Nickel-Catalyzed Cross-Electrophile Coupling between Benzyl Alcohols and Aryl Halides Assisted by Titanium Co-reductant

Article abstract of DOI:10.1021/acs.orglett.8b03367

A nickel-catalyzed cross-electrophile coupling reaction between benzyl alcohols and aryl halides has been developed using a homolytic C-O bond cleavage protocol that has recently been established. The treatment of a benzyl alcohol and aryl halide with a nickel catalyst and low-valent titanium reagent generated from TiCl₄(lutidine) (lutidine = 2,6-lutidine) and manganese powder afforded the cross-coupled product in high yield. A mechanistic study indicated the intermediacy of the benzyl radicals that originate from the benzyl alcohols.

Full text of DOI:10.1021/acs.orglett.8b03367

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Nickel-Catalyzed Cross-Electrophile Coupling between Benzyl
Alcohols and Aryl Halides Assisted by Titanium Co-reductant
Takuya Suga* and Yutaka Ukaji*
Division of Material Chemistry, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa,
Ishikawa 920-1192, Japan
S
* Supporting Information
ABSTRACT: A nickel-catalyzed cross-electrophile coupling reaction between
benzyl alcohols and aryl halides has been developed using a homolytic C−O bond
cleavage protocol that has recently been established. The treatment of a benzyl
alcohol and aryl halide with a nickel catalyst and low-valent titanium reagent
generated from TiCl4(lutidine) (lutidine = 2,6-lutidine) and manganese powder
afforded the cross-coupled product in high yield. A mechanistic study indicated the
intermediacy of the benzyl radicals that originate from the benzyl alcohols.
Scheme 1. Background of This Study
lcohols, although ubiquitous, have found limited direct
Ause as partners in transition-metal-catalyzed reactions,
except in processes such as allylic alcohol activation1 and
hydrogen-autotransfer catalysis.2 The development of an
alternative method that could replace esters, halides, or
carbonyl compounds with their precursor alcohols in catalytic
C−C bond-forming reactions would be a desirable advance-
ment and could exponentially extend the use of alcohols. Very
recently, we have discovered a concise protocol for generating
benzyl radicals in one step from benzyl alcohols by using an
inexpensive low-valent titanium reagent; this reaction was
successfully applied to radical conjugate additions (Scheme 1,
eq 1).3 Encouraged by this discovery, we proposed that our
protocol could offer an unexploited radical route toward
transition-metal-catalyzed alcohol transformations.4−7 In this
report, we describe the nickel-catalyzed radical cross-electro-
phile coupling reaction4,7 between alcohols and aryl halides
(Scheme 1, eq 2). Although uncommon in the literature, low-
valent titanium reagents have been used for incorporating
carbon radicals into transition-metal catalysis. Cuerva has
discovered that low-valent titanium reagents can react with
alkylnickel complexes to generate carbon radicals (Scheme 1,
eq 3).8 Weix has introduced the low-valent titanium-mediated
reduction of epoxides into the nickel-catalyzed radical cross-
electrophile coupling (Scheme 1, eq 4).9 Similarly, Rahaim has
merged the reduction of benzonitrile and the cross-electrophile
coupling very recently (Scheme 1, eq 5).10 In this context, our
present work newly unlocks alcohols for such titanium/nickel
cooperative reactions.
less suitable. We expected that the broad alcohol scope of our
radical generation protocol would overcome this limitation.3
We found that the desired cross-coupling took place when a
nickel catalyst and aryl halide were introduced into our typical
conditions3 for homolytic C−OH bond cleavage (Table 1).
