Improved Process for the Palladium-Catalyzed C-O Cross-Coupling of Secondary Alcohols

Article abstract of DOI:10.1021/acs.orglett.0c01668

An improved protocol for the Pd-catalyzed C-O cross-coupling of secondary alcohols is described. The use of biaryl phosphine L2 as the ligand was key to achieving efficient cross-coupling of (hetero)aryl chlorides with only a 20percent molar excess of the alcohol. Additionally, we observed an unusual reactivity difference between an electron-rich aryl bromide and the analogous aryl chloride, and deuterium-labeling suggested that currently unidentified pathways for reduction play an important role in explaining this disparity.

Full text of DOI:10.1021/acs.orglett.0c01668

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Letter
Improved Process for the Palladium-Catalyzed C−O Cross-Coupling
of Secondary Alcohols
Hong Zhang, Paula Ruiz-Castillo, Alexander W. Schuppe, and Stephen L. Buchwald*
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ABSTRACT: An improved protocol for the Pd-catalyzed C−O cross-coupling of secondary alcohols is described. The use of biaryl
phosphine L2 as the ligand was key to achieving efficient cross-coupling of (hetero)aryl chlorides with only a 20% molar excess of
the alcohol. Additionally, we observed an unusual reactivity difference between an electron-rich aryl bromide and the analogous aryl
chloride, and deuterium-labeling suggested that currently unidentified pathways for reduction play an important role in explaining
this disparity.
Scheme 1. General Catalytic Cycle of Pd-Catalyzed C−O
he synthesis of alkyl aryl ethers has seen significant
1
Cross-Coupling of Aryl Halides with Secondary Alcohols
Tadvances in the past decade.
Traditional approaches,
such as the Williamson ether synthesis,2 the Mitsunobu
reaction,3 and nucleophilic aromatic substitution,4 often
require specific and limited classes of substrates to achieve
efficient C−O bond formation. Transition-metal-catalyzed C−
O cross-coupling reactions, including Pd,5 Cu,6 and Ni7
catalysis, have also been improving to operate on an
increasingly broad scope of (hetero)aryl halides and aliphatic
alcohols. Alternative metal-free approaches involving sulfonate
esters8a or diaryliodonium salts8b−d also show great promise.
The Pd-catalyzed O-arylation of aliphatic alcohols has been
widely explored by our group and by others.5 As depicted in
Scheme 1, the slow rate of reductive elimination from
intermediate [LnPdII(Ar)(alkoxide)] (IV) is generally believed
to account for the diminished efficiency of C−O bond
formation, compared to the analogous C−N cross-coupling
processes.9 As a result, competitive β-hydride elimination can
lead to the overall reduction of the aryl halide and the
formation of undesired carbonyl side products. Between the
two classes of aliphatic alcohols bearing β-hydrogens,
secondary alcohols are typically considered more challenging
coupling partners. Previously, the coupling reaction of primary
alcohols has been shown to proceed with higher yields and less
reduction of aryl halide, compared to that of the corresponding
secondary alcohols under the same reaction conditions.5c,g,i,n
The most recent report from our group on the coupling
reaction of secondary alcohols introduced the use of a bulky
biaryl phosphine ligand RockPhos (L1, Figure 1) to facilitate
C−O bond formation.5i This method required the use of 2
equiv of alcohol substrate at somewhat elevated temperature
(90 °C) to provide moderate yields with a restricted scope of
alcohol substrates (Scheme 2A).
Two recent reports from the groups of Ma6a and
Stradiotto7a demonstrated great potential for utilizing Cu-
and Ni-catalyzed methods, respectively, to prepare secondary
Received: May 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01668
© XXXX American Chemical Society
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A

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Letter
and iodides with excellent efficiency.6a Compared to that of
more reactive aryl bromides and iodides, the coupling reaction
of aryl chlorides still required higher catalyst loading (10 mol
% Cu) as well as elevated temperature (100 °C). Ni-catalyzed
C−O cross-coupling of secondary alcohols with aryl halides
was achieved with the use of (Cy)PAd-DalPhos-based
precatalysts,7a proving the feasibility of such transformation
in the absence of photoredox catalysts.7b Although the Ni-
catalyzed coupling of aryl chlorides with secondary alcohols
was first achieved in this report, the method was limited to
activated substrates and also required elevated temperature
(110 °C). Additionally, all three metal-catalyzed methods
necessitated the use of 100% or more molar excess of alcohols
(i.e., more than 2 equiv of alcohol, with two exceptions7a) to
ensure successful C−O bond formation. Therefore, the
development of a method that operates under mild conditions,
preferably at room temperature, and that utilizes a smaller
excess of alcohol (i.e., less than 2 equiv of alcohol) for the
coupling reactions of (hetero)aryl chlorides and secondary
alcohols, remains a desirable goal.
