Iron-catalyzed negishi coupling toward an effective olefin synthesis

Article abstract of DOI:10.1021/ol901555r

A selective Iron-catalyzed cross-coupling of alkyl halldes with alkenylzinc reagents Is described. Primary and secondary alkyl chlorides, bromides, and iodides take part In the reaction to give the corresponding olefins In good to excellent yields In a stereospecific manner. High functional group compatibility Is also demonstrated by using combinations of substrates possessing rather reactive substituents.

Full text of DOI:10.1021/ol901555r

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4496-4499
Iron-Catalyzed Negishi Coupling Toward
an Effective Olefin Synthesis
Takuji Hatakeyama,† Naohisa Nakagawa,†,‡ and Masaharu Nakamura*,†
International Research Center for Elements Science, Institute for Chemical Research,
and Department of Energy and Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Uji, Kyoto 611-0011, Japan
masaharu@scl.kyoto-u.ac.jp
Received July 8, 2009
ABSTRACT
A selective iron-catalyzed cross-coupling of alkyl halides with alkenylzinc reagents is described. Primary and secondary alkyl chlorides,
bromides, and iodides take part in the reaction to give the corresponding olefins in good to excellent yields in a stereospecific manner. High
functional group compatibility is also demonstrated by using combinations of substrates possessing rather reactive substituents.
Nucleophilic substitution of alkyl electrophiles with alkenyl-
metal reagents is a useful method for olefin synthesis. In
particular, highly reactive alkenyl cuprates1,2 can be coupled
with a variety of primary alkyl tosylates, bromides, and
iodides. This type of reaction has greatly contributed to total
synthesis of natural products.3 During the past decades,
various cross-coupling reactions based on transition-metal
catalysts have been demonstrated as an alternative for
stoichiometric substitution: Fu and co-workers reported
efficient palladium-4 and nickel-catalyzed5 cross-coupling
reactions of primary alkyl halides with alkenyltin,4a,5b zinc,4b
zirconium,4c and boron5a reagents. Recently, Oshima and co-
workers reported cobalt-catalyzed cross-coupling of primary
and secondary alkyl halides with 1-(trimethylsilyl)ethenyl-
magnesium reagent.6 Nevertheless, there remain much to be
improved, for example, low selectivity and yield for alkyl
chlorides or secondary electrophiles.7
Iron catalysis has been intensively studied in the field of
cross-coupling reactions,8-10 and certain combinations of
iron salts and additives, such as FeCl3/N,N,N′,N′-tetrameth-
ylethylenediamine (TMEDA)10a,11 and Fe(acac)3/TMEDA/
hexamethylenetetramine (HMTA),10g,12 have proven to be
effective for the cross-coupling of alkyl halides with alk-
enylmagnesium reagents. Despite the recent progress, several
issues, such as functional group compatibility, a limited
substrate scope, and moderate yield and stereospecificity are
still to be solved in order to achieve efficient stereocontrolled
olefin synthesis by the iron-catalyzed alkenyl coupling.
Herein, we report a simple and effective protocol for olefin
† International Research Center for Elements Science (IRCELS), Institute
for Chemical Research.
‡ Department of Hydrocarbon and Energy Chemistry.
(1) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135–631, and
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Wiley-VCH: Weinheim, 2008. (b) Bolm, C.; Legros, J.; Le Paih, J.; Zani,
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10.1021/ol901555r CCC: $40.75
Published on Web 09/16/2009
 2009 American Chemical Society

