Dynamic Kinetic Cross-Electrophile Arylation of Benzyl Alcohols by Nickel Catalysis

Article abstract of DOI:10.1021/jacs.0c12462

Catalytic transformation of alcohols via metal-catalyzed cross-coupling reactions is very important, but it typically relies on a multistep procedure. We here report a dynamic kinetic cross-coupling approach for the direct functionalization of alcohols. The feasibility of this strategy is demonstrated by a nickel-catalyzed cross-electrophile arylation reaction of benzyl alcohols with (hetero)aryl electrophiles. The reaction proceeds with a broad substrate scope of both coupling partners. The electron-rich, electron-poor, and ortho-/meta-/para-substituted (hetero)aryl electrophiles (e.g., Ar-OTf, Ar-I, Ar-Br, and inert Ar-Cl) all coupled well. Most of the functionalities, including aldehyde, ketone, amide, ester, nitrile, sulfone, furan, thiophene, benzothiophene, pyridine, quinolone, Ar-SiMe3, Ar-Bpin, and Ar-SnBu3, were tolerated. The dynamic nature of this method enables the direct arylation of benzylic alcohol in the presence of various nucleophilic groups, including nonactivated primary/secondary/tertiary alcohols, phenols, and free indoles. It thus offers a robust alternative to existing methods for the precise construction of diarylmethanes. The synthetic utility of the method was demonstrated by a concise synthesis of biologically active molecules and by its application to peptide modification and conjugation. Preliminary mechanistic studies revealed that the reaction of in situ formed benzyl oxalates with nickel, possibly via a radical process, is an initial step in the reaction with aryl electrophiles.

Full text of DOI:10.1021/jacs.0c12462

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Dynamic Kinetic Cross-Electrophile Arylation of Benzyl Alcohols by
Nickel Catalysis
Peng Guo, Ke Wang, Wen-Jie Jin, Hao Xie, Liangliang Qi, Xue-Yuan Liu, and Xing-Zhong Shu*
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ABSTRACT: Catalytic transformation of alcohols via metal-
catalyzed cross-coupling reactions is very important, but it typically
relies on a multistep procedure. We here report a dynamic kinetic
cross-coupling approach for the direct functionalization of alcohols.
The feasibility of this strategy is demonstrated by a nickel-catalyzed
cross-electrophile arylation reaction of benzyl alcohols with
(hetero)aryl electrophiles. The reaction proceeds with a broad
substrate scope of both coupling partners. The electron-rich, electron-poor, and ortho-/meta-/para-substituted (hetero)aryl
electrophiles (e.g., Ar−OTf, Ar−I, Ar−Br, and inert Ar−Cl) all coupled well. Most of the functionalities, including aldehyde, ketone,
amide, ester, nitrile, sulfone, furan, thiophene, benzothiophene, pyridine, quinolone, Ar−SiMe3, Ar−Bpin, and Ar−SnBu3, were
tolerated. The dynamic nature of this method enables the direct arylation of benzylic alcohol in the presence of various nucleophilic
groups, including nonactivated primary/secondary/tertiary alcohols, phenols, and free indoles. It thus offers a robust alternative to
existing methods for the precise construction of diarylmethanes. The synthetic utility of the method was demonstrated by a concise
synthesis of biologically active molecules and by its application to peptide modification and conjugation. Preliminary mechanistic
studies revealed that the reaction of in situ formed benzyl oxalates with nickel, possibly via a radical process, is an initial step in the
reaction with aryl electrophiles.
