Iron-catalyzed arylmagnesiation of aryl(alkyl)acetylenes in the presence of an N-heterocyclic carbene ligand

Article abstract of DOI:10.1021/ol063132r

(Chemical Equation Presented) Addition of arylmagnesium bromides to aryl(alkyl)acetylenes proceeded in the presence of an iron catalyst and a N-heterocyclic carbene ligand to give high yields of the corresponding alkenylmagnesium reagents, which were transformed into tetrasubstituted alkenes by subsequent treatment with electrophiles.

Full text of DOI:10.1021/ol063132r

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1045-1048
Iron-Catalyzed Arylmagnesiation of
Aryl(alkyl)acetylenes in the Presence of
an N-Heterocyclic Carbene Ligand
Takafumi Yamagami, Ryo Shintani, Eiji Shirakawa,* and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo,
Kyoto 606-8502, Japan
thayashi@kuchem.kyoto-u.ac.jp; shirakawa@kuchem.kyoto-u.ac.jp
Received December 27, 2006
ABSTRACT
Addition of arylmagnesium bromides to aryl(alkyl)acetylenes proceeded in the presence of an iron catalyst and a N-heterocyclic carbene
ligand to give high yields of the corresponding alkenylmagnesium reagents, which were transformed into tetrasubstituted alkenes by subsequent
treatment with electrophiles.
Carbometalation of alkynes generating alkenylmetal species
is one of the most powerful methods of synthesizing
multisubstituted alkenes,1 and the use of iron catalysis for
this transformation has attracted increasing attention owing
to its high activity toward the reactions of organomagnesium
reagents.2 However, although heteroatom-containing alkynes
are known to undergo the carbometalation with high reactiv-
ity and selectivity due to the stabilizing effects caused by
their coordination,3 the carbometalation of those lacking the
heteroatoms remains to be developed.4 We have recently
reported the arylmagnesiation of simple dialkylacetylenes that
is realized for the first time by an iron/copper cocatalyst
system.5 Herein we report that the iron-catalyzed aryl-
magnesiation of aryl(alkyl)acetylenes is greatly improved by
addition of a catalytic amount of an N-heterocyclic carbene
ligand to give high yields of the corresponding trisubstituted
alkenylmagnesiums that are convertible into tetrasubstituted
alkenes by reaction with electrophiles.6,7
For the addition of 4-methoxyphenylmagnesium bromide
(2m) to 1-phenyl-1-hexyne (1a) in the presence of Fe(acac)3
as a catalyst, several additives were examined for their effects
