Nickel-catalyzed amination of aryl Pivalates by the cleavage of aryl C-O bonds

Article abstract of DOI:10.1002/anie.200907287

(Figure Presented) Catalytic animation: The title reaction demonstrates the use of aryl carboxylates as suitable electrophilic coupling substrates in catalytic amination reactions. Nheterocyclic carbene ligands and NaOtBupromote the amination of aryl pivalates through the cleavage of normally unreactive aryl carbon-oxygen bonds (see scheme; cod = cyclooctadiene).

Full text of DOI:10.1002/anie.200907287

Angewandte
Chemie
DOI: 10.1002/anie.200907287
Amination Methods
Nickel-Catalyzed Amination of Aryl Pivalates by the Cleavage of Aryl
À
C O Bonds**
Toshiaki Shimasaki, Mamoru Tobisu,* and Naoto Chatani*
The prevalence of aniline derivatives in the pharmaceutical,
agrochemical, and electronic industries has prompted the
development of new, general, and efficient methods for the
formation of aromatic carbon–nitrogen bonds.[1] Since the
pioneering work by Migita and co-workers,[2] significant
as aryl halide surrogates in catalytic amination reactions.
However, the reaction proceeds efficiently only with fused
aromatic substrates, such as 2-methoxynaphthalenes, and thus
limits its broad synthetic application. On the other hand, the
research groups of Shi and Garg independently reported the
use of aryl carboxylates as effective electrophiles in cross-
coupling reactions with organometallic reagents (i.e. the
Suzuki–Miyaura,[7a–c] Negishi,[7d] and Kumada–Tamao–Cor-
riu[7e] reactions). Inspired by their studies, we envisaged that
aryl carboxylates could be employed as more reactive,
halogen-free electrophiles in the catalytic amination reaction.
Herein, we report this unprecedented catalytic amination of
aryl carboxylates [Eq. (3)].
À
advancements have been made in palladium-catalyzed C N
bond-forming reactions. In particular, contributions from the
research groups of Buchwald and Hartwig have established
the powerful nature of this method by achieving the cross-
coupling of aryl halides with amines in the presence of a
suitable base [Eq. (1)].[3] Numerous publications have
reported palladium-catalyzed amination reactions, however,
the possibility of using electrophilic coupling partners other
than halides and sulfonates is yet to be disclosed. During the
course of our studies on the development of nickel-catalyzed
cross-coupling reactions, through the cleavage of carbon–
oxygen bonds in aryl methyl ethers,[4,5] we found that aryl
methyl ethers can be aminated directly [Eq. (2)].[4b,6] This
study demonstrates the potential utility of aryl methyl ethers
Although the feasibility of the reaction described in
Equation (3) was supported, in part, by the results of Shi and
Garg,[7] the success of the amination chemistry was uncertain
owing to the inherent susceptibility of the carbonyl carbon
atom towards nucleophilic attack by amines, which would
eventually lead to the undesired fission of the acyl–O bond.
Indeed, this undesired pathway occurred exclusively when
aryl pivalate 1a was treated with morpholine (2a) and
NaOtBu in the absence of the catalyst (phenol was formed
in 49% yield; Table 1, entry 1). On the other hand, the
amination reaction proceeded smoothly under the reaction
conditions suitable for aryl methyl ethers,[4b] that is,
[Ni(cod)2)] as a catalyst, IPr·HCl (1,3-bis(2,6-diisopropyl-
phenyl)imidazolium chloride) as the ligand, and NaOtBu as
an external base (Table 1, entry 2). Consistent with our
expectations, the use of 1a resulted in significantly milder
reaction conditions. In comparison to those conditions
required for aryl methyl ethers,[4b] our conditions were
milder in terms of reaction temperature, time, catalyst
loading, and the quantity of amine substrate (Table 1,
entry 3). Notably, the use of PCy3, which has been reported
[*] Dr. T. Shimasaki, Dr. M. Tobisu
Frontier Research Base for Global Young Researchers
Graduate School of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-7396
E-mail: tobisu@chem.eng.osaka-u.ac.jp
Prof. Dr. N. Chatani
Department of Applied Chemistry
Faculty of Engineering, Osaka University
Suita, Osaka 565-0871 (Japan)
Fax: (+81)6-6879-7396
E-mail: chatani@chem.eng.osaka-u.ac.jp
À
as the most effective ligand in nickel-catalyzed C C bond
formation of aryl carboxylates,[7] resulted in a lower yield of
3a under these conditions (Table 1, entry 4). In addition, the
use of a nickel(II) complex (a bench stable catalyst) led to the
undesired fission of the acyl–O bond. (Table 1, entry 5). The
choice of the substituent on the acyl group in 1 is crucial for
this catalytic amination to proceed. When phenyl acetate (1b)
was subjected to the catalytic conditions, no aminated product
was observed, even though 1b was almost completely
[**] This research was conducted in affiliation with the Program for the
Promotion of Environmental Improvement to Enhance Young
Researchers Independence, the Special Coordination Funds for
Promoting Science and Technology, and was supported by Grants-
in-Aid for Young Scientists (B; no. 21750100) from MEXT (Japan).
We also thank the Instrumental Analysis Center for their assistance
with the HRMS and elemental analyses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907287.
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2929

