Making Dimethylamino a Transformable Directing Group by Nickel-Catalyzed C-N Borylation

Article abstract of DOI:10.1002/chem.201503596

The dimethylamino (Me₂N) group is arguably the most versatile functional group capable of highly efficient and site-selective directed aromatic functionalizations at the ortho-, meta-, and para-positions depending on reaction conditions. While the repertoire of Me₂N-directed reactions is growing at a rapid pace, the lack of a general method to transform this group to other functionalities hampers its wider application in organic synthesis. Here we report nickel-catalyzed C-N borylations of aryl- and benzyl-dimethylamines that permit the conversion of a huge library of largely underutilized Me₂N-containing organic molecules into various functional molecules by taking advantage of the wealth of existing C-B functionalization methods.

Full text of DOI:10.1002/chem.201503596

DOI: 10.1002/chem.201503596
Communication
&
Organic Chemistry
Making Dimethylamino a Transformable Directing Group by
Nickel-Catalyzed CÀN Borylation
Hua Zhang,[a] Shinya Hagihara,[a] and Kenichiro Itami*[a, b]
of aromatics.[2–6] In a similar fashion, a range of transition-
Abstract: The dimethylamino (Me2N) group is arguably
metal-catalyzed CÀH functionalization reactions (DoCH) are
the most versatile functional group capable of highly effi-
known to be directed by the Me2N group.[7–16] More recently,
cient and site-selective directed aromatic functionaliza-
a palladium-catalyzed meta-selective aromatic CÀH functionali-
tions at the ortho-, meta-, and para-positions depending
zation (DmCH) employing the Me2N group as a directing
on reaction conditions. While the repertoire of Me2N-di-
group has been reported by the Dong group.[17] While the rep-
rected reactions is growing at a rapid pace, the lack of
ertoire of Me2N-directed reactions is growing at a rapid pace,
a general method to transform this group to other func-
the lack of a general method to transform this group into
tionalities hampers its wider application in organic synthe-
other functionalities hampers its wider application in organic
sis. Here we report nickel-catalyzed CÀN borylations of
synthesis.[10,17,18] We imagined that, if the CÀN borylation of
aryl- and benzyl-dimethylamines that permit the conver-
aryl- and benzyl-dimethylamines could be devised, it would
sion of a huge library of largely underutilized Me2N-con-
enable the conversion of a huge library of Me2N-containing or-
taining organic molecules into various functional mole-
ganic molecules into various functional molecules by taking
cules by taking advantage of the wealth of existing CÀB
advantage of the wealth of existing CÀB functionalization
functionalization methods.
methods.[19,20] We report herein a novel aromatic and benzylic
CÀN borylation method catalyzed by nickel–phosphine com-
plexes (Figure 1).
The dimethylamino (Me2N) group is arguably the most versa-
Prior to our investigation, only a handful of CÀN borylation
tile functional group capable of highly efficient and site-selec-
tive directed aromatic functionalizations (Figure 1). Classically,
reactions had been reported, in contrast to significant efforts
devoted to the development of transition-metal-catalyzed CÀ
N-bond-converting processes.[21–25] Wang developed the metal-
free borylation of anilines by use of diazonium salts, with sub-
strate classes limited to primary anilines.[26] The group of Cha-
tani achieved the nickel-catalyzed CÀN borylation of aromatic
amides.[27] However, remarkably, the borylation of tertiary ani-
lines and benzylic amines still remains unexplored. The recent
success of aryl and benzylic ammonium salts in cross-coupling
reactions encouraged us to explore the possibility of utilizing
these in CÀN borylation reactions.[28–39]
Figure 1. Transformations of the versatile dimethylamino group into various
functional groups enabled by aromatic/benzylic CÀN borylation.
We began by investigating the borylation of phenyl ammo-
nium salt 1a (0.2 mmol), which can be prepared from N,N-di-
methylaniline by simple N-methylation. Bis(pinacolato)diboron
(B2pin2, 0.4 mmol) was employed as the boron source in the
presence of nickel catalysts. After extensive screening, the best
result was obtained when the reaction was conducted in the
presence of [Ni(cod)2] (10 mol%; cod=1,5-cyclooctadiene), tri-
n-butylphosphine (PnBu3, 20 mol%), and NaOtBu (2.0 equiv) in
1,4-dioxane at 708C for 24 h affording phenylboronic pinacol
ester (2a) in 85% GC yield (Figure 2).
