Iron-catalyzed enyne cross-coupling reaction

Article abstract of DOI:10.1021/ol8020226

(Chemical Equation Presented) In the presence of 0.5-1 mol % of FeCl ₃ with lithium bromide as a crucial additive, alkynyl Grignard reagents, prepared from the corresponding alkynes and methylmagnesium bromide, react with alkenyl bromides or triflates to give the corresponding conjugated enynes in high to excellent yields. The reaction shows wide applicability to various terminal alkynes and alkenyl electrophiles.

Full text of DOI:10.1021/ol8020226

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5341-5344
Iron-Catalyzed Enyne Cross-Coupling
Reaction
Takuji Hatakeyama, Yuya Yoshimoto, Toma Gabriel, and Masaharu Nakamura*
International Research Center for Elements Science, Institute for Chemical Research,
Kyoto UniVersity, Uji, Kyoto, 611-0011, Japan
masaharu@scl.kyoto-u.ac.jp
Received August 28, 2008
ABSTRACT
In the presence of 0.5-1 mol % of FeCl3 with lithium bromide as a crucial additive, alkynyl Grignard reagents, prepared from the corresponding
alkynes and methylmagnesium bromide, react with alkenyl bromides or triflates to give the corresponding conjugated enynes in high to
excellent yields. The reaction shows wide applicability to various terminal alkynes and alkenyl electrophiles.
Conjugated enyne is a key structural and often functional
unit of various bioactive molecules, drug intermediates, and
organic electronic materials.1 Development of Pd-catalyzed
Csp-Csp2 coupling reactions (cf., the Negishi coupling, the
Sonogashira coupling, and the Heck reactions) have signifi-
cantly contributed to selective and efficient syntheses of the
unsaturated structure.2 Recent investigations aimed toward
the development of inexpensive and practical methods for
enyne coupling revealed that cobalt,3a nickel,3b-d and
copper3e-g can be effective catalysts for such a purpose.
Herein, we wish to disclose another practical enyne coupling
reaction, in which alkenyl halides or triflates and alkynyl-
magnesium reagents are cross-coupled by iron catalyst with
the aid of concomitant lithium halides.
organomagnesium reagent have already been examined in
the pioneering work of Kochi8 and the breakthrough work
of Cahiez,5a they were limited to alkyl and aryl metal
reagents. This is very likely due to the stability of the Fe-C
bond of alkynyl iron species, which allows the formation of
stable ferrate complexes to halt the catalytic cross-coupling
process.9,10 Based on our previous studies on iron catalysis,
we envisioned that suitable Lewis basic or acidic additives
could facilitate the reductive decomposion of the ferrate to
produce a catalytically active iron species.
We thus conducted a catalyst and promoter screening by
using the reaction between octynyl magnesium bromide 1a
and ꢀ-bromostyrene 2 as a benchmark reaction (Scheme 1).
1-Octynylmagnesium bromide 1a was prepared from 1-oc-
tyne and an equimolar amount of methylmagnesium bro-
Despite the recent remarkable progress in the field of iron-
catalyzed cross-coupling reactions,4-7 no successful example
of enyne coupling has been reported to date. Even though
various combinations of an alkenyl electrophile and an
Scheme 1
. Preparation of 1-Octynyl Magnesium Bromide and
(1) Recent reviews: (a) Chinchilla, R.; Na´jera, C. Chem. ReV. 2007, 107,
874–922. (b) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46,
834–871.
Iron-Catalyzed Cross-Coupling Reaction with ꢀ-Bromostyrene
(2) (a) Sonogashira, K. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons: New York,
2002; Vol. 1, pp 493-529. (b) Negishi, E.; Xu, C. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John
Wiley & Sons: New York, 2002; Vol. 1, pp 531-549. (c) Cross-Coupling
Reactions: A Practical Guide; Miyaura, N., Ed.; Springer: Berlin, 2002.
(d) Metal-Catalyzed Cross-coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: New York, 2004. (e) Negishi, E.; Hu, Q.;
Huang, Z.; Qian, M.; Wang, G. Aldrichimica Acta 2005, 38, 71–88.