Scheme 1. Strategies for Functionalization of Alcohols by
Cross-Coupling Reactions
1. INTRODUCTION
Alcohols are among the most accessible and versatile organic
compounds. Among the various approaches that can be used
to transform them into valuable chemicals, the transition-
metal-catalyzed cross-coupling based on C−O cleavage has
become an essential tool.1 Studies in this field have led to
numerous useful transformations for the couplings of C−O
electrophiles with nucleophilic species (e.g., R−MgX, R2Zn,
R−B).1 There are also several reports describing the coupling
of them with electrophiles.2,3 In general, these processes
require multistep operations, albeit a few sequential one-pot
protocols were realized (Scheme 1a).4 Moreover, they rely on
highly reactive activators, such as (CF3SO)2O, RSO2Cl, and
RCOCl, which are sensitive to H2O and nucleophilic
functionalities.5 Consequently, new coupling technologies for
the direct functionalization of alcohols are still desirable and
could have a substantial impact on organic synthesis.6 Herein,
we report a dynamic kinetic strategy that offers a
straightforward and highly functional-group-tolerant approach
to functionalize alcohols (Scheme 1b). The success of this
effort hinged on the use of dimethyl oxalate (DMO) as an
activator, which is relatively stable, easy to handle, and
inexpensive7 and is compatible with most functionalities. This
reagent undergoes equilibrium reaction with alcohols, and the
formed alkyl oxalates can participate in coupling reactions
while generating.8 The feasibility of this strategy was
demonstrated by the nickel-catalyzed cross-electrophile deox-
yarylation reaction of benzyl alcohols with aryl electrophiles.
Diarylmethanes are ubiquitous structural motifs in a
substantial number of pharmaceuticals and functional organic
materials.9 Among the various synthesis methods, described in
representative publications,10−13 the catalytic arylation of
Received: November 30, 2020
Published: December 28, 2020
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benzyl alcohols is of great interest. To date, approaches to
enable this transformation have been restricted to the Friedel−
Crafts reactions (Scheme 2a).14 These methods have
problems due to hydrolysis when exposed to silica gel
chromatography.19 Moreover, their synthesis requires methyl
chlorooxalate, which is highly incompatible with the
nucleophilic functionalities. We later wondered if alkyl methyl
oxalates could be generated by transesterification between
alcohols and unreactive DMO20 and undergo in situ cross-
coupling reactions.
Scheme 2. Synthesis of Diarylmethanes from Benzyl
Alcohols
With these considerations in mind, we investigated the
possibility of the transesterification between benzyl alcohol 1a
(1.0 equiv) and DMO (1.5 equiv) in DMF-d7. Our initial
studies revealed that the reaction did not occur with the
reagents themselves, or by Lewis acid catalysis (Scheme 3,
Scheme 3. Transesterification of 1a with DMO
significantly advanced over the past years; however, expanding
the scope to electron-poor arenes and achieving regiodefined
synthesis remain substantial challenges. The transition-metal-
catalyzed cross-couplings can be a powerful alternative, but
they remain largely unexplored. There are only a few elegant
studies that have achieved the arylation of benzyl alcohols by
using Grignard reagents and aryl boroxines (Scheme 2b).15
One elegant work has documented the cross-electrophile
arylation of benzyl alcohols using aryl iodides.16 In this study, a
stoichiometric amount of low-valent titanium complex is
required to activate alcohols to benzyl radicals,17 and both Ar−
Cl and Ar−OTf remain ineffective (Scheme 2c). Therefore,
new protocols for the regiodefined synthesis of diarylmethanes
from a broad range of benzyl alcohols and aryl fragments are
still highly desirable. Here, we demonstrate a nickel-catalyzed
dynamic kinetic cross-electrophile coupling to fulfill these
requirements (Scheme 2d). The reaction is characterized by its
mild conditions, broad substrate scope, excellent functional
group compatibility, and unique chemoselectivity that is
orthogonal to the existing methodologies. These features
make our approach generic and applicable for the concise
synthesis of biologically active compounds, the late-stage
modification of complex molecules, and peptide conjugation. It
thus could be considered as a good complementary to the
existing methods.10−16
condition a). Further studies revealed that the transester-
ification proceeded slowly in the presence of a nickel catalyst at
room temperature, resulting in 2a (yield 47%) after 60 h
(Scheme 3, condition b). After this time, the ratio of 1a/2a
remained unchanged because of the facile transesterification
between 2a and methanol (Scheme S3 in the Supporting
Information). Both Ni(0) and ligand were required for the
process. The activation of oxalate 2a via benzyl C−O cleavage
was not observed at room temperature. The use of conven-
t
tional esters (e.g., CH3CO2Et, PhCO2Me, PhCO2 Bu,
PhCO2Ph), instead of DMO, did not afford any trans-
esterification products (Table S1).
