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Ipso-Borylation of Aryl Ethers via Ni-catalyzed C–OMe Cleavage
Cayetana Zarate,† Rubén Manzano† and Ruben Martin*†§
†
§

Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007, Tarragona, Spain
Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluïs Companys, 23, 08010, Barcelona, Spain

Supporting Information Placeholder

ABSTRACT: A Ni-catalyzed ipso-borylation of aryl
ethers via C(sp2)– & C(sp3)–OMe cleavage is described.
The transformation is characterized by its wide substrate
scope under mild conditions and an exquisite divergence
in site-selectivity that can be easily switched by an appropriate selection of the boron reagent.

In recent years, C–O electrophiles have emerged as
powerful alternatives to aryl halides as coupling partners
in the cross-coupling arena.1,2 While the utilization of
activated aryl esters, carbamates or sulfonates has become routine, it comes as a surprise that aryl methyl
ethers, the simplest derivatives in the phenol series, have
received much less attention.2 This is likely due to the
high activation energy required for C–OMe scission and
the low propensity of methoxy residues to act as leaving
groups. Not surprisingly, these reactions remain essentially confined to C–C bond-formations using highly
reactive, well-defined, stoichiometric and, in many cases, air-sensitive organometallic reagents (Scheme 1, path
a).2 Intriguingly, a C–heteroatom bond-formation has
been virtually unexplored (path b),3 thus constituting a
unique opportunity to implement unconventional strategies not apparent at first sight in our chemical portfolio.
Scheme 1. Catalytic C(sp2)-OMe Bond-Cleavage.
C-C bondformation
C
R1
known

C-heteroatom
bond-formation
OMe

C M
path a

R1

M = MgX,ZnR2,
B(OR)2

X
path b

X = heteroatom

X
R1
virtually
unknown

The pivotal role of organoboron reagents as synthetic
intermediates has attracted the attention of both industrial and academic laboratories for decades.4 Not surprisingly, the recent years have witnessed the development
of a myriad of catalytic methods for their synthesis.5-8 At
present, the inclusion of aryl methyl ethers has merely
been employed as a control element for promoting C–B
bond-forming reactions at either ortho-, meta- or paraposition via ortho-metalation or the intermediacy of aryl
halides via electrophilic aromatic substitution (Scheme
2, path a),9,10 or C-H activation (path b).6 From a synthetic standpoint, the ability to promote a complementary ipso-borylation of aryl methyl ethers would be highly rewarding, offering a counterintuitive, yet practical,
new retrosynthetic approach to organoborane reagents
from simple precursors.11 At the outset of our investigations, it was unclear whether such scenario would be
feasible given the exceptional inertness of C–OMe
bonds,2 the natural proclivity of aryl ethers to promote
functionalization at ortho- or para-positions12 and the
virtual lack of precedents for C–heteroatom bondformation via C–OMe cleavage.3 If successful, such a
strategy would not only open up new vistas in C–B
bond-formation but also might represent a significant
step-forward for implementing aryl methyl ethers as
privileged counterparts in cross-coupling endeavours.2
As part of our interest in C–O bond-functionalization,13
we describe herein the first catalytic ipso-borylation of
aryl methyl ethers via C(sp2)– and even C(sp3)–O cleavage, thus exploiting a previously unrecognized opportunity in this field.14,15 This protocol is characterized by
its wide scope under mild conditions and by an exquisite

O
O
Me
B B
Me
Me
O
O
2a (2 equiv)
Ni(COD)2 (10 mol %)
OMe
PCy3 (20 mol %)

Me

divergence in site-selectivity that can be modulated by a
judicious choice of the corresponding boron reagent.
Scheme 2. Borylation Events of Aryl Methyl Ethers.
ortho- & para-selectivity
OMe
X-B(OR)2
path a
R1
R2
R1=H; R2= B(OR)2
R1=Br,I; R2= H
R1=B(OR)2; R2= H
R
OMe
R

