Nickel-Catalyzed Directed Cross-Electrophile Coupling of Phenolic Esters with Alkyl Bromides

Article abstract of DOI:10.1021/acs.orglett.0c03342

Herein, we demonstrate the successful use of robust phenolic esters as an electrophilic acyl source in the reaction with diverse primary and secondary unactivated alkyl bromides. The cleavage of the relatively inert C-O bond is facilitated by the neighboring coordinating hydroxyl or sulfonamide moiety. By circumventing the use of pregenerated organometallics, this method allows efficient preparation of a variety of o-hydroxyl and tosyl-protected o-amino aryl ketones with high compatibility with a wide range of functionalities.

Full text of DOI:10.1021/acs.orglett.0c03342

pubs.acs.org/OrgLett
Letter
Nickel-Catalyzed Directed Cross-Electrophile Coupling of Phenolic
Esters with Alkyl Bromides
Feiyan Yang, Decai Ding, and Chuan Wang*
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ABSTRACT: Herein, we demonstrate the successful use of robust
phenolic esters as an electrophilic acyl source in the reaction with
diverse primary and secondary unactivated alkyl bromides. The
cleavage of the relatively inert C−O bond is facilitated by the
neighboring coordinating hydroxyl or sulfonamide moiety. By
circumventing the use of pregenerated organometallics, this method
allows efficient preparation of a variety of o-hydroxyl and tosyl-
protected o-amino aryl ketones with high compatibility with a wide range of functionalities.
Scheme 1. Transition Metal-Catalyzed Cross-Coupling
Reactions Involving Electrophilic Acylating Agents
etones are not only versatile building blocks in organic
synthesis but also a ubiquitous structural unit in natural
K
products and synthetic pharmaceuticals. Nickel-catalyzed
cross-electrophile coupling of electrophilic acylating agents
with aryl or alkyl (pseudo)halides has emerged as a powerful
method for preparing ketones with high functionality tolerance
through circumventing the use of highly reactive pregenerated
organometallics.1 However, successful electrophilic acyl
sources in this field are limited to activated carboxylic acid
derivatives, e.g., acid halides,2 anhydrides,3 activated amides,4
thioesters,2a,5 and o-pyridinyl esters,6 which suffer from one or
more of the following issues, including instability against
moisture, susceptibility to undergo side reactions due to high
reactivity, and synthesis requiring malodorous starting
materials (Scheme 1A). Therefore, the use of more robust
esters in the cross-electrophile coupling is highly desired.7 On
the contrary, easily accessible phenolic esters have been
intensively studied as coupling partners in the palladium- or
nickel-catalyzed cross-coupling reactions with various nucleo-
philic reagents, such as organoborons,8 organozincs,9 ami-
nes,8d,e,10 imines,11 zinc cyanide,12 thiols,13 diborons,14 silyl
boron,15 stannyl boron,16 and heteroarenes17 (Scheme 1B).
These redox-neutral reactions could proceed in distinct
reaction pathways depending on the reaction conditions,
which leads to the formation of either carbonyl-containin-
g
8a−g,10a−c or decarbonylated products.8f−l,9,10d,11−18 However,
cross-electrophile coupling involving phenolic esters as
precursors is still elusive due to their low reactivity.
Directing group strategy19 has been successfully applied in
various types of cornerstone organic reactions, e.g., epox-
idation,20 aziridination,21 dihydroxylation,22 ring opening of
small heterocycles,23 and C−H functionalizations,24 rendering
these processes highly regioselective. Aiming to address the
challenge of using relatively inert phenolic esters in the nickel-
catalyzed cross-electrophile coupling, we envisioned that the
introduction of an appropriate orienting group into the vicinity
Received: October 8, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03342
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
of the phenyl ester moiety would facilitate its activation by the
catalyst, which enables the further transformation with alkyl
halides, providing a new route to synthesize ketones under
organometallic-free conditions (Scheme 1C).
To realize the directed coupling of phenolic esters, we
selected phenyl salicylic acid ester (1a) and a primary alkyl
bromide (2a) as the standard substrates for optimization of the
reaction conditions (Table 1). After screening various reaction
13). Moreover, increasing and decreasing the reaction
temperature showed detrimental effects on the reaction
efficiency (entries 14 and 15, respectively). When the reaction
was performed with 10 mol % catalyst loading, the yield
diminished to 68% (entry 16).