Figure 1. Ligands and precatalysts employed in Pd-, Cu-, and Ni-
catalyzed C−O cross-coupling of secondary alcohols.
Scheme 2. Literature Precedents of Transition-Metal-
Catalyzed C−O Cross-Coupling of Secondary Alcohols
We recently disclosed a catalyst system that employs one of
two ligands for Pd-catalyzed C−O cross-coupling reactions of
(hetero)aryl halides with primary alcohols.5b In particular, the
use of a new (now commercially available, CAS no. 2197989-
24-3) hybrid biaryl phosphine ligand L2 (Figure 1) allowed the
effective coupling of challenging electrophiles, including
unactivated aryl chlorides (e.g., electron-rich (hetero)aryl
chlorides). Herein, we report the Pd-catalyzed C−O cross-
coupling of secondary alcohols, facilitated by the use of L2,
with a diverse range of (hetero)aryl chlorides under improved
reaction conditions: more than half of the reactions proceeded
at room temperature, while only requiring a 20% molar excess
of alcohols. Additionally, we present examples of the O-
arylation of secondary alcohols with aryl bromides and the
observation of an unusual difference in reactivity between an
electron-rich aryl bromide and the corresponding aryl
chloride.5b,i,10
alkyl aryl ethers. The use of two oxalic diamide ligands and
sodium tert-butoxide enabled Cu-catalyzed C−O cross-
coupling of secondary alcohols with aryl chlorides, bromides,
Following the conditions previously reported for the cross-
coupling of primary alcohols,5b we employed palladacycle P2
Table 1. Evaluation for Pd-Catalyzed C−O Cross-Coupling of Electron-Rich Aryl Halides with Different Equivalents of s-
a
BuOH in 1,4-Dioxane and THF
b
b
b
entry
X
solvent
equiv of sec-BuOH
conversion (%)
yield of 3 (%)
yield of 4 (%)
1
2
3
4
5
6
7
8
9
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
dioxane
dioxane
dioxane
THF
THF
THF
THF
THF
THF
3
2
1.2
3
2
1.2
3
2
100
78
50
100
100
100
100
100
100
94
62
22
98
97
90
67
72
63
8
14
18
3
4
9
31
27
33
1.2
a
Reaction conditions: ArX (0.5 mmol), s-BuOH (x mmol), NaOt-Bu (0.6 mmol), P2 (2.0 mol %), solvent (0.5 mL, 1.0 M), rt, 18 h. dioxane = 1,4-
b
dioxane. THF = tetrahydrofuran. Determined by GC analysis using an internal standard. All yields presented are not normalized. In certain cases,
the sum of yields being over 100% is a result of the error in the analytical method used.
B
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(Figure 1) as the precatalyst and 1,4-dioxane as the solvent.
Electron-rich aryl chloride 1, containing a para-morpholino
substituent, and sec-butanol (s-BuOH) were chosen as model
coupling partners. Lowering the number of equivalents of s-
BuOH from 3 to 1.2 resulted in a decline in the efficiency of
the reaction: the conversion of the starting aryl chloride 1
decreased by 50%, and the ratio of the reduction side product
4 to the coupling product 3 increased substantially (Table 1,
entries 1−3). However, when the solvent was changed to THF,
lowering the number of equivalents of s-BuOH to 1.2 had a
negligible effect on the efficiency of the reaction (Table 1,
entries 4−6). Therefore, THF was selected as an appropriate
solvent for further exploration of the substrate scope.
Scheme 3. Pd-Catalyzed C−O Cross-Coupling of
a
(Hetero)aryl Chlorides with Secondary Alcohols
Although it is widely accepted that aryl bromides exhibit
higher reactivity in cross-coupling reactions than aryl
chlorides,5b,i,10 we observed an opposite trend between
electron-rich aryl chloride 1 and aryl bromide 2. First, under
the same set of reaction conditions (Table 1, entries 6 and 9),
while the reaction of 1 provided a 90% yield of desired aryl
ether 3, along with 9% reduction product 4, that of 2 only
provided a 63% yield of 3, with a notable increase in the
amount of 4 (33%) that was formed. Although this difference
could be partially ameliorated by adjusting the quantity of s-
BuOH to 2 equiv, a further increase of the amount of alcohol
utilized did not lead to an additional improvement in the yield
of 3 (Table 1, entries 7 and 8).