synthesis where readily available alkenylzinc reagents and
a wide variety of alkyl halides, including chlorides, are cross-
coupled by an iron catalyst in the presence of excess
TMEDA.
Table 1. Cross-Coupling of Styryl Metals (RM) with
Bromocycloheptane (2) in the Presence of Iron Salt and
Additive
Figure 1. Alkenyl metal reagents examined for the iron-catalyzed
cross-coupling with alkyl halides.
We conducted the reaction of a secondary alkyl bromide
with alkenylzinc reagents (1a and 1b) for screening of iron
precatalyst and additives (Table 1).13,14 The reaction between
1a and 2 proceeded very sluggishly in the presence of 5 mol
% of FeCl3 to give the desired coupling product 3 in 8%
yield with recovery of 70% of the bromide 2 (entry 1).
ꢀ-Styryl[(trimethylsilyl)methyl]zinc reagent 1b, prepared
a Reactions were carried out on a 0.5 mmol scale. b Prepared from
ꢀ-bromostyrene (E/Z ) 86/14). c Yields were determined by GLC analysis
using undecane as an internal standard. d Recovery of starting bromide.
e E/Z ) 80/20 f 1c was added dropwise over 0.5 h at 0 °C.
from 1a and (trimethylsilyl)methylmagnesium chloride13a, 15
e,
showed slightly higher reactivity, albeit lower selectivity, to
give 3 in 25% yield along with byproducts (4 in 4% and 5
in 17% yield) (entry 2). In these cases, formation of diene 6
was observed in the initial period of the reaction.16 Note
that high molecular-weight byproducts, derived from bro-
mocycloheptane 2 and the diene 6, formed in moderate
yields.17
(9) Selected papers: (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc.
1971, 93, 1487–1489. (b) Molander, G. A.; Rahn, B. J.; Shubert, D. C.;
Bonde, S. E. Tetrahedron Lett. 1983, 24, 5449–5452. (c) Cahiez, G.;
Avedissian, H. Synthesis 1998, 1199–1205. (d) Dohle, W.; Kopp, F.; Cahiez,
G.; Knochel, P. Synlett 2001, 1901–1904. (e) Fu¨rstner, A.; Leitner, A.;
Me´ndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124, 13856–13863. (f)
Sapountzis, I.; Lin, W.; Kofink, C. C.; Despotopoulou, C.; Knochel, P.
Angew. Chem. 2005, 117, 1682-1685; Angew. Chem., Int. Ed. 2005, 44,
1654-1658. (g) Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem. 2007, 119,
952-954; Angew. Chem., Int. Ed. 2007, 46, 934-936. (h) Dongol, K. G.;
Koh, H.; Sau, M.; Chai, C. L. L. AdV. Synth. Catal. 2007, 349, 1015–1018.
(i) Hatakeyama, T.; Nakamura, M. J. Am. Chem. Soc. 2007, 129, 9844–
9845. (j) Fu¨rstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.;
Lehmann, C. W. J. Am. Chem. Soc. 2008, 130, 8773–8787. (k) Hatakeyama,
T.; Yoshimoto, Y.; Gabriel, T.; Nakamura, M. Org. Lett. 2008, 10, 5541–
5544. (l) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M. J. Am.
Chem. Soc. 2009, 131, 11949–11963.
During the screening of additives, we found that the
amount of TMEDA was critical in achieving a selective
coupling reaction: the reaction with 3.5 equiv of TMEDA
gave 3 in 95% yield, while the reaction with 1.5 and 3.0
equiv of TMEDA gave 3 in 56% and 91% yield, respectively
(entries 3-5).18 Because TMEDA can coordinate not only
to the iron atom but also to the zinc and magnesium atoms,
it would be necessary to use a stoichiometric or slight excess
amount of TMEDA relative to the total amount of metal salts