After establishing the optimal reaction conditions, we started
to assess the substrate spectrum of this Ni-catalyzed reaction
(Scheme 2). First, the scope of alkyl halides was investigated.
Table 1. Variations of the Reaction Conditions from the
Optimal Conditions
Scheme 2. Evaluation of the Substrate Scope of Hydroxyl-
Directed Reactions by Variation of the Alkyl Halides
a
a,b
b
entry
variation from the standard conditions
yield (%)
1
2
3
4
none
L2 instead of L1
L3 instead of L1
L4 instead of L1
NiBr2 instead of NiBr2·diglyme
Ni(acac)2 instead of NiBr2·diglyme
Ni(OTf)2 instead of NiBr2·diglyme
Ni(COD)2 instead of NiBr2·diglyme
DMA instead of DMF
NMP instead of DMF
i-PrOH instead of DMF
toluene instead of DMF
Mn instead of Zn
92
50
trace
12
68
50
40
76
72
82
0
5
6f
7
8
9
10
11
12
13
14
15
16
0
44
75
68
68
40 °C instead of 60 °C
80 °C instead of 60 °C
10 mol % catalyst loading
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of phenyl salicylic acid ester (1a) using 1.5 equiv of alkyl
bromide 2a, 15 mol % NiBr2·diglyme, 15 mol % 1,10-phenanthroline,
b
and 4 equiv of Zn in 0.5 mL of DMF at 60 °C for 10 h. Yield of the
isolated product after column chromatography.
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of phenyl salicylic acid ester (1a) using 1.5 equiv of alkyl
bromides 2a−v, 15 mol % NiBr2·diglyme, 15 mol % 1,10-
phenanthroline (L1), and 4 equiv of Zn in 0.5 mL of DMF at 60
parameters, we identified the following optimal conditions: 15
mol % NiBr2·diglyme, 15 mol % 1,10-phenanthroline (L1),
and 4 equiv of Zn as a reductant in DMF (0.4 M) at 60 °C for
10 h. Under this condition, target coupling product 3aa was
obtained in 92% yield (entry 1). Notably, no decarbonylative
coupling product was detected. In the case of 4,4′-bipyridine
(L2) as a ligand, the desired reaction also proceeded, albeit in a
moderate yield (entry 2). When terpyridine L3 was employed,
only a trace amount of compound 3aa could be formed (entry
3). Furthermore, the reaction using phosphine ligand L4
afforded coupling product 3aa in a low yield (entry 4). Other
Ni(II) salts and Ni(COD)2 were also able to promote the
acylation reaction, but less efficiently (entries 5−8). In other
polar aprotic solvents like DMA and NMP, good results could
be achieved (entries 9 and 10, respectively), whereas the
coupling reaction was ceased in protic iPrOH (entry 11) and
nonpolar toluene (entry 12). Replacing Zn with Mn as a
reducing agent resulted in a dramatically decreased yield (entry
b
°C for 10 h. Yield of the isolated product after column
c
chromatography. Reactions were performed using the corresponding
d
iodides. Reactions were performed on a 5 mmol scale of 1a.
e
f
Determined by 1H NMR spectrocopy. Reaction performed with
enantiopure (1S,2S,4R)-menthyl bromide.
To our delight, diverse primary (2a−s) and secondary (2t−v)
alkyl bromides were successfully reacted with phenyl salicylic
acid ester (1a), furnishing a series of aryl ketones 3aa−av in
moderate to excellent yields wherein a wide range of valuable
functional groups, including alkyl chloride (3ai), aryl ether
(3aj), silyl ether (3ak and 3al), ketal (3am), ester (3aa and
3am−ar), and hydroxyl (3as), proved to be compatible.
Remarkably, the orthogonality of this process regarding
nondirected phenyl and naphthyl ester was confirmed in the
B
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reactions delivering 3ao and 3ar. Furthermore, alkyl iodides
were also tested as substrates in the case of 3ab and 3ap. The
desired reactions occurred, but the reaction efficiency was
lower than those using their bromo analogues. A limitation of
this method was observed in the case of tertiary alkyl halides,
benzyl halides, and aryl halides, which failed to afford the target
coupling products. It is noteworthy that the reaction could be
simply scaled up to 5 mmol, affording compound 3ab in 88%
yield.