A variety of (hetero)aryl chlorides and secondary alcohols
were surveyed to examine the generality of this method
(Scheme 3). The C−O cross-coupling reactions took place
under mild conditions, using only a 20% molar excess of
alcohols. Many traditionally challenging substrates, including
unactivated aryl chlorides (3, 5, 7) and five-membered
heterocycles (9, 10, 11), readily underwent C−O bond
formation at room temperature. Various heterocycles, such as
a quinoline (7), a pyridazine (8), a pyrazole (8), a thiadiazole
(9), a benzisothiazole (10), a benzimidazole (11), a pyrazine
(12), a quinazoline (13), a pyrazolopyrimidine (14), and a
pyridine (15), were tolerated as structural components in the
electrophiles. Functional groups such as an unprotected
tertiary hydroxyl group (6), a carbamate group (7), and a
lactone (14) were also compatible with the reaction
conditions. While sterically accessible alcohols proved to be
good coupling partners at room temperature, secondary
alcohols with moderate steric encumbrance at either the α-
carbon (12, 13) or the β-carbon (14, 15) required moderate
heating (40 °C) to react with activated heteroaryl chlorides
and afford corresponding heteroaryl ethers in ≥80% yields.
The coupling reactions between electron-rich aryl chlorides
and more sterically demanding nucleophiles, however,
remained challenging, as demonstrated in the reactions of
aryl chloride 1 (Table 2). As the steric congestion around the
α-carbon of the alcohol increased (Table 2, entries 1 and 2),
both the conversion and the yield of desired product decreased
by approximately 40%, while a small increase in reduction
product 4 was observed. We hypothesize that increasing the
steric bulk around the α-carbon could negatively impact the
binding tendency of alcohol nucleophiles to the oxidative-
addition complex II (Scheme 1), thus accounting for the less
efficient C−O bond formation. Although heteroaryl ethers 9,
12, and 13 were prepared and isolated in >80% yields, benzylic
alcohols proved to be more difficult coupling partners for
electron-rich aryl chloride 1 (Table 2, entries 3 and 4). The
steric environment of the benzylic carbon also played an
a
Reaction conditions: ArCl (1.0 mmol), alcohol (1.2 mmol), NaOt-
Bu (1.2 mmol), P2 (2.0−4.0 mol %), THF (1.0 mL, 1.0 M), rt−40
°C, 18 h. Isolated yields represent the average result of two runs.
b
THF (7.0 mL) and higher temperature were used due to the poor
solubility of the combination of aryl chloride, alcohol, and NaOt-Bu
under standard reaction conditions.
important role in the coupling process, as a change from a
methyl to an ethyl group led to a 60% decrease in conversion,
and only a trace amount of desired product was detected
(Table 2, entries 3 and 4).
As we continued to examine the scope of C−O cross-
coupling reactions of aryl bromides, we noticed that the
difference in reaction efficiency between the cross-coupling of
aryl bromides and aryl chlorides was greatest for highly
electron-rich substrates, such as 2 vs 1 (to prepare 3 in
Schemes 4 and 3, respectively). In contrast, for weakly
electron-rich, electron-neutral, and electron-deficient aryl
bromides (to prepare 5, 16, and 17, respectively), the cross-
coupling reactions proceeded with comparable levels of
efficiency (>80% yield, Scheme 4).
To gain an understanding of the difference in reactivity
between aryl halides 1 and 2, we performed experiments to
examine the cause of increased reduction in the cross-coupling
reaction of aryl bromide 2. In order to ascertain whether
reduction product 4 resulted solely from β-hydride elimination,
we prepared α-deutero-alcohol 18-d (98% d1, see the
Supporting Information) and examined its reaction with aryl
bromide 2. When 2 and protio-alcohol 18 were subjected to
C
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Table 2. Alcohol Evaluation for Pd-Catalyzed C−O Cross-
Scheme 5. Pd-Catalyzed C−O Cross-Coupling of Aryl
a
Coupling of Electron-Rich Aryl Chloride 1
Bromide 2 with (A) Cyclohexanol 18 and (B) Deutero-
a
cyclohexanol 18-d
a
Reaction conditions: 2 (0.5 mmol), 18 or 18-d (0.6 mmol), NaOt-
a
Bu (0.6 mmol), P2 (2.0 mol %), THF (0.5 mL, 1.0 M), rt, 18 h.
Reaction conditions: ArCl (0.5 mmol), alcohol (0.6 mmol), NaOt-
b
Determined by 1H NMR analysis using an internal standard.
Bu (0.6 mmol), P2 (2.0 mol %), THF (0.5 mL, 1.0 M), rt, 18 h.
c
d
b
c
1
Determined by GC analysis using an internal standard. Determined
Determined by GC using an internal standard. Determined by H
by HRMS analysis.
NMR using an internal standard.