2.2. Reaction Optimization. With these findings in hand,
we then explored the cross-electrophile reaction of alcohol 1a
with triflate 3a using a nickel catalyst (Table 1). After
screening of a range of reaction conditions, we found that the
combination of Ni(dppf)Cl2 (10 mol %), dppf (10 mol %),
phen (2 mol %), DMO (1.8 equiv), and Mn (3.0 equiv) in
DMF at 80 °C gave the best result, affording 4a in 79%
isolated yield (entry 1). The reaction without additional dppf
had a significantly decreased yield (entry 2). The presence of a
nitrogen ligand usually has positive effects on the yield (entries
1, 3−8). The inferior results were obtained when other nickel
sources were used (entries 9−11). The reaction with Zn as a
reductant is highly ineffective (entry 12). In the absence of
2. RESULTS AND DISCUSSION
2.1. Transesterification of Alcohol with DMO. Oxalates
have proved to be powerful activating groups for the
deoxygenative functionalization of alcohols.18 Very recently,
we and others disclosed that alkyl methyl oxalates are ideal
coupling partners for catalytic alkylation reactions.8 However,
some of these reagents are moisture-sensitive and often suffer
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a
a
Table 1. Optimization of Reaction Conditions
Table 2. Scope of Benzyl Alcohols
b
entry
variation from standard conditions
none
without dppf (10 mol %)
without phen (2 mol %)
L1 instead of phen
L2 instead of phen
L3 instead of phen
L4 instead of phen
L5 instead of phen
Ni(cod)2 instead of Ni(dppf)Cl2
Ni(dppe)Cl2 instead of Ni(dppf)Cl2
Ni(PPh3)2Cl2 instead of Ni(dppf)Cl2
Zn instead of Mn
no Ni or Mn
no DMO
4a (%)
c
1
2
3
4
5
6
7
8
82 (79)
56
60
72
68
50
72
68
69
63
71
15
0
d
9
e
10
f
11
12
13
14
0
a
Conditions A: Ni(dppf)Cl2 (10 mol %), dppf (10 mol %), phen (2
mol %), DMO (1.8 equiv), and Mn (3.0 equiv) in DMF at 80 °C for
b
30 h. 1a (0.2 mmol) and 3a (0.3 mmol) were used; the yields were
determined by GC analysis with dodecane as internal standard.
a
c
d
e
1b−1u (0.2 mmol) and 3a (0.3 mmol) were used; isolated yield.
Isolated yield. dppf (20 mol %) was used. dppe (10 mol %) was
b
f
Conditions B: NiBr2(diglyme) (10 mol %), dppf (10 mol %), phen
used instead of dppf. PPh3 (20 mol %) was used instead of dppf.
(10 mol %), pyridine (10 mol %), AlCl3 (10 mol %), DMO (1.8
equiv), and Mn (3.0 equiv) in DMF at 80 °C for 30 h. The reaction
was performed at 100 °C. 4-(MeO)PhOTf (0.3 mmol) was used.
c
nickel catalyst, reductant, or DMO, no reaction was observed
and the alcohol remained intact (entries 13 and 14).
d
2.3. Scope of the Reaction. The substrate scope of benzyl
alcohols is demonstrated in Table 2. Benzyl alcohols, including
unsubstituted (1g), electron-rich (1b−1f), and electron-poor
(1h−1l) compounds, were coupled well to afford diaryl-
methanes in good yields. Substitution around the aromatic ring
was tolerated (1b−1d). Functional groups such as aryl ethers
(1e, 1f), fluorides (1h, 1i), trifluoromethyl group (1j), and
nitriles (1k, 1l) were compatible with the reaction conditions.