The effect of alteration to the standard conditions (effect of
reaction parameters) is listed in Figure 2. In the absence of
[Ni(cod)2], essentially no borylation occurred. The use of nick-
el(II) salts as catalyst precursors resulted in somewhat lower
yields. Product 2a was obtained in lower yield without PnBu3.
The use of other monodentate phosphine ligands (PCy3, PCyp3,
PPh3) and diphosphine ligands (1,3-bis(diphenylphosphino)pro-
pane; dppp) resulted in much lower yields. N-Heterocyclic car-
the Me2N group induces ortho/para-selective electrophilic aro-
matic substitution (SEAr) reactions when directly attached to
an aromatic ring.[1] Through the strong complex-induced prox-
imity effect with organolithium reagents, the Me2N group fea-
tures prominently in directed ortho-metalation (DoM) reactions
[a] Dr. H. Zhang, Prof. Dr. S. Hagihara, Prof. Dr. K. Itami
Institute of Transformative Bio-Molecules (WPI-ITbM) and
Graduate School of Science, Nagoya University
Chikusa, Nagoya 464-8602 (Japan)
E-mail: itami@chem.nagoya-u.ac.jp
[b] Prof. Dr. K. Itami
JST-ERATO, Itami Molecular Nanocarbon Project
Nagoya University, Chikusa, Nagoya 464-8602 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503596.
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Scheme 1. Ni-catalyzed CÀN borylation of aryl ammonium salts 1. Reaction
conditions: 1 (0.2 mmol), B2pin2 (0.4 mmol), [Ni(cod)2] (10 mol%), PnBu3
(20 mol%), NaOtBu (2.0 equiv), 1,4-dioxane (1.5 mL), 708C, 24 h. Isolated
yield. [a] CsF (2.0 equiv), THF (1.5 mL).
Figure 2. Nickel-catalyzed CÀN borylation of phenyl ammonium salt 1a and
effect parameters.
bene ligands (IPr and IMes) were also less efficient. The use of
tert-butoxide-derived bases seems to be critical, with CsF and
K3PO4 giving little or no borylated product in 1,4-dioxane.
When DME or THF were used as the solvent, decreased yields
were observed. Either increasing or lowering the temperature
led to a decreased yield.
Table 1. Optimization of Ni-catalyzed CÀN borylation of benzylic ammo-
nium salt 3a.[a]
With the optimized reaction conditions in hand, a variety of
aryl ammonium salts 1 were subjected to CÀN borylation
(Scheme 1). Aryl ammonium salts substituted with a methyl
group in any position afforded the corresponding borylated
products (2b, 2c, and 2d) in good yields. The position of the
substituent seems to have no influence on the yield. Sub-
strates bearing electron-donating substituents worked well
under the standard conditions, whereas compared to electron-
donating substituents, electron-withdrawing substituents like F
and CF3 furnished the corresponding products in lower yields.
Ester and ketone groups could be tolerated under modified
conditions using CsF as the base and THF as the solvent (2i
and 2j).
After establishing the conditions for the CÀN borylation of
aryl ammonium salts, we investigated the CÀN borylation of
benzylic amine derivatives that are another class of substrates
used in a range of Me2N-directed reactions. Reaction condi-
tions were optimized using benzylic ammonium salt 3a as the
substrate (Table 1). Under conditions identical to those of aro-
matic CÀN borylation, 3a was successfully converted to the
corresponding benzylic boronate 4a in 70% yield (Table 1,
entry 1). While the use of THF as a solvent resulted in lower
yield (entry 2), DME turned out to be a somewhat superior sol-
vent (entry 3). As for the ligand, PnBu3 again proved to be a su-
perior ligand in CÀN borylation (entries 3–5). Nickel(II) salts
Entry
[Ni]
[L]
Solvent
Yield
[%][b]
1
2
3
4
5
6
7
8
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
NiBr2
PnBu3
PnBu3
PnBu3
PCy3
IPr HCl
PnBu3
PnBu3
PnBu3
dioxane
THF
70
50
72
33
55
66
81
82
DME
DME
DME
DME
DME
DME
NiCl2
Ni(NO3)2·6H2O
[a] Reaction conditions: 3a (0.2 mmol), B2pin2 (0.4 mmol), Ni catalyst
(10 mol%), ligand (20 mol%), NaOtBu (2.0 equiv), solvent (1.5 mL), 708C,
24 h. [b] Determined by GC analysis using n-dodecane as an internal stan-
dard.
