Chromium-catalyzed arylmagnesiation of alkynes

Article abstract of DOI:10.1021/ol0703938

Equation presented Arylmagnesiation of unfunctionalized alkynes in the presence of catalytic amounts of chromium(II) chloride and pivalic acid proceeds with high stereoselectivity. The alkenylmagnesium intermediate reacts with various electrophiles to afford the corresponding tetrasubstituted olefins in good yields.

Full text of DOI:10.1021/ol0703938

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1569-1571
Chromium-Catalyzed Arylmagnesiation
of Alkynes
Kei Murakami, 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 February 15, 2007
ABSTRACT
Arylmagnesiation of unfunctionalized alkynes in the presence of catalytic amounts of chromium(II) chloride and pivalic acid proceeds with
high stereoselectivity. The alkenylmagnesium intermediate reacts with various electrophiles to afford the corresponding tetrasubstituted olefins
in good yields.
Carbometalation of alkynes is a straightforward method for
the synthesis of multisubstituted olefins in organic synthesis.1
To date, most studies of the process have focused on employ-
ing heteroatom-containing alkynes such as homopropargyl
ethers and propargyl alcohols as substrates.2 As for the carbo-
metalation of unfunctionalized alkynes, however, much less
progress has been made.3-5 The development of facile, effi-
cient, and general methods for the carbometalation of unfunc-
tionalized alkynes remains an important challenge. Herein,
we wish to report that a simple chromium salt promotes aryl-
magnesiation of unfunctionalized alkynes with high efficiency.
Treatment of 6-dodecyne (1, 1.0 mmol) with phenylmag-
nesium bromide (2, 3.0 mmol, 2 M diethyl ether solution)
in toluene (3 mL) at 110 °C in the presence of chromium-
(II) chloride (0.075 mmol) for 18 h provided 6-phenyl-6-
dodecene (3) in an E/Z ratio of 91:9 in 81% yield (Table 1,
entry 1). We screened several transition metal catalysts such
as iron, cobalt, and nickel salts, none of which did show
any catalytic activity under similar reaction conditions.6 The
choice of reaction solvent is crucial. The use of THF instead
of toluene resulted in recovery of the starting material 1.
We next explored several additives to improve the yield
and the E/Z selectivity (Table 1). Surprisingly, the addition
of a catalytic amount of protic additives led to higher yield,
better stereoselectivity, and faster reaction rate.7 Although
(1) (a) 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. (b) Marek, I.; Normant, J. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998; pp 271-337. (c) Stu¨demann, T.; Knochel,
P. Angew. Chem., Int. Ed. 1997, 36, 93-95.
(2) For a review on metal-mediated carbometalation of alkynes and
alkenes containing heteroatoms, see: (a) Fallis, A. G.; Forgione, P.
Tetrahedron 2001, 57, 5899-5913. For a recent example on transition metal-
catalyzed carbometalation of alkynes containing heteroatoms, see: (b)
Zhang, D.; Ready, J. M. J. Am. Chem. Soc. 2006, 128, 15050-15051.
(3) The arylmetalation of unfunctionalized alkynes is very difficult to
achieve: Shirakawa, E.; Yamagami, T.; Kimura, T.; Yamaguchi, S.;
Hayashi, T. J. Am. Chem. Soc. 2005, 127, 17164-17165 and references
cited therein.
(5) (a) Nishikawa, T.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc.
2001, 123, 4629-4630. (b) Nishikawa, T.; Shinokubo, H.; Oshima, K. Org.
Lett. 2002, 4, 2795-2797. In these reports, we described chromium-
catalyzed annulation reactions of acetylenic compounds with methallyl-
magnesium chloride, probably initiated by carbometalation of alkyne units.
However, the carbometalation processes suffered from limitations as to the
scope of the alkynes and Grignard reagents. The alkynes available for use
are limited to 1,6-diynes and 1,6-enynes. In other words, the intramolecular
carbomagesiation of unfunctionalized alkynes did not proceed at all.
Additionally, we obtained promising results only with methallylmagnesium
chloride of high nucleophilicity. (c) Molander, G. A.; Sommers, E. M.
Tetrahedron Lett. 2005, 46, 2345-2349.
(4) For recent examples on transition metal-catalyzed carbometalation
of unfunctionalized alkynes, see: (a) Shirakawa, E.; Yamasaki, K.; Yoshida,
H.; Hiyama, T. J. Am. Chem. Soc. 1999, 121, 10221-10222. (b) Suginome,
M.; Shirakura, M.; Yamamoto, A. J. Am. Chem. Soc. 2006, 128, 14438-
14439.
(6) The use of chromium(III) chloride afforded 3 in a yield similar to
the chromium(II) chloride catalyst in the absence of pivalic acid. In the
presence of pivalic acid, chromium(II) chloride was superior to other
chromium salts.
10.1021/ol0703938 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/13/2007