Scheme 4. Evaluation of the Substrate Scope of
Sulfonamide-Directed Reactions
a,b
Subsequently, we continued to evaluate the substrate
spectrum with regard to the phenyl salicylic acid esters
(Scheme 3). Incorporation of an electron-donating (1b−f) or
Scheme 3. Evaluation of the Substrate Scope of Hydroxyl-
Directed Reactions by Variation of the Phenyl Salicylic Acid
a,b
Esters
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of o-tosyl amide-substituted phenyl benzoates 4a−d using 1.5
equiv of alkyl bromides 2, 15 mol % NiBr2·diglyme, 15 mol % 1,10-
phenanthroline (L1), and 4 equiv of Zn in 0.5 mL of DMF at 60 °C
b
for 10 h. Yield of the isolated product after column chromatography.
c
d
Determined by 1H NMR spectrocopy. Reaction performed with
enantiopure (1S,2S,4R)-menthyl bromide.
aryl ketones 5 were produced in moderate to good yields. In
comparison to the hydroxyl-directed reactions, a similar
outcome with regard to the substrate scope was achieved
wherein the efficiency was generally lower.
To demonstrate the utility of our method, derivatizations of
the cross-coupling products were carried out (Scheme 5). First,
compounds 3ab and 3ah were smoothly converted into
triflates 6 and 9, respectively. The former was subsequently
subjected to a Pd-catalyzed Suzuki−Miyaura coupling with
phenylboronic acid, furnishing product 7 in a high yield.
Furthermore, it has been reported in the literature that the
triflate group of 6 could be simply removed through a Pd-
catalyzed reduction, enabling the hydroxyl functionality as a
removable directing group.25 Taking advantage of both the
triflate and the ketone moiety contained in 9, we successfully
transformed it into a 3-ylidenephthalide 10 in excellent yield
via a Pd-catalyzed cyclocarbonylation.26 Notably, our method
permitted the selective alkylation of diester 1i wherein the
phenyl ester moiety at the para position remained intact. After
methylation of the hydroxyl group of 3ib, the corresponding
product could engage in a Pd-catalyzed cross-coupling with
aniline,10b affording a trifunctionalized benzene 11 in a good
yield over two steps.
Some control experiments were carried out to shed light on
the mechanism of the studied reaction (Scheme 6). As
demonstrated above, the outcome of the reactions using
diester 1i confirmed the significant influence of the hydroxyl
moiety. To further verify the directing effect, two control
reactions were conducted, in which the hydroxyl functionality
was either protected by methyl or relocated to the para
position (Scheme 6A,B). In both cases, the phenyl ester
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of phenyl salicylic acid esters 1b−k using 1.5 equiv of alkyl
bromide 2b or 2k, 15 mol % NiBr2·diglyme, 15 mol % 1,10-
phenanthroline (L1), and 4 equiv of Zn in 0.5 mL of DMF at 60 °C
b
for 10 h. Yield of the isolated product after column chromatography.
c
Reaction performed with 3 equiv of the alkyl bromide.
an electron-withdrawing (1g and 1h) substituent on the
various positions of the phenyl ring was tolerated, providing
the coupling products 3bk−hk in moderate to high yields.
Notably, complete proximally selective C−O bond cleavage
could be achieved in the case of phenolic diester 1i, leading to
the formation of ketone 3ik in a good yield. In addition, o-
hydroxyl ester 1j with a naphthyl backbone was also a
pertinent precursor. On the basis of this result, we successfully
applied our method in the preparation of a BINOL derivative
3kb.
At this juncture, we turned our attention to seek a new
directing group for this Ni-catalyzed reaction. Several amides
were tested, and the desired coupling reaction proceeded only
in the case of tosyl amide. The scope of both o-tosylamide-
substituted phenyl benzoates and alkyl bromides was surveyed,
and the results are summarized in Scheme 4. Under the
standard reaction conditions, a series of o-NHTs-substituted
C
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a
NiBr2·diglyme in the presence of Zn provided N-tosyl
benzenesulfonamide (12) in 22% yield (Scheme 6D). In
contrast, either the cross-coupling product or the decarboxy-
lated product was not formed when using stoichiometric
Ni(COD)2 (Scheme 6E). These results suggest that a catalytic
cycle initiated by a Ni(0) species without an intermediate
reduction is not possible. Furthermore, the recent study of
Diao et al. revealed that Zn is insufficient to reduce Ni(II) to
Ni(0) under conditions similar to ours.27 The formation of 12
in Scheme 3D could be interpreted as follows. The phenyl
ester moiety performs oxidative addition to Ni(I) via C−O
bond cleavage, and the decarbonylation process could occur in
the absence of an alkyl bromide as the coupling partner.
