Direct C-C bond construction from arylzinc reagents and aryl halides without external catalysts

Article abstract of DOI:10.1002/ejoc.201301404

Direct cross-coupling between an arylzinc reagent and an aryl halide was accomplished without any external catalyst, enabling efficient and selective formation of the corresponding biaryl compound with broad functional group compatibility. Direct cross-coupling between a diarylzinc compound and an aryl iodide was accomplished without using any external catalyst. The reaction is efficient and selective, enabling formation of the corresponding biaryl compounds with broad functional group compatibility. The reaction is proposed to proceed by a thermally initiated single electron transfer (SET) route. Copyright

Full text of DOI:10.1002/ejoc.201301404

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301404
Direct C–C Bond Construction from Arylzinc Reagents and Aryl Halides
without External Catalysts
Hiroki Minami,[a] Xuan Wang,[a,b] Chao Wang,*[a,b] and Masanobu Uchiyama*[a,b]
Keywords: Cross-coupling / Organozinc compounds / Halides / C–C bond formation / Biaryls
Direct cross-coupling between an arylzinc reagent and an
aryl halide was accomplished without any external catalyst,
enabling efficient and selective formation of the correspond-
ing biaryl compound with broad functional group compatibil-
ity.
Introduction
Results and Discussion
Among many types of cross-coupling reactions, the Negi-
shi reaction is regarded as one of the most efficient and
reliable, because organozinc reagents offer many advan-
tages, such as high reactivity and selectivity, facile prepara-
tion, low toxicity, and broad functional group compatibil-
ity.[7,8] After extensive experimentation with 2-iodonaph-
thalene (1a) and di-p-tolylzinc (2a), prepared from the cor-
responding aryllithium compound and zinc chloride, as the
model substrates (see Supporting Information), we found
that the direct coupling took place, and the desired product
3aa was obtained in high yield when the reaction was run
at 110 °C in THF (Scheme 1).
Cross-coupling reactions catalyzed by transition metals
(TMs) are a fundamentally important tool for forming C–
C and C–X bonds, both in academic research and on an
industrial scale.[1] The reaction occurs through an oxidative-
addition–transmetalation–reductive-elimination
catalytic
cycle, which generally involves the transfer of two electrons,
the TM determining the reactivity and/or selectivity. There-
fore, development of new TM catalysts (with ligands) has
long been a mainstream approach for exploring novel cou-
pling reactions, although the creation of such metal com-
plexes often presents a substantial challenge. An alternative
way is the SET (single electron transfer) reaction without
adding a TM catalyst, of which a representative is the
homolytic aromatic substitution (HAS) reaction.[2] Recent
advances in this area, including organocatalyzed HAS cou-
pling and SET-induced Kumada–Tamao coupling, have at-
tracted great interest.[3–5] However, issues such as low re-
gioselectivity and restricted substituent compatibility still li-
mit the practicability of these methods.[6] Here, we describe
the first direct cross-coupling reaction between an arylzinc
reagent and an aryl halide in the absence of any external
catalyst, enabling efficient, selective, and diversified synthe-
sis of biaryl compounds. This reaction is proposed to pro-
ceed by a thermally initiated SET route.
[a] Graduate School of Pharmaceutical Sciences, the University of
Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo-to 113-0033, Japan
E-mail: uchiyama@mol.f.u-tokyo.ac.jp
http://www.f.u-tokyo.ac.jp/~kisoyuki
[b] The Advanced Elements Chemistry Research Team, Center for
Sustainable Resource Science, and the Elements Chemistry
Laboratory, RIKEN,
Scheme 1. Direct cross-coupling between 2-iodonaphthalene 1a
and various diarylzinc compounds 2 (the yields shown are those
calculated after isolation).
2-1 Hirosawa, Wako-shi, Saitama-ken, 351-0198, Japan
E-mail: chaowang@riken.jp, uchi_yama@riken.jp
http://www.riken.jp/genso_kagaku/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301404.
Under the optimized conditions, various diarylzinc com-
pounds 2 were allowed to react with 1a as a model coupling
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H. Minami, X. Wang, C. Wang, M. Uchiyama
SHORT COMMUNICATION
partner. This reaction is not greatly influenced by sterics
(see compounds 3aa–3ac), and even the reaction of a very
bulky substrate proceeded well (as in 3ad). The reaction was
also not much affected by electronic factors (see com-
pounds 3ae–3ah), and the highly electron-withdrawing tri-
fluoromethyl group was well tolerated, with a high yield.
Reactions involving functional atoms such as silicon and
halogens (see compounds 3ag–k), as well as those involving
heterocycles (see 3al and 3am), were all successful, suggest-
ing further applicability of this method. Several issues are
noteworthy: (1) the reaction of bromide 4a with diarylzinc
did not take place under these conditions;[9] (2) the
monoarylzinc reagent (ArZnCl) was very unreactive, only
generating trace amounts of the coupling products; (3) lith-
ium salts facilitated the reaction, although they were not
necessary,[10] since lithium-free diphenylzinc was able to re-
act with 1a,[11] albeit with a little lower yield (66%);
(4) magnesium salts were very disadvantageous, because the
reaction became quite sluggish when 2a was prepared from
the Grignard reagent.