to ensure that TMEDA coordinates the iron catalyst. The
divalent iron precursor, FeCl2, as well as Fe(acac)3 was
comparable to FeCl3 (entries 6 and 7). Note that the reaction
with alkenylmagnesium reagent 1c in the presence of 3.5
equiv of TMEDA was far less selective (entry 8). The
conditions reported for alkenylmagnesium reagents11,12 were
not effective for the reaction between 1c and 2 (see the
Supporting Information).
(10) Iron-catalyzed cross-coupling of alkyl electrophile: (a) Nakamura,
M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686–
3687. (b) Nagano, T.; Hayashi, T. Org. Lett. 2004, 6, 1297–1299. (c) Martin,
R.; Fu¨rstner, A. Angew. Chem. 2004, 116, 4045-4047; Angew. Chem., Int.
Ed. 2004, 43, 3955-3957. (d) Bedford, R. B.; Bruce, D. W.; Frost, R. M.;
Hird, M. Chem. Commun. 2005, 4161–4163. (e) Bica, K.; Gaertner, P. Org.
Lett. 2006, 8, 733–735. (f) Bedford, R. B.; Betham, M.; Bruce, D. W.;
Danopoulos, A. A.; Frost, R. M.; Hird, M. J. Org. Chem. 2006, 71, 1104–
1110. (g) Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Angew. Chem.
2007, 119, 4442-4444; Angew. Chem., Int. Ed. 2007, 46, 4364-4366. (h)
Volla, C.-M. R.; Vogel, P. Angew. Chem. 2008, 120, 1325-1327; Angew.
Chem., Int. Ed. 2008, 47, 1305-1307. (i) Noda, D.; Sunada, Y.; Hatakeya-
ma, T.; Nakamura, M.; Nagashima, H. J. Am. Chem. Soc. 2009, 131, 6078–
6079.
(11) Gue´rinot, A.; Reymond, S.; Cossy, J. Angew. Chem. 2007, 119,
6641-6644; Angew. Chem., Int. Ed. 2007, 46, 6521-6524.
(12) Cahiez, G.; Habiak, V.; Duplais, C.; Moyeux, A. Org. Lett. 2007,
9, 3253–3254.
Table 2 illustrates the scope of the coupling reaction
between various alkyl halides and alkenylzinc reagents
(13) Iron-catalyzed Negishi coupling reaction : (a) Nakamura, M.; Ito,
S.; Matsuo, K.; Nakamura, E. Synlett 2005, 1794–1798. (b) Bedford, R. B.;
Huwe, M.; Wilkinson, M. C. Chem. Commun. 2009, 600–602. (c)
Hatakeyama, T.; Kondo, Y.; Fujiwara, Y.; Takaya, H.; Ito, S.; Nakamura,
E.; Nakamura, M. Chem. Commun. 2009, 1216–1218. (d) Cahiez, G.;
Foulgoc, L.; Moyeux, A. Angew. Chem. 2009, 121, 3013-3016; Angew.
Chem., Int. Ed. 2009, 48, 2969-2972. (e) Ito, S.; Fujiwara, Y.; Nakamura,
(15) (a) Bertz, S. H.; Eriksson, M.; Miao, G.; Snyder, J. P. J. Am. Chem.
Soc. 1996, 118, 10906–10907. (b) Berger, S.; Langer, F.; Lutz, C.; Knochel,
P.; Mobley, T. A.; Reddy, C. K. Angew. Chem. 1997, 109, 1603-1605;
Angew. Chem., Int. Ed. 1997, 36, 1496-1498.
(16) Iron(III) would be reduced to catalytically active low-valent,
possibly (0) or (II), iron species. See ref 9j and others cited therein.
(17) Iron(0) species catalyzed dimerization and oligomerization of dienes:
Dieck, H. t.; Dietrich, J. Angew. Chem. 1985, 97, 795-796; Angew. Chem.,
Int. Ed. 1985, 24, 781-783.
(18) Conventional additives, NMP (refs 9e and 10h), SIPr (ref 9i,l), and
DPPBz (ref 13b,c) are not as effective as TMEDA.
E.; Nakamura, M. Org. Lett. 2009, 11, 4306–4309, See also ref 9e
.
(14) We used anhydrous FeCl3 (> 99.99%, Aldrich, Inc.) as a precatalyst,
which has been reported rather free from the contamination of a trace amount
of copper; see: Buchwald, S. L.; Bolm, C. Angew. Chem. 2009, 121,
5694-5695; Angew. Chem., Int. Ed. 2009, 48, 5586-5587.
Org. Lett., Vol. 11, No. 20, 2009
4497

