Nickel catalyzed deoxygenative cross-coupling of benzyl alcohols with aryl-bromides

Article abstract of DOI:10.1016/j.tetlet.2020.151729

A nickel-catalyzed cross-electrophile coupling of benzyl alcohols with aromatic bromides has been developed. This deoxygenative cross-coupling occurs under mild reaction conditions at ambient temperature affording diarylmethanes, or 1,3-diarylpropenes from benzyl allyl alcohols. The system demonstrated good chemoselectivity tolerating an assortment of reactive functional groups.

Full text of DOI:10.1016/j.tetlet.2020.151729

Journal Pre-proofs
Nickel catalyzed deoxygenative cross-coupling of benzyl alcohols with aryl-
bromides
Vinoth Kumar Chenniappan, Devin Peck, Ronald J. Rahaim
PII:
S0040-4039(20)30152-0
DOI:
https://doi.org/10.1016/j.tetlet.2020.151729
TETL 151729
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
2 January 2020
4 February 2020
10 February 2020
Please cite this article as: Kumar Chenniappan, V., Peck, D., Rahaim, R.J., Nickel catalyzed deoxygenative cross-
coupling of benzyl alcohols with aryl-bromides, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.151729
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Nickel catalyzed deoxygenative cross-
coupling of benzyl alcohols with aryl-
bromides
Leave this area blank for abstract info.
Vinoth Kumar Chenniappan, Devin Peck, and Ronald J. Rahaim†*
HO
OH
5 mol% Ni(phen)Cl2
2.5 equiv TMS-Cl
2 equiv Mn
5 mol% Ni(phen)Cl2
2.5 equiv TMS-Cl
2 equiv Mn
Br
R1
R2
R1
R2
+
R2
R1
R1
+
DMA, r.t., 12 h
DMA, r.t., 12 h

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Nickel catalyzed deoxygenative cross-coupling of benzyl alcohols with aryl-bromides
Vinoth Kumar Chenniappan, Devin Peck, Ronald J. Rahaim*
a Department of Chemistry, Oklahoma State University, 107 Physical Sciences 1, Stillwater, Oklahoma 74078, United States.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A nickel-catalyzed cross-electrophile coupling of benzyl alcohols with aromatic bromides has
been developed. This deoxygenative cross-coupling occurs under mild reaction conditions at
ambient temperature affording diarylmethanes, or 1,3-diarylpropenes from benzyl allyl alcohols.
The system demonstrated good chemoselectivity tolerating an assortment of reactive functional
groups.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
nickel cross-coupling
cross-electrophile coupling
alcohol
diarylmethane
Keyword_5
Alcohols are a ubiquitous functional group that is a versatile
handle in bond forming reactions. They are readily available, can
be prepared in chiral nonracemic form, and are typically bench
stable. The ability to directly utilize alcohols in cross-coupling
reactions is highly desirable for this would greatly expand the
pool of available coupling partners. Several challenges face this
approach, namely overcoming the strong C-O bond strength, the
hydroxyl group being a poor leaving group, and potential
undesirable pathways being competitive such as ether formation
or oxidation of the alcohol through β-hydride elimination. To
circumvent these issues the alcohol is typically derivatized to a
carbonate1, carbamate2, ester3, ether4, or sulfonate5 for application
in cross-coupling or cross-electrophile6 reactions. While progress
on the cross-coupling of derivatized alcohols has occurred, the
direct coupling of alcohols is far less developed. Only a few
examples exist where benzyl alcohols have been coupled with
boron7 and Grignard reagents8, and a single example for a cross-
electrophile coupling with aryl iodides.9
absence of titanium (Table 1, entry 2). Based on this result and
Suga and Ukaji’s overlapping study we choose to determine the
generality of this nickel catalyzed deoxygenative cross-coupling.
Initial optimization studies focused on coupling of 4-
methoxybenzyl alcohol with 4-bromotoluene while using
titanocene dichloride as a co-catalyst (entry 1). Control reactions
established, for this substrate combination, that the titanium
catalyst was not needed, but the chlorotrimethylsilane (TMS-Cl)
additive to turn over the titanium catalyst was essential. No
coupling occurred in the absence of TMS-Cl (entry 3).
Examination of the TMS-Cl concentration showed as little as 0.2
equivalents could be used to promote product formation (entry
4). Increasing the concentration to 1.5 equivalents (entry 5)
dramatically improved the yield, but the maximal yield was
obtained with 2.5 equivalents (entry 6). Standard screening of
solvents, nickel salts, ligands, and metal reductants was
performed, where it was found that two nickel catalysts
efficiently promoted the coupling each in a separate solvent,
Ni(phen)Cl2 in DMA and Ni(di-OMe-bpy)Cl2 in DMF (entry 6).
For further studies, we opted to use the precomplexed
Ni(phen)Cl2 for consistency, even though NiCl2•glyme plus
phenanthroline (entry 5) afforded similar results, and because
phenanthroline is more cost effective than 4,4’-dimethoxy-2,2’-
bipyridine. Mono and bidentate phosphine ligands, along with
carbene ligands were ineffective. It was found that a slight excess
of 4-methoxybenzyl alcohol to 4-bromotoluene produced the
highest yield versus a 1 to 1 ratio or a slight excess of the aryl-
bromide (entry 10). This is in part do to with electron neutral and
rich aryl bromides homocoupling of the 4-methoxybenzyl
alcohol occurred in the background to a minor extent.
Recently our group developed
a dual catalytic cross-
electrophile coupling of nitriles in which titanium was used to
generate a putative imidoyl radical.10 As a continuation of
developing dual catalytic methods for the cross-coupling of in
situ generated carbon radicals, we became interested in extending
the Ni/Ti system to alcohols. Stoichiometric amounts of
titanium(III) reagents have been shown to promote alcohol
deoxygenation through formation of a carbon radical.11 It was
speculated that a Ni/Ti catalytic system could facilitate the
coupling of alcohols with aryl halides. While in the process of
developing this dual catalytic coupling, Suga and Ukaji reported
a nickel-catalyzed cross-electrophile coupling of benzyl alcohols
and aryl iodides that is promoted by a stoichiometric low-valent
titanium reagent through homolytic C-O bond cleavage.9 While
optimizing our Ni/Ti catalyzed cross-coupling of benzyl alcohols
we found in control reactions that the coupling occurred in the
To establish the scope of the coupling reaction under the
optimized conditions we first varied the aryl bromide component
(Table 2, 1-17). Both electron donating and withdrawing groups
were tolerated in the meta and para positions, whereas ortho