Next, the scope of the reaction was investigated with
various iodides, as shown in Scheme 2. Differently substi-
tuted iodonaphthalenes 1b and 1c, as well as derivatives of
phenyl iodides 1d–1k, underwent the reaction without diffi-
culty in moderate to excellent yields. It is noteworthy that
a wide range of functional groups proved to be compatible
with this reaction, though the yields were reduced in some
cases. The reason for the decreased yields was attributed to
the side reaction of Zn/I exchange. For electron-rich sub-
strates such as 1e, the coupling reaction seems to be slower,
and consequently the Zn/I exchange may become a compet-
itive pathway. For some electron-deficient iodides such as
1h, the exchange reaction is known to be a rapid process,
which may be faster than the main coupling reaction. In
general, this reaction appears to have broad potential use
for biaryl synthesis, being compatible with various substitu-
ents, including silyl, halogen, heterocycle, tosylate, nitrile,
amide, ester, and even rather reactive ketone moieties.
As for the mechanism, firstly, no regioisomers of 3 were
found, which excludes the route through aryne intermedi-
ates.[12] Secondly, electron-rich aryl iodides could partici-
pate in the reaction, even with the electron-deficient di-
arylzinc compounds. These results demonstrate that an aro-
matic nucleophilic substitution (SNAr) process is less likely
here.[13] Since an electron-withdrawing group on both 1 or
2 could enhance the reaction, it is conceivable that some
critical anionic intermediates, which could be stabilized by
electron-withdrawing substituents, may be involved in the
Scheme 2. Direct cross-coupling between various aryl iodides 1 and
diarylzinc compounds 2. Reactions for 1b, 1c–1g, and 1h–1k were
run at 130, 110, and 90 °C, respectively. The cyclization products
of 1e were not observed. Compound 3gc was obtained as a main
component in a mixture with PhOTs (ratio by 1H NMR: 3.6:1)
because of the competing exchange reaction.
the reaction of 1a and 2a was carried out in the dark. We
found that 3aa was formed in a similar yield, which rules
out the necessity of light initiation. The usage of degassed
solvent did not reduce the yield of 3aa, which suggests that
residual oxygen might not act as initiator.[15] It is worth
mentioning that no cyclization products were observed in
the case of 1-(3-butenyl)-2-iodobenzene 1e, which indicates
that the reaction probably does not involve a aryl free radi-
cal intermediate (Scheme 2).[5c]
Scheme 3. Proposed mechanism of the direct cross-coupling reac-
tion between aryl iodide 1 and diarylzinc 2 (RA: radical anion; RC:
reaction. Therefore, a SET reaction pathway was proposed, radical cation).
as shown in Scheme 3,[14] which is similar to the reaction of
Grignard reagents.[4] In the initiation step (1), a SET pro-
Since no reaction occurred when aryl bromide and di-
cess takes place between aryl iodide 1 and diarylzinc 2 lead- arylzinc were heated under the same or more severe condi-
ing to radical anion 1-RA and radical cation 2-RC. The tions,[9] it is suggested that bromide would be very ineffec-
iodide radical anion, 1-RA, takes part in the next propaga- tive for initiation relative to iodide according to the mecha-
tion step (2), reacting with another molecule of 2 to afford nism proposed in Scheme 4. Indeed, when a catalytic
a new biaryl radical anion, 3-RA, which then exchanges one amount of iodide 1d was added to the mixture of 4a and
electron with a second aryl iodide 1 to regenerate 1-RA and 2a as an initiator (Scheme 4), the corresponding coupling
trigger the subsequent cycle (3). To examine this hypothesis, product 3aa was formed, although some unreacted 4a was
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C–C Bond Construction from Arylzinc Reagents and Aryl Halides
also obtained. The lower yield also reveals that regeneration adding any catalysts. The reaction, which is proposed to
of the 4a-RA was not as effortless as that of 1-RA, hence proceed by a SET process, is efficient and selective, and a
the transformation was not complete.
wide range of functional groups is tolerated. We expect that
it will find a wide range of applications. Further research
to establish the reaction scope and to evaluate its utility
toward both organic synthesis and polymer science, as well
as to understand the reaction mechanism with the help of
theoretical and/or spectroscopic methods, is in progress.
Experimental Section
Scheme 4. Aryl iodide 1 initiated the direct cross-coupling reaction
between diarylzinc 2 and aryl bromide 4 (yields are based on GC
analysis with n-dodecane as internal standard).