Treatment of intermediate 13 with water would generate 12.
It is known that alkyl bromides can interact with low-valent
nickel to afford free alkyl radicals.3b,27,28 To verify if the same
process occurs in our reaction, 6-bromohex-1-ene (2w) was
employed as a radical clock under the standard reaction
conditions, and the results argue for a reaction pathway
involving escape-bound radical intermediates.29
Scheme 5. Derivatizations of the Cross-Coupling Products
On the basis of the results of the control experiments and
the radical clock studies, we tentatively propose a plausible
mechanism in Scheme 7. Initially, Ni(I)Br is produced under
a
Reaction conditions: (a) Tf2(O) (1.5 equiv), NEt3 (1.5 equiv),
DCM, 0 °C to rt, 24 h; (b) Pd(PPh3)4 (5 mol %), PhB(OH)2 (1.5
equiv), Na2CO3 (2.5 equiv), DME/H2O (1:2), 100 °C, overnight; (c)
Pd(OAc)2 (10 mol %), dppp (10 mol %), NEt3 (2.5 equiv), 1 atm of
CO, DMF, 60 °C, overnight; (d) NiBr2·diglyme (15 mol %), 1,10-
phenanthroline (15 mol %), Zn (4 equiv), DMF, 60 °C, 10 h; (e)
MeI (3 equiv), K2CO3 (4 equiv), DMF, 55 °C, 8 h; (f) Pd(IPr)(allyl)
Cl (3 mol %), K2CO3 (1.5 equiv), H2O (10 equiv), toluene, 110 °C,
16 h.
Scheme 7. Proposed Reaction Mechanism
Scheme 6. Control Experiments
reductive conditions, which undergoes hydroxyl- or sulfona-
mide-directed oxidative addition with phenolic esters 1 or 4.
The resultant Ni(III) complex I is reduced by Zn to afford a
Ni(I) species II, which interacts with alkyl bromides 2 to
generate free alkyl radicals III. The subsequent oxidation of
Ni(II) intermediate IV by alkyl radicals III results in the
formation of a Ni(III) complex V, which upon facile reductive
elimination provides the coupling product 3 or 5 and
regenerates Ni(I)Br for the next catalytic cycle.
In summary, we developed a nickel-catalyzed directed cross-
electrophile coupling between phenolic esters and unactivated
alkyl bromides. The directing effect of hydroxyl and
sulfonamide moiety enables the efficient cleavage of the
relatively inert phenolic C−O bond under mild reductive
conditions, providing a new approach to various o-hydroxyl
and tosyl-protected o-amino aryl ketones with a high tolerance
of a broad range of functional groups. Relying on the hydroxyl
remained unreacted, indicating that both the presence and the
position of the orienting hydroxyl group play a pivotal role in
this Ni-catalyzed reaction. Next, pregenerated n-octyl zinc
bromide was employed as the starting material instead of the
corresponding organo bromide, and no conversion of ester 1a
was detected, excluding the reaction pathway of Negishi cross-
coupling (Scheme 6C). The stoichiometric reaction of 4a with
D
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03342.
Representative experimental procedures and necessary
characterization data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Chuan Wang − Hefei National Laboratory for Physical
Science at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui
230026, P. R. China; Center for Excellence in Molecular
Synthesis of CAS, Hefei, Anhui 230026, P. R. China;
orcid.org/0000-0002-9219-1785; Email: chuanw@
ustc.edu.cn
Authors
Feiyan Yang − Hefei National Laboratory for Physical Science
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P. R.
China
Decai Ding − Hefei National Laboratory for Physical Science
at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, P. R.
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03342
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by National Natural Science
Foundation of China (Grant 21772183), the Fundamental
Research Funds for the Central Universities
(WK2060190086), “1000-Youth Talents Plan” start-up fund-
ing, and the University of Science and Technology of China.
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via C−N Bond Activation. Org. Lett. 2017, 19, 2536−2539. (b) Zhuo,
J.; Zhang, Y.; Li, Z.; Li, C. Nickel-Catalyzed Direct Acylation of Aryl
and Alkyl Bromides with Acylimidazoles. ACS Catal. 2020, 10, 3895−
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(5) (a) Ai, Y.; Ye, N.; Wang, Q.; Yahata, K.; Kishi, Y. Zirconium/
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