0611144

This paper describes cobalt-mediated cross-coupling reactions of alkyl halides with 1-(trimethylsilyl)ethenylmagnesium bromide and 2-(trimethylsilyl) ethynylmagnesium bromide, respectively. The cobalt system allows for employing secondary as well as prima

Full text of DOI:10.1021/ol0611144

ORGANIC
LETTERS
2006
Vol. 8, No. 14
3093-3096
Cobalt-Mediated Cross-Coupling
Reactions of Primary and Secondary
Alkyl Halides with
1-(Trimethylsilyl)ethenyl- and
2-Trimethylsilylethynylmagnesium
Reagents
Hirohisa Ohmiya, Hideki Yorimitsu,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Received May 6, 2006
ABSTRACT
This paper describes cobalt-mediated cross-coupling reactions of alkyl halides with 1-(trimethylsilyl)ethenylmagnesium bromide and
2-(trimethylsilyl)ethynylmagnesium bromide, respectively. The cobalt system allows for employing secondary as well as primary alkyl halides
as the substrates. The reactions offer facile formations of alkyl−alkenyl and alkyl−alkynyl bonds. The reaction mechanism would include
single-electron transfer from a cobalt complex to alkyl halide to generate the corresponding alkyl radical. The cobalt system thus enables
sequential radical cyclization/alkenylation and cyclization/alkynylation reactions of 6-halo-1-hexene derivatives.
In organic synthesis, conventional nucleophilic substitution
of alkyl halides with very reactive organometallic reagents
(Mg and Li, for instance) is one of the most straightforward
methods of carbon-carbon bond formation.1 Contrary to the
seeming simplicity of this reaction, however, its synthetic
utility is quite limited. In particular, nucleophilic substitution
reactions of secondary alkyl halides do not proceed smoothly,
leaving most of the starting material untouched or suffering
from E2 elimination. Organocopper reagents are also known
as being highly reactive in the nucleophilic substitution.2
However, it seems very difficult to perform the reactions of
unactivated secondary alkyl halides with organometalic
reagents in the presence of stoichiometric or catalytic
amounts of copper compounds. Among them, there are very
few copper-mediated alkenylations of secondary alkyl ha-
lides.3 Similar reactions with alkynylcopper reagents have
not been reported so far. As an alternative to the copper
systems, the development of transition-metal-catalyzed cross-
coupling reactions (Ni, Pd, Fe, Co, etc.) of alkyl halides has
been achieving remarkable progress.4 To date, nearly all of
the investigations on the cross-coupling reactions of alkyl
halides have focused on the use of alkyl and arylmetal
nucleophiles. As for the coupling reaction of secondary alkyl
(3) Coupling reaction of 2-iodooctane with 1,3-butadien-2-ylmagnesium
chloride: Nunomoto, S.; Kawakami, Y.; Yamashita, Y. J. Org. Chem. 1983,
48, 1912-1914.
(4) For reviews: (a) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed.
2005, 44, 674-688. (b) Terao, J.; Kambe, N. J. Synth. Org. Chem. Jpn.
2004, 62, 1192-1204. (c) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal.
2004, 346, 1525-1532. (d) Fu¨rstner, A.; Martin, R. Chem. Lett. 2005, 34,
624-629. (e) Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79, 663-
672.
(1) Wakefield, B. J. Organolithium Methods; Academic Press: London,
1988; Chapter 8. (b) Wakefield, B. J. Organomagnesium Methods in
Organic Synthesis; Academic Press: London, 1995; Chapter 8.
(2) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
10.1021/ol0611144 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/08/2006

halide,5 reports of transition-metal-catalyzed coupling reac-
tions with alkenyl nucleophiles are rare.3,5g,6 There are very
few reports on the alkynylation of secondary alkyl halides.7
The transition-metal-mediated alkenylation and alkynylation
of secondary alkyl halides remain as interesting challenges
in the field of carbon-carbon bond formation.