Typical Procedure for the Reaction Between Aryl Iodides 1 and Di-
arylzinc Reagents 2: Aryl iodide 1 (0.25 mmol) and THF (2 mL)
were added to diarylzinc compound 2 (0.375 or 0.5 mmol, prepared
by mixing zinc chloride and the corresponding aryllithium com-
pound and then removing the solvent) in a reaction tube with a
gas-tight Teflon stopper. The reaction tube was rapidly switched
between vacuum and argon three times so that the trace amount
of oxygen would be removed without evacuating THF (if all the
materials are added in a glovebox, this step is not needed). The
reaction mixture was then heated at 110 °C for 18 h (or under other
conditions as noted) before cooling down to 0 °C. Diluted hydro-
chloric acid (1 mol/L) or a saturated solution of ammonium chlor-
ide was then added to quench the reaction. The aqueous layer was
extracted with diethyl ether (3ϫ 10 mL), and the combined organic
phase was washed with brine and dried with sodium sulfate. The
solvent was removed under vacuum, and the residue was purified
by column chromatography on silica gel to give the coupling prod-
uct 3.
The coupling reaction between 1-bromo-4-iodobenzene
5a and 2c provided further support for the proposed mecha-
nism (Scheme 5). After the first arylation at the most reac-
tive iodo site, the resulting radical anion intermediate 4l-
RA should have two probable reaction pathways, (a) and
(b). Accordingly, 3lc would be generated after the second
arylation at the activated bromo site.[3,14] Indeed, mono-
and diarylation products 4l and 3lc were finally obtained in
60% and 16% yields, respectively.[16] In marked contrast,
the reaction of structurally similar 1-bromo-4-phenylben-
zene with 2c did not occur at all under the same conditions.
Supporting Information (see footnote on the first page of this arti-
cle): All experimental procedures, characterization data, and copies
1
of the H and 13C NMR spectra.
Acknowledgments
Scheme 5. Mono- and diarylation of 1-bromo-4-iodobenzene 5a
This research was partly supported by Japan Society for the Pro-
motion of Science (JSPS) [Grants-in-Aid for Scientific Research (S)
(No. 24229001) (to M. U.) and Grant-in-Aid for Young Scientists
(B-1) (No. 24790035) (to C. W.)], and the Foreign Postdoctoral Re-
searcher (FPR) programs of RIKEN (to C. W.). This research was
also supported by the Takeda Science Foundation, the Asahi Glass
Foundation, the Daiichi-Sankyo Foundation of Life Science, the
Mochida Memorial Foundation, the Tokyo Biochemical Research
Foundation, NAGASE Science Technology Development Founda-
tion, and the Sumitomo Foundation (to M. U.). We also thank Dr.
Kazuya Takahashi (Nishina Center for Accelerator-Based Science,
RIKEN) for the ICP-MS analysis.
(the yields shown are those calculated after isolation).
The low yield of 3ak (Scheme 2) can be ascribed to the
successive arylation at the RA-activated bromo site as well.
These changes of reactivity at the bromo site are difficult
to explain in terms of a SNAr mechanism, but they are con-
sistent with the mechanism involving radical anions. Com-
pared with the case of iodide 1, bromide 4, and their radical
anions seem to be quite inert toward diarylzinc, giving rise
to considerable barriers for the initiation, propagation, as
well as regeneration.
To examine whether any TM was present, ICP-MS
analysis was performed on the diarylzinc and halide, but
only Fe, Ni, and Cu were detected at very low abundance
(3 ppb to 0.6 ppm).[17] Although this may not entirely rule
out the participation of TM,[18] the results of the present
mechanistic investigations suggested that the SET process
may be more likely.
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We report here a protocol for the direct cross-coupling
reaction between arylzinc reagents and aryl halides without
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H. Minami, X. Wang, C. Wang, M. Uchiyama
SHORT COMMUNICATION
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[15] The degassed anhydrous THF was made by a procedure involv-
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[6] When substituted benzenes or arenes were used in the present
organocatalytic HAS reactions, mixtures of regioisomers of the
coupling products were usually formed. Currently, only the in-
tramolecular version proceeds selectively. See citation in the
Supporting Information.
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sumed to be because the reactivity of RA-bearing zinc species
in the current system is much lower than that using the combi-
nation of potassium tert-butoxide and N-based catalysts. Work
to clarify the reasons and details of this difference is ongoing.
[17] ICP-MS was performed to analyze 1e, 2a, and 4a as representa-
tive coupling partners. As a result, Fe (0.2–0.6 ppm), Ni (2.9–
15 ppb), and Cu (3.8–70 ppb) were detected. Other metals in-
cluding Co, Ru, Rh, Pd, Ag, Ir, Pt, and Au were found to be
less than 1 ppb (within the detection limit).
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.
[8] For examples on cross- and homocoupling of organozinc com-
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Received: September 14, 2013
Published Online: November 5, 2013
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Eur. J. Org. Chem. 2013, 7891–7894