B(OR)2
m>p>>o
meta-selectivity

X-B(OR)2
path b
C-H
activation

1a

Entry
OMe

Ni catalyst
B2(OR)4
path c
this work

HCO2Na (3 equiv)
PhMe, 95 ºC, 15 h

Me
O
B

Me
O

3a

3a (%)b

1
2

We began our investigations by evaluating the reaction
of 1a with B2(nep)2 (2a). After extensive experimentation,16 we found that a cocktail containing Ni(COD)2,
PCy3 and HCO2Na promoted the targeted reaction at 95
ºC, affording 3a in 80% isolated yield. Although
HCO2Na has commonly been employed as reducing
agent in cross-coupling reactions,17 marginal formation
of naphthalene was detected in the crude mixtures
(<9%). Interestingly, the utilization of other bases provided inferior results (entries 11 and 12).18 As anticipated, the nature of the ligand employed had a profound
influence on the reaction outcome (entries 5-7). Strikingly, the inclusion of otherwise related PCy2Ph had a deleterious effect on reactivity, thus showing the subtleties
of our protocol (entry 5). Similarly, N-heterocyclic carbenes provided 3a in lower yields (entries 6 and 7).19
Notably, a difference in reactivity was found when operating under a NiCl2(PCy3)2, Ni(PCy3)2(C2H4) or
[Ni(PCy3)2]2N2 regime (entries 8-10). Although tentative, we believe that COD might be acting as a noninnocent ancillary ligand to stabilize the putative
Ni(PCy3)2 species and prevent decomposition pathways.20 The lack of reactivity of B2(pin)2 (2b; entry 13)
is noteworthy, suggesting an intimate interplay between
steric effects and productive C–B bond-formation. In
line with this notion, ethoxy, isopropoxy or benzyloxy
groups gave lower conversions to 3a.16 As anticipated,
control experiments revealed that all reaction parameters
were critical for success (entries 2-4).16
Table 1. Optimization of the Reaction Conditions.a

0

without HCO2Na

42

5

PCy2Ph instead of PCy3

0

6

IPr·HCl instead of PCy3d

0

7

ICy·HBF4 instead of PCy3d

48

8

NiCl2(PCy3)2 instead of Ni(COD)2/PCy3

0

9

Ni(PCy3)2(C2H4) instead of Ni(COD)2/PCy3

61

10

[Ni(PCy3)2]2(N2) instead of Ni(COD)2/PCy3

64

11

PhCO2Na instead of HCO2Na

73

12

CsF instead of HCO2Na

65

13

Ipso-selectivity

Unconventional Ipso C-OMe borylation
Exquisite divergence in site-selectivity
C(sp2)– & C(sp3)–OMe cleavage

without PCy3

4

R

without Ni(COD)2

3

B(OR)2

Deviation from standard conditions
none

B2(pin)2 (2b) instead of B2(nep)2 (2a)

2

88 (80)c
0

a

Conditions: 1a (0.50 mmol), 2a (1.00 mmol), Ni(COD)2
(10 mol%), PCy3 (20 mol %), HCO2Na (1.50 mmol) in
PhMe (2.0 mL) at 95 ºC, 15 h. b GC yields using decane as
internal standard. c Isolated yield. d +NaOtBu (25 mol%).

With a reliable procedure in hand, we next turned our
attention to explore the preparative scope of our catalytic
ipso-borylation technique via C(sp2)–OMe bondcleavage (Table 2). As shown, a wide variety of naphthyl ethers possessing a diverse set of substitution patterns could perfectly be tolerated, obtaining in all cases
good yields of 3a-3k. The chemoselectivity profile of
our method was nicely illustrated by the fact that silyl
groups (3b), silyl ethers (3e), esters (3f and 3k), ketones
(3g) and amines (3i) could all be equally accommodated.
Importantly, the presence of nitrogen-containing heterocycles did not interfere with productive C−B bondformation (3d and 3h). As shown for 3j, the reaction
was not hampered by the presence of ortho-substituents.
It is worth noting that no racemization of the chiral center in 3k was observed when exposing enantioenriched
1k (96% ee) under our optimized reaction conditions.
Intriguingly, the inclusion of CsF and B2pin2 (2b) cleanly afforded 3l and 3m via C(sp3)–OMe cleavage.21-23
Likewise, benzyl methyl ethers posessing β-hydrogens
posed no problems, obtaining 3n in 81% yield.24,25
Table 2. Ipso-Borylation of Naphthyl Methyl Ethers

B2(OR)4
Ni(COD)2 (10 mol %)
PCy3 (20 mol %)

OMe
R1

C(sp2)–OMe

cleavagea,b
Bnep

R1
3a-n

Bnep

TIPSO

CO2tBu
55% (3d)
Bnep

(3e)c

NMe2

Me

62% (3i)

MeO2C
Me

67% (3j)

C(sp3)–OMe cleavageb,c

Bnep

72% (3k)

Bpin
Bpin

Bpin

Me
62% (3m)

