Buchwald–Hartwig Amination of Nitroarenes

Article abstract of DOI:10.1002/anie.201706982

The Buchwald–Hartwig amination of nitroarenes was achieved for the first time by using palladium catalysts bearing dialkyl(biaryl)phosphine ligands. These cross-coupling reactions of nitroarenes with diarylamines, arylamines, and alkylamines afforded the corresponding substituted arylamines. A catalytic cycle involving the oxidative addition of the Ar?NO₂ bond to palladium(0) followed by nitrite/amine exchange is proposed based on a stoichiometric reaction.

Full text of DOI:10.1002/anie.201706982

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Accepted Article
Title: The Buchwald-Hartwig Amination of Nitroarenes
Authors: Yoshiaki Nakao, Fumiyoshi Inoue, Myuto Kashihara, and M.
Ramu Yadav
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10.1002/anie.201706982
Angewandte Chemie International Edition
COMMUNICATION
The Buchwald–Hartwig Amination of Nitroarenes
Fumiyoshi Inoue, Myuto Kashihara, M. Ramu Yadav, and Yoshiaki Nakao*
Abstract: The Buchwald–Hartwig amination of nitroarenes has
been achieved for the first time by using palladium catalysts bearing
dialkyl(biaryl)phosphanes. The cross-coupling reactions of
nitroarenes with diarylamines, arylamines, and alkylamines are
demonstrated to afford the corresponding substituted arylamines. A
catalytic cycle involving the oxidative addition of Ar–NO2 bond to
palladium(0) followed by the reaction with amines is proposed based
on a stoichiometric reaction.
performed in less polar solvents such as toluene (43%; entry 15),
whereas 1,4-dioxane and DMF resulted in lower yields (entries
16 and 17).
Table 1. Optimization of the Reaction Conditions for the Amination of 1a with
2a.[a]
Pd(acac)2 (5.0 mol%)
ligand (15 mol%)
base (0.60 mmol)
NO2
NPh2
The arylamine moiety represents a prevalent motif in a variety of
pharmaceuticals and functional materials. The Buchwald–
Hartwig amination is a highly efficient and versatile method to
access substituted arylamines.[1] In these reactions, aryl halides
have originally been used as electrophiles for the cross-coupling
with organotin amides[2] and amines[3] in the presence of Pd-
based catalysts to furnish arylamines. Subsequently, various
aryl pseudohalides, including aryl sulfonates, such as aryl
triflates,[4] tosylates,[5] ethers,[6] esters,[7] sulfamates,[8] and
carbamates,[9] have been introduced as electrophilic coupling
partners to surrogate the aryl halides, which may cause
undesirable halogen-based contamination.[10] The use of
nitroarenes as pseudohalides in the Buchwald–Hartwig
amination may also circumvent these problems and thus be
useful in an academic and industrial context, as nitroarenes are
readily available and serve as building blocks for functionalized
arenes.[11] Herein, we report the first example of the Pd-
catalyzed Buchwald–Hartwig amination.
+
HNPh2
solvent (1.0 mL)
130 °C, 24 h
Me
Me
1a
(0.20 mmol)
2a
(0.30 mmol)
3aa
R1
R2
R3
1 Cy2P
R2
iPr
iPr
iPr
H
BrettPhos (L1)
XPhos (L2)
CPhos (L3)
SPhos (L4)
RuPhos (L5)
R
OMe
H
H
H
H
H
iPr
R3
NMe2
OMe
OiPr
H
R2
R1
H
H
H
CyJohnPhos (L6)
PPh2
PPh2
PPh2
P
Fe
PPh2
PtBu3 (L9)
DPPF (L7)
rac-BINAP (L8)
Entry
Ligand
Base
Solvent
Yield (%)
Following our recent studies on the Suzuki–Miyaura coupling
of nitroarenes,[12] we examined the reaction of 4-nitrotoluene (1a;
0.20 mmol) with diphenylamine (2a; 0.30 mmol) in the presence
of Pd(acac)2 (5.0 mol%), phosphane ligands (15 mol%), and
K3PO4•nH2O (0.60 mmol)[13] in n-heptane at 130 °C for 24 h
(Table 1). Among the ligands examined for the aminations by
Buchwald, BrettPhos[14] (L1) was the most effective to afford 4-
methyl-N,N-diphenylaniline (3aa) in 55% yield (entry 1). XPhos