10.1021/ol8020226 CCC: $40.75
Published on Web 11/06/2008
2008 American Chemical Society

mide11 at 60 °C for 4 h. FeCl3 (0.5 mol %) and
12
ꢀ-bromostyrene 2 (E:Z ) 85:15) were added at 0 °C to the
THF solution of 1a (1.2 equiv). The reaction mixure was
stirred at 50 °C for 24 h, and the yield of the desired enyne
Table 1. Effect of Lewis Basic and Acidic Additives
entrya
additive (X mol %)
yield of 3 (%)b recovery of 2 (%)
1
3 was determined by H NMR.
1
2
3
4
5
6
7
8
none (–)
12
2
83
69
76
76
75
36
18
9
71
72
65
93
Table 1 summarizes the result of the screening of Lewis
basic or acidic promoters. As in entry 1, conversion of
ꢀ-bromostyrene was sluggish without any addtives to give
3 in 12% yield. Previously reported effective additives for
the iron-catalyzed coupling reactions were tested. Those
additives are the following: N-methyl-2-pyrrolidone5a-d (9.0
equiv, NMP), tricyclohexylphosphine6g (1 mol %, PCy3), 1,3-
bis(2,6-i-propylphenyl)imidazolinium hydrochloride6g (2 mol
%, SIPr·HCl), hexamethylenetetramine6i (5 mol %, HMTA),
and N,N,N′,N′-tetramethylethylenediamine (10 mol %, TME-
DA). These additives, however, did not improve the product
yield (entries 2-5). A stoichiometric amount of TMEDA6a
(1.2 equiv) accerelated the reaction to give 3 in 60% yield
NMP (900)
HMTA/TMEDA (5/10)
SIPr·HCl (2)
PCy3 (1)
TMEDA (120)
LiCl (120)
LiBr (120)
LiBr (60)
LiBr (20)
MgBr2 (120)
ZnCl2 (120)
15
11
17
60
82
85
27
21
28
1
9
10
11
12
a Reactions were carried out on a 1.0 mmol scale. b The yield was
1
determined by H NMR analysis by using dibromomethane as an internal
standard.
(3) Selected papers: (a) Shirakawa, E.; Sato, T.; Imazaki, Y.; Kimura,
T.; Hayashi, T. Chem. Commun. 2007, 4513–4515. (b) Walker, J. A.; Bitler,
S. P.; Wudl, F. J. Org. Chem. 1984, 49, 4733–4734. (c) Madec, D.; Pujol,
S.; Henryon, V.; Fe´re´zou, J. P. Synlett 1995, 435–438. (d) Wang, L.; Li,
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C. G.; Venkataraman, D. Synthesis 2005, 1706–1712. (f) Li, J. H.; Li, J. L.;
Wang, D. P.; Pi, S. F.; Xie, Y. X.; Zhang, M. B.; Hu, X. C. J. Org. Chem.
2007, 72, 2053–2057. (g) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844–
4850.
(entry 6). Note that additional TMEDA or prolonged reaction
time did not improve the yield.
We next examined a series of metal salts and found that
a considerable improvement of the yield could be achieved
with 120 mol % of LiCl or LiBr13 (entries 7 and 8). It is
noteworthy that 1-octynyllithium, prepared from 1-octyne
and n-BuLi, did not give enyne 3 under the same conditions.
Reduced amount of LiBr (20 and 60 mol %) or use of
additional magnesium salts was not effective (entries 9-11).
In sharp contrast to Negishi coupling, addition of ZnCl2
(transmetalation to zinc)2b did not work at all under the
present conditions (entry 12). In all cases, enyne 3 was
obtained as a 88:12 mixture of geometrical isomers (E:Z)
along with the formation of hexadeca-7,9-diyne in 1-5%.
To examine the substrate scope of the reaction, we carried
out the cross-coupling reaction using a variety of alkenyl
electrophiles and alkynyl magnesium bromides (1a-1f,
Figure 1) in the presence of FeCl3 (0.5-3 mol %) and LiBr
(120 mol %).