Table 1. Effect of Additives on the Chromium-Catalyzed
Phenylmagnesiation of 6-Dodecyne (1)
Table 2. Chromium-Catalyzed Arylmagnesiation of Alkynes
temp time yielda
R1
R2
Ar
(°C)
(h)
(%)
E/Zb
temp
(°C)
time
(h)
yield
(%)a
entry
entry
additive
none
none
MeOH
PhOH
tBuOH
AcOH
E/Zb
1
2
3
4
5c
C5H11 C5H11 2-MeC6H4
C5H11 C5H11 3-MeC6H4
C5H11 C5H11 4-MeC6H4
C5H11 C5H11 4-ClC6H4
110 10
55
80
81
61
69
53
68
51
67
70
>99:1
>99:1
>99:1
88:12
87:13
>99:1
92:8e
1
2
3
4
5
6
7
8c
9
110
60
18
18
2
2
2
0.25
0.25
0.25
18
81
0
91:9
110
110
110
0.5
0.5
2
110
110
110
110
110
110
60
77
77
75
79
81
87
75
95:5
95:5
95:5
>99:1
>99:1
>99:1
96:4
C5H11 C5H11 3-MeOC6H4 110 18
6d C6H13 tBu
Ph
Ph
Ph
110
110
4
2
7
8
9
C6H13 Ph
95:5e
65:35
PhCOOH
tBuCOOH
tBuCOOH
Me
Me
Ph
Ph
Me3Si Ph
Ph Ph
60 18
60 18
10
110
0.5
a Isolated yield. b Determined by 1H NMR. c When the reaction was
performed in a 10-mmol scale, an 78% yield of 6-phenyl-6-dodecene (3)
was obtained.
a Isolated yield. b Determined by 1H NMR. c The reaction was carried
out without tBuCOOH. d CrCl2 (20 mol %) and tBuCOOH (20 mol %) were
used. e A small amount of the corresponding regioisomer was observed
(entry 7; 10% yield, entry 8; 1% yield).
the reaction required 18 h at 110 °C when no additive was
employed, the processes with alcohols (methanol, phenol,
and tert-butyl alcohol) went to completion within 2 h (entries
1 vs 3-5). Further investigation revealed that the use of
carboxylic acids not only resulted in faster reactions (0.25 h)
but also increased the ratio of E/Z isomers to greater than
99:1 (entries 6 and 7). The yield depended on the steric
bulkiness of the carboxylic acid, and pivalic acid showed
the best result to provide (E)-6-phenyl-6-dodecene (3) in 87%
yield after 0.25 h (entry 8). The chromium salt/pivalic acid
system proceeded even at 60 °C to afford the corresponding
phenylated product 3 in 75% yield albeit the reaction was
slow. It is worth noting that the additive-free process did
not produce 3 at all at the same temperature (entries 2 vs 9).
This arylmagnesiation was readily scalable. Treatment of 10
mmol of 6-dodecyne (1) with phenylmagnesium bromide (2,
30 mmol) in the presence of chromium(II) chloride (0.75
mmol) and pivalic acid (1.0 mmol) in toluene (30 mL) in a
similar manner provided 3 in an E/Z ratio of >99:1 in 78%
yield. The reason for the dramatic effect of the additives is
not clear at this stage.
(entries 4 and 5). The use of 2,2-dimethyl-3-decyne provided
the corresponding product with complete regioselectivity
(entry 6). The regioselectivity was simply governed by the
steric factor of the two substituents of the alkyne. The
reactions of the phenyl-substituted alkynes afforded modest
yields of the arylmagnesiation products (entries 7 and 8).
Diphenylacetylene also reacted with phenylmagnesium bro-
Scheme 1. Reactions of Various Electrophiles with the
Arylmagnesiation Product 4a
Various combinations of alkynes and aryl Grignard
reagents were examined in the chromium/pivalic acid-
catalyzed process (Table 2). All the reactions afforded the
corresponding E adducts exclusively or predominantly,
except for the reaction of 1-(trimethylsilyl)propyne (entry
9). Arylmagnesium reagents having a methyl substitution at
the ortho, meta, or para position effected the arylmagnesia-
tion, and all the reactions afforded the corresponding E
isomers exclusively (entries 1-3). 3-Methoxy- and 4-chlo-
rophenylmagnesium bromides participated in the reaction
a
t
Reagents and conditions: (a) CrCl2 (7.5 mol %), BuCOOH
(10 mol %), PhMgBr (3.0 mmol), toluene, 110 °C, 0.25 h; (b) D2O;
(c) CH2dCHCH2Br (4.0 mmol), CuCN‚2LiCl (10 mol %), 0 °C, 3
h; (d) PhCHO (4.0 mmol), 0 °C, 3 h; (e) Pd2(dba)3 (2.5 mol %),
P(o-tolyl)3 (5 mol %), ArI (4.0 mmol), 25 °C, 3 h; (f) Pd2(dba)3
(2.5 mol %), P(o-tolyl)3 (5 mol %), PhC(Br)dCH2 (4.0 mmol),
25 °C, 12 h; (g) MeI (4.0 mmol), CuCN‚2LiCl (20 mol %), 0 °C,
3 h; (h) I2 (4.0 mmol), 0 °C, 3 h.
(7) (a) Vogl, E. M.; Groger, G.; Shibasaki, M. Angew. Chem., Int. Ed.
1999, 38, 1570. (b) Funabashi, K.; Jackmann, M.; Kanai, M.; Shibasaki,
M. Angew. Chem., Int. Ed. 2003, 42, 5489-5492. (c) Liu, X.; Fox, J. M.
J. Am. Chem. Soc. 2006, 128, 5600-5601.
1570
Org. Lett., Vol. 9, No. 8, 2007