(L2) also furnished 3aa in 41% yield (entry 2), while CPhos (L3),
SPhos (L4), RuPhos (L5), and CyJohnPhos (L6) were not as
effective as L1 and L2 (entries 3–6). Other phosphane ligands
conventionally employed in the Buchwald–Hartwig amination
such as DPPF, BINAP, and P(t-Bu)3 did not generate 3aa
(entries 7–9). A subsequent investigation of bases (entries 10–
14) revealed that pre-dried K3PO4 raised the yield of 3aa to 75%
(entry 10), whereas K2CO3 and Cs2CO3 resulted in poorer yields
(entries 11 and 12). Strong bases such as KOt-Bu and NaOt-Bu,
which are commonly used in the amination, did not afford 3aa
(entries 13 and 14), presumably due to a competitive reduction
of the nitro group via electron transfer. The formation of
triarylamines proceeded in higher yields when the reaction was
1
2
L1
L2
K3PO4•nH2O
K3PO4•nH2O
n-heptane
n-heptane
55
41
3
4
5
6
L3
L4
L5
L6
L7
L8
L9
L1
L1
L1
L1
L1
L1
L1
L1
K3PO4•nH2O
K3PO4•nH2O
K3PO4•nH2O
K3PO4•nH2O
K3PO4•nH2O
K3PO4•nH2O
K3PO4•nH2O
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
toluene
6
2
19
<1
<1
<1
<1
75
2
7[b]
8[b]
9
[c]
10
K3PO4
11
12
13
14
15
16
17
K2CO3
Cs2CO3
KOt-Bu
NaOt-Bu
56
1
<1
43
17
5
[c]
K3PO4
[a]
Fumiyoshi Inoue, Myuto Kashihara, Dr. M. Ramu Yadav, Prof. Dr.
Yoshiaki Nakao
[c]
K3PO4
1,4-dioxane
DMF
[c]
Department of Material Chemistry, Graduate School of Engineering
Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510 (Japan)
E-mail: nakao.yoshiaki.8n@kyoto-u.ac.jp
K3PO4
[a] Yields were calculated by GC analysis with C15H32 (19.0 mg, 0.090 mmol)
as an internal standard. [b] 7.5 mol% of the ligand was used. [c] K3PO4•nH2O
was dried under reduced pressure (<1.0 mmHg) at 160 °C for 3 h prior to
use.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201706982
Angewandte Chemie International Edition
COMMUNICATION
1i
Subsequently, we studied the scope of the nitroarenes in this
reaction, using 2a as the amine-coupling partner under the
previously established optimized reaction conditions (Table 2).
The amination of 1a, nitrobenzene (1b), 4-nitrobiphenyl (1c), 4-
methoxynitrobenzene (1d), and 3,5-xylylnitrobenzene (1e) on a
0.60 mmol scale afforded the corresponding aryldiphenylamines
in good yields (entries 1–5). An acetal-protected acetyl group
was tolerated (entry 6), and the nitro group of 4-
fluoronitrobenzene (1g) was substituted exclusively by 2a (entry
7). It should be noted here that classical aromatic nucleophilic
substitution reactions usually convert the fluoro group of 1g to
an amino functionality as in 9-(4-nitrophenyl)-9H-carbazole (1h),
which would subsequently react with 2a under modified reaction
conditions (entry 8). Modifications of the aminations, i.e., choice
of ligands and/or base, allowed nitroarenes bearing sterically
demanding substituents 1i and 1j (entries 9 and 10) or a Lewis-
basic functional group 1k and 1l (entries 11 and 12) to
participate in the transformation. Nitronaphthalenes 1m and 1n
can be cross-coupled with bis(4-tert-butylphenyl)amine (2b) to
give the corresponding diarylnaphthylamines (3mb and 3nb;
entries 13 and 14). Heteroaromatic nitro compounds such as 3-
nitropyridine and 2-nitrothiophene did not afford the
corresponding triarylamines, whereas 1-methyl-5-nitroindole
(1o) furnished the corresponding amination product in 52%
(entry 15).
10[f]
2a
78 (3ja)
NO2
OMe
1j
1k
1l
11[b],[c],[g]
12[b],[c],[d],[g]
13[b],[h]
2a
2a
2b
51 (3ka)
50 (3la)
74 (3mb)
MeO2C
NO2
MeO2S
NO2
NO2
1m
1n
14[h]
2b
2a
65 (3nb)
52 (3oa)
NO2
15[b]
NO2
N
Me
1o
[a] Isolated yields. [b] 1.8 mmol of diarylamine was used. [c] L3 was used
instead of L1. [d] K3PO4•nH2O was used instead of dried K3PO4. [e] 1,4-
Dioxane was used instead of n-heptane. [f] L2 was used instead of L1. [g]
Toluene was used instead of n-heptane. [h] 2b was used instead of 2a.