81% (3n)d

a

As for Table 1 (entry 1) using 2a. b Isolated yields, average of at least two independent runs. c 120 ºC. d As for
Table 1 (entry 1), but employing 2b (1.00 mmol) and CsF
(1.50 mmol) at 120 ºC. d Determined by GC (decane as
internal standard). Bnep: 5,5-dimethyl-1,3,2-dioxaborolane;
Bpin: 4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

A close inspection into the literature data indicates that
regular arenes are several orders of magnitude less reactive than non π-extended systems in C–O bond-cleavage
protocols.26,27 At present, such lack of reactivity has
been overcome primarily by employing stoichiometric
and highly reactive organometallic species,1,2 thus representing a drawback from a practical and synthetic point
of view. In light of these precedents, we wondered
whether our Ni-catalyzed ipso-borylation event could be
applied to more challenging aryl methyl ethers. Although such scenario proved to be difficult, we speculated that the presence of suitable ortho-substituents might
facilitate the elusive C–OMe bond-cleavage in anisole
derivatives. As shown in Table 3, this was indeed the
case for a variety of aryl methyl ethers possessing orthoesters (5a-5c), trifluoromethyl groups (5d) or amides
(5e).28,29 Importantly, the presence of such groups in
para or meta position gave negligible conversion to
products, thus providing compelling evidence that electronic effects are not the only factor coming into play.30
In contrast to the results of Table 1 (entry 13), we found
that B2(pin)2 (2b) could be utilized for effecting the
C(sp2)–OMe bond-cleavage (5b, 5e).31 As for Table 2,
we found that a C(sp3)–OMe bond-cleavage was within
reach (5f and 5g).
Table 3. Ipso-Borylation of Aryl Methyl Ethers.

a,b

56% (5d)d

59% (5c)

Bpin

Bpin

O
56% (5e)c,e

Bnep

Bnep

CF3

CO2tBu

NEt2

N
Me
57% (3h)

R
R=CO2Me, 66% (3f)
R=COtBu, 55% (3g)

Bnep
Bnep

54% (5a; R = Bnep)
71% (5b; R = BPin)c
BPin

Bnep

Bnep

5a-g

R

Bnep

84% (3c)

B(OR)2
R1

Base (3 equiv)
PhMe, 95-120 ºC

4a-g

N

R
R=H, 80% (3a)
R=SiEt3, 73% (3b)

61% (3l)

OMe

R1

Base (3 equiv)
PhMe, 95-120 ºC

1a-n

65%

B(OR)2

B2(OR)4 (2a or 2b)
Ni(COD)2 (10 mol %)
PCy3 (20 mol %)

57% (5f)c,f

50% (5g)c,f

a

As for Table 1 (entry 1). b Isolated yields, average of at
least two independent runs. c Using 2b (1.0 mmol). d
HCO2Na (0.50 mmol) e GC yield using decane as internal
standard. f CsF (1.00 mmol) at 120 ºC.

On the basis of the results of Tables 1-3, we concluded
that the nature of the boron reagent might not be entirely
innocent in the reaction outcome. Challenged by such
perception, we speculated that an orthogonal siteselective C–B bond-formation via C–OMe bondcleavage could be achieved. To such end, we examined
the reactivity of 6a and 6b under a 2a or 2b regime
(Figure 1). Interestingly, while the utilization of 2b lead
exclusively to 7a and 7b via C(sp3)–OMe cleavage, a
C(sp2)–B bond-formation was invariably observed with
2a.32 At present, we have no explanation for such intriguing dichotomy. Encouraged by these results, we wondered whether our Ni-catalyzed ipso-borylation could be
employed as a manifold to promote an unprecedented
ipso-halogenation of aryl methyl ethers,33 thus complementing classical ortho- or para-electrophilic aromatic
halogenation techniques.34 As shown in Figure 1 (bottom), this turned out to be the case and a one-pot borylation/iodination sequence allowed for rapidly obtaining
8a and 8b in good overall yield.35 Taken together, the
results of Tables 2-3 and Figure 1 tacitly suggest that our
novel ipso Ni-catalyzed C–OMe borylation will foster
new explorations in carbon-heteroatom bond-forming
reactions via unconventional C–O bond-cleavage.
Figure 1. Orthogonal Borylation via C–OMe Cleavage.a,b
C(sp3)–OMe cleavage with B2pin2 (2b)
OMe
Bpin
MeO

Ni/PCy3 + 2b

Bpin

65% (7a)

