Chemoselective, Scalable Nickel-Electrocatalytic O-Arylation of Alcohols

Article abstract of DOI:10.1002/anie.202107820

The formation of aryl-alkyl ether bonds through cross coupling of alcohols with aryl halides represents a useful strategic departure from classical S_N2 methods. Numerous tactics relying on Pd-, Cu-, and Ni-based catalytic systems have emerged over the past several years. Herein we disclose a Ni-catalyzed electrochemically driven protocol to achieve this useful transformation with a broad substrate scope in an operationally simple way. This electrochemical method does not require strong base, exogenous expensive transition metal catalysts (e.g., Ir, Ru), and can easily be scaled up in either a batch or flow setting. Interestingly, e-etherification exhibits an enhanced substrate scope over the mechanistically related photochemical variant as it tolerates tertiary amine functional groups in the alcohol nucleophile.

Full text of DOI:10.1002/anie.202107820

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Chemoselective, Scalable Nickel-Electrocatalytic O-Arylation of
Alcohols
Authors: Phil S. Baran, Hai-Jun Zhang, Longrui Chen, Martins S.
Oderinde, Jacob T. Edwards, and Yu Kawamata
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202107820
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10.1002/anie.202107820
Angewandte Chemie International Edition
COMMUNICATION
Chemoselective, Scalable Nickel-Electrocatalytic O-Arylation of
Alcohols
Hai-Jun Zhang,[a] Longrui Chen,[a] Martins S. Oderinde,[b] Jacob T. Edwards,[c] Yu Kawamata,[a] and
Phil S. Baran*[a]
[a]
Hai-Jun Zhang, Longrui Chen, Yu Kawamata, Phil S. Baran
Department of Chemistry
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
E-mail: pbaran@scripps.edu
[b]
[c]
Martins S. Oderinde
Department of Discovery Synthesis
Bristol Myers Squibb Research & Early Development
Princeton, NJ 08540, USA.
Jacob T. Edwards
Bristol Myers Squibb
Redwood City, CA 94063, USA.
Supporting information for this article is given via a link at the end of the document.
Abstract: The formation of aryl-alkyl ether bonds through cross
coupling of alcohols with aryl halides represents a useful strategic
departure from classical SN2 methods. Numerous tactics relying on
Pd-, Cu-, and Ni-based catalytic systems have emerged over the past
several years. Herein we disclose a Ni-catalyzed electrochemically
driven protocol to achieve this useful transformation with a broad
substrate scope in an operationally simple way. This electrochemical
method does not require strong base, exogenous expensive transition
metal catalysts (e.g. Ir, Ru), and can easily be scaled up in either a
batch or flow setting. Interestingly, e-etherification exhibits an
enhanced substrate scope over the mechanistically related
photochemical variant as it tolerates tertiary amine functional groups
in the alcohol nucleophile.
B[8h]) and Cu (conditions C[9n] and D[9o]) in combination with
recently described ligands struggled to forge the C-O bond.
Methods based on Ni such as conditions E[13] and photochemical
conditions F[11a] also failed to deliver 1 presumably due to their
SN2 vs coupling: coupling as modular approach for aryl alkyl ethers
HO
NH
Br
+
+
Cl
MeN
Br
2
3
4
SN2 twice (91%, 54%)
+
Miyaura borylation (44%)
Conventional disconnection
[SN2] [Coupling]
O
N
Aryl-alkyl ether bond construction is one of the most often-
employed transformations in the pharmaceutical industry.[1] Such
linkages are often forged using classical substitution chemistry
such as SN2 displacement represented by Williamson ether
synthesis[2] and Mitsunobu reaction[3] or nucleophilic aromatic
substitution.[4] The synthesis of BET inhibitor intermediate 1
(Figure 1) is emblematic of this approach wherein a phenol 4 is
alkylated with an alkyl halide 3, followed by the second alkylation
to attach the piperazine unit 2 and Miyaura borylation for installing
the requisite C-B bond.[5] Although the approach is quite
straightforward, step-count and overall yield are not satisfactory.