on the catalytic activity and selectivity, and it was found
that the addition of a catalytic amount of an N-heterocyclic
(4) (a) Eisch, J. J.; Kaska, W. C. J. Am. Chem. Soc. 1966, 88, 2976-
2983. (b) Eisch, J. J.; Amtmann, R.; Foxton, M. W. J. Organomet. Chem.
1969, 16, P55-59. (c) Eisch, J. J.; Amtmann, R. J. Org. Chem. 1972, 37,
3410-3415. (d) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem.
1972, 44, C1-C3. (e) Duboudin, J. G.; Jousseaume, B. J. Organomet. Chem.
1978, 162, 209-222. (f) Stu¨demann, T.; Knochel, P. Angew. Chem., Int.
Ed. 1997, 36, 93-95. (g) Yorimitsu, H.; Tang, J.; Okada, K.; Shinokubo,
H.; Oshima, K. Chem. Lett. 1998, 27, 11-12.
(5) Shirakawa, E.; Yamagami, T.; Kimura, T.; Yamaguchi, S.; Hayashi,
T. J. Am. Chem. Soc. 2005, 127, 17164-17165.
(6) Recent reviews on the iron-catalyzed reactions: (a) Bolm, C.; Legros,
J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217-6254. (b) Fu¨rstner,
A.; Martin, R. Chem. Lett. 2005, 34, 624-629.
(7) Examples of the combination of iron catalyst and carbene ligand:
(a) Bedford, R. B.; Betham, M.; Bruce, D. W.; Danopoulos, A. A.; Frost,
R. M.; Hird, M. J. Org. Chem. 2006, 71, 1104-1110. (b) Bica, K.; Gaertner,
P. Org. Lett. 2006, 8, 733-735. (c) Saino, N.; Kogure, D.; Kase, K.;
Okamoto, S. J. Organomet. Chem. 2006, 691, 3129-3136. (d) Hilt, G.;
Bolze, P.; Kieltsch, I. Chem. Commun. 2005, 1996-1998.
(1) Knochel, P. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: New York, 1991;
Vol. 4, Chapter 4.4, pp 865-911.
(2) Iron-catalyzed carbometalation of alkynes or alkenes: (a) Caporusso,
A. M.; Lardicci, L.; Giacomelli, G. Tetrahedron Lett. 1977, 18, 4351-
4354. (b) Caporusso, A. M.; Giacomelli, G.; Lardicci, L. J. Chem. Soc.,
Perkin Trans. 1 1979, 3139-3145. (c) Nakamura, M.; Hirai, A.; Nakamura,
E. J. Am. Chem. Soc. 2000, 122, 978-979. (d) Hojo, M.; Murakami, Y.;
Aihara, H.; Sakuragi, R.; Baba, Y.; Hosomi, A. Angew. Chem., Int. Ed.
2001, 40, 621-623. (e) Fu¨rstner, A.; Me´ndez, M. Angew. Chem., Int. Ed.
2003, 42, 5355-5357. (f) Lepage, O.; Kattnig, E.; Fu¨rstner, A. J. Am. Chem.
Soc. 2004, 126, 15970-15971. (g) Fukuhara, K.; Urabe, H. Tetrahedron
Lett. 2005, 46, 603-606. (h) Zhang, D.; Ready, J. M. J. Am. Chem. Soc.
2006, 128, 15050-15051.
(3) A review on carbometalation of heteroatom-containing alkynes and
alkenes: Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57, 5899-5913.
10.1021/ol063132r CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/10/2007