The reaction of ferrocene-derived alcohol afforded the desired
product in good yield (1m). The reactions of heterobenzylic
alcohols, including furan (1n, 1o), thiophene (1p), pyridine
(1q), benzothiophene (1r), and quinolone (1s), afforded
heteroaryl-containing diarylmethanes in good yields. The use
of Lewis acid, AlCl3 (10 mol %), improved the yields of desired
products (e.g., 1n−1q). Our studies revealed that AlCl3 could
slow down the transesterification of alcohols to form oxalates,
and it also had a positive effect on the coupling of oxalates with
aryl triflates (see below). The role of pyridine is currently
unclear. We assume it may act as a ligand as realized in Gong’s
work.21 At present, the reactions of secondary and tertiary
alcohols were much less effective (1t and 1u).
a
Table 3. Scope of Aryl Triflates
a
1a (0.2 mmol) and 3b−3m (0.3 mmol) were used; the reaction time
was 30 h; isolated yield. Conditions B in Table 2.
b
A wide range of aryl triflates reacted with 1a to afford the
coupling products with good to high yields (Table 3).
Substituents at the para- (3b, 3c, 3h−3j), meta- (3d), and
ortho-positions (3e, 3f) were tolerated. The reaction with a
sterically hindered substrate was effective (3e). Both electron-
rich (3b−3g) and electron-poor (3h, 3j) aryl triflates reacted
efficiently. Functional groups such as ketone (3h), aryl fluoride
(3j), free indole (3k), and alcohol (3l) were tolerated. N-
Benzyl morpholine is an important motif found in various
pharmaceuticals.22 This moiety could be installed by coupling
with benzyl alcohol (3m).
Aryl chlorides are among the most attractive aryl electro-
philes because of their low cost and the wide diversity of
available compounds. While their application in cross-
couplings has received ongoing attention over the past
decades,23 the cross-electrophile reaction using aryl chlorides
remains largely unexplored.24 We then studied the reactions of
1a with aryl chlorides to investigate the potential of our
method for the utilization of these promising, but challenging,
substrates (Table 4). Electron-neutral (5a), electron-rich (5b,
5c, 5g), and electron-poor (5d−5f) aryl chlorides all coupled
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a
Table 4. Reactions of Aryl Chlorides 5 with Alcohol 1a
Table 5. Reactions of Aryl Bromides and Iodides with
Alcohol 1a
a
a
1a (0.2 mmol) and 5a−5p (0.3 mmol) were used; the reaction time
b
was 30 h; isolated yield. AlCl3 (10 mol %) was added.
well, resulting in the diarylmethanes with moderate to good
yields. While the pinacol coupling of aldehydes by reductive
nickel catalysis was reported,25 aryl chloride 5e was selectively
functionalized under our conditions. The presence of an aryl
ester was tolerated (5f). Nucleophilic aryl species were
selectively functionalized, thus enabling the nucleophilic
functionalities such as phenol (5g) and indoles (5h, 5i) to
be available for additional transformation. The reactions with
substituted 2-chloro-pyridines were effective (5j−5l). The
reactions of pyrazine, pyridazine, and pyrimidine chlorides
afforded no or low yield of desired products (5m−5o). A
moderate yield of coupling product was obtained when 2-
chlorothiophene was used (5p).
a
1a (0.2 mmol) and 6a−6t (0.3 mmol) were used; the reaction time
b
was 30 h; isolated yield. The reaction was performed at 70 °C.
a
Scheme 4. Synthesis of Metal-Substituted Diarylmethanes
In general, the cross-electrophile reaction requires the
coupling partners to be orthogonally paired in reactivity.
However, our method proved to be less sensitive to the
reactivity of aryl halides. Besides inert aryl chlorides, reactive
substrates such as aryl bromides and iodides coupled efficiently
with benzyl alcohol 1a (Table 5). Both electron-rich (6a−6d,
6q−6s) and electron-poor (6e−6h, 6t) aryl halides were
tolerated. The reaction is highly selective for the functionaliza-
tion of aryl halides, leaving a number of functionalities intact,
e.g., aryl ether (6c, 6d, 6s), aryl fluoride (6e, 6t),
trifluoromethyl group (6f), ester (6g), sulfone (6h), phenol
(6i), alcohol (6j), strained four-membered ring (6k), and free
indole (6l). 2-Bromopyridines and 2-bromothiophene gave no
or low yield of coupling product (6m and 6n), albeit their
chloride substrates coupled well (Table 4, 5j−5l, 5p). The use
of furanyl bromides gave synthetic useful yields of desired
products (6o and 6p).