N
Bpin
Me
BET inhibitor intermediate 1
• Better availability of starting materials
• Broader functional group tolerance
Modular disconnection
[Coupling]
Br
OH
N
Commercially available
building blocks 5 and 6
+
MeN
Bpin
5
6
Screening for coupling of 5 and 6
H
N
The explosive success of transition-metal catalyzed N-arylation
A: [Pd]/RockPhos
B: [Pd]/L1
<5%
<5%
N.D.
N.D.
<5%
N.D.
50%
19%
Ph
Ph
[6]
methods
has inspired the invention of mild methods for an
N
N
O
2
L2
analogous union of alcohols and aryl halides [7] by using Pd,[8]
Cu,[9] and Ni[10-15] catalysis. This coupling strategy is an attractive
alternative to classic SN2-based retrosynthesis; the aryl halide
building blocks are often easier to access, and the conditions
employed can sometimes be more chemoselective. Continuing
with this case study, the coupling approach (Figure 1) requires
building blocks 5 and 6, which are both commercially available.
However, the key C-O bond formation was found to be
challenging even under the latest state-of-the-art conditions. For
example, catalytic reactions based on Pd (conditions A[8i] and
C: [Cu]/L2
Ph
Ph
PAd2
Me
N
O
D: [Cu]/L3
N
N
E: [Ni]/cat. Zn0, no light
F: [Ni]/[Ir]/blue LEDs
NH
L1
Me
L3
2
G: [Ni]/electricity (this work)
H: [Ni]/AC current
Figure 1. Comparison between SN2-based strategies and coupling approach in
the synthesis of BET inhibitor intermediate 1. Whereas the SN2 approach suffers
from low overall yield and known methods (A-F) for ether cross coupling fail, e-
etherification proceeds smoothly. The yields shown in conditions A-H are crude
1H-NMR yields.
1
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10.1002/anie.202107820
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COMMUNICATION
incompatibility with the tertiary amine motif, which is ubiquitous in
pharmaceutical molecules. This study reports the development of
a Ni-catalyzed electrochemical etherification (e-etherification) that
can succeed in this demanding context (conditions G) without
recourse to specialized experimental setups (e.g. electrolysis with
sinusoidal AC current,14 conditions H) or expensive metals and
ligands. This electrochemical method exhibits a broad substrate
scope, high chemoselectivity, and represents an economically
viable and sustainable means to conduct such etherification
reactions on scale.
arenes (23, 24) as well as heterocycles (27-33, 45, 46), and C-B
bond (38, 41-50) were found intact. Sensitive or polar (N-H
containing) motifs such as carbamates (18, 27, 31-33), Lewis-
basic heterocycles (34, 35, 40, 44), amides (25, 26) and ketals
(28, 37, 49) showed no complications under the reaction
conditions. Regarding the scope of alcohol coupling partner, both
primary and secondary alcohol were compatible whereas tertiary
alcohols were found to be inefficient. The efficient coupling of
nucleosides and polyfunctionalized fragments is also notable (36-
37). Taken together, this e-etherification method provides an easy
access to small molecules and building blocks for pharmaceutical
drug discovery efforts.
The development and optimization of the Ni-catalyzed aryl
halide etherification commenced with the lessons learned during
studies on the analogous e-amination reaction,[16] and employed
bromoarene 7 and cyclopentanol 8 to access ether 9 (Figure 2).
Prior detailed mechanistic and optimization studies for e-
amination pointed to the importance of the ligand/Ni ratio, the use
of DBU as a base, and nBu4NBr as the electrolyte. In the case of
etherification, those variables proved critical; however the
maximum yield obtained using those conditions was only 10%
yield. Remarkably, by simply changing the ligand from L5 to L7
and adding 3Å molecular sieves the yield improved to 62%.
Control experiments reinforced several important aspects of this
reaction. First, electricity is necessary for the reaction to proceed
(shutting off electrical current immediately halts the reaction).
Second, the Ni-catalyst is playing a crucial role for the product
formation under basic conditions as the omission of Ni or DBU
resulted in no ether formation. Third, replacement of electricity
with a chemical reductant (Zn powder) resulted in no product
formation. These results are consistent with chemical,[17-18]
photochemical,[11a,11c,19-21] and electrochemical[16b] mechanistic
studies, consistent with the Ni-catalytic cycle being driven in a
paired electrolysis fashion,[16,22] requiring both oxidation and
reduction. Although it was recently found that sinusoidal AC
current may improve yield in such Ni-catalyzed electrochemical
coupling,14 this method was not applicable in our case as the
optimal anode and cathode are made of different material.
