Preparation of Organozinc Reagents via Catalyst Controlled Three-Component Coupling between Alkyne, Iodoarene, and Bis(iodozincio)methane

Article abstract of DOI:10.1021/acs.orglett.7b00917

Three-component coupling between an alkyne, iodoarene, and bis(iodozincio)methane yields allylic zinc with a tetrasubstituted alkene moiety in the presence of a nickel catalyst. The reaction proceeds via aryl nickelation of the alkyne and subsequent cross-coupling with bis(iodozincio)methane. Meanwhile, the same combination in the presence of a palladium and cobalt catalyst gives tetrasubstituted alkenylzinc. The reaction proceeds via a palladium-catalyzed cross-coupling of iodoarene with bis(iodozincio)methane followed by a cobalt-catalyzed benzylzincation of alkyne.

Full text of DOI:10.1021/acs.orglett.7b00917

Letter
pubs.acs.org/OrgLett
Preparation of Organozinc Reagents via Catalyst Controlled Three-
Component Coupling between Alkyne, Iodoarene, and
Bis(iodozincio)methane
Yukako Shimada, Zenichi Ikeda, and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto
615-8510, Japan
S
* Supporting Information
ABSTRACT: Three-component coupling between an alkyne,
iodoarene, and bis(iodozincio)methane yields allylic zinc with a
tetrasubstituted alkene moiety in the presence of a nickel catalyst.
The reaction proceeds via aryl nickelation of the alkyne and
subsequent cross-coupling with bis(iodozincio)methane. Meanwhile,
the same combination in the presence of a palladium and cobalt catalyst gives tetrasubstituted alkenylzinc. The reaction proceeds
via a palladium-catalyzed cross-coupling of iodoarene with bis(iodozincio)methane followed by a cobalt-catalyzed
benzylzincation of alkyne.
of alkyne followed by cross-coupling with 1.9 Employing a
lthough an organozinc reagent was the first practical
Acarbanion equivalent, today Grignard reagent is more
palladium catalyst instead of a nickel one results in the cross-
commonly used to add a C-nucleophile into a carbonyl
compound.1 Regardless, organozinc has been studied for
certain highly selective molecular transformations because it
possesses a high chemoselectivity in the reaction as well as a
high functional group tolerability.2 One example is asymmetric
inductions such as the Soai reaction.3
coupling between iodoarene and 1 to afford arylmethylzinc
iodide,7c which can perform arenylmethylmetalation to alkynes
in the presence of a cobalt catalyst.10
As shown in Table 1, various combinations of NiCl2 and
arylphosphine ligands were examined for the three-component
coupling between diphenylacetylene (2a), p-iodotoluene (3a),
and 1. The formed allylic zinc 4aa in situ is protonated by 1 M
HClaq and isolated as 2,3-diphenyl-3-(p-tolyl)-1-propene 5aa.
Because highly functionalized organozinc reagents are still
useful, an efficient method for their preparation is still being
investigated. The presence of LiCl dramatically improves the
classical reduction of organic halides with zinc metal from the
viewpoint of efficiency and functional group tolerability;4
higher order zincates are also good reagents to afford highly
functionalized arylzinc.5 The transition metal catalyzed carbo-
and hydrozincation of alkynes gives the alkenylzinc species via a
C−C bond forming reaction.6 We have also developed a new
homologation strategy with chemoselectivity to prepare
functionalized allyl-, homoallyl-, and arylmethylzinc species by
the cross-coupling of bis(iodozincio)methane (1) with the
corresponding organic halides.7
Table 1. Ligand for Nickel-Catalyzed Diphenyl Acetylene/p-
a
Iodotoluene/Bis(iodozincio)methane Coupling
b
entry Ar−I NiCl2 (mol %)
PAr3 (mol %)
PPh3 (20)
product
%
1
2
2.0
2.0
2.0
2.0
2.0
1.4
1.4
1.4
1.4
2.2
10
10
10
10
10
10
10
5
9
5
P(p-MeOC6H4)3 (20)
P(p-ClOC6H4)3 (20)
P(2-furyl)3 (20)
In this paper, we show a novel method to prepare organozinc
species by a three-component coupling of alkyne, iodoarene,
and 1 in the presence of a transition-metal catalyst.8 As shown
in Scheme 1, the reaction in the presence of a nickel catalyst
gives allylic zinc; the predominant reactions are arylnickelation
3
37
70
65
26
93
46
75
98
4
5
P(3,5-(CF3)2C6H3)3 (20)
P(2-furyl)3 (20)
6
7
P(3,5-(CF3)2C6H3)3 (20)
P(2-furyl)3 (10)
8
9
5
P(3,5-(CF3)2C6H3)3 (10)
Scheme 1. Catalyst Controlling of Alkyne/Aryl Iodide/
Bis(iodozincio)methane Coupling
c
10
2
P(3,5-(CF3)2C6H3)3 (3)
a
b
c
2a (0.5 mmol) and 1 (0.6 mmol) were used. Isolated yields. 2.0
equiv of 1 (1.0 mmol) were used.
Received: May 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00917
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Electron-deficient phosphines give better yields (entries 1−5)
for 5aa. After optimization, using 2 mol % of nickel dichloride
and 3 mol % of tris[3,5-bis(trifluoromethyl)phenyl]phosphine
yields 5aa quantitatively (entry10).
