Cross-Coupling of Organolithium with Ethers or Aryl Ammonium Salts by C?O or C?N Bond Cleavage

Article abstract of DOI:10.1002/chem.201603436

Various aryl-, alkenyl-, and/or alkyllithium species reacted smoothly with aryl and/or benzyl ethers with cleavage of the inert C?O bond to afford cross-coupled products, catalyzed by commercially available [Ni(cod)₂] (cod=1,5-cyclooctadiene) catalysts with N-heterocyclic carbene (NHC) ligands. Furthermore, the coupling reaction between the aryllithium compounds and aryl ammonium salts proceeded under mild conditions with C?N bond cleavage in the presence of a [Pd(PPh₃)₂Cl₂] catalyst. These methods enable selective sequential functionalizations of arenes having both C?N and C?O bonds in one pot.

Full text of DOI:10.1002/chem.201603436

DOI: 10.1002/chem.201603436
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Cross-Coupling Reactions |Hot Paper|
Cross-Coupling of Organolithium with Ethers or Aryl Ammonium
Salts by CÀO or CÀN Bond Cleavage
Ze-Kun Yang+,[a] Dong-Yu Wang+,[a] Hiroki Minami,[a] Hiroyuki Ogawa,[a] Takashi Ozaki,[a]
Tatsuo Saito,[a] Kazunori Miyamoto,[a] Chao Wang,*[a, b] and Masanobu Uchiyama*[a, b]
Abstract: Various aryl-, alkenyl-, and/or alkyllithium species
reacted smoothly with aryl and/or benzyl ethers with cleav-
age of the inert CÀO bond to afford cross-coupled products,
catalyzed by commercially available [Ni(cod)2] (cod=1,5-cy-
clooctadiene) catalysts with N-heterocyclic carbene (NHC) li-
gands. Furthermore, the coupling reaction between the aryl-
lithium compounds and aryl ammonium salts proceeded
under mild conditions with CÀN bond cleavage in the pres-
ence of a [Pd(PPh3)2Cl2] catalyst. These methods enable se-
lective sequential functionalizations of arenes having both
CÀN and CÀO bonds in one pot.
boron-based transfer agents,[5] or a protocol that uses an in
situ deprotonation.[6] A remarkable improvement in the applic-
ability of organolithium for cross-coupling reactions was
achieved in 2013, when Feringa et al. re-examined the Muraha-
shi coupling and optimized both the selectivity (versus the lith-
ium–halogen exchange) and efficiency.[7] Since then, several
new protocols for Murahashi couplings have been reported,
enabling reactions between various types of organolithium
compounds and halides.[8,9] Herein, we describe our recent
studies on the TM-catalyzed cross-coupling of organolithium
with ethers and ammonium salts by a CÀO or CÀN bond cleav-
age with simultaneous CÀC bond formation, and without lithi-
um–halogen-exchange side reactions.