Exclusion of air by using a simple Ar-balloon is sufficient to
efficiently perform this reaction, and no laborious procedures for
degassing (or a glovebox) are needed. As described below,
during scale-up a modified procedure can be used in flow that
does tolerate air. DMA and NMP were found to be ideal solvents
as they render reactions good solubility and have high
conductivity. Finally, the use of a Ni-L7 precatalyst, NiCl2(dtbbpy)3,
improved the operational simplicity of the reaction without any
reduction in yield (64%). This readily prepared, bench-stable, and
non-hygroscopic Ni-precatalyst (see SI for preparation) was
utilized for the remainder of these studies.
Effect of reaction parameters
NiBr2.glyme (10 mol %)
dtbbpy L7 (30 mol %)
CF3
DBU (2.0 equiv.)
nBu4NBr (0.2 M)
OH
CF3
DMAc (3 mL), 3Å MS
O
!
undivided cell
RVC(+)/Ni foam(-)
Ar, rt, 4 mA, 4.5 h
Br
1.0 equiv., 0.2 mmol
Ligand and precomplex
7
8
3.0 equiv.
9: 62%
Yield (%)
Yield (%)
Solvent
Phenanthroline instead of dtbbpy
Bpy instead of dtbbpy
CH3CN instead of DMAc
DMF instead of DMAc
NMP instead of DMAc
Control experiments
'&
$%
'&
$+
4,4’-(MeO)2bpy instead of dtbbpy
#&
$%
"#
"(
,-./(01234$56752/896:6;37:
Yield (%)
NiCl2(dtbbpy)3 as precatalyst
No electricity
'&
3.0 equiv. Zn instead of e–
Yield (%)
Base
'&
'&
'&
'&
(%
No NiBr2.glyme
K2CO3 instead of DBU
Et3N instead of DBU
'&
'&
No DBU
Under air
TMG instead of DBU
Electrolyte
'&
Yield (%)
No 3Å MS
LiBr instead of nBu4NBr
nBu4NPF6 instead of nBu4NBr
()
Conditions in ref [16b]
(e-amination 2.0)
*+
*)
R
R
R = H, bpy (L5)
R = MeO, 4,4’-(MeO)2bpy (L6)
R = tBu, dtbbpy (L7)
N
N
N
N
Phenanthroline (L4)
Figure 2. Effects of various reaction parameters. Yields determined by gas
chromatography.
Table 1 provides a snapshot of the broad scope of e-
etherification with 41 out of >80 examples shown (see SI for full
scope and limitations). The use of a relatively mild organic base
DBU and room temperature conditions enabled a range of
functional groups to be tolerated. For example, reductively labile
C-X bonds (X = Br, Cl, F) and fluoroethers (10-22, 39, 40, 41, 47
48), ester (49) and ketones (42, 50) were well tolerated. Even an
aromatic aldehyde (43) was compatible in this reaction. Of note,
only small amount of di-etherification product was observed when
1,4-dibromobenzene was used as the starting material due to
much lower reactivity of 16 to low-valent Ni species. In addition,
oxidatively labile groups such as 3º amines (26), electron-rich
2
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COMMUNICATION
Table 2 illustrates the synthesis of known ether products
wherein conventional strategies were used in prior routes and
also compares the e-etherification with known Cu, Pd, and Ir/Ni-
based methods. The room temperature conditions of e-
etherification avoids the use of highly basic metal alkoxides or
insoluble inorganic bases, does not require rigorous
deoxygenation procedures (simple air/argon exchange), and
deletes precious metal catalysts. With regards to the prior routes
Electrochemical O-arylation: practical C(sp2)–O bond construction with high FG tolerance
Ni(dtbbpy)3Cl2 (10 mol %)
DBU (2 equiv.), nBu4NBr (0.2 M)
Compatible functional groups
(Hetero)aryl-Br
(Hetero)aryl OR
+
R-OH
C-X (X = Br, Cl, F) , OCHF2, NBoc, heterocycles,
amide, 3o amine, silyl, ketal, alkene, alkyne,
polyene, ester, ketone, aldehyde, Bpin, perfluoro
3Å MS, DMAc, rt, Ar, 4 mA, 4.5-12 h
(+)RVC/(-)Ni foam, undivided cell
>80 examples
(1 equiv., 0.2 mmol)
(3 equiv.)
