Iron-catalyzed carbolithiation of alkynes having no heteroatoms

Article abstract of DOI:10.1039/b900345b

Alkyl- and aryllithium compounds were found to add to alkynes having no heteroatoms in the presence of an iron or iron-copper catalyst to give various trisubstituted vinyllithium compounds.

Full text of DOI:10.1039/b900345b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Iron-catalyzed carbolithiation of alkynes having no heteroatomsw
Eiji Shirakawa,* Daiji Ikeda, Tsubasa Ozawa, Shogo Watanabe and Tamio Hayashi*
Received (in Cambridge, UK) 7th January 2009, Accepted 26th January 2009
First published as an Advance Article on the web 19th February 2009
DOI: 10.1039/b900345b
Alkyl- and aryllithium compounds were found to add to alkynes
having no heteroatoms in the presence of an iron or iron–copper
catalyst to give various trisubstituted vinyllithium compounds.
(entry 3). Under these conditions, only 15 min was required
for satisfactory conversion (entry 4). The yield was slightly
increased on further addition of PPh3 (10 mol%) and
reduction of the amount of 1a to 1.5 equiv. (entries 5 and 6).
Although each entry thus far resulted in a low 5a/6a value, 5a
predominated (5a : 6a = 98 : 2) at 1 min reaction time with
12% conversion of 2a (entry 7), showing that the initial
product is syn adduct 3a, which isomerizes to 4a under the
reaction conditions. It was found that the reaction with an
excess amount of 2a over 1a improved the stereoselectivity,
though the yield based on 1a is not high (entry 8). Considering
that a certain amount of butyllithium (1a) is consumed for the
reduction of FeCl3 to a catalytically active low valent species,
the reduction with zinc metal was conducted before the
addition of 1a. Thus, pretreatment with zinc (20 mol%)
increased the yield to 85% (entry 9). Use of reduced amounts
of 2a lowered the stereoselectivities (entries 10 and 11),
whereas the yield was decreased with an increased amount
of 2a (entry 12). Treatment of 1a (3.0 equiv.) with 2a in the
presence of TMEDA and PPh3 but in the absence of an iron
catalyst gave phenylallene (38%) and 3-phenylpropyne (10%),
generated through deprotonation of propargyl protons, but no
butyllithiation products (entry 13).
Carbometalation of alkynes is a highly effective method to
prepare multisubstituted alkenes because the metal moiety of
the resulting alkenylmetals can be further transformed to
various organic groups.1,2 Organolithium compounds are
one of the most easily available organometals but their high
basicity has severely restricted their use in the alkylmetalation
of alkynes.3,4 Namely, the deprotonation of not only acetylenic
protons but also propargylic protons generally predominates
over the addition.5,6 Alkyllithiation of alkynes having
propargyl protons is possible when the addition is accelerated
through intramolecular reaction7 or by a heteroatom directing
group such as an alkoxy or amino group on alkynes,8 but
simple alkyl groups on alkynes are prone to suffer deprotonation.
Significant improvement was achieved by Hosomi and
co-workers with the introduction of iron catalysts, where even
a methyl group on alkynes is compatible with alkyllithiation,
though the disclosed alkynes are limited to those having an
ether or amine moiety at the opposite site to the alkyl
group.9,10 Here we report an improved iron catalyst system,
which is applicable to alkyllithiation of alkynes having no
heteroatoms. We also found that a Fe–Cu cooperative catalyst
is effective for aryllithiation of alkynes.10a
Table 2 illustrates the scope of the iron-catalyzed alkyllithia-
tion in use of two sets of conditions, methods A and B.
When the products do not have E/Z isomers (R1 = R2),
operationally more simple method A was chosen, where
1.5 equiv. of alkyllithium 1 to alkyne 2 is used (cf. entry 6 of
Table 1). In the case where R1 and R2 are different, we used
method B, which employs 1.5 equiv. of 2 to 1 in combination
with zinc as a reductant, to minimize the E/Z isomerization
(cf. entry 9 of Table 1). Aryl(butyl)acetylenes having an
electron-withdrawing or -donating group on the benzene ring
accepted the addition of butyllithium (1a) generally in high
yields (entries 1–6). Butyllithiation of 1-phenyl-1-hexyne
Suitable reaction conditions for alkyllithiation of alkynes
were surveyed in the reaction of butyllithium (1a) with
1-phenylpropyne (2a) using 5 mol% of an iron catalyst
(Table 1). The reaction conditions optimized by Hosomi and
co-workers9 for butyllithiation of heteroatom-containing
alkynes were found not to be effective for the addition to 2a.
