Single-Electron-Transfer-Induced Coupling of Alkylzinc Reagents with Aryl Iodides

Article abstract of DOI:10.1002/ejoc.201600367

Alkylzinc reagents prepared from an alkyllithium and zinc iodide were found to undergo coupling with aryl and alkenyl iodides in the presence of LiI in a mixed solvent consisting of THF and diglyme (1:1). Alkyllithiums, prepared by halogen–lithium exchange between an alkyl iodide and tert-butyllithium, are also converted to alkylarenes through alkylzinc reagents.

Full text of DOI:10.1002/ejoc.201600367

DOI: 10.1002/ejoc.201600367
Communication
Cross-Coupling
Single-Electron-Transfer-Induced Coupling of Alkylzinc Reagents
with Aryl Iodides
Keisho Okura[a] and Eiji Shirakawa*[b]
Abstract: Alkylzinc reagents prepared from an alkyllithium and of THF and diglyme (1:1). Alkyllithiums, prepared by halogen–
zinc iodide were found to undergo coupling with aryl and alk- lithium exchange between an alkyl iodide and tert-butyllithium,
enyl iodides in the presence of LiI in a mixed solvent consisting are also converted to alkylarenes through alkylzinc reagents.
Introduction
of LiI (2 equiv.) further improved the conversion and the yield
(Table 1, entries 4 and 5).[10] No coupling took place with salt-
free BuZnI prepared from 1-iodobutane and zinc powder
(Table 1, entry 6), but an additional amount of LiI (4 equiv.)
promoted the coupling to some extent (Table 1, entry 7). These
results show that the reactivity of an alkylzinc reagent is largely
dependent on the type of halogen existing in the reaction mix-
ture. Considering the effect of the halogen atom, the reactivity
is possibly governed by higher order structures such as
BuZnX·nLiX. BuZnX·LiX is known to form a butylzincate
Li+[BuZnX2]–, and Li+[BuZnCl2]– and Li+[BuZnI2]– tend to form
oligomeric and monomeric complexes, respectively.[11,12] Al-
The transition-metal-catalyzed cross-coupling reaction of orga-
nometals with aryl halides is widely used to introduce substitu-
ents into benzene rings.[1] On the other hand, we reported a
transition-metal-free version of the cross-coupling reaction of
aryl Grignard reagents with aryl iodides, for which a single elec-
tron, produced by single-electron transfer (SET) from an aryl
Grignard reagent to an aryl iodide, acts as the catalyst.[2–4] We
also reported that arylzinc reagents undergo coupling with aryl
halides through the SET mechanism with the aid of LiCl,[5]
which acts as an accelerator in the Grignard cross-coupling, and
this led to expansion of the scope of the aryl halides from iod-
ides to bromides.[6] However, transition-metal-free cross-cou-
pling has only been applied to arylmetals.[7,8] Herein, we report
that the SET-induced coupling of alkylzinc reagents with aryl
iodides takes place with the aid of LiI; LiCl does not work at all
in this reaction, in contrast to the aryl–aryl coupling case.