(See SI for full scope)
Scope of (Hetero)aryl-Br
Br
CF3
OCHF2
Cl
O
nHex
O
R1
R1 = R2 = Cl, 10: 79%
Cl
R2
R1 = Cl, R2 = H, 11: 56%
R1 = Cl, R2 = F, 12: 58%
R1 = H, R2 = CHF2, 13: 50%
R1 = H, R2 = OCF3, 14: 61%
R1 = OCF3, R2 = H, 15: 71%
O
O
F
F
O
nBu
OMe
O
O
NBoc
18: 60%
16: 55%
17: 72%
19: 73%
20: 61%
F
F
CF2H
nHex
OMe
SO2NHnBu
O
O
O
NHnBu
O
O
Me
Me
O
Me
Me
O
O
O
O
NMe2
nHex
nHex
Me
21: 78%
O
22: 54%
O
23: 63%
24: 32%
25: 65%
nHex
26: 48%a
O
nHex
O
O
S
O
N
N
O
Boc
O
Me
S
nHex
O
S
Me
N
Boc
S
N
Boc
Me
27: 68%
nHex
28: 57%
29: 86%
30: 60%
31: 29%
32: 30%
OMe
R
O
O
nC16H33
O
O
O
N
O
TBSO
O
nHex
TBSO
TBSO
N
Boc
O
O
TBSO
Me
Me
OTBS
OTBS
37: 49%
R = H, 34: 70%
R = Me, 35: 80%
33: 61%
36: 74%
Coupling with functionalized alcohols
Bpin
Cl
F
Me
Me
Bpin
Bpin
Bpin
Me
CF3
Me
CHO
O
O
N
O
O
O
O
O
O
( )5
Me
39: 57%
Cl
Me
OMe
38: 58%
40: 76%
Bpin
41: 53%
Bpin
42: 56%
Bpin
43: 61%
Bpin
Bpin
Bpin
Me Me
O
Me
H
Me
Me
O
O
O
X
O
O
N
O
CH2F
O
H
O
O
CF2CF2CF3
OtBu
H
CH2F
48: 46%
X = O, 45: 88%
X = S, 46: 72%
44: 69%
47: 57%
49: 62%
50: 36%
Table 1. Selected scope of aryl bromides and alcohols (See SI for the full scope). All yields are isolated yields. [a] Using 6 equiv. of alcohol.
3
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Comparison of the electrochemical O-arylation with other methods
Bpin
Bpin
O
Bpin
Electrochemical O-arylation
NHBoc
O
NHBoc
O
[Previous]: Previous synthesis
[Cu]a: CuI + Oxalic diamide
O
Me
Bn
Me
53
51
52
[Pd]b: (allylPdCl)2 + RockPhos
[Photocatalysis]c: (dtbbpy)NiCl2 + [Ir]
63%
59%
49%
[Previous] 11% (1 step)
[Previous] 21% (2 steps)
[Previous] 30% (4 steps)
[Cu] N.D., [Pd] 85%
[Cu] N.D., [Pd] 14%
[Cu] N.D., [Pd] 41%
Bpin
Bpin
O
O
O
Bpin
O
Br
OH
( )3
NBoc
O
O
O
O
54
55
58%
56
57
58
65%
72%
55%
82%
[Previous] 0.8% (7 steps) [Previous] 3.9% (5 steps) [Previous] 15% (1 step)
[Cu] 19%, [Pd] 85% [Cu] N.D., [Pd] 7% [Cu] 30%, [Pd] 40%
Bpin
[Previous] 21% (2 steps)
[Previous] 15% (1 step)
[Cu] N.D., [Pd] 51%
[Cu] 65%, [Pd] 42%
Me
Me
Bpin
NHBoc
Me
O
B
Me
O
B
OH
O
Cl
NHBoc
Me
Me
O
O
O
O
O
OH
O
O
59
80%
60
50%
61
50%
62
63
54%
59%
[Previous] 22% (2 steps) [Previous] 15% (2 steps)
[Previous] 29% (4 steps)
[Cu] N.D., [Pd] 15%
[Previous] 16% (2 steps)
[Cu] N.D., [Pd] N.D.