Thus, treatment of 1a (3.0 equiv.) with 2a (1.0 equiv.) in the
presence of Fe(acac)3 (5 mol%) in toluene at ꢀ20 1C for 2 h
gave only 5% yield of (E)- and (Z)-2-methyl-1-phenyl-
1-hexene (5a and 6a) in 98 : 2 ratio after methanolysis
(entry 1). Another set of conditions (FeCl3 in Et2O), which
was the second best in the Hosomi’s paper, worked much
better here to give 5a and 6a in 61% yield with 82%
conversion of 2a, though the stereoselectivity was low
(66 : 34) (entry 2). Addition of 20 mol% of N,N,N0,N0-
tetramethylethylenediamine (TMEDA) to this combination
increased the yield to 85% with full conversion of 2a
using method
Alkynes having an alkyl group other than butyl reacted
stereoselectively with butyllithium under method
B proceeded in a high yield (entry 7).
B
conditions (entries 8–10). The reaction of other alkyllithium
compounds gave addition products in high stereoselectivities
(entries 11 and 12).
Attempts to apply the catalyst system of the alkyllithiation
to aryllithiation failed11 but the Fe–Cu cooperative catalysis
that is effective for arylmagnesiation of alkynes10a also worked
here. Thus, the reaction of phenyllithium (7a: 2.0 equiv.) with
1-phenylpropyne (2a: 1.0 equiv.) in the presence of Fe(acac)3
(5 mol%), CuBr (10 mol%) and PBu3 (40 mol%) in Et2O at
30 1C for 3 h gave 62% yield of (E)-1,2-diphenylpropene (8a)
and its stereo- and regioisomers (9a and 10a) in 93 : 5 : 2
ratio (Scheme 1). The aryllithiation proceeded in high
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, Japan.
E-mail: shirakawa@kuchem.kyoto-u.ac.jp; Fax: 81 75 753 3988
w Electronic supplementary information (ESI) available: Experi-
mental section, spectroscopic data and NMR spectra. See DOI:
10.1039/b900345b
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1885–1887 | 1885

View Article Online
Table 1 Iron-catalyzed butyllithiation of 1-phenylpropyne followed by methanolysisa
Entry
Amount 1a/2a (equiv.)
Additives (mol%)
t/min
Consumed 2a (equiv.)b,c
Yieldc,d (%)
Ratio 5a : 6ac
1e
2
3
4
5
6
7
8
3.0/1.0
3.0/1.0
3.0/1.0
3.0/1.0
3.0/1.0
1.5/1.0
1.5/1.0
1.0/1.5
1.0/1.5
1.0/1.0
1.0/1.2
1.0/2.0
3.0/1.0
—
—
120
120
120
15
15
15
1
15
15
15
0.32
0.82
0.99
0.94
0.97
0.97
0.12
0.96
0.99
0.96
0.97
1.06
0.63
5
61
85
81
83
88
4
64
85
88
85
72
o1
98 : 2
66 : 34
49 : 51
63 : 37
57 : 43
51 : 49
98 : 2
92 : 8
90 : 10
65 : 35
85 : 15
94 : 6
—
TMEDA/20
TMEDA/20
TMEDA/20, PPh3/10
TMEDA/20, PPh3/10
TMEDA/20, PPh3/10
TMEDA/20, PPh3/10
TMEDA/20, PPh3/10, Zn/20
TMEDA/20, PPh3/10, Zn/20
TMEDA/20, PPh3/10, Zn/20
TMEDA/20, PPh3/10, Zn/20
TMEDA/20, PPh3/10
9
10
11
12
13f
15
15
120
a
The reaction was carried out in Et2O (1.0 mL) at ꢀ20 1C under a nitrogen atmosphere using BuLi (1a: 1.53–1.66 M in hexane) and
b
c
d
1-phenylpropyne (2a) in the presence of FeCl3 (0.020 mmol). The amount of consumed 2a. Determined by GC. The yield based on 2a
e
(entries 1–7 and 13) or 1a (entries 8–12). Fe(acac)3 and toluene were used instead of FeCl3 and Et2O, respectively. In the absence of FeCl3.