such as NiBr2 and NiCl2 could also be used as catalyst precur-
sors (entries 6 and 7), but even more pleasingly, we found that
Ni(NO3)2·6H2O, which is much more stable and cheaper than
[Ni(cod)2] (Ni(NO3)2·6H2O, $167.5 for 1 kg; [Ni(cod)2], $65.6 for
2 g from Sigma-Aldrich), functioned as a pre-catalyst providing
4a in 82% yield (entry 8).
A variety of benzylic ammonium salts 3 were subjected to
CÀN borylation under the influence of Ni(NO3)2·6H2O/PnBu3
(Scheme 2). Benzylic ammonium salts substituted with
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dehydroxylation of the tertiary alcohol can be conducted
under the Pozharskii’s conditions[43] followed by reductive
N-methylation to produce 7 in 97% yield. The NMe2 group in
7 could be transformed to a Bpin group by N-methylation with
methyl triflate followed by the CÀN borylation under our con-
ditions to furnish 8 in 48% overall yield. The boronate 8 could
then be subjected to palladium-catalyzed carbonylation to
give ortho-substituted methyl benzoate 9 in 76% yield.
The CÀN borylation can also be coupled with a Me2N-direct-
ed SEAr reaction. For example, the Me2N group can direct the
para-selective bromination of 10 with NBS in the presence of
a catalytic amount of NH4OAc (96% yield). The obtained bro-
mide 11 undergoes smooth Suzuki–Miyaura coupling produc-
ing the corresponding biphenyl derivative 12. The sequence of
N-methylation followed by nickel-catalyzed CÀN borylation fur-
nished 13, which was further subjected to a second Suzuki–
Miyaura coupling with aryl bromide to produce Me2N-contain-
ing terphenyl 14 in good overall yield.[44] Since the Me2N
group can be installed into organic molecules by various ways
as exemplified in this case, the utility of the Me2N-converting
CÀN borylation is enormous.
Scheme 2. Ni-catalyzed CÀN borylation of benzylic ammonium salts 3. Reac-
tion conditions: 3 (0.2 mmol), B2pin2 (0.4 mmol), Ni(NO3)2·6H2O (10 mol%),
PnBu3 (20 mol%), NaOtBu (2.0 equiv), DME (1.5 mL), 708C, 24 h. Isolated
yield. [a] NaOtBu (1.5 equiv), THF (1.5 mL). [b] 508C.
Shown in Scheme 3B are select examples of benzylic amine
functionalization enabled by CÀN borylation. As in the case of
N,N-dimethylaniline (5), Me2N-directed ortho-lithiation took
place with benzyldimethylamine (15). The thus-formed aryllithi-
um species could be trapped with I2 to set the stage for the
subsequent Suzuki–Miyaura coupling, yielding biphenyl deriva-
tive 17 in good overall yield. N-Methylation of 17 followed by
CÀN borylation catalyzed by the Ni(NO3)2·6H2O/PnBu3 system
afforded the corresponding boronate 18 in 65% yield over
two steps. Boronate 18 was then successfully converted to
GPR120 agonist 19 by a copper-catalyzed oxidative aryloxyla-
tion reaction and subsequent hydrolysis. GPR120, a receptor of
unsaturated long-chain fatty acids, is an emerging new target
for treatment of type 2 diabetes and metabolic diseases.[45–48]
Rather than the two-step, Me2N-directed ortho-arylation pro-
tocol shown above, benzylic amine derivative 20 could be em-
ployed in a one-step Pd-catalyzed ortho CÀH arylation with
iodobenzene to afford substituted benzylamine 21. Subse-
quent CÀN borylation provided benzylic boronate 22 in 57%
yield. Benzylic boronates also have a number of interesting re-
activities. For example, the homologation of 22 took place by
treatment with CH2ClBr/nBuLi to give 23 in 64% yield.[49] After
hydrolysis, the resulting alkylboronic acid underwent oxidative
cyclization in the presence of a palladium catalyst. The result-
ing 9,10-dihydrophenanthrene 24 is an extremely useful struc-
ture in the synthesis of p-conjugated materials.[50] Benzylic
amine 20 could also undergo palladium-catalyzed meta CÀH
arylation under Dong’s conditions to afford 25. The subse-
quent CÀN borylation followed by Suzuki–Miyaura coupling
then furnished densely substituted diarylmethane derivative
27 in good overall yield.