Table 1. Effect of constituents of butylzinc reagents in the coupling with 4-
iodotoluene.[a]
Results and Discussion
Treatment of 4-iodotoluene (2m) with BuZnCl·LiCl (2 equiv.),
prepared by transmetalation between BuLi (1a: 2 equiv.) and
ZnCl2 (2.2 equiv.), in THF/diglyme/hexane (1.2:1.2:1) at 110 °C
for 24 h gave 4-butyltoluene (3am), but only in 1 % yield with
6 % conversion of 2m (Table 1, entry 1). The addition of LiCl
(2 equiv.) did not enhance the reactivity (Table 1, entry 2). In
contrast, the addition of LiI drastically increased the conversion
and the yield and gave 3am in 69 % yield, but toluene and 4,4′-
bitolyl were also produced in considerable amounts (9 and 5 %,
respectively; Table 1, entry 3).[9] BuZnI·LiI prepared from ZnI2
instead of ZnCl2 was also effective, and an additional amount
Entry
ZnX2
LiX
Constituent of
BuZnX·nLiX
Conversion
[%][b]
Yield
[%][b]
1
2
3
4
5
ZnCl2
ZnCl2
ZnCl2
ZnI2
none
LiCl
LiI
none
LiI
BuZnCl·LiCl
BuZnCl·2LiCl
BuZnCl·LiCl·LiI
BuZnI·LiI
6
4
85
86
98
1
1
69
68
86
(85)[c]
<1
28
ZnI2
BuZnI·2LiI
6[d]
–
–
none
LiI
BuZnI
BuZnI·2LiI
1
36
7[d,e]
[a] Department of Chemistry, Graduate School of Science, Kyoto University,
Kyoto, Kyoto 606-8502, Japan
[b] Department of Applied Chemistry for Environment, School of Science and
Technology, Kwansei Gakuin University,
[a] The reaction was performed at 110 °C for 24 h in THF/diglyme/hexane
(1.2:1.2:1, 0.85 mL) under a nitrogen atmosphere by using 4-iodotoluene (2m)
(0.20 mmol) and a butylzinc reagent prepared from a zinc halide (0.44 mmol)
Sanda, Hyogo 669-1337, Japan
and butyllithium (1a) (1.6 M in hexane, 0.25 mL, 0.40 mmol) in the presence
E-mail: eshirakawa@kwansei.ac.jp
or absence of a lithium halide (0.40 mmol). [b] Determined by GC. [c] Yield
http://sci-tech.ksc.kwansei.ac.jp/en/
of isolated product based on 2m. [d] A lithium halide free butylzinc iodide
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600367.
(1.4
M in THF, 0.28 mL, 0.40 mmol) prepared from 1-iodobutane and zinc dust
(1.5 equiv.) was used. [e] LiI (0.80 mmol) was used.
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Communication
though we are not certain what effect the structural difference
Alkyllithiums prepared through halogen–lithium exchange
exerts, a mononuclear complex of an alkylzincate is likely to be were also converted into alkylarenes through alkylzinc reagents
effective for the coupling reaction with aryl halides.
(Scheme 2). A pentane solution of tBuLi was added to alkyl
iodide 1′ in pentane/Et2O. Stirring at –78 °C for 1 h and then at
25 °C for 1 h was followed by treatment with a THF solution of
ZnI2 at 0 °C for 3 h. After the addition of diglyme and evacua-
tion at 1.30 kPa for 10 min to remove the low-boiling solvents,
the resulting alkylzinc reagent was subjected to the reaction
with aryl iodide 2 by using THF as an additional solvent at
110 °C for 24–72 h to give the corresponding coupling product.
The alkyl–aryl coupling was found to be applicable to various
aryl iodides and alkylzinc reagents (Table 2). Iodobenzene deriv-
atives having no substituents underwent the coupling with
butylzinc iodide (Table 2, entries 1 and 2). Substituted phenyl
iodides also participated in the coupling, and the electronic
character of the substituents did not largely affect the reactivity
and the yield (Table 2, entries 3–8). The coupling of the butyl-
zinc reagent with phenyl iodide 2s having an ester moiety gave
ethyl 4-butylbenzoate (3as) in 53 % yield but also the corre-
sponding butyl ester and carboxylic acid in yields of 13 and
10 %, respectively. Simple treatment of the crude product trans-
formed the carbon–carbon bond-forming products into methyl
4-butylbenzoate (3as′) (Table 2, entry 7).[13] High yields were
attained in the reaction of the corresponding methylzinc rea-
gent (Table 2, entries 9–11).
Table 2. Coupling of alkylzinc reagents with aryl iodides.[a]
Scheme 2. Coupling of alkylzinc reagents, prepared through halogen–lithium
exchange, with aryl iodides.