(4) (a) Iron Catalysis in Organic Chemistry; Plietker, B. Ed.; Wiley-
VCH: Weinheim, 2008. (b) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem.
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Chem. 2004, 2081–2091. (d) Fu¨rstner, A.; Rube´n, M. Chem. Lett. 2005,
34, 624–629.
(5) (a) Cahiez, G.; Avedissian, H. Synthesis 1998, 1199–1205. (b) Dohle,
W.; Kopp, F.; Cahiez, G.; Knochel, P. Synlett 2001, 1901–1904. (c) Fu¨rstner,
A.; Leitner, A. Angew. Chem., Int. Ed. 2002, 41, 609–612. (d) Fu¨rstner,
A.; Leitner, A.; Me´ndez, M.; Krause, H. J. Am. Chem. Soc. 2002, 124,
13856–13863. (e) Fu¨rstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003,
42, 308–311. (f) Hocek, M.; Dvor´akov´a, H. J. Org. Chem. 2003, 68, 5773–
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W. J.; Hird, M. Chem. Commun. 2004, 2822–2823. (e) Sapountzis, I.; Lin,
W.; Kofink, C. C.; Despotopoulou, C.; Knochel, P. Angew. Chem., Int. Ed.
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2006, 71, 1104–1110. (h) Bica, K.; Gaertner, P. Org. Lett. 2006, 8, 733–
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3254. (b) Gue´rinot, A.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed.
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(8) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93, 1487–
1489. (b) Tamura, M.; Kochi, J. K. Synthesis 1971, 93, 303–305. (c) Tamura,
M.; Kochi, J. K. J. Organomet. Chem. 1971, 31, 289–309. (d) Tamura, M.;
Kochi, J. K. Bull. Chem. Soc. Jpn. 1971, 44, 3063–3073. (e) Neumann, S.;
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J. K. J. Org. Chem. 1976, 41, 502–509.
Figure 1. Alkynylmagnesium reagents examined for the cross-
coupling.
(9) Berben, L. A.; Long, J. R. Inorg. Chem. 2005, 44, 8459–8468.
(10) Bolm et al. recently reported an iron-catalyzed Sonogashira coupling
of terminal alkynes and iodoarenes, under less basic or nucleophilic
conditions than those described here. The present enyne coupling reaction
did not proceed with Bolm’s iron-catalyst system. Carril, M.; Correa, A.;
Bolm, C. Angew. Chem., Int. Ed 2008, 47, 4862–4865.
Table 2 illustrates the iron-catalyzed cross-coupling reac-
tions under the optimum conditions described above. As
shown in entry 1, the reaction between 1a and 2 completed
at 60 °C for 24 h to give enyne 3 in 95% yield. Iron(II)
(11) Deprotonation can be achieved at room temperature by using
ethylmagnesium bromide.
(12) FeCl2, Fe(acac)3, and other iron salts showed comparable catalytic
activity as described in entry 1, Table 2.
(13) Other lithium salts were also examined: LiI (32%), LiOTf (86%),
LiClO4 and LiBF4 (0%). The combined use of lithium salt and TMEDA
was not as effective as lithium salt itself.
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Org. Lett., Vol. 10, No. 23, 2008

less reactive than 1a-1e, reacted with 4 and 6 to give enynes
16 and 17 in 60% and 91% yield, respectively (entries 11
and 12). As shown in entries 13 and 14, the present reaction
turned out to be stereoselective15 to some degree: trans-1-
bromopropene 18E (99% E) gave trans-isomer 19E as a
major product (93% E), and 18Z (99% Z) gave cis-isomer
19Z as a major (65% Z).