2
Tetrahedron Letters
substituted aryl bromides would not couple but 1-
arylprop-2-en-1-ol affording the linear product as major. The
stereoselectivity of the reaction was also high favoring formation
of the E-isomer.
bromonaphthalene (2) afforded the desired product. The system
demonstrated good chemoselectivity with substituted aryl
bromides tolerating halogens (9-10), silyl ethers (5), esters (7 &
13), amides (6), sulfonamides (17), nitriles (12), ketones (14),
furans (15), thiophenes (16), and indoles (17). Additionally, a
chloride12 (9), triflate (8), and pivalate ester (7) were also
tolerated leaving a handle for iterative cross-couplings. For aryl
bromides containing electron withdrawing groups, homocoupling
became competitive. To address this the equivalences of the
coupling partners were flipped to using an excess (2 equivalence)
of the aryl bromide. Variation of the benzyl alcohol was
conducted next, where movement of the methoxy group (18-20)
from the para position resulted in lower yields with meta (19)
being the lowest. The methoxy group could be replaced with a
dimethylamine (21) but was lower yielding potentially due to the
amine reacting with the TMS-Cl. Electron deficient benzyl
alcohols (22, EWG = F, CF3, and CO2Me) were found to be
completely unreactive.
Table 2. Substrate scope of nickel-catalyzed benzyl alcohol
cross-couplinga,b
MeO
MeO
Me
MeO
1, 99%
2, 76%
OMe
OMe
MeO
3c, 96%
5, 80%
7, 93%
9, 72%
11d, 44%
4c, 80%
6, 56%
MeO
MeO
OTBS
OPiv
MeO
MeO
NHAc
OTf
F
Table 1. Optimization and control reactions
OH
5 mol% Ni(phen)Cl2
2.5 equiv TMS-Cl
2 equiv Mn
Br
8, 73%
+
DMA, r.t., 12 h
MeO
Me
OMe
Me
MeO
MeO
Cl
MeO
1.5 equiv 1.0 equiv
10, 75%
12d, 61%
Entry
Deviation from above
+ 10 mol% Cp2TiCl2
none
%Yielda
1
2
97
96
0b
CF3
MeO
MeO
CN
3
No TMS-Cl
4
0.2 equiv TMS-Cl
1.5 equiv TMS-Cl
NiCl2●dme + phen
25
82
99
95
42
62
42
MeO
CO2Me
5
O
13d, 57%
15d, 63%
14d, 60%
16d, 67%
6c
7c
8
NiCl2●dme + di-OMe-bpy in DMF
1 equiv Mn
O
S
MeO
MeO
9
Zn instead of Mn
OMe
10
1 equiv PMB-OH & 1.5 equiv 4-MeAr-Br
a) Isolated yield after flash chromatography, run on a 0.5 mmol scale
b) %conversion by GC/MS
N
MeO
MeO
Ts
Me
17, 89%
18, 41%
c) 10 mol% nickel source + 10 mol% ligand
MeO
MeO
Based on the trend with the methoxy group (meta < ortho <
para), it was questioned if further activation of the C-O bond
would enable the coupling of electron deficient benzyl alcohols.
To accomplish this, it was reasoned that modifying the alcohol to
a 1-arylprop-2-en-1-ol, a secondary benzyl allyl alcohol, would
weaken the C-O bond facilitating coupling of benzyl alcohols
that would otherwise be unreactive. The premise for this
modification was further supported by a recent dual Ni/Zr
catalytic system that directly cross-coupled allylic alcohols.13 It
had already been determined that simple benzyl alcohol was not a
competent coupling partner with less than 10% conversion to
product (Table 4, entry 3). As such, to test the feasibility of this
activation we initially reacted 1-phenylprop-2-en-1-ol to the
conditions, where this activated alcohol was fully consumed
affording 23 in 65% (Table 3). This modification increased the
yield for ortho substituted substrates (Table 2, 18 vs Table 3, 24),
and enabled the coupling of benzyl alcohols containing electron
withdrawing groups (25-27). The reaction was regioselective
favoring bond formation at the least substituted carbon of the 1-
Me
Me
Me
Me
19, 15%
20, 84%
22, 0%
EWG
Me2N
21d, 31%
a) Conditions: benzyl alcohol (0.75 mmol), aryl bromide (0.5 mmol),
Ni(phen)Cl2 (0.025 mmol), TMS-Cl (1.25 mmol), Mn (1.0 mmol) in 2 mL of
DMA, at r.t. for 12 hours.
b) isolated yields after flash chromatography
c) isolated as an inseparable mixture with 1,2-bis(4-methoxyphenyl)ethane
d) 0.5 mmol benzyl alcohol to 1.0 mmol aryl bromides was used.
e) yield determined by GC/MS with internal standard
Control reactions were run to gain further insight into the
mechanism of this coupling. It has been established that nickel
can undergo oxidative addition into benzyl ethers.4 As TMS-Cl is