Communications
Table 1: Optimization of reaction conditions.[a]
Table 2: Nickel-catalyzed cross-coupling of phenyl pivalate 1a with
amines.[a]
Entry
1 (R)
Ligand
T [8C]
t [h]
Yield [%][b]
Entry
Amine
Product
Yield
[%][b]
1[c]
2[d]
3
1a (COtBu)
1a
1a
1a
1a
1b (COMe)
1c (COPh)
1d (CONEt2)
none
120
120
80
80
80
80
80
80
12
12
3
3
3
3
3
3
0
>99
91
51
0
0
26
>99
IPr·HCl
IPr·HCl
PCy3
1
2b
(n=1)
2c
(n=2)
2d
(n=3)
3b
3c
3d
87[c]
4[e]
5[f]
6[g]
7[h]
8
2
74
none
IPr·HCl
IPr·HCl
IPr·HCl
3[d]
56
4
5
6
2e
2 f
2g
3e
3 f
3g
95
74
87
[a] Reaction conditions: To a sealed tube was added 1 (0.5 mmol), 2a
(0.6 mmol), [Ni(cod)2] (0.025 mmol), IPr·HCl (0.05 mmol), NaOtBu
(0.7 mmol), and toluene (2.5 mL). [b] Yield of isolated product based on
1. [c] In the absence of [Ni(cod)2], phenol was formed in 49% yield (as
determined by GC analysis). [d] Reaction conditions: 2a (0.75 mmol),
[Ni(cod)2] (0.05 mmol), IPr·HCl (0.1 mmol) and NaOtBu (0.9 mmol).
[e] Used PCy3 (0.1 mmol). [f] Used [NiCl2(PCy3)2] (0.025 mmol) as a
catalyst. [g] Phenol was formed in 30% yield (as determined by GC
analysis). [h] Phenol was formed in 27% yield (as determined by GC
analysis). cod=cycloocta-l,5-diene, Cy=cyclohexyl.
7
2h
3h
79
8
2i
2j
3i
3j
75
60
9[e]
consumed (phenol was formed in 30% yield; Table 1,
entry 6). On the other hand, the use of a benzoyl group (as
in 1c) afforded 3a in a much lower yield compared to 1a
(Table 1, entry 1 vs. entry 7). This lower yield resulted from
significant cleavage of the acyl–O bond (phenol was formed in
27% yield). Importantly, these catalytic conditions have also
been applied to the direct amination of carbamate 1d
(Table 1, entry 8), thus enabling possible application to
tandem ortho-directed functionalization/cross-coupling reac-
tions.[8]
[a] Reaction conditions: To a sealed tube was added 1a (0.5 mmol), 2
(0.6 mmol), [Ni(cod)2] (0.025 mmol), IPr·HCl (0.05 mmol), NaOtBu
(0.7 mmol), and toluene (2.5 mL). [b] Yield of isolated product. [c] The
yield was determined by GC analysis. [d] Used [Ni(cod)2] (0.05 mmol)
and IPr·HCl (0.1 mmol). [e] Used 2j (1.0 mmol), [Ni(cod)2] (0.05 mmol)
and IPr·HCl (0.1 mmol) for 12 h.
Having optimized the reaction conditions, we next
examined the scope of this reaction with respect to the
amine nucleophile (Table 2). The pivaloyl moiety in 1a was
replaced with a wide range of secondary amines under our
catalytic conditions. The use of five- to seven-membered
cyclic amines afforded the corresponding aromatic amines
efficiently (Table 2, entries 1–4). In addition to simple mono-
basic amines, those amines bearing multiple basic sites were
also employed successfully (Table 2, entries 5 and 6). More-
over, bicyclic trans-decahydroisoquinoline (2h) efficiently
underwent the amination (Table 2, entry 7). Acyclic secon-
dary amines also served as appropriate nucleophiles for this
catalytic amination (Table 2, entries 8 and 9). Cyclohexyl-
amine and N-methylaniline did not afford the corresponding
arylated products under the present reaction conditions, this
may be a consequence of their lower nucleophilicity.