Table 1. Cobalt-mediated Alkenylation and Alkynylationa
Along the lines of our studies on cobalt-mediated coupling
reactions,8 here we wish to report cobalt-mediated cross-
coupling reactions of alkyl halides with 1-(trimethylsilyl)-
ethenylmagnesium bromide and 2-(trimethylsilyl)ethynyl-
magnesium bromide.9 The cobalt-mediated coupling reactions
utilize radical oxidative addition that begins with single-
electron transfer from a cobalt complex to alkyl halide.5n,8a,b,e,f
The single-electron transfer enables the use of unactivated
secondary alkyl halide in the cross-coupling reaction.
Substrate (0.5 mmol) was added to a suspension of
Co(acac)3 (0.2 mmol) in TMEDA (1 mL). Then, a Grignard
reagent, 1-(trimethylsilyl)ethenylmagnesium bromide or 2-
(trimethylsilyl)ethynylmagnesium bromide (2.0 mmol, a
suspension in 1.5 mL of TMEDA), was added over 3 s at
25 °C. An exothermic reaction immediately took place. After
the mixture was stirred at 25 °C for 15 min, usual workup
followed by silica gel column purification afforded the
corresponding coupling product.
The cobalt-mediated alkenylation and alkynylation of a
variety of alkyl halides proceeded smoothly (Table 1). Not
(5) Alkylation of unactivated secondary alkyl electrophiles: (a) Burns,
D. H.; Miller, J. D.; Chan, H.-K.; Delaney, M. O. J. Am. Chem. Soc. 1997,
119, 2125-2133. (b) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
14726-14727. (c) Fisher, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594-
4595. (d) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482-
10483. Arylation of unactivated secondary alkyl halides: (e) Zhou, J.; Fu,
G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (f) Powell, D. A.; Fu, G.
C. J. Am. Chem. Soc. 2004, 126, 7788-7789. (g) Powell, D. A.; Maki, T.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 510-511. (h) Nakamura, M.;
Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686-
3687. (i) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297-1299. (j)
Fu¨rstner, A.; Martin, R.; Angew. Chem., Int. Ed. 2004, 43, 3955-3957. (k)
Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005, 1794-
1798. (l) Bedford, R. B.; Bruce, D. W.; Frost, R. M.; Goodby, J. W.; Hird,
M. Chem. Commun. 2004, 2822-2823. (m) Bedford, R. B.; Betham, M.;
Bruce, D. W.; Danopoulos, A. A.; Frost, R. M.; Hird, M. J. Org. Chem.
2006, 71, 1104-1110. (n) Ohmiya, H.; Yorimitsu, H.; Oshima, K. J. Am.
Chem. Soc. 2006, 128, 1886-1889.
(6) Alkenylation of primary alkyl halides: (a) Menzel, K.; Maki, T.;
Fu, G. C. J. Am. Chem. Soc. 2003, 125, 3718-3719. (b) Zhou, J.; Fu, G.
C. J. Am. Chem. Soc. 2003, 125, 12527-12530. (c) Wiskur, S. L.; Korte,
A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 82-83. Alkynylation of primary
alkyl halides: (d) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
13642-13643. (e) Yang, L.-M.; Huang, L.-F.; Luh, T.-Y. Org. Lett. 2004,
6, 1461-1463.
(7) Very recently, palladium-catalyzed alkynylation of secondary alkyl
halides is reported: Altenhoff, G.; Wu¨rtz, S.; Glorius, F. Tetrahedron Lett.
2006, 47, 2925-2928.
(8) (a) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2001, 123, 5374-5375. (b) Ohmiya, H.; Wakabayashi, K.; Yorimitsu, H.;
Oshima, K. Tetrahedron 2006, 62, 2207-2213. (c) Ohmiya, H.; Yorimitsu,
H.; Oshima, K. Chem. Lett. 2004, 33, 1240-1241. (d) Mizutani, K.;
Yorimitsu, H.; Oshima, K. Chem. Lett. 2004, 33, 832-833. (e) Tsuji, T.;
Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2002, 41, 4137-4139.