3
a) Conditions: 1-arylprop-2-en-1-ol (0.5 mmol), aryl bromide (0.75 mmol),
being used as an additive, we examined if the reaction was
occurring through a silyl ether. Subjection of the silyl protected
PMB-OH to the reaction conditions with and without added
chlorotrimethylsilane afforded none of the product (Scheme 3).
Additionally, only trace amounts of the silyl ether were seen by
GC/MS when monitoring the couplings. It is established that
chlorotrimethylsilane can convert benzyl alcohols to benzyl
chlorides, as such, we investigated the potential of TMS-Cl to
convert the alcohol to a chloride under our reaction conditions.14
We saw full conversion of 4-methoxybenzyl alcohol, 4-
methylbenzyl alcohol, and benzyl alcohol to the benzyl chlorides
with 1.5 equivalents of TMS-Cl in DMA (Scheme 2). To further
examine the possibility that the coupling was occurring through
an in situ generated benzyl chloride we subjected a variety of
benzyl chlorides to the reaction conditions (Table 3). A similar
trend was seen where electron rich benzyl chlorides coupled
(entry 1) but electron deficient ones were unreactive (entries 4 &
5). The discrepancy occurs in entries 2 and 3, where 4-
methylbenzyl chloride and benzyl chloride efficiently coupled
but there alcohol counter parts afforded less than 10% of the
product. Additionally, when the coupling of these alcohols was
monitored by GC/MS the resultant benzyl chlorides were not
detected and the alcohols were isolated back (>80%). These
results indicate that, in the presence of the nickel catalyst and
manganese metal, the TMS-Cl is not converting the alcohol to a
chloride. Nickel catalyzed cross-electrophile couplings have been
shown to occur through radical intermediates, as such the
coupling was performed in the presence of 1 equivalent of
TEMPO (Table 5, entry 1) which inhibited the reaction indicating
the possibility of radical intermediates. It has been demonstrated
that zinc metal in DMA can convert benzyl chlorides to benzyl
radicals.15 To examine if this was occurring the coupling was
setup in the absence of the nickel catalyst, with and without 1
equivalent of TEMPO (Table 5, entries 2 & 3). As expected, in
both cases none of the product was formed. Examination of these
reaction mixtures by GC/MS did not show the presence of any of
the anticipated radical coupling byproducts. More detailed
mechanistic studies are needed to gain a better picture.
Ni(phen)Cl2 (0.025 mmol), TMS-Cl (1.25 mmol), Mn (1.0 mmol) in 2 mL of
DMA, at r.t. for 12 hours.
b) isolated yields after flash chromatography.
c) E:Z = 88:12, linear:branched = >95:5
d) E:Z = >95:5, linear:branched = >95:5
e) E:Z = >95:5, linear:branched = 87:13
OR
5 mol% Ni(phen)Cl2
X equiv TMS-Cl
Br
2 equiv Mn
+
DMA, r.t., 12 h
MeO
Me
OMe
Me
1.5 equiv
R = H,
2.5 equiv TMS-Cl, 99%
R = SiMe3, 1.5 equiv TMS-Cl, 0%
R = SiMe3, 0 equiv TMS-Cl, 0%
Scheme 1. Control reactions to probe if a silyl ether is the
active cross-coupling partner
2.5 equiv TMS-Cl
OH
Cl
DMA, r.t., 12 h
R
R
R = OMe, 95%
R = Me, 95%
R = H, 98%
Scheme 2. Examination of the reaction conditions to generate
a benzyl chloride from the alcohol
Table 4. Comparison of benzyl alcohols versus benzyl
chlorides a,b
X
5 mol% Ni(phen)Cl2
2.5 equiv TMS-Cl
2 equiv Mn
Br
+
DMA, r.t., 12 h
R
Me
R
Me
1, 28-31
1.5 equiv
Entry
R
X = OH
X = Cl c
Product ID
Table 3. Cross-coupling benzyl allyl alcohols with aryl
bromidesa,b
1
2
3
4
5
OMe
Me
96%
<10%
<10%
0%
95%
93%d
94%
0%
1
Entry
Benzylic Alcohol S.M.
Product
23c, 65%
24d, 70%
25d, 58%
26d, 47%
28
29
30
31
OH
H
1
CO2Me
CF3
CF3
0%
0%
a) 0.5 mmol scale
OMe
OMe OH
b) isolated yields after flash chromatography
c) No TMS-Cl was used
2
3
4
Me
Me
d) isolated as an inseparable mixture with 1,2-di-p-tolylethane
F
F
OH
Table 5. Radical scavenging experiments with TEMPO
OH
x mol% Ni(phen)Cl2
2.5 equiv TMS-Cl
2 equiv Mn
Br
+
x equiv TEMPO
DMA, r.t., 12 h
MeO
Me
OH
OMe
1.5 equiv
Me
Cl
Me
x mol%
Cl
Entry
x equiv TEMPO
%Yield
Ni(phen)Cl2
1
2
3
5
0
0
1
1
0
<4%
CF3
CF3 OH
0
0
5
Me
27e, 47%

