Mizoroki-heck-type reaction mediated by potassium tert-butoxide

Article abstract of DOI:10.1002/anie.201008220

In the absence of transition-metal catalysts, a Mizoroki-Heck-type reaction proceeded to give stilbene derivatives in a simple manner using an aryl halide, a styrene derivative, KOtBu, EtOH, and DMF (see scheme; DMF=N,N- dimethylformamide).

Full text of DOI:10.1002/anie.201008220

DOI: 10.1002/anie.201008220
Synthetic Methods
Mizoroki–Heck-Type Reaction Mediated by Potassium tert-
Butoxide**
Eiji Shirakawa,* Xuejing Zhang, and Tamio Hayashi*
Table 1: Coupling of 4-iodotoluene with styrene.[a]
The Mizoroki–Heck reaction is a versatile method used to
prepare styrene derivatives from readily available aryl halides
and alkenes.[1] A major drawback of this method is the
necessary use of an expensive palladium complex as a
catalyst.[2] Addition of an aryl radical, which is generated
from an aryl halide, to an alkene and subsequent elimination
of a hydrogen radical in a similar way to homolytic aromatic
substitution[3] is a possible approach for a new pathway
leading to Mizoroki–Heck-type reactions. However, attack of
aryl radicals to alkenes usually results in an addition reaction
but not a substitution reaction.[4] Herein, we report that the
substitution reaction of aryl halides with styrene derivatives
takes place by just using KOtBu, EtOH, and DMF, possibly
through a radical mechanism.[5,6]
Treatment of 4-iodotoluene (1a) with styrene (2o:
5 equiv), KOtBu[7] (3 equiv), and EtOH (20 mol%) in DMF
at 808C for 2 hours gave 73% yield of 4-methylstilbene (3ao)
with 17% yield of toluene (Table 1, entry 1).[8] Use of DMF as
a solvent is essential: the reaction in MeCN, 1,4-dioxane, or
toluene did not give 3ao at all (Table 1, entries 2–4).[9] The
reaction took place also in the absence of EtOH but the yield
of 3ao was slightly lower (Table 1, entry 5). A low conversion
of 1a was observed when either sodium or lithium tert-
butoxide was used, both of which have lower basicity than
KOtBu (Table 1, entries 6 and 7). A decrease in the amount of
styrene severely affected the yield (Table 1, entry 8).
Entry
Solvent
MOtBu
Conv. of
Yield of
Yield of
1a [%][b]
3ao [%][b]
4a [%][b]
1
2
3
4
DMF
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOtBu
LiOtBu
KOtBu
>99
4
20
6
>99
5
73
<1
<1
<1
58
<1
<1
39
17
<1
6
–
15
4
MeCN
1,4-dioxane
toluene
DMF
DMF
DMF
5[c]
6
7
8
>99
<1
32
8[d]
DMF
[a] The reaction was carried out in DMF (0.50 mL) at 808C for 2 h under
nitrogen using 4-iodotoluene (1a: 0.23 mmol), styrene (2o: 1.2 mmol),
MOtBu (0.69 mmol), and EtOH (0.046 mmol). [b] Determined by GC
analysis. [c] In the absence of EtOH. [d] Styrene (0.28 mmol) was used.
DMF=N,N-dimethylformamide.
with a high conversion (Table 2, entry 6). Almost no reaction
took place with p-tolyl bromide or chloride (Table 2, entries 7
and 8), whereas not only iodide but also bromide and even
chloride underwent coupling when the organic moiety was a
1- or 2-naphthyl group (Table 2, entries 9–13). Substitution by
a conjugating group such as phenyl and alkenyl also enhanced
the reactivity of aryl bromides and chlorides (Table 2,
entries 14–17). Styrenes having an electron-donating or
electron-withdrawing substituent were arylated in the reac-
tion with 1a (Table 2, entries 18 and 19). Notably, 4-chlor-
ostyrene reacted with styrene (2o) at the chloroarene moiety
(Table 2, entry 17) and with aryl halide 1a at the alkene
moiety (Table 2, entry 19). Almost no conversion of 1a was
observed in the reaction with a styrene having a strong
electron-withdrawing CF3 group (Table 2, entry 20). The
reaction was applicable to an ortho-substituted styrene and
to the synthesis of a polymethoxylated stilbene (Table 2,
entries 21 and 22). Benzofuran accepted arylation at the 2-
position under the same reaction conditions (Table 2,
entry 23). Unfortunately, the reaction of alkyl-substituted
alkenes, acrylic acid derivatives, or vinyl ethers did not give
synthetically significant yields of products under the present
conditions.