Only two previous diarylmethane syntheses via cross-
coupling reactions using benzyl alcohols have been reported.11
Shi has recently described a hydroxy-Kumada−Tamao−Corriu
coupling12 and hydroxy-Suzuki−Miyaura coupling (Scheme 1,
eq 6).13 These reactions exhibited excellent performance when
the substrates were benzyl alcohols that have extended π-
conjugation systems at the arene moieties (e.g., 2-naphthale-
nemethanol). However, monocyclic alcohols were likely to be
Received: October 22, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03367
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Letter
a
yield (Table 1, entry 16). The results of the further ligand
screening are summarized in Table S3.
Table 1. Optimization of Reaction Conditions
The range of tolerated benzyl alcohols 1 was investigated
using iodobenzene 2a as a coupling partner and either 4a or 4b
as a catalyst (Table 2). Similar to the simplest benzyl alcohol
Table 2. Scope of Benzyl Alcohols
b
3a
entry
deviations from standard conditions
(%)
1
2
none
w/o 4a
86
0
3
4
5
6
7
8
9
10
11
12
13
Me4Phen instead of 4a
NiCl2(PPh3)2 instead of 4a
NiBr2(dme) instead of 4a
w/o TiCl4(lutidine)
TiCl4(tmeda) instead of 5
Cp2TiCl2 instead of 5
benzene instead of THF
DMA instead of THF
w/o Mn
Zn instead of Mn
w/o added 2,6-lutidine
NiBr2(dme) (1 mol %) + Me4Phen instead of 1.8 mol % of
4a
0
9
25
0
42
62
>5
>5
0
28
78
77
c
14
c
15
NiBr2(dme) (1 mol %) + (MeO)2Phen instead of 1.8 mol %
of 4a
NiCl2((MeO)2Phen)·2H2O 4b (1.8 mol %) instead of 1.8
mol % 4a
81
d
16
88
a
Abbreviations: lutidine = 2,6-lutidine; Me4Phen = 3,4,7,8-tetrame-
thylphenanthroline; (MeO)2Phen = 4,7-dimethoxyphenanthroline;
tmeda = N,N,N′,N′-tetramethylethylenediamine; dme = 1,2-dime-
b
c
thoxyethane. 1H NMR yield unless otherwise noted. Catalyst was
prepared by premixing 1 mol % NiBr2(dme) and 1.2 mol % ligand in
d
THF. Isolated yield.
a
b
Isolated yield. The catalyst used is shown parenthetically. 1.0 mmol
For example, the treatment of benzyl alcohol 1a and 1.2 equiv
of iodobenzene 2a with 1.8 mol % of NiCl2(Me4Phen)·2H2O
4a, TiCl4(lutidine)14 5 (lutidine = 2,6-lutidine), manganese
powder, and 2,6-lutidine in THF at reflux temperature afforded
the cross-coupling product 3a in 86% yield (Table 1, entry 1).
To prove the necessity of each component, several control
experiments were conducted. No coupling product was
observed in the absence of the nickel catalyst (Table 1, entries
2 and 3). The advantage of the phenanthroline ligand was
obvious, but other ligands worked to some extent (Table 1,
entries 4 and 5). Without the titanium coreductant 5, again, no
coupling reaction took place (Table 1, entry 6). The reaction
using TiCl4(tmeda) and Cp2TiCl2 also afforded 3a, albeit with
decreased yields (Table 1, entries 7 and 8). The reaction in
benzene or N,N-dimethylacetamide only resulted in the
recovery of 1a (Table 1, entries 9 and 10). A reductant was
indispensable for the reaction (Table 1, entry 11). The use of
zinc instead of manganese decreased the yield of 3a (Table 1,
entry 12). The effect of the added 2,6-lutidine was not
apparent for 1a and 2a, but an obvious positive effect was
observed for several other substrates (Table 1, entry 13) (see
also Table S2). The yield did not drop significantly, even with
1 mol % of nickel catalysts prepared from NiBr2(dme) and
ligands. Me4Phen (Table 1, entry 14) and (MeO)2Phen (Table
1, entry 15) exhibited the best performance of all of the ligands
that we tested. Isolated NiCl2((MeO)2Phen)·2H2O 4b was as
reactive as 4a, giving the coupling product in 88% isolated
scale.