Entry
R
Ar
Yield [%][b]
Product
If we consider that the present alkyl–aryl coupling follows
the SET mechanism operative in the aryl–aryl coupling,[2,3,5,6]
the pathway shown in Scheme 3 can be drawn. Considering
the striking effect of I–, alkylzinc species are described as
Li+[RZnI2]– in all cases, though it is unclear what kind of alkyl-
zinc species exists in each step. Initiation by SET from Li+[RZnI2]–
to Ar–I gives [Ar–I]·–, which reacts with Li+[RZnI2]–.[14] SET from
the resulting anion radical, [R–Ar]·–, to I–Ar gives R–Ar and re-
generates [I–Ar]·–. The involvement of the [I–Ar]·– intermediate
is strongly supported by the fact that the reaction of 2-(3-but-
enyl)phenyl iodide (2u) with BuZnI·2LiI under the standard con-
ditions gives certain amounts of reductive cyclization products
(i.e., compounds exo-7 and endo-7) in addition to coupling
product 3au (Scheme 4).[15] Considering that o-homoallyl-
phenyl radical I is known to cyclize readily, the reductive cycliza-
tion products are most likely produced from aryl radical I, which
is undoubtedly formed through elimination of LiI from Li+[2u]·–.
We already showed that aryl radicals derived from aryl halides
are not intermediates in coupling reactions with aryl Grignard
reagents.[3,16] Then, we examined whether this also holds true
for the present alkyl–aryl coupling by conducting a similar ex-
periment. Thus, treatment of BuZnI·2LiI with phenylazo(tri-
1
2
3
4
5
6
7
8
Bu (1a)
Bu (1a)
Bu (1a)
Bu (1a)
Bu (1a)
Bu (1a)
Bu (1a)
Bu (1a)
Me (1b)
Me (1b)
Me (1b)
2-naphthyl (2n)
Ph (2o)
85
75
85
72
72
3an
3ao
3am
3ap
3aq
3ar
3as′
3at
3bn
3bq
3br
4-MeC6H4 (2m)
4-F3CC6H4 (2p)
4-MeOC6H4 (2q)
4-PhC6H4 (2r)
4-EtO2CC6H4 (2s)
2-EtC6H4 (2t)
2-naphthyl (2n)
4-MeOC6H4 (2q)
4-PhC6H4 (2r)
81
75[c]
72
9
10
11
97
92
95
[a] The reaction was performed at 110 °C for 24 h in THF/diglyme/hexane
(1.2:1.2:1, 0.85 mL) or THF/diglyme/Et2O (1:1:1, 0.85 mL) under a nitrogen
atmosphere by using an alkylzinc reagent, prepared from zinc iodide
(0.44 mmol) and an alkyllithium (1a: a hexane solution, 0.25 mL; 1b: a Et2O
solution, 0.30 mL), and aryl iodide 2 (0.20 mmol) in the presence of LiI
(0.40 mmol). [b] Yield of isolated product based on 2. [c] The yield of methyl
4-butylbenzoate (3as′) obtained by treatment of the crude product with
NaOMe in MeOH at 25 °C for 6 h and then with MeOH/HCl at 25 °C for 36 h.
In addition to aryl iodides, alkenyl iodides underwent the
coupling (Scheme 1). The stereochemistry was retained in the
reaction of the butylzinc reagent with 1-octenyl and styryl iod-
ides, as in cross-coupling reactions with the use of arylmagne-
sium and arylzinc reagents.
Scheme 1. Coupling of the butylzinc reagent with alkenyl iodides.
Scheme 3. Plausible mechanism.
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Communication
phenyl)methane (PAT) as a Ph· precursor[17] did not give butyl-
benzene (3ao) at all (Scheme 5). This result shows that, under
the standard conditions, BuZnI·2LiI shows no reactivity towards
Ph·, which rather reacts with the solvents to give benzene (6o)
as the major product (Scheme 5). No involvement of σ-radical
intermediates is supported by retention of the stereochemistry
in the coupling of alkenyl iodides shown in Scheme 1.[18–20]
[1]
[2]
For reviews, see: a) A. de Meijere, F. Diederich (Eds.), Metal-Catalyzed
Cross-Coupling Reactions, Wiley-VCH, Weinheim, Germany, 2004, vol. 1
and 2; b) J.-P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651–2710.
For coupling with aryl iodides, see: E. Shirakawa, Y. Hayashi, K. Itoh, R.
Watabe, N. Uchiyama, W. Konagaya, S. Masui, T. Hayashi, Angew. Chem.