acetoxy, and carbamate, participate in the coupling reaction
(entries 11-13).
Table 2. Cross-Coupling of Alkenylzinc Reagents and Alkyl
1-Bromo-4-(2-bromoethyl)benzene possessing two poten-
tial reactive sites, Csp2-Br and Csp3-Br, reacted with 1d
via a selective Csp3-Br bond cleavage (entry 14). The
selective cleavage can be explained by the radical character
of the catalytically active organoiron species. The interme-
diacy of alkyl radicals was supported by the reaction of
(bromomethyl)cyclopropane with 1b, which gave the ring-
opening diene as the sole cross-coupling product (entry 15).
Halides
The present method is stereospecific and chemoselective,
as demonstrated in Scheme 1. (Z)-(4-Cyanostyryl)zinc re-
agent 1g, prepared from (Z)-4-(2-bromovinyl) benzonitrile
7g (96% Z) in two steps,19 was thus coupled with ethyl
7-bromoheptanoate 8 under the conditions described above
to give 9 in 87% yield without any loss of geometrical purity
(96% Z). Similarly, the reaction between (Z)-(4-methoxy-
carbonylstyryl)zinc reagent (90% Z) 1h and 7-bromohep-
tanenitrile 10 took place stereoselectively to give 11 in 92%
yield (89% Z). The cyano and alkoxycarbonyl groups
remained untouched.20
Scheme 1. Stereospecific Negishi Coupling between a
Z-Alkenylzinc Reagent and an Alkyl Bromide Both Bearing a
Functional Group
a Reactions were carried out according to the procedure for entry 5 in
Table 1 on a 1.0 mmol scale. b Isolated yield. c Three equivalents of 1d
was used. d Two equivalents of 1d-f was used. e NMR yield. f E/Z ) 93/7.
g E/Z ) 90/10.
(1b,d-f, Figure 1) under the present conditions. As shown
in entries 1-8, the reactions of primary and secondary alkyl
halides with (2-methylprop-1-enyl)zinc reagent 1d smoothly
proceeded at 30-40 °C to give the desired product in good
to excellent yields. It is noteworthy that a variety of alkyl
chlorides, which resulted in low yielding according to the
previous reports, take part in the alkenyl coupling (entries 3
and 6-8). In all the cases examined, the reduction byproduct
(alkane) was obtained in 1-3% yields as a minor side
product, and the elimination byproduct (alkene) was almost
negligible. 1-(Trimethylsilyl)vinylzinc reagent 1e, slightly
less reactive than 1d, can be cross-coupled with secondary
alkyl halides in good yields (entries 9 and 10). Alkyl
bromides possessing a functional group, such as cyano,
In summary, we have demonstrated that the iron-catalyzed
cross-coupling reaction of primary and secondary alkyl
halides with alkenylzinc reagents provides the corresponding
olefins in a highly selective manner. The present method is
high-yielding, chemoselective, stereospecific, and free of rare
metals and phosphine ligands, and it shows its potential in
efficient and versatile access to functional molecules bearing
a carbon-carbon double bond.
(19) Direct insertion of zinc into organic bromides: Krasovskiy, A.;
Malakhov, V.; Gavryushin, A.; Knochel, P. Angew. Chem. 2006, 118,
6186-6190; Angew. Chem., Int. Ed. 2006, 45, 6040-6044.
(20) Aliphatic ketones underwent deprotonation under the reaction
conditions and interfered with the cross-coupling reaction (data not shown).
4498
Org. Lett., Vol. 11, No. 20, 2009

Acknowledgment. We thank Japan Society for the
Promotion of Science (JSPS) and the Ministry of Education,
Culture, Sports, Science and Technology of Japan (MEXT)
for financial supports, Grant-in-Aids for Scientific Research
on Priority Areas “Synergy of Elements” (M.N., 18064006)
and “Chemistry of Concerto Catalysis” (T.H., 20037033),
and Grant-in-Aids for Young Scientists (S, M.N., 2075003;
B, T.H., 2175098), and the Global COE Program “Interna-
tional Center for Integrated Research and Advanced Educa-
tion in Materials Science”. Financial support from Tosoh
Finechem and Tosoh Corps. is gratefully acknowledged. We
also thank Dr. H. Seike (Kyoto University) for his experi-
mental support and valuable discussions.
Supporting Information Available: Experimental pro-
cedures and physical properties of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901555R
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