The present tert-butoxide-promoted arylation of alkenes
was applied to various aryl halides and styrene derivatives
(Table 2).[10] Aryl and heteroaryl iodides underwent the
coupling with styrene (2o), where substitution with a
methoxy, phenyl, or methyl group on the benzene ring is
compatible (Table 2, entries 1–5). In contrast, the reaction of
phenyl iodides having an electron-withdrawing CF3 group
gave no coupling product with 2o but reduction product 4g
[*] Prof. E. Shirakawa, Dr. X. Zhang, Prof. T. Hayashi
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo, Kyoto, 606-8502 (Japan)
Fax: (+81)75-753-3988
E-mail: shirakawa@kuchem.kyoto-u.ac.jp
[**] This work was supported financially by a Grant-in-Aid for Scientific
Research (the Global COE Program “Integrated Materials Science”
on Kyoto University) from Ministry of Education, Culture, Sports,
Science and Technology (Japan). We are grateful to Ms. Yuki
Yamamoto, Dr. Kenji Kitayama, and Mr. Ikuo Takahashi (Daicel
Chemical Industries, Ltd.) for ICP analysis. We thank Dr. Kazufumi
Kohno (Tokyo University of Agriculture and Technology) for carrying
out duplicate experiments.
Formation of the reduction product 4 of aryl halide 1
suggests involvement of aryl radical intermediates, which are
À
generated through single-electron transfer (SET) to Ar X to
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008220.
À
À
give the radical anion [Ar X]C , and subsequent facile
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Table 2: Coupling of aryl halides with styrene derivatives mediated by
Table 3: Reaction of aryl halides with KOtBu in the presence of 1,4-
KOtBu.[a]
cyclohexadiene.[a]
Entry Aryl halide 1
Ar2 (2)
t [h] Yield [%][b]
Entry
R, X (1)
Solvent
Conv. of
Yield of
1 [%][b]
4 [%][b]
À
1
2
3
4
5
6
7
8
Ph I (1b)
4-MeOC6H4 I (1c)
Ph (2o)
Ph (2o)
Ph (2o)
Ph (2o)
Ph (2o)
Ph (2o)
Ph (2o)
Ph (2o)
Ph (2o)
2
2
66
65
À
1[c]
2
Ph, I (1d)
Ph, I (1d)
Ph, I (1d)
Me, Cl (1a’’)
Ph, I (1d)
DMF
DMF
DMF
DMF
MeCN
79
>99
>99
7
24
73
73
6
À
4-PhC6H4 I (1d)
2-MeC6H4 I (1e)
2-pyridyl I (1 f)
4-CF3C6H4 I (1g)
4-MeC6H4 Br (1a’)
4-MeC6H4 Cl (1a’’)
1-naphthyl I (1h)
1-naphthyl Br (1h’) Ph (2o)
1-naphthyl Cl (1h’’) Ph (2o)
2-naphthyl Br (1i’)
2-naphthyl Cl (1i’’)
4-PhC6H4 Br (1d’)
4-styrylC6H4 Cl (1j’’) Ph (2o)
4-vinylC6H4 Br (1k’) Ph (2o)
4-vinylC6H4 Cl (1k’’) Ph (2o)
4-MeC6H4 I (1a)
2
71
À
2.5
2
61
57
3[d]
4
À
À
2
5
17
2
6
<1
2[c]
5
<5
3
À
<1[d]
68
65
À
[a] The reaction was carried out in DMF (0.50 mL) at 808C for 0.25 h
under nitrogen using an aryl halide (1: 0.23 mmol), KOtBu (0.69 mmol),
1,4-cyclohexadiene (5: 1.1 mmol), and EtOH (0.046 mmol). [b] Deter-
mined by GC analysis. [c] In the absence of 5. [d] In the absence of EtOH.
À
9
À
10
11
12
13
14
15
16
17
18
19
20
21
22
23
À
6
63
À
Ph (2o)
Ph (2o)
Ph (2o)
3
76
À
3
83
À
2
62
À
2
69
jugating group such as phenyl and alkenyl as well as extended
aromaticity with fused rings such as naphthalene.[14] The
reactivity order of aryl halides here is consistent with aryl
radical generation through radical anion intermediates, if we
consider the following: 1) Aryl iodides are easily reduced to
radical anions and thus fully consumed irrespective of their
substituents in the reaction with styrene, though those having
an electron-withdrawing group are converted exclusively into
arene 4 (Table 2, entry 6), probably through further reduction
of aryl radicals to aryl anions. 2) Substitution by a conjugating
group or extended conjugation by introduction of a naphtha-
lene ring makes aryl bromides and chlorides sufficiently
reactive (compare Table 2, entries 7–8 vs. 10–17). 3) p-Tolyl
iodide (1a) fails to react when the coupling partner is an
electron-deficient styrene, which accepts an electron more
easily than 1a (Table 2, entry 20).