a methyl group at the ortho- or meta-position afforded the cor-
responding borylated products (4b and 4c) in good yields.
The borylation of benzylic ammonium salts bearing methoxy
and fluoro groups produced the desired boronic esters 4e and
4 f in 80 and 63% yield, respectively. 1-Naphthylmethyl and
2-naphthylmethyl boronic esters (4g and 4h) were obtained in
good yields under modified conditions using THF as the sol-
vent. Notably, indole substrate 3i could also be borylated to
form the corresponding product 4i in 47% yield at 508C.
On the basis of the above results and previous studies, we
propose a mechanism for this borylation process. The oxidative
addition of aryl or benzylic ammonium salt (1 or 3) to the Ni0–
PnBu3 species with the elimination of NMe3 is likely the first
step. When nickel(II) salts are applied as precatalysts, the active
Ni0 species should be generated by the action of PnBu3 and/or
B2pin2. The thus-formed organonickel(II) triflate then under-
goes s-bond metathesis with B2pin2 to afford (boryl)organo-
nickel(II) species. It is likely that the tert-butoxide base facili-
tates this s-bond metathesis step.[40–42] Finally, the reductive
elimination of the CÀB bond produces the borylated product
(2 or 4), regenerating the active Ni0 species.
Finally the synthetic versatility of the nickel-catalyzed CÀN
borylation is demonstrated. As shown in Scheme 3, when cou-
pled with a range of Me2N-directed aromatic functionalization
reactions and CÀB transformations, the CÀN borylation permits
the synthesis of a range of substituted aromatics in a regiocon-
trolled and diversity oriented fashion. Depicted in Scheme 3A
are the examples of aromatic amine functionalization. N,N-di-
methylaniline (5) could be ortho-lithiated by the nBuLi–tetra-
methylethylenediamine (TMEDA) system and the thus-generat-
ed aryllithium underwent carbonyl addition to benzophenone
to produce 6. Further synthetic manipulation is possible. For
example, with the aid of the neighboring Me2N group, formal
In summary, we have developed a novel and efficient CÀN
borylation of aryl and benzylic ammonium salts promoted by
nickel-based catalysts. This simple yet powerful method
merges an array of Me2N-directed aromatic functionalization
reactions (ortho/para electrophilic aromatic substitution, ortho
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Scheme 3. Synthetic versatility of CÀN borylation. Reaction conditions: a) nBuLi, TMEDA, benzophenone, ether, HOAc; b) conc. HCl, reflux; NH4OH; (HCHO)n,
NaBH4, CF3CH2OH, reflux; c) TfOMe (3 equiv), CH2Cl2, 708C, 72 h; [Ni(cod)2] (10 mol%), PnBu3 (20 mol%), B2pin2 (2 equiv), NaOtBu (2 equiv), dioxane, 708C,
24 h; d) Pd(OAc)2 (10 mol%), PPh3 (20 mol%), p-benzoquinone (1 equiv), CO, MeOH, RT, 12 h; e) NH4OAc (10 mol%), NBS (1 equiv), MeCN, RT, 12 h; f) (4-fluoro-
phenyl)boronic acid (1.25 equiv), [Pd(PPh3)4] (2 mol%), K3PO4 (2 equiv), MeOH/H2O, 958C, 16 h; g) TfOMe (1.1 equiv), CH2Cl2, 12 h; [Ni(cod)2] (10 mol%), PnBu3
(20 mol%), B2pin2 (2 equiv), NaOtBu (2 equiv), dioxane, 708C, 24 h; h) 4-bromo-N,N-dimethylaniline, [Pd(PPh3)4] (5 mol%), Na2CO3 (10 equiv), toluene/EtOH/