73% (7b)
R1

Orthogonal
C–OMe cleavage
1=H; R2=OMe (6b)
R

OMe
R2

Orthogonal
C–OMe cleavage
1=OMe; R2=H (6a)
R

6a or 6b

OMe
I

59% (8a)c

I
OMe

Ni/PCy3 + 2a; then [I]+
Ipso-halogenation
C(sp2)–OMe cleavage with B2nep2 (2a)

64% (8b)d

a

C(sp3)–OMe cleavage: 6a or 6b (0.50 mmol), 2b (1.00
mmol), Ni(COD)2 (10 mol%), PCy3 (20 mol%), CsF (1.50
mmol) in PhMe (2.0 mL) at 120 ºC. b C(sp2)–OMe cleavage: as for Table 1 (entry 1), followed by NaI (1.50 mmol)
and chloramine T·3H2O (1.50 mmol) in 4mL THF/H2O
(1:1) at rt. c Borylation conducted at 120 ºC. d Borylation
conducted with HCO2Na (0.15 mmol)

In summary, we have developed the first ipso-borylation
of aryl methyl ethers via Ni-catalyzed C–OMe bondcleavage, complementing classical ortho-, meta- and
para-borylation techniques. This protocol is distinguished by its broad substrate scope and by an intriguing
selectivity switch depending on the boron reagent employed. Further investigations into related projects will
be reported in due course.

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ASSOCIATED CONTENT

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Supporting Information. Experimental procedures and
spectral data. This material is available free of charge via
the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION
Corresponding Author
* rmartinromo@iciq.es

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Funding Sources
No competing financial interests have been declared.

ACKNOWLEDGMENT
We thank ICIQ, the European Research Council (ERC277883), MINECO (CTQ2012-34054 & Severo Ochoa
Excellence Accreditation 2014-2018; SEV-2013-0319) and
Cellex Foundation for support. Johnson Matthey, Umicore
and Nippon Chemical Industrial are acknowledged for a
gift of metal & ligand sources. C.Z. and R.M. thank
MINECO for a FPU and COFUND scholarship.

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2011, 50, 7097. (e) Yu, D. G.; Li, B. J.; Zheng, S. F.; Guan,
B. T.; Wang, B. Q.; Shi, Z. J. Angew. Chem. Int. Ed. 2010,
49, 4566. (f) Tobisu, M.; Shimasaki, T.; Chatani, N. Angew.
Chem., Int. Ed. 2008, 47, 4866, and citations therein.
π-Extended systems are known to bind stronger than regular
arenes low valent metal complexes in a η2-fashion, probably
due to the retention of a certain degree of aromaticity: Bauer,
D. J.; Krueher, C. Inorg. Chem. 1977, 16, 884. Alternatively,
π-extended systems might generate easier Meisenheimer-type
complexes (ref. 23f) or scenarios dealing with the intermediacy of dearomatized products (ref. 13f)
No C–B bond-formation was found when utilizing electrondonating dimethylamino groups in ortho-position. For the
utilization of other anisole derivatives, see ref. 16.
In sharp contrast with the utilization of ortho tert-butyl esters, we found that ortho methyl esters provided lower yields
(~25% GC yields), thus revealing an intimate interplay between steric effects and C–B bond-formation.
No biaryl formation via Suzuki-Miyaura coupling of in situ
generated aryl boronates with aryl ethers was observed.
Intriguingly, while 5e was cleanly obtained with B2pin2, an
otherwise related reaction with B2(nep)2 did not result in productive C–B bond-formation.
Unreacted starting material and marginal reduction of C–
OMe bond account for the mass balance.
For halogenation of in situ generated aryl boronates, see for
example: (a) Shi, H.; Babinski, D. J.; Ritter, T. J. Am. Chem.
Soc. 2015, 137, 3775. (b) Murphy, J. M.; Liao, X.; Hartwig,
J. F. J. Am. Chem. Soc. 2007, 129, 15434.
Bew, S. P. In Comprehensive Organic Functional Group
Transformations II; Eds., Katritzky, A. R.; Taylor, R. J. K.
Elsevier, Oxford, 2005.

(35) The isolation of the corresponding aryl neopentyl boronates
was particularly cumbersome due to the instability of the boronic esters during purification by column chromatography.

OMe
R1

B2(nep)2 or B2(pin)2
Ni catalyst

R2
R1

Catalytic Ipso Borylation of Aryl Methyl Ethers
via C–OMe Cleavage

OMe

Bnep
R1
R2

PhMe, 95 ºC
Unconventional Ipso C-OMe borylation
Exquisite divergence in site-selectivity
C(sp2)– & C(sp3)–OMe cleavage

R1

Bpin

25 examples
up to 81% yield