Scheme 4. Pd-Catalyzed C−O Cross-Coupling of Aryl
a
Bromides with Secondary Alcohols
arises from β-hydride (deuteride) elimination, and some stems
from (as yet) unidentified processes. It is conceivable that the
reduction byproduct may arise from protodemetalation of the
oxidative addition complex [LnPdII(Ar)X] (II, Scheme 1).
Similar findings have been reported by Hartwig, in his studies
of the Pd-catalyzed amination of aryl bromides in the presence
of bidentate ligands.11
In conclusion, we have developed a significantly improved
procedure for the Pd-catalyzed C−O cross-coupling of
secondary alcohols. This protocol employs a previously
disclosed hybrid biaryl phosphine ligand L2, while using
THF as the reaction solvent in lieu of 1,4-dioxane as in our
previous report. A variety of (hetero)aryl ethers were obtained
in higher yields from the corresponding (hetero)aryl halides
under more user-friendly reaction conditions than in our
earlier method. For instance, a 20% molar excess of alcohols
sufficed to allow the cross-coupling reaction of (hetero)aryl
chlorides at room temperature or 40 °C. An interesting but
unconventional reactivity difference between an electron-rich
aryl bromide 2 and chloride 1 was discovered. A deuterium-
labeling study suggested the possibility of as yet unidentified
pathways responsible for the greater reduction of aryl bromide
2, indicating the need for further studies to establish a better
detailed understanding of the mechanism of the Pd-catalyzed
C−O coupling under these conditions.
a
Reaction conditions: ArBr (1.0 mmol), alcohol (2.0 mmol), NaOt-
Bu (1.2 mmol), P2 (2.0−2.5 mol %), THF (1.0 mL, 1.0 M), rt, 18 h.
Isolated yields represent the average result of two runs. 1.5 equiv of
alcohol. THF (5.0 mL) and higher temperature were used due to the
poor solubility of the combination of aryl chloride, alcohol, and NaOt-
b
c
Bu under standard reaction conditions.
the standard cross-coupling conditions, the desired product 19
and the reduction product 4 were observed in 47% and 54%
yield, respectively, as determined by H NMR analysis, while
1
ketone 20 was formed in 31% yield, as judged by GC analysis
(Scheme 5A). Ketone 20 is believed to result from β-hydride
elimination from the intermediate [LnPdII(Ar)(alkoxide)] (IV,
Scheme 1) and should theoretically be formed in a 1:1 ratio
with 4. Therefore, these results indicate that β-hydride
elimination only accounts for a fraction of the formation of
4. When 2 and 18-d were subjected to the cross-coupling
conditions, the desired product 19-d was formed in 65% yield
and contained the same amount of deuterium (98%) as in 18-d
(estimated by 1H NMR analysis, Scheme 5B). Reduction
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01668.
1
product 4-d was formed in 36% yield (by H NMR analysis)
and was 80% d1 (by HRMS analysis). Ketone 20 was detected
in 20% yield by GC analysis. Taken together, these
experiments demonstrate that not all reduction side product
Experimental procedures and characterization data for
new compounds (PDF)
D
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as an Approach to Challenging Carbohydrate−Aryl Ethers. Org. Lett.
2015, 17, 4846−4849.
AUTHOR INFORMATION
Corresponding Author
■
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Stephen L. Buchwald − Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States; orcid.org/0000-0003-
3875-4775; Email: sbuchwal@mit.edu
Authors
Hong Zhang − Department of Chemistry, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139,
United States; orcid.org/0000-0002-4921-3395
Paula Ruiz-Castillo − Department of Chemistry, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139,
United States
Alexander W. Schuppe − Department of Chemistry,
Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States; orcid.org/0000-0001-
6002-9110
Complete contact information is available at:
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Notes
The authors declare the following competing financial
interest(s): MIT has or has filed patents on ligands/
precatalysts that are described in the paper from which
S.L.B. and former coworkers receive royalty payments.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institutes of Health (R35-GM122483) and Arnold
and Mabel Beckman Foundation for a postdoctoral fellowship
to A.W.S. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the
National Institutes of Health. We acknowledge MilliporeSigma
(formerly Aldrich) for the generous donation of 1-
adamantylzinc bromide solution, and Ryan King (MIT) for
one batch of 2-iodo-2′,4′,6′-triisopropyl-3,6-dimethoxybiphen-
yl used in this work. We thank Dr. Jeffrey Yang (MIT) and Dr.
Bryan Ingoglia (MIT) for helpful discussions. We thank Dr.
Scott McCann (MIT), Dr. Richard Liu (MIT), and Dr.
Christine Nguyen (MIT) for their assistance with the
preparation of this manuscript.
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