Aryl organometallic reagents have found broad application
in cross-couplings, including the Hiyama reaction (Ar−Si), the
Suzuki−Miyaura reaction (Ar−B), and the Stille reaction (Ar−
Sn).1 Our method has demonstrated a unique selectivity that is
orthogonal to the conventional cross-couplings, thus enabling
Ar−M to be available for further functionalization (Scheme 4).
For example, the reaction is highly selective for the arylation of
alcohols, leaving Ar−SiMe3 (7a−7c), Ar−Bpin (7d, 7e), and
a
Standard conditions, 3a (0.3 mmol) was used for reactions with
alcohols 7a−7f (0.2 mmol), 1a (0.2 mmol) was used for reactions
b
with aryl electrophiles 8a−8f (0.3 mmol); isolated yield. 5 Å MS (30
c
d
mg) was added. 3 Å MS (30 mg) was added. Concentration is 0.4
M.
Ar−SnBu3 (7f) intact. Metallo groups at the ortho- (7a), meta-
(7b, 7d), and para-positions (7c, 7e, 7f) were tolerated.
Similar results were obtained when boron-substituted (8a−8c)
and silyl-substituted (8d−8f) aryl electrophiles were employed.
The conventional coupling reactions generally require the
additional step for preactivation of alcohols (Scheme 1a).
When polynucleophilic alcohols are employed, this process not
only needs multiple protection/deprotection operations but
also suffers from the selectivity challenge. By contrast, the
dynamic kinetic strategy is based on the equilibrium reaction.
It allows for the direct arylation of the benzylic alcohol in the
presence of other nucleophilic groups (Table 6). For example,
the reactions were highly selective for the arylation of benzylic
alcohols over nonactivated primary and secondary alcohols,
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a
Table 6. Direct Arylation of Benzylic Alcohols of
Polynucleophilic Substrates
Scheme 5. Modification of Biologically Active Compounds
a
a
Conditions B in Table 2; aryl electrophiles (0.2 mmol) and alcohol
1n (0.4 mmol); 4,4′-dimethyl-2,2′-bipyridine (10 mol %) was used
b
instead of phen; isolated yields. Aryl electrophiles (0.1 mmol) and
c
alcohol 1n (0.4 mmol) were used. Conditions A in Table 1; ArOTf
a
9a−9l (0.2 mmol) and 5f (0.3 mmol) were used; DMO (0.3 mmol)
3q (5 mmol), alcohol 7c (7.5 mmol), and 3 Å MS (200 mg) were
b
d
was used for 9a−9g; isolated yield. ArBr 6d (0.3 mmol) was used.
used; the reaction time was 40 h. See the Supporting Information for
c
Conditions B in Table 2 and ArOTf 3a (0.3 mmol) were used.
reaction conditions.
Scheme 6. Concise Synthesis of Pharmaceutical and
Biologically Active Compounds
although they all underwent the transesterification with DMO
(9a, 9b, 9d−9g). Only a trace of R−Oxa was detected at the
end of the reactions, where the R−O moiety derived from non-
benzylic alcohols. The high selectivity was also realized when
the tertiary alcohol substrate 9c was employed. Both cyclic/
acyclic alcohols (9a−9e) and polyalcohols (9f and 9g) were
tolerated. The presence of phenol (9h and 9i), indole (9j and
9k), and amide (9l) groups was tolerated, and they did not
result in the oxalate protection.
a
2.4. Synthetic Application. Heteroaryl-containing diaryl-
methanes are ubiquitous substructures found in various
biologically active molecules.26 Potentially, the construction
of these structural units in complex molecules could be
achieved by the coupling of complex aryl electrophiles with
heterobenzylic species.12,13 However, the task will be very
challenging when electron-rich heterobenzylic substrates are
employed. First, as noted by Zhang et al.,27 the stability and
reactivity issues associated with electron-rich heterobenzylic
halides would restrict their application on the cross-couplings.