1a, polycyclic 2-naphthalenemethanol 1b afforded the coupling
product in high yield. An alkyl substituent at the para- or ortho-
position did not affect the yield (1c and 1d). Various
functional groups were tolerant of the reaction conditions. 4-
Fluoro- and 4-chlorobenzyl alcohol were suitable (1e and 1f).
Electron-deficient benzyl alcohols such as 4-(trifluoromethyl),
4-(methoxycarbonyl), and 4-cyanobenzyl alcohol afforded the
desired products in good to high yields (1g−i). Trifluor-
omethanesulfonate 1j retained its functionality through the
reaction. An electron-donating methoxy group did not
interfere in the reaction significantly (1k). Heteroaromatic 2-
thiophenemethanol 1l also underwent the coupling reaction
efficiently. Unfortunately, in sharp contrast to our previous
radical conjugate addition reaction,3 sterically demanding
alcohols 1m and 1n were not suitable.
The scope of the aryl halides is provided in Table 3. In cases
of technical difficulty during isolation, NMR yields are also
given. The reaction accepted many representative aryl iodides
other than iodobenzene (2a). Both 4- and 2-methyliodoben-
zene 2b and 2c afforded coupling products in good yields. 4-
Fluoro- and 4-chloroiodobenzene 2d and 2e were also good
substrates. Aryl iodides bearing either electron-withdrawing (4-
trifluoromethyl, 4-methoxycarbonyl, and 4-cyano) or electron-
donating (4-methoxy and 4-dimethylamino) groups underwent
B
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Letter
nickel catalyst 4b using 4-tert-butylbenzyl alcohol 1c (Figure
1). In both cases, the reactions began after 1−2 h induction
Table 3. Scope of Aryl Halides
Figure 1. Time-course dependence of alcohol consumption. The
reaction conditions were as follows: 1c (0.4 mmol), Mn (2.0 equiv),
and 5 (1.1 equiv) in THF (2 mL) at 70 °C (oil bath temperature).
For the solid line, 2a (1.2 equiv) and 4b (1.8 mol %) were added. The
reactions were carried out in separate batches for each point. The
1
yields were estimated by H NMR. The detailed data are given in
Figure S2.
a
b
c
Isolated yield. 1H NMR yield before isolation. Considerable
amount of 1,2-diphenylethane was obtained (23% NMR yield).
d
Amount of aryl halide.
periods,15 followed by the gradual consumption of starting
material 1c at similar rates. Compound 1c was converted to a
mixture of the corresponding dimer of the benzyl radical and
the deoxygenated product in the absence of 4b and
iodobenzene 2a (hashed line). Meanwhile, 3c was nearly the
sole product obtained in the presence of 4b and 2a (solid line).
We also found that an increased catalyst loading did not
accelerate the reaction (Scheme 3). For example, reactions
the desired reaction, although the presence of cyano and
dimethylamino groups decreased the yields (2f−j). Aryl
bromides were also suitable substrates. Higher loadings (3
equiv) of the bromides were necessary to obtain satisfactory
yields for bromobenzene and 4-bromoanisole 2k and 2l, while
methyl 4-bromobenzoate 2m afforded the product quantita-
tively even with 1.2 equiv. To further ensure the utility of this
reaction, we examined all combinations of electron-deficient/
electron-rich substrates by employing 4-methoxy/methoxycar-
bonyl alcohols/iodobenzenes (Scheme 2). Fortunately, all
combinations afforded the coupling products in good to high
yields, regardless of the electronic natures of the substrates
(63−89% yields).