Table 2. Iron-Catalyzed Enyne Coupling in the Presence of
Lithium Bromide
Scheme 2. Possible Mechanism of Iron-Catalyzed Enyne Coupling
A possible mechanism of the iron-catalyzed enyne cou-
pling is shown in Scheme 2. Based on the initial formation
of the diyne upon mixing the alkynyl metal and the
precatalyst FeCl3, a trivalent iron salt would presumably be
first reduced to a low-valent state (A), such as Fe(0) or Fe(I),
which probably possesses one or a few alkynyl groups. In
the absence of a lithium salt, the initial reduction is rather
sluggish and highly dependent on the strucure of the alkynyl
moiety because of the notable stability of Fe(II) alkynyl ate
complexes.3a,9 Oxdative addition of an alkenyl bromide to
the low-valent ferrate complex A gives the higher-valent
ferrate complex B, which undergoes reductive elimination
to produce the corresponding enyne. The resulting ferrate
complex C reacts with alkynylmagnesium bromide to
regenerate A. The partial loss of the stereochemical purity
of (E)- and (Z)-propenyl bromides indicates the involvement
of an electron transfer process at the oxidative addition step.16
In summary, we have found a pronounced acceleration
effect of lithium salts on the cross-coupling of alkynylmag-
nesium reagents under iron catalysis to achieve a new
transition-metal-catalyzed enyne coupling reaction. The
present reaction possesses several synthetically attractive
a Reactions were carried out at 60 °C for 24 h on a 1.0 mmol scale in
the presence of 1 mol % of FeCl3 unless otherwise noted. b Isolated yield.
c E:Z ) 85:15 d 0.5 mol % of FeCl3 was used. e E:Z ) 88:12 f 0.5 mol %
of FeCl2 was used. g 0.5 mol % of Fe(acac)3 was used. h Reaction time
was 12 h. i E:Z ) 92:8 j E:Z ) 85:15 k 3 mol % of FeCl3 was used. l Reaction
temperature was 80 °C.
salts, FeCl2 and Fe(acac)3, showed comparable catalytic
activity to give 3 in 89% and 86% yield, respectively. The
reactions with 2-bromopropene and 1-trimethylsilylpropene
smoothly took place to give enynes 5 and 7 in 76% and
>99% yield, respectively (entries 2 and 3).
(14) (2-Trimethylsilyl)ethynylmagnesium bromide shows lower reactivity
to give the corresponding enyne in 39% yield.
(15) The iron-catalyzed coupling reactions between alkylmagnesium
bromide and alkenyl halide take place stereoselectively. See refs 5a and
8a-e.
(16) (a) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351–360. (b) Kauffmann,
T. Angew. Chem., Int. Ed. 1996, 35, 386–403. (c) Bogdanovic, B.;
Schwichardi, M. Angew. Chem., Int. Ed. 2000, 39, 4610–4612. (d)
Uchiyama, M.; Matsumoto, Y.; Nakamura, S.; Ohwada, T.; Kobayashi, N.;
Yamashita, N.; Matsumiya, A.; Sakamoto, T. J. Am. Chem. Soc. 2004, 126,
8755–8759. (e) Fu¨rstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard,
R.; Lehmann, C. J. Am. Chem. Soc. 2008, 130, 8773–8787.
Alkenyltriflate 8 also took part in the coupling reaction
(entry 4).3a Silylethers remained intact under the present
reaction conditions (entries 5-7). This method can be
applicable for silylethynyl Grignard reagents141d and 1e
(entries 8-10). Phenylethynylmagnesium bromide 1f, slightly
Org. Lett., Vol. 10, No. 23, 2008
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features: (1) simple procedure, (2) high selectivity, (3) high
yield, and (4) freedom from expensive metals and ligands.
The acceleration effect of certain lithium salts would also
be helpful for further development of iron-catalyzed cross-
coupling reactions.
Program ”International Center for Integrated Research and
Advanced Education in Materials Science” (Y.Y.), Joint
Project of Chemical Synthesis Core Research Institution from
MEXT, and a Grant-in-Aid for Young Scientists from JSPS
(S, M.N., 2075003). Financial support from the Uehara
Memorial Foundation is also acknowledged.
Acknowledgment. We thank the Ministry of Education,
Culture, Sports, Science, and Technology of Japan for
financial support, and a Grant-in-Aid for Scientific Research
on Priority Areas “Synergistic Effects for Creation of
Functional Molecules” (M.N., 18064006) and “Chemistry
of Concerto Catalysis” (T.H. 20037033), the Global COE
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.
OL8020226
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Org. Lett., Vol. 10, No. 23, 2008