Scheme 2 shows the various allylic zinc species prepared
using the nickel-catalyzed three-component coupling. The
α-adduct 6c is formed by the isomerization of the γ-adduct that
has the more serious steric hindrance compare to 6b via retro-
allylation.11 The copper-mediated coupling reaction with allyl
bromide gives 6d with α-selectivity. Products 6c and 6d are
obtained as an E/Z-mixture. These chemoselective processes
make the preparation of highly functionalized arylboronic acids
possible.
Scheme 2. Various Allylic Zinc Formation by Nickel-
Catalyzed Alkyne/Aryl Iodide/Bis(iodozincio)methane
Coupling
The regioselectivity in the case of unsymmetrical alkynes is
low. For example, treatment of p-anisyl 4-trifluoromethyl
acetylene and p-iodotoluene (3a) with 1 in the presence of a
nickel catalyst affords a mixture of regioisomers. Exceptionally,
the reaction using 2-(phenylethylnyl)thiophene (2′) as the
alkyne and 3a gives corresponding alkene 5′a selectively. It may
be the result of the preferential formation of allylic zinc 4′a,
which is stabilized by the coordination of thiophene to zinc
intramolecularly (Scheme 4).12
Scheme 4. Regioselective Formation of Allylic Zinc from
Unsymmetrical Alkyne 2′
Cross-coupling between iodoarene 3 and 1 proceeds
preferentially, even in the presence of alkynes, when employing
a palladium catalyst instead of a nickel one, affording
arenylmethylzinc as reported previously7c (Scheme 5). The
Scheme 5. Additive for the Palladium/Cobalt-Catalyzed
Reaction
applicability of various iodoarenes demonstrates the functional
group tolerability. For example, ester, Bpin, and methoxy
groups remain intact during the transformation.
The reaction of the obtained allylic zinc species with various
electrophiles was also examined. Allylic zinc 4ac prepared from
diphenyl acetylene (2a), p-BpinC6H4I (3c), and the dizinc 1
can be treated with various electrophiles (Scheme 3).
Treatment of 4ac with paraformaldehyde gives γ-adduct 6b,
while that with benzaldehyde affords α-adduct 6c. The
regioselective formation of 6b implies that the σ-metal species
4ac reacts with formaldehyde at the γ-position to produce the
kinetically favored product. The regioselective formation of
product 5 in Scheme 2 is also explainable in the same way. The
addition of a Co catalyst in the presence of a coordinative
additive prompts carbozincation to the alkyne to give the
alkenylzinc species.9 The addition of LiCl produces alkenylzinc
7aa with a high stereoselectivity.
Scheme 3. Reactions of Allylic Zinc with the Bpin Group
Alkenylzinc formation from dizinc 1, diphenylacetylene (2a),
and various iodoarenes was examined using the Pd/Ni/LiCl
system (Scheme 6). Iodoarenes with an electron-donating
substituent such as methyl and methoxy give the corresponding
E-alkenylzinc selectively with good yields, while those carrying
electron-withdrawing groups retard the Co-catalyzed step. To
obtain the products in these cases, EtCN was added as an
additive, resulting in a loss of stereoselectivity.
Thus, the three-component coupling between alkyne, aryl
iodide, and bis(iodozincio)methane can be sorted based on the
catalyst. This method yields various allylzinc and alkenyl zinc
products.
B
DOI: 10.1021/acs.orglett.7b00917
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
K.; Utimoto, K.; Matsubara, S. Chem. - Eur. J. 2006, 12, 721.
(c) Shimada, Y.; Haraguchi, R.; Matsubara, S. Synlett 2015, 26, 2395−
2398.
Scheme 6. Various Alkenylzinc Formation by Palladium/
Cobalt-Catalyzed Reaction
(8) Xue, F.; Zhao, J.; Hor, T. S. A.; Hayashi, T. J. Am. Chem. Soc.
2015, 137, 3189−3192.
(9) Selective reaction of bis(iodozincio)methane (1) as a
zinciomethylation reagent in the presence of organomonozinc species
such as allylic or benzylic zinc might be explained by the higher
nucleophlicity of 1, which benefits to the transmetalation step with the
transition metal intermediate.
(10) (a) Murakami, K.; Yorimitsu, H.; Oshima, K. Chem. - Eur. J.
2010, 16, 7688−7691. (b) Murakami, K.; Yorimitsu, H. Beilstein J. Org.
Chem. 2013, 9, 278−302.
(11) (a) Tan, K.-T.; Chng, S.-S.; Cheng, H.-S.; Loh, T.-P. J. Am.
Chem. Soc. 2003, 125, 2958−2963. (b) Nokami, J.; Yoshizane, K.;
Matsuura, H.; Sumida, S. J. Am. Chem. Soc. 1998, 120, 6609−6610.
(12) The use of aryl alkyne acetylene also gives the adduct 5 as a
mixture of regioisomers. The reaction with the terminal alkyne does
not proceed.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00917.
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: matsubara.seijiro.2e@kyoto-u.ac.jp.
ORCID
Seijiro Matsubara: 0000-0001-8484-4574
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by JSPS KAKENHI Grant No.
15H05845.
■
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■
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DOI: 10.1021/acs.orglett.7b00917
Org. Lett. XXXX, XXX, XXX−XXX