Second, the synthesis of their organometallic reagents is very
difficult.28 Therefore, to our knowledge, there has been no
report on the coupling of electrophiles with 2-furan/3-pyridine
methyl species. Herein, we demonstrate that the dynamic
kinetic method offers a practical solution to address this
problem, which allows for reactive benzylic oxalate to
participate in the coupling while generating in situ. It thus
established a method capable of incorporation of a 2-furan
methyl group into biologically active molecules (Scheme 5), of
concise synthesis of pharmaceutical compounds (Scheme 6),
and of peptide modification and conjugation (Scheme 7),
which are challenging issues for the literature methods.10−16
The phenol and chloroarene are frequently found in
biologically active compounds. Our method provides an
approach to transfer them into diarylmethanes (Scheme 5).
For example, aryl triflates derived from isoeugenol (11),
a
See the Supporting Information for detailed reaction conditions and
b
procedures. Conditions B in Table 2; Alcohol 1q (16 mmol) and 19
(8 mmol) were used; the reaction time was 40 h. Alcohol 22 (0.2
mmol), 23 (0.4 mmol), NiCl2(dppf) (20 mol %), 4,5-diazafluoren-9-
one (20 mol %), DMO (2.0 equiv), Mn (4.0 equiv) were used.
c
bilicante (12), phenolphthalein (14), and estrone (16) could
be selectively functionalized to 2-benzylfuran compounds
under our conditions. Loratadine (13) and buclizine (15)
were coupled with 2-furanmethanol efficiently. The use of a
metallosubstrate enables multistep modification. For example,
the reaction of estrone-derived aryl triflate with 4-silyl-benzyl
alcohol afforded 17 in 51% yield (1.06 g), which could further
react with benzothiophene to afford compound 18.
The utility of this method was further demonstrated by a
concise synthesis of pharmaceutical and biologically active
compounds. Furegrelate is a potent inhibitor of thromboxane
synthase.29 With reductive cross-coupling, furegrelate was
accessed in two steps from alcohol 1q and triflate 19 with a
51% yield on a gram scale (Scheme 6a). Our attempt to
produce this compound by some reported coupling methods
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bromide (6c, 6u), and triflate (3n, 3q), and the biologically
active compounds (3n, 3q) could be attached (Scheme 7b).
Moreover, this method has shown the potential application of
peptide conjugation. For example, met-enkephalin 25 and
peptide 30 were selectively conjugated under the reductive
conditions, affording peptide 36 in a useful yield (Scheme 7c).
2.5. Mechanistic Investigation. In the absence of DMO,
the reaction of alcohol 1a with 3a did not afford any desired
product, and alcohol 1a was recovered quantitatively (Table 1,
entry 14). The transesterification of 1a with DMO proceeded
smoothly under nickel catalysis (Scheme 3). Moreover, under
the standard conditions without DMO, the reaction of oxalate
2a with triflate 3a afforded coupling product 4a in 83% yield
(Scheme 8). These results suggest a pathway that may involve
the formation of benzyl oxalate.
Scheme 7. Application in Peptide Modification and
Conjugation
a
a
Scheme 8. Reaction of Oxalate 2a with 3a
a
Conditions A in Table 1, but DMO was not used.
2.5.1. Transesterification. Utley and co-workers have found
that the transesterification of alcohol and oxalate could be
catalyzed by in situ electrogenerated base.36 To reveal whether
a similar process was involved in our catalytic system, several
control experiments were performed. In addition to Ni(0), the
transesterification of alcohol 1a and DMO proceeded well
either in the presence of Mn (1.0 equiv) or of K2CO3 (10 mol
%), affording 2a in 45% and 31% yield, respectively (Scheme
9a). Moreover, monitoring of the progress of the reaction
clearly showed that the transesterification was significantly
accelerated by adding K2CO3 (10 mol %), but it was strongly
a
Conditions B in Table 2; the reaction time was 40 h; isolated yield.
b
c
25 (0.1 mmol) and 1a, 1r, 1n, 7f (0.2 mmol) were used. 30 (0.1
d
mmol) and 5f, 6c, 6u, 3n, 3q (0.2 mmol) were used. 25 (0.1 mmol)
and 30 (0.1 mmol) were used; the reaction time was 45 h.
was unsuccessful (Scheme S1). GC-24, an agonist for the
human thyroid hormone receptor, is a potential agent for the
treatment of obesity and arteriosclerosis.30 The presently most
concise approach to produce this compound relies on a 10-step
synthesis.11d With our method, the synthesis of GC-24 was
accomplished in four steps, with the cross-electrophile
coupling as the key step (Scheme 6b).