(f) Ohmiya, H.; Tsuji, T.; Yorimitsu, H.; Oshima, K. Chem. Eur. J. 2004,
10, 5640-5648.
(9) Recent reports on cobalt-catalyzed coupling reactions, see: (a) Cahiez,
G.; Avedissian, H. Tetrahedron Lett. 1998, 39, 6159-6162. (b) Avedissian,
H.; Be´rillon, L.; Cahiez, G.; Knochel, P. Tetrahedron Lett. 1998, 39, 6163-
6166. (c) Nishii, Y.; Wakasugi, K.; Tanabe, Y. Synlett 1998, 67-69. (d)
Korn, T. J.; Knochel, P. Angew. Chem., Int. Ed. 2005, 44, 2947-2951. (e)
Sezen, B.; Sames, D. Org. Lett. 2003, 5, 3607-3610. (f) Gomes, P.;
Gosmini, C.; Pe´richon, J. Org. Lett. 2003, 5, 1043-1045. (g) Amatore,
M.; Gosmini, C.; Pe´richon, J. Eur. J. Org. Chem. 2005, 989-992.
a Conditions: R-X (0.50 mmol), Co(acac)3 (40 mol %), and Grignard
reagent (2.0 mmol) were used. b The yield was determined by 1H NMR.
c Conditions: R-X (0.50 mmol), Co(acac)3 (20 mol %), and Grignard
reagent (1.5 mmol) were used. d The trans isomer was exclusively detected.
e (+)IM ) (+)-isomenthyl; the (R,R)-product was obtained with 98% de.
f Exo/endo ) 93:7.
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Org. Lett., Vol. 8, No. 14, 2006

only primary alkyl halides but also secondary ones partici-
pated in the coupling reaction. Alkyl iodides and bromides
are the choice of the coupling partner. The reaction of
chlorocyclohexane resulted in poor yield (entry 3). Optically
pure bromo acetal 8 underwent diastereoselective alkenyla-
tion without suffering from â-alkoxy elimination, furnishing
optically pure 2-alkoxy-3-alkenyl-1-oxacyclopentane 21 in
good yield (entry 16). Interestingly, the alkenylations of exo-
and endo-9 provided the exo-product 22 predominantly with
the same diastereoselectivity, which indicates the existence
of a planar carbon center with no original stereochemical
information (entry 17, 18). Unfortunately, tert-butyl bromide
and iodide provided none of the relevant product and gave
a mixture of the reduction and the â-elimination products.
The reaction of 1-bromoethylbenzene resulted in failure and
gave ethylbenzene and styrene.
Table 2. Cobalt-Mediated Sequential Cyclization/Alkenylation
or -Alkynylation
No coupling product was formed when Co(acac)3 was
omitted.10 The use of CoCl2 or Co(acac)2 slightly lowered
the yield by approximately 20% under otherwise identical
conditions.11 The choice of solvent had a significant impact
on the yield. TMEDA (N,N,N′,N′-tetramethylethylenedi-
amine) proved to be the best reaction medium. Other solvents
such as THF, dioxane, and ether did not promote the reaction
at all. The use of TMEDA as an additive (300 mol %) in
THF resulted in much lower yield of the corresponding
product (20-30%). Several ligands such as N,N,N′,N′-
tetramethyl-1,2-cyclohexanediamine,5n (1S,2S)-N,N,N′,N′-tet-
ramethyl-1,2-diphenylethylenediamine, and 1,3-bis(diphen-
ylphosphino)propane were less effective. Various alkenyl-
and alkynylmagnesium reagents were examined. However,
we obtained promising results only with trimethylsilyl-sub-
stituted Grignard reagents. Triisopropylsilyl-substituted al-
kenyl- and alkynylmagnesium reagents did not give satisfac-
tory results. Employing phenylethynyl or 1-decynyl Grignard
reagent gave the desired adducts in no more than 20% yields.