Scheme 3. Effect of Catalyst Loading
We conducted several mechanistic studies to rule out the
possible two-electron oxidative addition of the C−O[Ti] bond
to Ni0. First, the time-course dependence of alcohol
consumption was compared between reactions with or without
Scheme 2. Cross Couplings between Both Functionalized
Benzyl Alcohols and Iodobenzenes
with either 1.8 or 9 mol % catalyst loadings afforded the
coupling product in ca. 40% yield after 4 h. These results
clearly indicate that the reaction rate is dependent only on the
self-decomposition of the benzyl titanate intermediate
(ArCH2O[Ti]) to generate the benzyl radical, and the Ni
catalyst does not participate in the C−O bond-cleavage step.
The proposed reaction mechanism is depicted in Scheme 4.5
Ni0 A reacts with iodobenzene to generate arylnickel B,
followed by the one-electron oxidative addition of the benzyl
radical to give C. Reductive elimination of the product
furnishes D, and D is further reduced to A to close the catalytic
cycle. The benzyl radical is supplied from the outside of the
C
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Synthesis through Borrowing Hydrogen Catalysis. Chem. Rev. 2018,
118, 1410−1459.
Scheme 4. Proposed Reaction Mechanism
(3) Suga, T.; Shimazu, S.; Ukaji, Y. Low-Valent Titanium-Mediated
Radical Conjugate Addition Using Benzyl Alcohols as Benzyl Radical
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̈
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catalytic cycle by low-valent titanium-mediated homolytic C−
O bond cleavage.16
In summary, we have established a cross-electrophile
coupling reaction between benzyl alcohols and aryl halides
through titanium-mediated homolytic C−O bond cleavage.
This reaction has broad scope for both coupling fragments, and
no large excesses of substrates are required, except in the cases
of some aryl bromides. Mechanistic studies indicated that the
reaction proceeds via a benzyl radical, as we expected. This
work provides a new use for alcohols in transition-metal
catalysis.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03367.
■
S
Experimental details, analytical data for new compounds,
and additional experimental results (PDF)
1H, 13C, and 19F NMR spectral data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: suga-t@se.kanazawa-u.ac.jp.
*E-mail: ukaji@staff.kanazawa-u.ac.jp.
ORCID
Takuya Suga: 0000-0002-7527-9611
Yutaka Ukaji: 0000-0003-3185-3113
Notes
(7) (a) Amatore, M.; Gosmini, C. Direct Method for Carbon-
Carbon Bond Formation: The Functional Group Tolerant Cobalt-
Catalyzed Alkylation of Aryl Halides. Chem. - Eur. J. 2010, 16, 5848−
5852. (b) Everson, D. A.; Shrestha, R.; Weix, D. J. Nickel-Catalyzed
Reductive Cross-Coupling of Aryl Halides with Alkyl Halides. J. Am.
Chem. Soc. 2010, 132, 920−921. (c) Erickson, L. W.; Lucas, E. L.;
Tollefson, E. J.; Jarvo, E. R. Nickel-Catalyzed Cross-Electrophile
Coupling of Alkyl Fluorides: Stereospecific Synthesis of Vinyl-
cyclopropanes. J. Am. Chem. Soc. 2016, 138, 14006−14011.
(d) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A. H.;
Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-
Coupling To Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017, 139,
5684−5687. (e) Woods, B. P.; Orlandi, M.; Huang, C.-Y.; Sigman, M.
S.; Doyle, A. G. Nickel-Catalyzed Enantioselective Reductive Cross-
Coupling of Styrenyl Aziridines. J. Am. Chem. Soc. 2017, 139, 5688−
5691. (f) Chen, H.; Jia, X.; Yu, Y.; Qian, Q.; Gong, H. Nickel-
Catalyzed Reductive Allylation of Tertiary Alkyl Halides with Allylic
Carbonates. Angew. Chem., Int. Ed. 2017, 56, 13103−13106. See also
ref 5c.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Mitsui Chemicals Award
in Synthetic Organic Chemistry, Japan, a UBE Industries
Foundation Award, and the Kanazawa University SAKIGAKE
project.
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E
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