vived under the present reaction conditions (Table 3, entry 3).
Also, a styryl substituent on the aryl pivalate was tolerated
(Table 3, entry 4). Several other aryl substituents, acetals
(Table 3, entry 5) and amines (Table 3, entry 6), were toler-
ated under these amination conditions. In addition, the
chloride moiety was aminated at a faster rate than pivalates
under the present catalytic conditions (see the Supporting
Information for details). The pivaloyl groups bonded to fused
aromatic rings, such as naphthalene (Table 3, entries 7 and 8)
and phenanthrene (Table 3, entry 9), were efficiently ami-
nated. The pivalates of heteroaromatic derivatives also
underwent the catalytic amination (Table 3, entry 10).
The difference in reactivity between aryl methyl ethers
À
and aryl carboxylates in the nickel-catalyzed C O bond
functionalization provides a new strategy for the sequential
elaboration of the aromatic framework (Scheme 1). The
pivalate group in 24 was aminated under the catalytic
conditions with the methoxy group remaining intact. The
methoxy group in 25 was arylated through our previously
reported cross-coupling reaction using an organoboron
reagent and furnished 26.[4a]
Next, the scope of this reaction was examined with respect
to aryl pivalates (Table 3). Both electron-rich (Table 3,
entry 1) and -deficient (Table 3, entry 2) aryl pivalates
afforded the aminated products in good yields. Although
nickel-catalyzed substitution reactions of aryl fluorides have
previously been reported,[5d,7d,9] fluoride functionalities sur-
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Table 3: Nickel-catalyzed amination of aryl pivalates with 2a.[a]
catalytic amination reactions would allow an orthogonal-
functionalization strategy of aromatic compounds.[11] Addi-
tional studies to further expand the scope of the nickel-
À
catalyzed C O bond functionalization are ongoing.
Entry
Aryl pivalate
Product Yield
[%][b]
Experimental Section
Typical procedure for the nickel-catalyzed amination of aryl pivalates
(Table 1, entry 3): Catalyst [Ni(cod)2] (6.9 mg, 0.025 mmol), IPr·HCl
(21.3 mg, 0.05 mmol), NaOtBu (67.3 mg, 0.7 mmol), 1a (89.1 mg,
0.5 mmol), 2a (52.3 mg, 0.6 mmol) and toluene (2.5 mL) were added
to a vial (10 mL) with a teflon sealed screwcap in a glovebox filled
with nitrogen. The reaction mixture was stirred at 708C for 3 h. After
cooling to room temperature, the crude mixture was purified by flash
column chromatography on silica gel (eluent: n-hexane/CH2Cl2 4:1),
and afforded 4-phenylmorpholine as a colorless oil (74.6 mg, 91%).
1
2
3
4
4, R=OMe
6, R=CF3
8, R=F
5
7
9
11
71
73
73
87
10, R=(E)-styryl
(E only)
5
6
7
12
14
13
15
17
81
87
99
Received: December 26, 2009
Published online: March 12, 2010
Keywords: amination · aromatic amines · aryl carboxylates ·
16
18
.
bond cleavage · nickel
8
19
91
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À
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À
Scheme 1. Tandem C O bond transformations.
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