Int. Ed. 2012, 51, 218–221; Angew. Chem. 2012, 124, 222–225.
For mechanistic studies on coupling with aryl halides, see: N. Uchiyama,
E. Shirakawa, T. Hayashi, Chem. Commun. 2013, 49, 364–366.
We also reported the coupling of aryl Grignard reagents with alkenyl
halides, see: E. Shirakawa, R. Watabe, T. Murakami, T. Hayashi, Chem.
Commun. 2013, 49, 5219–5221.
[3]
[4]
[5]
E. Shirakawa, F. Tamakuni, E. Kusano, N. Uchiyama, W. Konagaya, R. Wa-
tabe, T. Hayashi, Angew. Chem. Int. Ed. 2014, 53, 521–525; Angew. Chem.
2014, 126, 531–535.
[6]
[7]
E. Shirakawa, K. Okura, N. Uchiyama, T. Murakami, T. Hayashi, Chem. Lett.
2014, 43, 922–924.
Uchiyama and co-workers reported the transition-metal-free coupling of
arylmetals with aryl halides. For diarylzinc reagents, see: a) H. Minami,
X. Wang, C. Wang, M. Uchiyama, Eur. J. Org. Chem. 2013, 7891–7894; for
arylaluminum reagents, see: b) H. Minami, T. Saito, C. Wang, M. Uchi-
yama, Angew. Chem. Int. Ed. 2015, 54, 4665–4668; Angew. Chem. 2015,
127, 4748–4751.
[8]
In the report on the copper-catalyzed coupling of perfluoroalkyl iodides
with aryl iodides by use of a stoichiometric amount of Et2Zn to give
perfluoroalkylarenes, the coupling is reported to take place even in the
absence of CuI, albeit to a much lower extent. H. Kato, K. Hirano, D.
Kurauchi, N. Toriumi, M. Uchiyama, Chem. Eur. J. 2015, 21, 3895–3900.
Iodine–zinc exchange between 4-iodotoluene (2m) and the butylzinc
reagent is likely to take place to give a p-tolylzinc reagent, which is
converted into toluene and 4,4′-bitolyl through hydrolysis and cross-cou-
pling, respectively.
Scheme 4. Coupling of the butylzinc reagent with 2-(3-butenyl)phenyl iodide.
[9]
[10]
Use of THF/diglyme as a mixed solvent is critical. The reaction in THF
alone gave 3am only in 56 % yield (73 % conversion) under the condi-
tions of Table 1, entry 5. On the other hand, the reaction in diglyme
alone showed poor reproducibility, and the conversion of 2m ranged
from 80 to >99 %. The use of toluene, DME, or DMF as a co-solvent with
THF was much less effective than diglyme; the yields of 3am (conver-
sions of 2m) were 68 (99), 54 (70), or 43 % (50 %), respectively.
a) K. Koszinowski, P. Böhrer, Organometallics 2009, 28, 100–110; b) K.
Koszinowski, P. Böhrer, Organometallics 2009, 28, 771–779.
Although we are not certain why butylzinc reagents (BuZnI·2LiI) pre-
pared by transmetalation (Table 1, entry 5) and a redox process followed
by addition of LiI (Table 1, entry 7) show different reactivities, the latter
reagent, relative to the former reagent, possibly cannot attain sufficient
affinity between BuZnI and LiI to promote the coupling efficiently.
Treatment of the crude product with NaOMe in MeOH at 25 °C for 6 h
and then with MeOH/HCl at 25 °C for 36 h gave methyl 4-butylbenzoate
(3as′).
In the carbon–carbon bond-forming step, Li+ possibly works as a Lewis
acid toward the iodine of the [I–Ar]·– anion radical to promote its elimi-
nation as I–. In the monoethylation of tetrafluoroethene with diethylzinc,
LiI is used as an effective additive in which Li+ is considered to work as
a Lewis acid toward fluorine to promote its elimination as F–: a) M. Oha-
shi, R. Kamura, R. Doi, S. Ogoshi, Chem. Lett. 2013, 42, 933–935; for a
review of effects of lithium salts, see: b) D. Seebach, A. K. Beck, A. Studer,
in: Modern Synthetic Methods (Eds.: B. Ernst, C. Leumann), Helvetica Chim-
ica Acta/VCH, Basel/Weinheim, Germany, 1995, vol. 7, p. 1–178.
a) A. N. Abeywickrema, A. L. J. Beckwith, J. Chem. Soc., Chem. Commun.