H2O, 1008C, 24 h; i) nBuLi, I2, Et2O, RT; j) p-tolylboronic acid (2 equiv), [Ph(PPh3)4] (2 mol%), Na2CO3 (2 equiv), toluene/EtOH/H2O, 1008C, 12 h; k) TfOMe
(1.3 equiv), Et2O, 12 h; Ni(NO3)2·6H2O (10 mol%), PnBu3 (20 mol%), B2pin2 (2 equiv), NaOtBu (2 equiv), THF, 708C, 24 h; l) methyl 3-(4-hydroxyphenyl)propa-
noate (2 equiv), Cu(OAc)2 (10 mol%), tBuOOtBu (2 equiv), toluene, 1008C, 24 h; LiOH (3 equiv), THF/H2O, RT; m) [Pd(PPh3)4] (5 mol%), AgOAc (1.5 equiv), PhI
(10 equiv, Cu(OAc)2·H2O (50 mol%), AcOH, CF3CH2OH, 958C, 60 h; n) TfOMe (1.3 equiv), Et2O, 12 h; Ni(NO3)2·6H2O (10 mol%), PnBu3 (20 mol%), B2pin2
(2 equiv), NaOtBu (2 equiv), THF, 708C, 24 h; o) BrCH2Cl (2 equiv), nBuLi (2 equiv), THF, À788C to RT; p) NaIO4 (3 equiv), HCl, THF/H2O, RT; Pd(OAc)2 (20 mol%),
Ag2CO3 (1 equiv), p-benzoquinone (0.5 equiv), tBuOH, 1008C, 16 h; q) Pd(OAc)2 (10 mol%), AsPh3 (25 mol%), norbornene, AgOAc, methyl 2-iodobenzoate,
CsOAc, LiOAc·H2O, Cu(OAc)2·H2O, HOAc, PhCl, 1008C, 24 h; r) TfOMe (1.3 equiv), Et2O, 12 h; Ni(NO3)2·6H2O (10 mol%), PnBu3 (20 mol%), B2pin2 (2 equiv),
NaOtBu (2 equiv), THF, 708C, 24 h; s) [Pd(PPh3)4] (8 mol%), PPh3, Ag2O, K2CO3, 1-(4-iodophenyl)ethanone, DME, 858C, 20 h.
metalation, ortho arylation, meta arylation, etc.) with a variety
of CÀB bond transformations (oxidation, homologation, cross-
coupling, carbonylation, oxidative cyclization, etc.). Although
both of these organic transformations have been developed
independently, the development described herein permits the
strategic merging of these two versatile transformations
through the use of the Me2N group as a transformable direct-
ing group. We believe that the present new reaction will have
an effect on the way chemists plan and execute the synthesis
of highly substituted aromatic compounds.
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General procedure for aromatic CÀN borylation
A 20 mL glass vessel equipped with J. Young O-ring tap containing
a magnetic stirring bar was dried with a heat-gun under reduced
pressure and filled with nitrogen after cooling to room tempera-
ture. After adding aryl ammonium salt 1 (0.2 mmol) and bis(pinaco-
lato)diboron (101.6 mg, 0.4 mmol), the vessel was introduced
inside an argon-atmosphere glovebox. In the glovebox, [Ni(cod)2]
(5.5 mg, 0.02 mmol) and sodium tert-butoxide (38.4 mg, 0.4 mmol)
were added to the vessel, which was sealed with an O-ring tap
and then taken out of the glovebox. Then, PnBu3 (8.1 mg,
0.04 mmol) and 1,4-dioxane (1.5 mL) were added to the vessel
under a nitrogen atmosphere. The vessel was heated at 708C for
24 h in an oil bath with stirring. After cooling the reaction mixture
to room temperature, the mixture was concentrated and directly
purified by preparative thin-layer chromatography (PTLC; hexane/
ethyl acetate as the eluent) to afford the borylation product 2.
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Keywords: catalysis · CÀN borylation · dimethylamino group ·
directing group · nickel
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Received: September 8, 2015
Published online on October 5, 2015
Chem. Eur. J. 2015, 21, 16796 – 16800
www.chemeurj.org
16800
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