Table 2. Scope of Nitroarenes.
Entry
Nitroarenes
Diarylamines
Yield (%)[a]
73 (3aa)
83 (3ba)
Thereafter, we examined the scope of amines using 4-
nitroanisole (1d) as an electrophile, K3PO4•nH2O, and 1,4-
dioxane as a reaction solvent, which gave superior yields in
these cases (Table 3). We discovered that polar solvents were
necessary due to the limited solubility of the amines in other
solvents, and that K3PO4•nH2O performed better than K3PO4 in
polar solvents. Indeed, the reaction of aniline (2c) afforded the
corresponding diarylamine 3dc, while the corresponding
triarylamine was not detected, i.e., 3dc was not consumed as a
nucleophile, probably on account of steric reasons (entry 1). N-
Methylaniline (2d) participated in the amination albeit in modest
yield (entry 2). Piperidine (2e) can also be used in this
transformation and furnish the corresponding tertiary amine in
61% yield (entry 3). 3,5-Xylylnitrobenzne (1e) was efficiently
aminated by benzylamine (2f) (entry 4), whereas simple
alkylamines such as hexylamine (2g) were also suitable for this
reaction (entry 5). In both cases, tertiary amines were not
obtained.
1
2
1a
2a
2a
NO2
1b
3[b]
2a
2a
2a
74 (3ca)
66 (3da)
77 (3ea)
NO2
Ph
1c
1d
NO2
4
5
MeO
Me
NO2
Me
1e
NO2
6
2a
56 (3fa)
O
O
Table 3. Scope of Amines.
Me
1f
Entry
1[b]
Amines
Yield (%)[a]
NO2
7
2a
2a
62 (3ga)
57 (3ha)
64 (3dc)
F
H2N
1g
2c
8[b],[c],[d],[e]
NO2
2
3
41 (3dd)
61 (3de)
Me
N
H
N
2d
1h
N
H
9[d],[f]
2a
64 (3ia)
NO2
Me
2e
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10.1002/anie.201706982
Angewandte Chemie International Edition
COMMUNICATION
A 15-mL vial was charged with Pd(acac)2 (9.1 mg, 0.030 mmol),
BrettPhos (0.090 mmol), 1 (0.60 mmol), and brought into a nitrogen-filled
glovebox. In the glovebox, to the vial K3PO4 (382 mg, 1.8 mmol), 2 (0.90
mmol or 1.8 mmol), and n-heptane 3.0 mL) were added. The vial was
sealed with a Teflon screw cap and taken out of the glovebox. The
resulting mixture was stirred for 24 h at 130 °C. After the reaction, the
mixture was filtered through a pad of Celite®. All volatiles were removed
in vacuo and the residue was purified by medium pressure liquid
chromatography (MPLC) using Biotage® SNAP Ultra to give the
corresponding product. The following manipulations were performed
before purification in some cases: To the crude, Et2O (10 mL) and H2O2
(30 wt% in H2O, 1.5 mL) were added and the resulting mixture was
stirred for 10 minutes at room temperature. H2O (10 mL) was added and
the organic layer was separated. The remained aqueous layer was
washed with EtOAc (10 mL) and the organic layer was combined, dried
over MgSO4, and filtered.
4[c]
81 (3ef)
72 (3dg)
H2N
2f
5
H2N
2g
[a] Isolated yields. [b] DMF was used instead of 1,4-dioxane. [c] 1e was used
instead of 1d.
A
plausible reaction mechanism for the amination of
nitroarenes is described in Scheme 1. As previously
demonstrated, nitroarenes react with palladium(0) comlex A to
form η2-arene–palladium(0) complexes such as B. This step is
followed by oxidative addition the C–NO2 bond to afford C.
Subsequently, an amine nucleophile could react with C in the
presence of a base to afford arylpalladium amide D, which could
reductively eliminate arylamine 3 and concomitantly exchange
the arene ligands to regenerate A. Oxidative adduct 4 was
prepared according to our previous report[12] and was reacted
with 2f at 50 °C in the presence of K3PO4•nH2O to furnish N-
benzylaniline in 53% yield (eq. 1). This result supports the
proposed catalytic cycle, in which the oxidative addition is
turnover-limiting.
Acknowledgements
This work was supported by the “JST CREST program Grant
Number JPMJCR14L3 in Establishment of Molecular
Technology towards the Creation of New Functions”, the “JSPS
KAKENHI Grant Number JP15H05799 in Precisely Designed
Catalysts with Customized Scaffolding”, and TOSOH
Corporation.