À
2
62
À
6
61
À
4-MeOC6H4 (2p)
4-ClC6H4 (2q=1k’’)
4-CF3C6H4 (2r)
2-MeC6H4 (2s)
3,5-(MeO)2C6H3 (2t)
benzofuran (2u)
5.5
2
2
56
À
4-MeC6H4 I (1a)
4-MeC6H4 I (1a)
4-MeC6H4 I (1a)
4-MeOC6H4 I (1c)
67
<1[d]
74
À
À
2
À
3
3
56
4-MeC6H4 I (1a)
55[e]
À
[a] The reaction was carried out in DMF (0.50 mL) at 808C under
nitrogen using an aryl halide (1: 0.23 mmol), an alkene (2: 1.2 mmol),
KOtBu (0.69 mmol), and EtOH (0.046 mmol). [b] Yield of isolated
product based on 1. Unless otherwise noted, conversion of 1 was >99%.
[c] 46% conversion of 1, where 3- and 4-(tert-butoxy)toluene compounds
were the main products. [d] Less than 5% conversion of 1. [e] 2-(4-
Tolyl)benzofuran was obtained in 55% yield.
elimination of XÀ.[11] As metal alkoxides are known to act as
single-electron donors towards aromatic compounds, alkyl
iodides, and ketones,[12] SET from KOtBu to aryl halides is
possibly in operation here. Treatment of 4-iodobiphenyl (1d:
1 equiv) with KOtBu (3 equiv) and EtOH (20 mol%) in DMF
at 808C for 0.25 hours gave reduction product 4d in 24%
yield with 79% conversion of 1d (Table 3, entry 1).[13] The
yield of 4d was largely improved by addition of 1,4-cyclo-
hexadiene (5; 4.6 equiv), which is an efficient hydrogen
radical donor, thus strongly suggesting the existence of aryl
radical intermediates (Table 3, entry 2). The yield was almost
the same in the absence of EtOH (Table 3, entry 3). In
contrast, a low yield with a low conversion was observed in
the reaction of p-tolyl chloride (1a’’; Table 3, entry 4), which
was not consumed at all also in the reaction with styrene (2o;
Table 1, entry 8). The correlation, which was observed also in
the solvent effect (Table 3, entry 5), implies that aryl radical
generation is a critical step in the coupling reaction.
Thus far, generated aryl radicals must add to styrene (2o),
but the subsequent steps and the role of EtOH are unclear at
present (Scheme 1). As adduct 7 has to lose a proton and an
Radical anions are known to be generated more easily
when the starting arenes have lower absolute values of
reduction potential and/or half-wave potential, which are
lowered with substitution by an electron-withdrawing group
including halogen (lowering effect: I > Br> Cl) and/or con-
Scheme 1. A plausible reaction mechanism.
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Angew. Chem. Int. Ed. 2011, 50, 4671 –4674

Ackermann, R. Born in Mizoroki–Heck Reaction (Ed.: M.
Oestreich), Wiley, Chichester, 2009, pp. 383 – 403.
electron to be converted into coupling product 3, the
subsequent pathways can be diverted into three types (a–c)
according to the timing of elimination of these species. In
path a, a proton is first removed to give radical anion 8, which
may give an electron to 1 to therefore give 3 and regenerate
the radical anion of 1 through SRN1 mechanism (a1)[11] or is
oxidized by tBuOC (a2). Path b includes elimination of both
species at once as HC, whereas oxidation of 7 is followed by
deprotonation in path c. Considering the high oxidation
ability of tBuOC, which is generated upon SET, it can possibly
act as an oxidant as in paths a2, b, or c. As shown in Scheme 2,
[3] For reviews of homolytic aromatic substitution with aryl radicals,
see: a) R. Bolton, G. H. Williams, Chem. Soc. Rev. 1986, 15, 261 –
289; b) J. Fossey, D. Lefort, J. Sorba, Free Radicals in Organic
Chemistry, Wiley, Chichester, 1995, Chapter 14, pp. 166 – 180;
c) A. Studer, M. Bossart in Radicals in Organic Synthesis, Vol. 2
(Eds.: P. Renaud, M. P. Sibi), Wiley-VCH, Weinheim, 2001,
chap. 1.4, pp. 62 – 80.
[4] For a recent review, see: M. R. Heinrich, Chem. Eur. J. 2009, 15,
820 – 833.