Introduction
The study of organolithium compounds has a long and rich
history, and the chemistry is employed in many areas of sci-
ence.[1] The use of organolithium as a nucleophilic partner in
the transition metal (TM)-catalyzed cross-coupling can be
traced back to 1975, when Murahashi et al. reported the first
reaction between organolithium and an organic halide cata-
lyzed by Pd.[2] However, since then, the utilization of organo-
lithium in modern TM-catalyzed cross-coupling chemistry has
been largely neglected, in favor of organoboron (Suzuki–
Miyaura reaction), organozinc (Negishi reaction), organomag-
nesium (Kumada–Tamao reaction), and organotin (Stille reac-
tion) reagents,[3] despite many advantages of organolithium
compounds including low cost, commercial availability, and
facile accessibility. The major problem that restricts the applica- Results and Discussion
bility of a cross-coupling with organolithium is the competing
Ni-catalyzed cross-coupling between organolithium and
ethers/silyl ethers
lithium–halogen exchange (dehalogenation), which is usually
quite fast and, thus, lowers the selectivity. In recent years, new
approaches for the Murahashi reaction have been reported,
such as the usage of a flow microreactor for the biaryl cou-
pling,[4] roundabout routes with stoichiometric silicon or
Many phenol/alcohol derivatives such as sulfonates, phos-
phates, and carboxylates are currently available as CÀO electro-
philes in place of halides for TM-catalyzed cross-coupling reac-
tions.[10] Among them aryl alkyl ethers (ArOR) appear particular-
ly attractive,[11] featuring easy accessibility, structural diversity,
low cost, and a high atom efficiency. In 1979, Wenkert et al. re-
ported the first cross-coupling reaction of an ether with
a Grignard reagent in the presence of a Ni catalyst.[12] In recent
decades, several groups, including ours, have developed vari-
ous types of etheric cross-coupling reactions, including
Kumada–Tamao–Corriu,[13] Suzuki–Miyaura,[14] Negishi,[15] and
other reactions.[16] In 2014 and 2015, Rueping et al. reported
a Ni-catalyzed alkylation of aryl or alkenyl ethers with TMS-
CH2Li (TMS=trimethylsilyl), in which the C(sp2)ÀO bond cleav-
age occurred in the absence of a ligand.[17] Around the same
time, we independently explored the potential of a cross-cou-
pling between organolithium and ethers.[18] We selected phe-
[a] Z.-K. Yang,+ D.-Y. Wang,+ H. Minami, H. Ogawa, T. Ozaki, Dr. T. Saito,
Dr. K. Miyamoto, Dr. C. Wang, Prof. Dr. M. Uchiyama
Graduate School of Pharmaceutical Sciences, The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo-to 113-0033 (Japan)
E-mail: chaowang@mol.f.u-tokyo.ac.jp
uchiyama@mol.f.u-tokyo.ac.jp
[b] Dr. C. Wang, Prof. Dr. M. Uchiyama
Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable
Resource Science, and RIKEN Elements Chemistry Laboratory
2-1 Hirosawa, Wako-shi, Saitama-ken, 351-0198 (Japan)
E-mail: chaowang@riken.jp
uchi_yama@riken.jp
[+] These authors contributed equally to this work.
Supporting information and the ORCID for the author of this article can be
found under http://dx.doi.org/10.1002/chem.201603436.
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nyllithium (1a, prepared by a Li/I exchange between iodoben-
zene and tBuLi) and 2-methoxynaphthalene (2aMe) as model re-
actants for the optimization of the reaction conditions
(Table 1).
Table 2. Tuning of the catalyst/ligand loadings.
Table 1. Screening of ligands for the Ni-catalyzed cross-coupling between
phenyllithium (1a) and 2-methoxynaphthalene (2aMe). Internal standard for
GC analysis: n-dodecane (similarly hereafter).
Entry
[Ni(cod)2] [mol%]
SIMes·HCl [mol%]
GC yield 3aa [%]
1
2
3
4
5
6
2
5
5
7.5
10
10
4
10
15
15
20
10
69
86
83
86
93
92
Entry
Ligand
Solvent
GC yield 3aa
(Scheme 1). It is noteworthy that the OR groups (1e OMe,
1 f OTBS, 1g OMOM) on the phenyl ring remained intact
during the reaction, which indicates that cleavage of the ethe-
real CÀO bond is chemoselective. We examined steric effects
and found that the very bulky ortho-substituted phenyllithium
(1b) reacted smoothly, although the reaction required heating
to 708C and the product yield was slightly decreased. As for
heterocycles, the reaction of 1 with several p-rich heteroaro-
matic compounds proceeded in good yields (3la–oa), whereas
thiophenyllithium, furanyllithium, and p-deficient heteroaro-
matic compounds such as pyridinyllithium showed a rather
low reactivity. In addition, alkenyl (1p–q) and alkyllithium (1r–
s) reacted smoothly, albeit the yield was somewhat decreased
(3pa–sa).