Scheme 9. Experimental Insight into the Transesterification
Process
The late-stage modification of peptides has emerged as a
significant task of current interest.31 Tyrosine is a natural
amino acid found in almost all proteins. Although significant
progress has been made in the catalytic diversification of
tyrosine in peptides, the modification via Csp2−Csp3 bond
formation remains a challenge.32 Meanwhile, unlike the
conventional cross-couplings, the cross-electrophile reaction
for peptide modification has seldom been investigated.33
We recently reported a reductive nickel catalysis for the
installation of an alkyl group at tyrosine in peptides.3h
However, the reactions with benzylic substrates were
unsuccessful. We demonstrate here that the dynamic kinetic
method can be an alternative approach for this purpose. For
instance, the peptide met-enkephalin (Tyr-Gly-Gly-Phe-Met)
25 has important biological activity, and its structural
diversification is very important.34 With our method, the
benzyl group could be selectively installed at the tyrosine
position. Various benzyl alcohols, including aryl (1a),
heteroaryl (1r, 1n), and metalloaryl (7f) compounds, were
tolerated (Scheme 7a). No racemization at the stereogenic
centers of the product was observed.35 On the other hand,
peptide 30 could be selectively arylated with aryl chloride (5f),
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inhibited by the use of AlCl3 (10 mol %) (Scheme 9b). These
results suggest the transesterification process is likely to be
catalyzed by base generating in situ.
On the basis of the above results, a plausible pathway for the
transesterification process is outlined in Scheme 10, which is
reactive, AlCl3 both lowering the concentration of oxalates
and enhancing the reactivity of aryl triflates may help to
improve the selectivity for the cross-product.37
2.5.3. Nickel-Catalyzed Cross-Coupling of Aryl Electro-
philes with Benzyl Oxalates. Both benzyl oxalate and aryl
electrophile will react with Ni(0) to give benzyl−NiII(L)X and
Ar−NiII(L)X intermediates. To determine which intermediate
is formed first, we studied the relative reactivity of oxalate 2a
and aryl triflate 3b with Ni(0) (Scheme 12a).38 We found that
Scheme 10. Proposed Transesterification Mechanism
Scheme 12. Experiments to Reveal if Benzyl Oxalate or Aryl
Electrophile Reacts with Nickel First
analogous to the proposal for electrocatalysis.36 Initiation step:
In the presence of reducing reagent, DMO undergoes a single-
electron reduction with Mn/Ni(0) to afford radical anion
intermediate. The following proton exchange process gives
alcohol anions. Base-catalyzed transesterification: the proposed
pathway is shown in step 2, which involves alkaline
transesterification and benzyl alcohol anion regeneration
processes.
2.5.2. Role of AlCl3. When heterobenzylic alcohols were
employed, the addition of AlCl3 (10 mol %) improved the
yields of desired products (e.g., 1n−1q in Table 2). The results
in Scheme 9b show that AlCl3 could slow down the
transesterification of alcohols to form oxalates. The control
experiments in Scheme 11, part 1, reveal that it has a positive
effect on the coupling of oxalate 2q with triflate 3a, improving
the yield of the cross-product 4q. This might be due to it
enhancing the reactivity of aryl triflate (Scheme 11, part 2).
Taken together, because heterobenzylic oxalate is more
a
The yields were determined by GC analysis with dodecane as
b
Scheme 11. Effect of AlCl3
internal standard. Yield with respect to the amount of Ni(0).
3 times more 2a than 3b was consumed when 5 equiv of them
was subjected to Ni(0) for 10 h. Meanwhile, dimer 38 from
oxalate was a major component, but no byproduct from aryl
triflate was observed. These results are consistent with a
pathway in which benzyl oxalate might react with nickel first.