carbene ligand greatly improved the yield of the arylmag-
nesiation (Table 1). Thus, the reaction of 1a with 2m (2
The addition of D2O to the arylmagnesiation product
resulting from the reaction of 1a with 2m in the presence of
the Fe(acac)3/IPr catalyst (entry 1 in Table 1) gave the alkene
3am-d where the olefinic carbon at the 1 position is
incorporated with deuterium in 99%. The high content of
deuterium demonstrates the formation of alkenylmagnesium
species before hydrolysis.
Table 1. Iron-Catalyzed Arylmagnesiation of
1-Phenyl-1-hexyne (1a): Additive Effecta
Table 2 summarizes the results obtained for arylmagne-
siation of aryl(alkyl)acetylenes catalyzed by the Fe/IPr
entry
additive
yield (%)b
E:Zc
1
2
3
4
5
6
7
IPr
91
78
88:11 (:1)
89:9 (:2)
IPrd
none
Table 2. Iron-Catalyzed Arylmagnesiation of Alkynes: Scopea
23f
16f
23f
33f
79
85:13 (:2)
72:21 (:7)
82:17 (:1)
86:12 (:2)
92:7 (:1)
P(n-Bu)3
P(t-Bu)3
PPh3
P(n-Bu)3e + CuBrd
a The reaction was carried out in THF (1.0 mL) at 60 °C for 16 h under
a nitrogen atmosphere using 4-methoxyphenylmagnesium bromide (2m, 0.40
mmol) and 1-phenyl-1-hexyne (1a, 0.20 mmol) in the presence of Fe(acac)3
(0.010 mmol) and additive (0.040 mmol). b Isolated yield. c Determined by
1H NMR and GC-MS. The values in parentheses show the ratio of
regioisomers to 3am. d The reaction was conducted with 10 mol % additive
loading. e The reaction was conducted with 40 mol % additive loading.
f Determined by H NMR using an internal standard (MeNO2).
1
entry
alkyne
Ar2
product
yield (%)b
E:Zc
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1e
1f
1g
1h
1e
1a
1a
1e
1e
2m
2m
2m
2m
2n
2n
2n
2n
2m
2o
3am
3bm
3cm
3dm
3an
3en
3fn
3gn
3hm
3eo
3ap
3aq
3er
91
91
87
84
93d
80
87
75e
69
73
75
59e
73
69e
89:11
85:15
95:5
78:22
89:11
87:13
87:13
92:8
83:17
82:18
76:24
91:9
82:18
94:6
equiv) in the presence of Fe(acac)3 (5 mol %) and 1,3-bis-
(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr)8 (20 mol %)
in THF at 60 °C for 16 h gave, after addition of H2O, 91%
yield of the addition product, which consists of (E)-2-(4-
methoxyphenyl)-1-phenyl-1-hexene ((E)-3am) and its (Z)
isomer ((Z)-3am) in a ratio of 88/11 together with a small
amount (1%) of its regioisomer (entry 1).9 The amount of
the carbene ligand IPr can be reduced to 10 mol % with a
small decrease of the yield of the addition product 3am (entry
2). The reaction without IPr ligand under otherwise the same
reaction conditions gave only 23% yield of 3am (entry 3),
demonstrating the high efficiency of the carbene ligand in
the present arylmagnesiation. Use of phosphine ligands, P(n-
Bu)3, P(t-Bu)3, and PPh3 in place of the carbene IPr did not
improve the yield (entries 4-6), the yields being as low as
that without ligand. The Fe/Cu cocatalyst system consisting
of Fe(acac)3 (5 mol %), P(n-Bu)3 (40 mol %), and CuBr (10
mol %), which we have reported previously for arylmagne-
siation,5 was as effective as the present Fe/IPr catalyst, giving
the addition products in 79% yield (entry 7).
9
10
11
12
13
14
2p
2q
2r
2s
3es
a The reaction was carried out in THF (1.0 mL) at 60 °C for 16 h under
a nitrogen atmosphere using an arylmagnesium bromide (0.40 mmol) and
an alkyne (0.20 mmol) in the presence of Fe(acac)3 (0.010 mmol) and IPr
(0.040 mmol). b Isolated yield. c Determined by 1H NMR and GC-MS.
Formation of less than 3% of regioisomers was observed. d Determined by
1H NMR using an internal standard (MeNO2). e The reaction time is 24 h.
system. The addition of 4-methoxyphenylmagnesium bro-
mide (2m) was successful for the alkynes 1a-1d bearing
primary and secondary alkyl groups at the alkyne terminal
(entries 1-4). Unfortunately, the present Fe/IPr catalyst
system was not as effective for the alkyne substituted with
a tert-butyl group. Introduction of a methoxy group to the
benzene ring on the alkyne at the ortho, meta, or para position
(8) (a) Jafarpour, L.; Huang, J.; Stevens, E. D.; Nolan, S. P. Organo-
metallics 1999, 18, 3760-3763. (b) Jafarpour, L.; Stevens, E. D.; Nolan,
S. P. J. Organomet. Chem. 2000, 606, 49-54.
(9) Examples of the metal-catalyzed cis-trans isomerization of alkenyl-
magnesium bromide: (a) Zembayashi, M.; Tamao, K.; Kumada, M.
Tetrahedron 1975, 16, 1719-1722. (b) Duboudin, J. G.; Jousseaume, B. J.
Organomet. Chem. 1975, 96, C47-C49.
1046
Org. Lett., Vol. 9, No. 6, 2007