f
Table 2 Iron-catalyzed alkyllithiation of alkynes followed by methanolysisa
Entry
Method
R1
R2
R3
t/h
1.5
1.5
3
24
1.5
1.5
0.25
0.25
1.0
1.0
1.0
Yieldb (%)
Ratio 5 : 6c
1
2
3
4
5
6
7
8
9
A
A
A
A
A
A
B
B
B
B
B
B
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Hex
i-Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Hex
i-Bu
Et
Ph
3-CF3C6H4
4-ClC6H4
2-MeC6H4
3-MeOC6H4
2-MeOC6H4
Ph
Ph
Ph
Ph
Ph
Ph
81
82
79
65
96
82
84
79
82
81
75
72
—
—
—
—
—
—
—
93 : 7
94 : 6
92 : 8
95 : 5
10
11
12
Me
Me
0.25
499 : 1
a
The reaction was carried out in Et2O at ꢀ20 1C under a nitrogen atmosphere using an alkyllithium (1) and an alkyne (2) in the presence of FeCl3,
N,N,N0,N0-tetramethylethylenediamine (TMEDA) and PPh3. Method A: 1 = 0.68 mmol, 2 = 0.45 mmol, FeCl3 = 23 mmol, TMEDA = 90 mmol,
PPh3 = 45 mmol. Method B: 1 = 0.40 mmol, 2 = 0.60 mmol, FeCl3 = 20 mmol, TMEDA = 80 mmol, PPh3 = 40 mmol, in combination with Zn
b
c
(0.080 mmol). Isolated yield based on 2 (entries 1–6) or 1 (entries 7–12). Determined by GC.
alkene 5b-d having
a deuterium atom on the phenyl-
substituted alkene carbon, showing that alkenyllithium 3b
was actually produced by the alkyllithiation (Scheme 2).
Transformation of butyllithiation product 3b upon reaction
with other electrophiles demonstrates synthetic utility of the
carbolithiation reactions. Thus, the reaction mixture above
was treated with benzaldehyde or 1,2-dibromoethane to give
allyl alcohol 11 or alkenyl bromide 12, respectively, in a high
yield (Scheme 2).
Scheme 1
Production of syn-adducts is likely to show that insertion of
alkynes into the Fe–C bond generated by the reaction of an
iron complex with an organolithium compound is operative in
the addition step. A plausible catalytic cycle based on that in
the Fe–Cu-catalyzed arylmagnesiation of alkynes10a is shown
stereo- and regioselectivities also between 3,5-xylyllithium (7b)
and 1-phenyl-1-octyne (2b).
Quenching the reaction mixture from addition of butyl-
lithium (1a) to 1-phenyl-1-hexyne (2c) with MeOH-d4 gave
ꢁc
This journal is The Royal Society of Chemistry 2009
1886 | Chem. Commun., 2009, 1885–1887

View Article Online
Program ‘‘Integrated Materials Science’’ on Kyoto University)
from Ministry of Education, Culture, Sports, Science and
Technology, Japan.
Notes and references
1 P. Knochel, Comprehensive Organic Synthesis, ed. B. M. Trost,
I. Fleming and M. F. Semmelhack, Pergamon Press, New York,
1991, vol. 4, pp. 865–911.
2 For
a review including synthesis of tetrasubstituted alkenes
through carbometalation of alkynes, see: A. B. Flynn and
W. W. Ogilvie, Chem. Rev., 2007, 107, 4698–4745.
3 See pp. 872–873 in ref. 1.
4 Among the previous alkylmetalations of alkynes, alkylcupration
and the zirconium-catalyzed methylalumination are two of the
most effective ones. For alkylcupration, see: (a) J. F. Normant and
A. Alexakis, Synthesis, 1981, 841–870. For methylalumination, see:
(b) E. Negishi, D. E. van Horn and T. Yoshida, J. Am. Chem. Soc.,
1985, 107, 6639–6647.
Scheme 2
5 Alkyl(aryl)acetylenes are known to readily undergo mono- and
dideprotonation
upon
reaction
with
alkyllithiums.