3
1
Keywords: C–N activation • amination • palladium
L–Pd0
A
[1]
For reviews, see: a) D. S. Surry, S. L. Buchwald, Angew. Chem. Int.
Ed. 2008, 47, 6338; Angew. Chem. 2008, 120, 6438; b) J. F.
Hartwig, Acc. Chem. Res. 2008, 41, 1534.
NO2
Pd0L
LPdII
[2]
[3]
M. Kosugi, M. Kameyama, T. Migita, Chem. Lett. 1983, 927.
a) J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36, 3609; b) A. S.
Guram, R. A. Rennels, S. L. Buchwald, Angew. Chem. Int. Ed. Engl.
1995, 34, 1348; Angew. Chem. 1995, 107, 1456.
NR1R2
D
B
[4]
[5]
[6]
J.P. Wolfe, S. L. Buchwald, J. Org. Chem. 1997, 62, 1264.
B. C. Hamann, J. F. Hartwig, J. Am. Chem. Soc. 1998, 120, 7369.
M. Tobisu, T. Shimasaki, N. Chatani, Angew. Chem. Int. Ed. 2008, 47,
4866; Angew. Chem. 2008, 120, 4944.
KNO2 + K2HPO4
LPdII
2 + K3PO4
NO2
C
[7]
[8]
[9]
T. Shimasaki, M. Tobisu, N. Chatani, Angew. Chem. Int. Ed. 2010, 49,
2929 Angew. Chem. 2010, 122, 2991.
Scheme 1. Plausible Mechanism for the Buchwald–Hartwig Amination of
S. D. Ramgren, A. L. Silberstein, Y. Yang, N. K. Garg. Angew. Chem.
Int. Ed. 2011, 50, 2171; Angew. Chem. 2011, 123, 2219.
T. Mesganaw, A. L. Silberstein, S. D. Ramgren, N. F. F. Nathel, X.
Hong, P. Liu, N. K. Garg. Chem. Sci. 2011, 2, 1766.
Nitroarenes.
[10] A. M. Norberg, L. Sanchez, Maleczka, Jr., R. E. Curr. Opin. Drug
Discovery Dev. 2008, 11, 853.
K3PO4•nH2O (0.17 mmol)
MeO Cy2P
MeO
NO2
Ph
Pd
iPr
+
(1)
Ph
H2N
Ph
N
[11] N. Ono, The Nitro Group in Organic Synthesis; Wiley-VCH: New York,
2001.
1,4-dioxane, 50 °C, 28 h
H
iPr
2f
(90 µmol)
3bf
(53%)
iPr
[12] M. R. Yadav, M. Nagaoka, M. Kashihara, R-L. Zhong, T. Miyazaki, S.
Sakaki, Y. Nakao, J. Am. Chem. Soc. 2017, 139, 9423.
[13] The use of K3PO4 as a base for the amination of aryl halides, see: a) D.
W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1998, 120,
9722; b) J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H. Shaughnessy,
L. M. Alcazar-Roman, J. Org. Chem. 1999, 64, 5575.
4
(30 µmol)
In summary, we have developed the Pd-catalyzed
Buchwald–Hartwig amination of nitroarenes. Using conventional
Buchwald–Hartwig ligands allowed us to transform a range of
substituted nitrobenzenes into triarylamines, diarylamines,
alkylarylamines, and dialkylarylamines in moderate to good
yields. Further efforts to develop novel coupling processes
through Ar–NO2 bond cleavage are currently underway in our
laboratories and will be reported in due course.
[14] B. P. Fors, D. A. Watson, M. R. Biscoe, S. L. Buchwald, J. Am. Chem.
Soc. 2008, 130, 13552.
Experimental Section
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10.1002/anie.201706982
Angewandte Chemie International Edition
COMMUNICATION
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itle
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COMMUNICATION
Fumiyoshi Inoue, Myuto Kashihara,
M. Ramu Yadav and Yoshiaki Nakao*
R2
N
cat. Pd/BrettPhos
K3PO4
R2
N
NO2
R3
Page No. – Page No.
R1
R1
+
R3
H
130 °C
The Buchwald–Hartwig Amination of
Nitroarenes
The Buchwald–Hartwig amination of nitroarenes by using palladium catalysts
bearing dialkyl(biaryl)phosphanes. The cross-coupling of nitroarenes with
diarylamines, arylamines, and alkylamines to afford the corresponding substituted
arylamines is demonstrated.
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