mide, giving triphenylethylene in 70% yield (entry 10).
Unfortunately, the use of terminal alkynes resulted in failure.
With the reliable carbomagnesiation reaction in hand, we
investigated the utility of the intermediary alkenylmagnesium
compound 4 (Scheme 1). The intermediate reacted with
various electrophiles such as deuterium oxide, allyl bromide,
benzaldehyde, iodomethane, or iodine to give the corre-
sponding tetrasubstituted alkenes with high stereoselectivity
in good overall yield. As for trapping of 4 with allyl bromide
or iodomethane, the addition of a catalytic amount of CuCN‚
2LiCl improved the yield of the corresponding products 6
and 10. The alkenylmagnesium intermediate 4 was useful
for palladium-catalyzed cross-coupling reactions of aryl
iodides such as iodobenzene and 4-iodoanisole, and the two
aryl groups were introduced smoothly with high stereose-
lectivity. The conjugated diene 9 was also prepared from
the arylmagnesiation product 4 via palladium-catalyzed cross-
coupling reaction.
In summary, the arylmagnesiation of unfunctionalized
alkynes has been achieved by using a chromium salt.
Notably, the addition of a catalytic amount of pivalic acid
dramatically enhanced the reactivity and stereoselectivity.
The procedure is highly efficient to construct multisubstituted
ethene units.
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. H.O. acknowledges JSPS for financial support.
Supporting Information Available: Experimental details
and characterization data for new compounds. This material
is available free of charge via the Internet at http://
pubs.acs.org.
OL0703938
Org. Lett., Vol. 9, No. 8, 2007
1571