(a) J. E. Mulvaney, T. L. Folk and D. J. Newton, J. Org. Chem.,
1967, 32, 1674–1675; (b) J. Y. Becker, J. Organomet. Chem., 1976,
118, 247–252; (c) J. Y. Becker, J. Organomet. Chem., 1977,
127, 1–5.
6 For examples of carbolithiation of alkynes having no propargylic
protons, see: (a) J. E. Mulvaney, Z. G. Gardlund and
S. L. Gardlund, J. Am. Chem. Soc., 1963, 85, 3897–3898;
(b) J. E. Mulvaney and D. J. Newton, J. Org. Chem., 1969, 34,
1936–1939; (c) A. K. Brisdon, I. R. Crossley, R. G. Pritchard,
G. Sadiq and J. E. Warren, Organometallics, 2003, 22, 5534–5542.
7 (a) W. F. Bailey, T. V. Ovaska and T. K. Leipert, Tetrahedron
Lett., 1989, 30, 3901–3904; (b) G. Wu, F. E. Cederbaum and
E. Neghishi, Tetrahedron Lett., 1990, 31, 493–496; (c) W. F. Bailey
and T. V. Ovaska, Tetrahedron Lett., 1990, 31, 627–630;
(d) W. F. Bailey and T. V. Ovaska, J. Am. Chem. Soc.,
Scheme 3
in Scheme 3. Alkyllithium 1, which is more nucleophilic than
aryl Grignard reagents, seems not to require a copper
co-catalyst to transmetalate with alkenyliron complex 14
giving alkyllithiation product 3. In contrast, it is likely that
less nucleophilic aryllithium 7 does not have ability to trans-
metalate directly with 14 but with a copper complex to
give diarylcuprate 15, which undergoes transmetalation with
alkenyliron 14 to regenerate aryliron complex 13. The
resulting cuprate (16) having an alkenyl group reacts with
aryllithium 7 to give aryllithiation product 17 with regeneration
of diarylcuprate 15.
1993, 115, 3080–3090; (e) M. Oestreich, R. Frohlich and
¨
D. Hoppe, Tetrahedron Lett., 1998, 39, 1745–1748;
(f) M. Oestreich, R. Frohlich and D. Hoppe, J. Org. Chem.,
1999, 64, 8616–8626.
¨
8 (a) L.-I. Olsson and A. Claesson, Tetrahedron Lett., 1974, 15,
2161–2162; (b) L.-I. Olsson and A. Claesson, Acta Chem. Scand.,
Ser. B, 1976, 30, 521–526.
9 M. Hojo, Y. Murakami, H. Aihara, R. Sakuragi, Y. Baba and
A. Hosomi, Angew. Chem., Int. Ed., 2001, 40, 621–623.
10 For examples of the iron-catalyzed carbometalation of alkynes
other than ref. 9, see: (a) E. Shirakawa, T. Yamagami, T. Kimura,
S. Yamaguchi and T. Hayashi, J. Am. Chem. Soc., 2005, 127,
17164–17165; (b) D. Zhang and J. M. Ready, J. Am. Chem. Soc.,
2006, 128, 15050–15051; (c) T. Yamagami, R. Shintani,
E. Shirakawa and T. Hayashi, Org. Lett., 2007, 9, 1045–1048.
For an example of arylmagnesiation of alkynes having no hetero-
atoms catalyzed by a metal (Cr) other than iron (ref. 10a and c),
see; (d) K. Murakami, H. Ohmiya, H. Yorimitsu and K. Oshima,
Org. Lett., 2007, 9, 1569–1571.
In conclusion, we have disclosed that alkyl- and aryllithium
compounds undergo stereo- and regioselective carbometalation
reactions with alkynes having no heteroatoms under iron or
iron–copper catalysis.
This work has been supported financially in part by a
Grant-in-Aids for Scientific Research on Priority Areas
(No.19028029, ‘‘Chemistry of Concerto Catalysis’’) and for
a Grant-in-Aid for Scientific Research (the Global COE
11 The reaction of 7a with 2a (cf. Scheme 1) under the conditions of
method A in Table 2 at ꢀ20 or 30 1C gave only 5% (E : Z = 499 : 1)
or 14% (E : Z = 85 : 15) yield of the adducts with 6 and 70%
conversion of 2a, respectively.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 1885–1887 | 1887