did not disturb the arylmagnesiation with 4-methylphenyl-
magnesium bromide (2n) (entries 6-8). The chloride sub-
stituent on the alkyne 1h was intact under the present reaction
conditions to give the corresponding arylation product 3hm
in a good yield (entry 9). Moderate to high yields of the
addition products were obtained in the reaction of aryl
Grignard reagents bearing methyl, methoxy, and fluoro 2o-
2r on the aryl ring (entries 10-13). In all the reactions shown
in Table 2, the formation of regioisomers resulting from the
arylmagnesiation in the opposite direction was observed in
less than 3%. Although the arylmagnesiation of aryl(alkyl)-
acetylenes was thus realized by use of the Fe/IPr catalyst,
that of dialkylacetylenes was not efficiently catalyzed by the
present Fe/IPr system, 4-octyne giving only 19% yield of
the addition product in the reaction with 2m.
In our previous report using the Fe/Cu cocatalyst system,5
we proposed a catalytic cycle where the addition of an
aryliron species to alkyne is a key step and the transmeta-
lation between the resulting alkenyliron and arylmagnesium
bromide is promoted through the formation of an organo-
copper species. In the present system, which is not assisted
by the copper cocatalyst, strong coordination of the carbene
ligand probably stabilizes low valent iron intermediates to
prevent them from being decomposed, and as a result the
alkenyliron intermediate has a chance to undergo the
transmetalation with the arylmagnesium reagent before its
decomposition forming iron metals10 (Scheme 1).
(eq 2). The addition of allyl bromide to the reaction mixture
resulting from addition of the Grignard reagent 2m to alkyne
1a gave 78% yield of the tetrasubstituted alkene 7. Iodination
giving alkenyl iodide 8 was effected in high yield (91%) by
treatment of the alkenylmagnesium with ZnCl2 followed by
addition of iodine to the alkenylzinc intermediate.11
Scheme 1. Proposed Mechanism for Iron-Catalyzed
Arylmagnesiation
Although the present Fe/IPr system did not catalyze the
cross-coupling of the alkenylmagnesium species with an aryl
halide, addition of a nickel catalyst realized the one-pot
arylmagnesiation and cross-coupling sequence (eq 3). Thus,
The addition of the Grignard reagent 2n to a homopro-
pargyl ether, 4-methoxy-1-phenyl-1-butyne (4), under the
present conditions using the Fe/IPr catalyst gave, after
hydrolysis, the product 5 arylated at the 2-position prefer-
entially over its regioisomer 6 (eq 1). This regiochemistry
is opposite to that expected from the results reported so far
for the addition to homopropargyl ethers and alcohols, where
intramolecular coordination of oxygen to iron is a decisive
factor controlling the regiochemistry.2d,h,3 In the present
system, the strongly coordinating and sterically bulky carbene
ligand may interfere with the intramolecular coordination of
oxygen.
addition of phenyl iodide and NiCl2(PPh3)2 catalyst12 (5 mol
%) to the alkenylmagnesium, generated from the Grignard
reagent 2n and alkyne 4, brought about the alkenyl-aryl
coupling to give 72% yield of triaryl-substituted alkene 9.13
(11) The iodination of alkenylzinc reagents giving alkenyl iodides has
been reported: Nishikawa, T.; Yorimitsu, H.; Oshima, K. Synlett 2004,
1573-1574.
(12) (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972,
94, 4374-4376. (b) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem.
Commun. 1972, 144. (c) Murahashi, S.; Yamamura, M.; Yanagisawa, K.;
Mita, N.; Kondo, K. J. Org. Chem. 1979, 44, 2408-2417.
(13) For a recent example of the carbometalation/cross-coupling se-
quence: Kamei. T.; Itami, K.; Yoshida, J. AdV. Synth. Catal. 2004, 346,
1824-1835.
The alkenylmagnesium species generated by the iron-
catalyzed arylmagnesiation can be trapped with electrophiles
(10) The coordination of a carbene to organomagnesium species has been
also reported: (a) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128,
15604-15605. (b) Arduengo, A. J., III.; Dias, H. V. R.; Davidson, F.;
Harlow, R. L. J. Organomet. Chem. 1993, 462, 13-18.
Org. Lett., Vol. 9, No. 6, 2007
1047

In summary, we found that the iron-catalyzed arylmag-
nesiation of aryl(alkyl)acetylenes is efficiently realized by
use of an N-heterocyclic carbene ligand. The alkenylmag-
nesium species formed with high regioselectivity were further
transformed into tetrasubstituted alkenes by subsequent
carbon-carbon bond-forming reactions.
Education, Culture, Sports, Science and Technology, Japan
(21 COE on Kyoto University Alliance for Chemistry).
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Support has been provided in part by
a Grant-in-Aid for Scientific Research, the Ministry of
OL063132R
1048
Org. Lett., Vol. 9, No. 6, 2007