[Previous] 12% (2 steps)
[Cu] N.D., [Pd] N.D.
[Cu] N.D., [Pd] 35%
[Cu] N.D., [Pd] 39%
[Photocatalysis] 70%
[Photocatalysis] 71%
[Photocatalysis] 56%
O
Bpin
Bpin
SO2NHnBu
Bpin
Me
N
H
Me
N
Me
O
O
O
N
O
O
NMe2
Me
NMe2
64
65
66
67
26
Cl
N
59%
46%
48%
27%
48%
[Previous] 4.7% (3 steps)
[Cu] 13%, [Pd] 27%
[Previous] 10.3% (4 steps)
[Cu] N.D., [Pd] 52%
[Previous] 23.9% (2 steps)
[Cu] N.D., [Pd] 70%
[Previous] 4.6% (2 steps)
[Cu] N.D., [Pd] 42%
[Previous] N.A.
[Cu] N.D., [Pd] 95%
[Photocatalysis] 44%
[Photocatalysis] N.D.
[Photocatalysis] N.D.
[Photocatalysis] N.D.
[Photocatalysis] N.D.
Table 2. Improved access to various compounds by electrochemical O-arylation. Yields under other coupling conditions are also shown. See SI for the
experimental conditions for each compound. The yields of electrochemical O-arylation are isolated yields. [a] Ref. [9n], crude 1H-NMR yields. [b] Ref. [8i], crude
1H-NMR yields. [c] Ref. [11a], isolated yields.
to access such valuable intermediates, a strong reliance on SN2
and Mitsunobu chemistry along with Miyaura borylation leads to
lengthy and low yielding routes. In the case of oxetane-containing
structures such as 54 and 56, recourse to oxetane ring synthesis
after ether bond formation is required (See SI for full summary of
all past routes). Most notably, e-etherification succeeded in
delivering ether products even with substrates on which
analogous photochemical conditions did not work (65-67, 26),
demonstrating broader substrate scope that can be achieved by
the electrochemical means. The unique success of e-
etherification in such instances despite having mechanistic
similarities to the photochemical variant might be ascribed to the
more strongly oxidizing conditions that favor reoxidation of Ni(II)
to Ni(III) versus tertiary amine oxidation.
As depicted in Figure 3, the reaction conditions can be used for
batch preparation of 69, a valuable building block for drug
discovery using a commercial potentiostat from 2 mmol to 60
mmol. Most significantly, adaptation to flow carries several salient
advantages as exemplified for the decagram synthesis of ether
71. These include: (1) the use of simple inexpensive carbon felt
electrodes; (2) no precautions to remove air; and (3) no need for
exclusion of water using molecular sieves. As such, a 100 mmol
run on aryl bromide 70 can be completed in only 16 hours to
deliver 70% isolated yield of 71. Furthermore it is possible to
reduce the amount of the electrolyte to substoichiometric quantity
(0.75 equiv.) if needed (See Supporting Information for details).
In conclusion, an electrochemical method for the
etherification of aryl bromides has been developed that exhibits a
broad substrate scope tolerating numerous sensitive
functionalities. To the best of our knowledge, this work exhibits
the widest substrate scope among all the related methods
In addition to superior functional group tolerance to other
methods, another important advantage of the current method
stems from the ease with which scale-up can be accomplished.
4
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10.1002/anie.202107820
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COMMUNICATION
Reaction scalability: From 2 mmol – 100 mmol scale
O
N
O
O
Electrochemical
O-arylation
O
Boc
Electrochemical
O-arylation
N
N
N
SEM
N
SEM
Br
CF3
O
Br
O
Under air
70
71
Under air
68
69
Conditions: (S)-1-Boc-3-hydroxypyrrolidine (3.0 equiv.), Ni(dtbbpy)3Cl2 (10 mol %),
Conditions: 2,2,2-trifluroethanol (3.0 equiv.), Ni(dtbbpy)3Cl2 (10 mol %), DBU
DBU (2 equiv.), nBu4NBr (0.4 M), DMAc, rt, (+)C felt/(–)C felt, 4 V, 7 h
(2 equiv.), nBu4NBr (0.4 M), DMAc, rt, (+)C felt/(–)C felt, 6 V, 16 h
70% (20.2 g)
Continuous flow scaleup (100 mmol, 26.8 g)
Batch scaleup (60 mmol, 20.5 g)
61% (16.4 g)
ElectraSyn (2 mmol, 0.68 g)
65%
Figure 3. Electrochemical O-arylation performed on various scale from 2 mmol to 100 mmol. All yields are isolated yields.