1
2
3
4
5
6
7
8
–
PCy3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O
73
62
–
DCYPE
ItBu·HBF4
ICy·HCl
IPr·HCl
IMes·HCl
SIPr·HCl
SIMes·HCl
SIMes·HCl
SIMes·HCl
76
66
72
72
71
86
70
6
9
10
11
THF
Besides the Li/halogen exchange reaction, the directed
ortho-lithiation is also commonly used for the preparation of
organolithium compounds.[19] While the present coupling reac-
tions of lithium reagents 1 obtained by the Li/halogen ex-
change proceeded smoothly (Scheme 1 and Scheme 2A), the
reaction became rather sluggish when 1DoM prepared by an
ortho-lithiation was employed (Scheme 2B). However, addition
of LiBr to the 1DoM solution gave 3ga in a comparable yield to
that obtained with 1 prepared by the Li/halogen exchange.
This result demonstrates that lithium salts play an important
role in determining the reactivity of organolithium,[20] as well
as the yield of this cross-coupling reaction.
Interestingly, the coupling reaction proceeded in 73% yield
at room temperature in toluene in the presence of a catalytic
amount of [Ni(cod)2] (cod=1,5-cyclooctadiene) without any
additional ligands (Table 1, Entry 1). No marked improvement
of the yields was observed with other ligands (Table 1, Entries
2–8), including PCy3, which has been widely used in Ni-mediat-
ed CÀO cleavage reactions. An exceptional reactivity (86%
yield) was obtained when the reaction was performed with
SIMes (Table 1, Entry 9). Note that the reaction became rather
sluggish in etheric solvents such as Et2O and THF (Table 1, En-
tries 10 and 11). Further tuning of the catalyst and ligand load-
ings indicated that a combination of [Ni(cod)2] (10 mol%) and
SIMes (10 mol%) was optimal (Table 2).
Next, we examined the scope and limitations of the cross-
coupling of various methyl ethers (2Me) (Scheme 3). Substituted
2-methoxynaphthalenes (2b–d), 1-methoxynaphthalene (2e),
and 2,7-dimethoxynaphthalene (2 fdi) bearing two CÀO moiet-
ies, were efficiently converted to the corresponding biaryl
products in good to excellent yields. It is known that 1- and 2-
methoxynaphthalenes are usually more reactive than anisole
derivatives in Ni-catalyzed CÀO bond cleavage reactions. In
contrast, most anisole derivatives (2h–j) showed quite high re-
activities in the current coupling, with a few exceptions such
as 2g. Strikingly, the CÀC bond formation of 2h was achieved
efficiently without racemization at the sensitive benzylic/alpha-
amino position. These results demonstrate the potential appli-
cability of this method for late-stage derivatizations of func-
tional molecules. The p-deficient/rich heteroaromatic methyl
ethers 2k–m underwent significantly slower reactions, even at
high temperatures. The benzyl ether 2n containing a C(sp3)ÀO
Under the optimal conditions, we evaluated the scope of
the present coupling reaction of various organolithium species
1 (prepared by a Li/halogen exchange between ArBr/ArI and
tBuLi) by taking 2aMe as a representative aryl methyl ether
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Scheme 1. Ni-catalyzed cross-coupling reactions of various organolithium species 1 with 2-methoxynaphthalene (2aMe).
Scheme 2. Aryllithium 1g prepared by different methods and the coupling reaction with the ether 2aMe
.
Scheme 3. Ni-catalyzed cross-coupling reactions of various organolithium species 1 with the ether 2aMe
.
bond also reacted with 1 under the same conditions to afford
the desired coupling product 3an in 57% yield.
The scope of the OR groups in 2a was then briefly examined
using 1a as the lithium reagent (Scheme 4). Various alkyl
ethers 2aEt, 2aiPr, and silyl ethers 2aTBS could be employed in
this coupling, albeit in slightly lower yields than that of 2aMe
.
However, when the trimethylsilyl ether 2aTMS was used, only 2-
naphthol was obtained; deprotection of the TMS group pro-
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Table 3. Screening of ligands for the Pd-catalyzed cross-coupling between
phenyllithium 1a and ammonium triflate 4aOTf
.