[5] KOtBu in combination with or without a bidentate nitrogen-
containing ligand is used in the coupling of aryl halides with
(hetero)arenes, where generation of aryl radicals from aryl
halides is considered to be involved; a) S. Yanagisawa, K. Ueda,
T. Taniguchi, K. Itami, Org. Lett. 2008, 10, 4673 – 4676; b) W. Liu,
H. Cao, H. Zhang, H. Zhang, K. H. Chung, C. He, H. Wang, F. Y.
Kwong, A. Lei, J. Am. Chem. Soc. 2010, 132, 16737 – 16740;
c) C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X. Zhou, X.-Y. Lu, K.
Huang, S.-F. Zheng, B.-J. Li, Z.-J. Shi, Nat. Chem. 2010, 2, 1044 –
1049. We have reported that coupling of aryl halides with arenes
mediated by NaOtBu proceeds through a homolytic aromatic
substitution pathway, where a catalytic amount of a phenanthro-
line derivative is essential for generation of the aryl radical from
aryl halides; d) E. Shirakawa, K. Itoh, T. Higashino, T. Hayashi,
J. Am. Chem. Soc. 2010, 132, 15537 – 15539. For a discussion on
the mechanism of these reactions, see e) A. Studer, D. P. Curran
Angew. Chem. 2011, in press; Angew. Chem. Int. Ed. 2011, in
press.
Scheme 2. Reaction of a-cyclopropylstyrene that gives ring-opening
products.
[6] The coupling of iodobenzene with styrene in the absence of any
transition-metal catalysts is reported to take place at a high
temperature and a high pressure in supercritical water, thus
giving stilbene in a moderate yield. R. Zhang, F. Zhao, M. Sato,
Y. Ikushima, Chem. Commun. 2003, 1548 – 1549.
[7] For the reactions shown in Table 1–Table 3, KOtBu, which was
purchased from Wako Pure Chemicals Industries, Ltd. (product
number 163–08425), was used as received. Its ICP-AES and ICP-
MS analysis showed that the contents of Co, Ni, Ru, Rh, Pd, Ag,
Ir, Pt, and Au are less than 0.05 ppm and those of Fe and Cu are
1.0 ppm and 1.1 ppm, respectively. See also Ref. [8].
[8] The reaction using a sublimed grade KOtBu (99.99% purity,
Aldrich Co., product number 659878) or a KOtBu purified
through sublimation by us gave coupling product 3ao in a similar
yield (80% or 79% yield, respectively). The contents of Fe and
Cu in the sublimed KOtBu are < 0.2 ppm (under detection limit)
and 0.25 ppm, respectively (ICP-AES analysis). These results
amply indicate that the coupling is promoted by KOtBu itself
rather than catalyzed by contaminated transition metals. We
asked Dr. Kazufumi Kohno to repeat the reaction and he
confirmed that the reaction under the same conditions gave 3ao
in 71% yield.
the reaction of a-cyclopropylstyrene (9) with p-tolyl iodide
(1a) gave a mixture of (E)- and (Z)-1-(p-tolyl)-2-phenyl-2-
pentenes (10) in addition to their double bond isomers 11,
albeit in a moderate combined yield (32%). Products 10 are
likely to be derived from ring-opening products 13 of addition
product 12 (corresponds to 7 in Scheme 2). As cyclopropyl-
methyl radicals such as 12 are known to readily undergo ring
opening,[15] this result supports the reaction pathway that
includes addition of aryl radicals to styrenes. Base-catalyzed
isomerization of 10 is likely to give 11.
In conclusion, we have disclosed transition-metal-free
Mizoroki–Heck-type reaction, which proceeds through aryl
radical intermediates and gives various stilbene derivatives by
simply using KOtBu, EtOH, and DMF.
Received: December 28, 2010
Revised: February 25, 2011
Published online: April 6, 2011
[9] N,N-Dimethylacetamide and dimethylsulfoxide also were effec-
tive as solvents but addition of their enolates to styrene and the
coupling products took place and thus the yield of 3ao was
slightly lower than that obtained when DMF was used.
[10] The products are all E isomers. The corresponding Z isomer or
1,1-disubstitued product was not observed in any reaction in
Table 2.
À
Keywords: alkenes · aryl radicals · C C coupling ·
single-electron transfer · synthetic methods
.
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[11] J. F. Bunnett, Acc. Chem. Res. 1978, 11, 413 – 420. See also
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[2] The Mizoroki–Heck reaction catalyzed by a metal other than
palladium is also known but is rare. For a review, see: L.
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www.angewandte.org
4673

Communications
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most likely to be produced through 4-phenylbenzyne, was
observed as by-products. These by-products were produced
also in the coupling reaction but in lower amounts.
[15] For examples, see: a) V. W. Bowry, J. Lusztyk, K. U. Ingold, J.
Am. Chem. Soc. 1991, 113, 5687 – 5698; b) V. W. Bowry, K. U.
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