1986, 464–465; b) H. Yasuda, Y. Uenoyama, O. Nobuta, S. Kobayashi, I.
Ryu, Tetrahedron Lett. 2008, 49, 367–370.
[11]
[12]
Scheme 5. Treatment of the butylzinc reagent with phenylazo(tri-
phenyl)methane as a phenyl radical precursor.
[13]
[14]
Conclusion
In conclusion, we developed the first example of the alkylmetal
version of the single-electron-transfer-induced cross-coupling
reaction of organometals with aryl and alkenyl iodides, in which
LiI plays a critical role.
[15]
[16]
Acknowledgments
This work was financially supported in part by the Japan Society
for the Promotion of Science (JSPS) through a Grant-in-Aid for
Scientific Research (B) (25288046, grant to E. S.) and by the
Nagase Science and Technology Foundation (grant to E. S.).
DFT calculation on the Grignard aryl–aryl cross-coupling (ref.[2]) implies
that the coupling proceeds through an aryl radical intermediate in a
unique situation. B. E. Haines, O. Wiest, J. Org. Chem. 2014, 79, 2771–
2774.
PAT is known to decompose into Ph·, N2, and Ph3C· in chlorobenzene at
45 °C (t1/2 = 2.6 h): a) G. A. Russell, R. F. Bridger, Tetrahedron Lett. 1963,
4, 737–740; b) R. G. Kryger, J. P. Lorand, N. R. Stevens, N. R. Herron, J. Am.
Chem. Soc. 1977, 99, 7589–7600; c) T. Suehiro, A. Suzuki, Y. Tsuchida, J.
Yamazaki, Bull. Chem. Soc. Jpn. 1977, 50, 3324–3328.
[17]
Keywords: Alkylation · Arenes · C–C coupling · Cross-
coupling · Electron transfer · Radical reactions
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[18] Alkenyl radicals are known to isomerize readily to give a stereoisomeric
mixture, see: a) C. Galli, P. Gentili, A. Guarnieri, Z. Rappoport, J. Org.
Chem. 1996, 61, 8878–8884; b) C. Galli, A. Guarnieri, H. Koch, P. Menca-
relli, Z. Rappoport, J. Org. Chem. 1997, 62, 4072–4077; see also ref.[4]
[19] The possibility that alkylarenes are obtained through iodine–zinc ex-
change followed by nucleophilic substitution between the resulting aryl-
zincs and alkyl iodides is excluded by the following experiment. Treat-
ment of 1-iododecane with PhZnI·2LiI (1.0 equiv.) in THF/diglyme/Bu2O
(2.4:2.4:1) at 110 °C for 24 h hardly gave decylbenzene, whereas 1-iodo-
decane was converted (37 % conversion) into decane and 1-decene in
yields of 14 and 6 %, respectively. For the production of alkylarenes from
alkyllithiums and aryl bromides through bromine–lithium exchange fol-
lowed by nucleophilic substitution, see: R. E. Merrill, E. Negishi, J. Org.
Chem. 1974, 39, 3452–3453.
[20] Additional experiments show that aryl and alkyl radicals, which would
be generated from aryl iodides and alkylzinc reagents, respectively, are
not intermediates leading to the coupling products. For details, see the
Supporting Information.
Received: March 24, 2016
Published Online: ■
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Communication
Cross-Coupling
K. Okura, E. Shirakawa* ................... 1–5
Single-Electron-Transfer-Induced
Coupling of Alkylzinc Reagents with
Aryl Iodides
The transition-metal-free coupling of transfer-induced cross-coupling reac-
alkylzinc reagents with aryl and alk- tion of organometallic compounds
enyl iodides is accomplished as the other than arylmetals.
first examples of a single-electron-
DOI: 10.1002/ejoc.201600367
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