[8]
Selected examples of Pd-catalyzed O-arylation of alcohols: a) G. Mann,
J. F. Hartwig, J. Am. Chem. Soc. 1996, 118, 13109 – 13110; b) M.
Palucki, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119, 3395
– 3396; c) G. Mann, J. F. Hartwig, J. Org. Chem. 1997, 62, 5413 – 5418;
d) K. E. Torraca, X. Huang, C. A. Parrish, S. L. Buchwald, J. Am. Chem.
Soc. 2001, 123, 10770 – 10771; e) A. V. Vorogushin, X. Huang, S. L.
Buchwald, J. Am. Chem. Soc. 2005, 127, 8146 – 8149; f) G. J. Withbroe,
R. A. Singer, J. E. Sieser, Org. Process Res. Dev. 2008, 12, 480-489; g)
E. J. Milton, J. A. Fuentes, M. L. Clarke, Org. Biomol. Chem. 2009, 7,
2645 – 2678; h) S. Gowrisankar, A. G. Sergeev, P. Anbarasan, A.
Spannenberg, H. Neumann, M. Beller, J. Am. Chem. Soc. 2010, 132,
11592 – 11598; i) X. Wu, B. P. Fors, S. L. Buchwald, Angew. Chem. Int.
Ed. 2011, 50, 9943 – 9947; Angew. Chem. 2011, 123, 10117 – 10121; j)
S. Gowrisankar, H. Neumann, M. Beller, Chem. Eur. J. 2012, 18, 2498 –
2502; k) P. E. Maligres, J. Li, S. W. Krska, J. D. Schreier, I. T. Raheem,
Angew. Chem. Int. Ed. 2012, 51, 9071 – 9074; Angew. Chem. 2012, 124,
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2879; m) C. W. Cheung, S. L. Buchwald, Org. Lett. 2013, 15, 3998 –
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A. K. Prasad, Chem. Eur. J. 2014, 20, 14218 – 14225; o) T. M.
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published thus far. It offers a useful alternative to classic SN2-
based methods for ether synthesis, and represents a practical,
scalable, and inexpensive gateway to such structures that does
not rely on precious metal additives or complex ligands.
Acknowledgements
This project was financially supported by National Science
Foundation Center for Synthetic Organic Electrochemistry CHE-
2002158, National Institutes of Health grant GM-118176, and
SIOC fellowship (postdoctoral fellowship to H.-J.Z.). We thank Dr.
D.-H. Huang and Dr. L. Pasternack (Scripps Research) for
assistance with NMR spectroscopy, to Dr. J. Chen, B. Sanchez,
and E. Sturgell (Scripps Automated Synthesis Facility) for
assistance with HRMS.
Keywords: Electrochemistry • O-Arylation • Coupling • Nickel •
Chemoselective
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Entry for the Table of Contents
C–B bond
3º amine
O
Br
Me
Bpin
Ni
N
FG
FG
+
N
HO
Electrochemical
O-arylation
O
>80 examples
Scalable
[This work] 50%
[Cu]
[Ni/photocatalysis]
Mild conditions
High FG tolerance
[Pd]
✖
✖
✖
Highly chemoselective and practical O-arylation was achieved by electrochemically-driven nickel catalysis. This method exhibits broad
substrate scope comparable to the state-of-the-art Pd, Cu and photochemically facilitated Ni catalysis. Notably, this e-etherification
successfully forged ether bonds in demanding settings where other methods did not work. Combined with excellent scalability, this
work represents a modular, mild, and simple ether bond formation to address the increasing demand for etherification transforms in
contemporary medicinal chemistry.
7
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