Entry
1
Ligand[a]
Solvent[b]
GC yield 3aa
[Pd2(dba)2] (5 mol%)
PtBu3 (10 mol%)
[Pd2(dba)2] (5 mol%)
tfp (10 mol%)
THF
THF
–
2
32
Scheme 4. Influence of the alkoxy group (OR) of the aryl alkyl ethers 2 for
their reaction with organolithium species 1.
3
4
5
6
7
8
9
PEPPSI-IPr (5 mol%)
[PdCl2(dppf)] (5 mol%)
[Pd(PPh3)4] (5 mol%)
[PdCl2(PPh3)2] (5 mol%)
[PdCl2(PPh3)2] (5 mol%)
[PdCl2(PPh3)2] (5 mol%)
[PdCl2(PPh3)2] (5 mol%)
THF
THF
THF
THF
NMP/THF
toluene/THF
1,4-dioxane
16
43
42
61
–
ceeded preferentially, probably due to the strong nucleophilici-
ty of the organolithium compounds. We have long been inves-
tigating the chemistry of zincates[19a] and have previously re-
ported that dianion-type zincates react with ether in the pres-
ence of Ni catalysts.[15a] Indeed, the phenyl zincate 1aZn, which
was prepared easily by an I/Zn exchange of iodobenzene and
Li2ZnMe4,[21,22] underwent the cross-coupling reaction with
2aTMS under the same conditions to afford 3aa in 64% yield
(Scheme 5).
39
–
[a] dba=Dibenzylideneacetone, dppf=1,1’-bis(diphenylphosphino)ferro-
cene, tfp=tris(2-furanyl)phosphine, PEPPSI-IPr=[1,3-bis(2,6-diisopropylphe-
nyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride. [b] NMP=
N-methylpyrrolidone.
monium salt 4aOTf as model reactants, we found that the com-
monly used [Pd(PPh3)Cl2] gave the highest yield (61%) in THF.
In addition, we found that the counter anion of the ammoni-
um salt played a crucial role in determining the yield of this
coupling, and IÀ was the best, although ammonium triflate has
mostly been employed in previous work (Table 4).
Scheme 5. Ni-catalyzed cross-coupling between the phenyl zincate 1aZn and
2a.
Table 4. Tuning of the catalyst/ligand loadings and the counter anion X in
4aX.
Pd-catalyzed cross-coupling between organolithium and
aryl ammonium salts
Like phenols and alcohols, amine groups also widely occur in
natural products, pharmaceuticals, dyes, and other functional
molecules. Many amines are commercially available, but trans-
formation of NR2 groups is generally difficult, due to the high
stability of the CÀN bond. This limits the utility of amine deriv-
atives for direct CÀN bond conversions.[23] On the other hand,
quaternary organo–ammonium salts can be easily prepared
from various aryl/alkyl amines, and their CÀN bonds exhibit
higher reactivities than those of amines. As pioneered by Wen-
kert et al. in 1988,[24] applications of ammonium salts for cross-
coupling and related reactions have been rapidly developed in
recent years.[25] In most reported cases, Ni catalysts gave the
best outcomes, but the current coupling reaction between the
lithium reagents 1 and the ammonium salts 4 was less effec-
tive under Ni catalysis in various solvents (THF, toluene, Et2O,
1,4-dioxane, and NMP). The use of Pd catalysts gave better re-
sults (Table 3). After extensive experimentation to screen Pd
sources and ligands with the lithium reagent 1a and the am-
Entry
PhLi (1a)[a]
X
GC yield 3aa
1
2
3
4
type A
type B
type C
type C
OTf
OTf
BF4
I
–
58
46
93
[a] Type A: purchased from KANTO (1.06 molLÀ1 solution in cyclohexane/
Et2O, 7:3); type B: type A with LiI (1.5 equiv) as additive; type C: prepared
by Li/Br exchange between tBuLi and PhI.