To further confirm this assumption, complex Ar−NiII(dppf)
Cl 41 was synthesized from the reaction of Ni(cod)2/dppf with
Ar−Cl. We would expect that, if the reaction begins with Ar−
Cl, the initial rate of reaction with Ar−NiII(dppf)Cl 41 (1.0
equiv) would be faster than that of the reaction catalyzed by
Ni(dppf)Cl2 (10 mol %).6g However, the result in Scheme 12b
is opposite to what we expected. This result further confirms
that the reaction of benzyl oxalate with nickel is an initial step
in the reaction with aryl electrophiles.
Most of oxalate 2a was converted to dimer 38 under the
standard conditions without DMO (Scheme 13, part 1,
condition a). To determine whether benzyl oxalate was
activated via a radical process, several experiments were
conducted. (1) Hantzsch ester (HE) is a hydrogen atom donor
capable of trapping carbon radicals, and it has been widely
applied for detecting radical intermediates.39 In the presence of
HE (1 equiv), the formation of dimer 38 was inhibited,
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orthogonal to the conventional cross-couplings. These features
make our approach a very robust and powerful alternative to
the existing methods for the regiodefined synthesis of
biarylmethanes, which occur widely in pharmaceuticals and
functional organic materials. The synthetic utility of this
method was demonstrated by the modification of biologically
active compounds, by concise synthesis of pharmaceuticals,
and by its applications in peptide modification and
conjugation. The success of this process is dependent on the
finding of in situ activation of alcohols with DMO, which can
be merged with the cross-coupling protocol. This work has
established a new framework for deoxygenative functionaliza-
tion of alcohols via the cross-coupling method. We thus
anticipate our assay to be a starting point for more useful
discoveries in these promising fields. Further expansion of the
scope of the dynamic kinetic cross-electrophile reaction are
ongoing in our laboratory.44
Scheme 13. Radical Trapping and Radical Clock
Experiments
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12462.
■
sı
a
b
Standard conditions in Table 1, but DMO was not used. The
c
theoretical yield is 50%. Ni(cod)2 (1.0 equiv), dppf (1.0 equiv), phen
(20 mol %) were used.
General information, experimental procedures, new
compound characterization, spectroscopic data, and
NMR spectra (PDF)
whereas a significant increase in benzyl−H 37 was observed
(Scheme 13, part 1, condition b). (2) α-Cyclopropylstyrene 42
is a well-known radical clock substrate probe.40 The reaction of
2a with α-cyclopropylstyrene 42 afforded the ring-expanded
product 43 either under the standard conditions or in the
presence of [Ni(cod)2/dppf/phen] (Scheme 13, part 2). These
results suggest that the benzyl oxalates might be activated by a
nickel catalyst via a radical process.
AUTHOR INFORMATION
Corresponding Author
■
Xing-Zhong Shu − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China; orcid.org/
0000-0002-0961-1508; Email: shuxingzh@lzu.edu.cn
On the basis of the above results and literature reports,41 we
tentatively propose a catalytic cycle as shown in Scheme 14.
Authors
Peng Guo − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Scheme 14. Proposed Reaction Mechanism
Ke Wang − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Wen-Jie Jin − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Hao Xie − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Liangliang Qi − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China
Xue-Yuan Liu − State Key Laboratory of Applied Organic
Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, China; orcid.org/
0000-0002-8862-9924
The nickel/manganese-catalyzed transesterification of alcohol
with DMO affords benzyl oxalate 2. The reaction of oxalate 2
with Ni(0), possibly via a radical process,42 followed by
reduction with Mn, would afford benzyl−Ni(I). The oxidative
addition of benzyl−Ni(I) intermediate with aryl electrophiles,
followed by reductive elimination, would afford the desired
product.43
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12462
3. CONCLUSION
Notes
The authors declare no competing financial interest.
In summary, we have reported the first dynamic kinetic cross-
electrophile reaction that enables the deoxyarylation of benzyl
alcohols with aryl electrophiles. This protocol is distinguished
by its broad substrate scope, excellent functional group
compatibility, and the unique chemoselectivity that is
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
for its financial support (21772072, 22071084).
■
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