An attempted alkylation reaction resulted in failure. The use
of a phenylmagnesium reagent instead of the alkenyl and
alkylmagnesium reagents afforded the phenylated product
in high yield.5n
Taking advantage of the generation of alkyl radical from
alkyl halides by means of single-electron transfer, we next
turned our attention to the alkenylation and alkynylation that
follow radical cyclization. Namely, this reaction mechanism
would consist of the following sequence: (1) generation of
an alkyl radical from an alkyl halide by single-electron
transfer from a cobalt complex, (2) radical cyclization, (3)
capture of the alkyl radical by a cobalt complex, and (4)
reductive elimination. A series of substrates bearing an alkene
moiety were examined, and the results are summarized in
Table 2. For example, iodo acetal 23 was converted to the
corresponding alkenylated cyclic acetal 27 under the alken-
ylation conditions (entry 1). Sequential cyclization/alkyny-
lation proceeded similarly (entry 2). It is worth noting that
the diastereoselectivity observed in the reaction of iodo acetal
a Diastereomeric ratios are shown in parentheses. b The products were
isolated as lactones after Jones oxidation of the initially formed cyclic
acetals.
23 was identical with that of free-radical cyclization reac-
tion of 23 with tributyltin hydride.12 The identity of the dia-
stereoselectivity strongly suggests that both the cobalt-medi-
ated and tin-mediated cyclizations would proceed via the
same transition states. The sequence mentioned above is thus
most probable. Nitrogen-containing substrate 25 was also
(10) The use of catalytic amounts of Co(acac)3 was examined (Table 1,
entry 2). The conditions were less effective; 52% yield of 10 with 10 mol
% of Co(acac)3, 66% with 20 mol %, and 76% with 30 mol %.
(11) The reason Co(III) is more effective than Co(II) in this reaction is
not clear.
(12) Mayer, S.; Prandi, J.; Bamhaoud, T.; Bakkas, S.; Guillou, O.
Tetrahedron 1998, 54, 8753-8770.
Org. Lett., Vol. 8, No. 14, 2006
3095

subjected to the cyclization in the presence of Co(acac)3 to
yield pyrrolidine derivatives 31 and 32 (entries 5 and 6).
Treatment of an optically pure 26 led to a highly diastereo-
selective cyclization/alkenylation reaction followed by Jones
oxidation to yield an alkenylated lactone 33 (entry 7).13 An
alkynylated analogue 34 was also available, although the
yield was modest (entry 8). These lactones, 33 and 34, can
be precursors of prostaglandins and related compounds.14
In summary, we have found that cobalt efficiently mediates
a cross-coupling reaction of alkyl halides with 1-(trimeth-
ylsilyl)ethenyl- and 2-(trimethylsilyl)ethynylmagnesium re-
agents. The procedure is simple and permits the use of
primary and secondary alkyl halides. The cobalt-mediated
reaction proceeds via a radical pathway.15 This cobalt-
mediated coupling reaction provides a new tool for carbon-
carbon bond formation.
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Government
of Japan.
Supporting Information Available: Experimental details
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0611144
(13) Initially formed cyclic acetals could be isolated before oxidation
1
but showed complex H NMR spectra (Table 2, entries 7 and 8).
(14) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
John Wiley & Sons: New York, 1989; Chapter 11. (b) Tanami, T.; Kameo,
K.; Ono, N.; Nakagawa, T.; Annou, S.; Tsuboi, M.; Tani, K.; Okamoto, S.;
Sato, F. Bioorg. Med. Chem. Lett. 1998, 8, 1507-1510.
(15) The cobalt species that is active for this coupling reaction can be a
Co(0)- or Co(I)-ate complex. See ref 8a,b.
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Org. Lett., Vol. 8, No. 14, 2006