With the optimized conditions in hand, we examined the
scope and limitations of the present coupling reaction by a CÀ
N bond cleavage (Scheme 6). Aryllithium compounds with
electron-donating and -deficient groups on the phenyl ring
were found to be generally suitable for this coupling, giving
the desired products in moderate to high yields. A sterically
demanding aryllithium did not shut down the reaction (3ba).
Interestingly, this reaction is applicable to phenyl ammonium
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Scheme 6. Pd-catalyzed cross-coupling reactions between the organolithium species 1 and the ammonium salts 4.
Scheme 7. Synthesis of a disubstituted naphthalene by successive cross-coupling reactions.
salts 4m–o to give the desired biphenyl compounds in high to
excellent yields.
alkyl or alkenyl ethers/ammonium salts, etc.), the reaction
mechanism, and synthetic applications of the present method
to biologically active substances are in progress.
Finally, we demonstrated that the two newly developed
methods enable selective and sequential functionalizations of
arenes that bear both CÀN and CÀO bonds in one pot
(Scheme 7). Substrate 5 firstly reacted with 1a in the presence
of a Pd catalyst to give 2-methoxy-6-phenylnaphthalene (2p)
by cleavage of the CÀN bond, and 2p could be directly utilized
without fine purification for the next coupling reaction with
methyllithium (1s) in the presence of the Ni/NHC catalyst,
leading to the methylated product 3sp in 85% yield by a CÀO
bond cleavage. This result opens up a new route for highly re-
giocontrolled syntheses of multi-substituted arenes by succes-
sive CÀX (X=O and N) bond cleavages on poly-functionalized
aromatic rings.
Acknowledgements
This work was supported by the JSPS KAKENHI (S) (No.
24229011) (to M.U.) and the JSPS TEI-SOKU Program (PU14008)
(to C.W.). This research was also partly supported by grants (to
M. U.) from the Takeda Science Foundation, the Asahi Glass
Foundation, the Daiichi-Sankyo Foundation of Life Sciences,
the Mochida Memorial Foundation, the Tokyo Biochemical Re-
search Foundation, the Nagase Science Technology Develop-
ment Foundation, the Yamada Science Foundation, and the Su-
mitomo Foundation.
Conclusions
Keywords: ammonium salt
organolithium · transition metal catalyst
·
cross-coupling
·
ether
·
In conclusion, we have developed two new cross-coupling re-
actions of organolithium compounds through CÀO and CÀN
bond cleavages. The use of industrially/naturally abundant
ether/amine resources is highly desirable, and these methods
provide simple and direct routes for the selective CÀC forma-
tion from various phenol/aniline precursors. These methodolo-
gies also enable late-stage transformations of function-guaran-
teed versatile multi-substituted phenol/aniline compounds. We
believe that this work provides new possibilities for organo-
lithium compounds, as well as new routes for the activation of
inert bonds. Further investigations on the reaction scope (e.g.,
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Received: July 20, 2016
Published online on && &&, 0000
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FULL PAPER
Cut and paste! Various aryl-, alkenyl-,
and/or alkyllithium species smoothly re-
acted with aryl and/or alkyl ethers with
cleavage of the inert CÀO bond, cata-
lyzed by an Ni catalyst. The coupling re-
action between the aryllithium reagents
and aryl ammonium salts also proceed-
ed under mild conditions by a CÀN
bond cleavage in the presence of a Pd
catalyst. These methods enable selective
and sequential functionalizations of
arenes having both CÀN and CÀO
bonds, in one pot.
&
Cross-Coupling Reactions
Z.-K. Yang, D.-Y. Wang, H. Minami,
H. Ogawa, T. Ozaki, T. Saito, K. Miyamoto,
C. Wang,* M. Uchiyama*
&& – &&
Cross-Coupling of Organolithium with
Ethers or Aryl Ammonium Salts by CÀ
O or CÀN Bond Cleavage
&
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Chem. Eur. J. 2016, 22, 1 – 8
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8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!