4
Tetrahedron Letters
In conclusion, in the process of developing a dual catalytic
Ni/Ti cross-coupling of benzyl alcohols is was found that
chlorotrimethylsilane promotes the nickel catalyzed
extracted with ethyl acetate twice. The combined organic layers
were washed with water then brine, dried over magnesium
sulfate, filtered, and concentrated down. The crude material was
purified by flash chromatography.
deoxygenative cross-coupling of methoxy substituted benzyl
alcohols at room temperature. The system tolerated a variety of
functionalized aryl bromides, affording diarylmethanes in 44% to
99%. Expansion of the alcohol coupling partner was achieved by
modifying the alcohol to a secondary benzyl allyl alcohol
affording 1,3-diarylpropenes with good selectivity.
Note – For compound 1, the coupling was setup outside of the
glovebox, with all reagents weighed out on a bench top and the
reaction placed under an argon atmosphere through three
vacuum-purge cycles. This afforded the desired product in only a
slight diminished yield, 91% vs. 99%
General Procedure
In an argon filled glovebox an oven dried 10-20 mL
microwave vial was charged with Ni(phen)Cl2 (0.025 mmol,
0.008 g) and -325 mesh manganese powder (1 mmol, 0.055 g).
The vial was sealed with a septa crimp cap and removed from the
glove box. To the vial was sequentially injected aryl bromide (0.5
mmol), benzyl alcohol (0.75 mmol), and TMS-Cl (1.25 mmol,
0.159 mL).16 The mixture was stirred for 5 minutes followed by
the injection of degassed DMA (2 mL) and stirring the reaction
for 12 hours at room temperature. The reaction mixture was
poured into a separatory funnel containing water, which was
Acknowledgments
We thank Oklahoma State University and R.J.R. for supporting this
project. D.P. thanks the Niblack Research Scholars Program for
support. Mass spectrometry analyses were performed in the
Genomics and Proteomics Center at Oklahoma State University,
using resources supported by the NSF MRI and EPSCoR programs
(award DBI/0722494).
1.
1) The direct nickel catalyzed cross-coupling of
benzyl alcohols
2) Cross-electrophile coupling of aryl bromides
with benzyl alcohols under mild conditions
3) Synthesis of diarylmethanes and 1,3-
Supplementary Material
1H and 13C NMR spectra for all products (PDF).
References and notes
diarylpropenes from alcohols
2.
Graphical Abstract
Declaration of interests
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:

5
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13
Jia, X. -G.; Guo, P.; Duan, J.; Shu, X. -Z. Dual nickel and Lewis
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12 While aryl chlorides were unreactive at room temperate, attempts to
couple them at 50 °C only resulted in homocoupling.