Well-Designed N-Heterocyclic Carbene Ligands for Palladium-Catalyzed Denitrative C-N Coupling of Nitroarenes with Amines

Article abstract of DOI:10.1021/acscatal.9b02760

The C-N bond formation is one of the fundamental reactions in organic chemistry, because of the widespread presence of amine moieties in pharmaceuticals and biologically active compounds. Palladium-catalyzed C-N coupling of haloarenes represents one of the most efficient approaches to aromatic amines. Nitroarenes are ideal alternative electrophilic coupling partners, since they are inexpensive and readily available. The denitration and cross-coupling using nitroarenes as the electrophilic partners is challenging, because of the low reactivity of the Ar-NO₂ bond toward oxidative addition. We report here the C-N coupling of nitroarenes and amines using palladium/5-(2,4,6-triisopropylphenyl)imidazolylidene[1,5-a]pyridines as the catalyst. The ligands are readily available from commercial chemicals. The reaction shows broad substrate scope and functional group tolerance. The method is applicable to both aromatic and aliphatic amines, and many secondary and tertiary aromatic amines bearing various functional groups were obtained in high yields.

Full text of DOI:10.1021/acscatal.9b02760

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Letter
Well-designed N-Heterocyclic Carbene Ligands for Palladium-
Catalyzed Denitrative C-N Coupling of Nitroarenes with Amines
Wei Chen, Kai Chen, Wanzhi Chen, Miaochang Liu, and Huayue Wu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02760 • Publication Date (Web): 01 Aug 2019
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Well-designed N-Heterocyclic Carbene Ligands for
Palladium-Catalyzed Denitrative C-N Coupling of
Nitroarenes with Amines
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†
†
†
‡
‡
Wei Chen , Kai Chen , Wanzhi Chen* , Miaochang Liu , and Huayue Wu*
†
Department of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou 310027,
China.
‡
College of Chemistry and Materials Engineering, Wenzhou University, 588 New
Chaoyang Street, Wenzhou, 325027, China.
ABSTRACT: The C-N bond formation is one of the fundamental reactions in organic
chemistry due to the widespread presence of amine moieties in pharmaceuticals and
biologically active compounds. Palladium-catalyzed C-N coupling of haloarenes
represents one of the most efficient approaches to aromatic amines. Nitroarenes are ideal
alternative electrophilic coupling partners since they are cheap and readily available. The
denitration and cross-coupling using nitroarenes as the electrophilic partners is
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challenging because of the low reactivity of Ar-NO2 bond towards oxidative addition. We
report here the C-N coupling of nitroarenes and amines using palladium/5-(2,4,6-
triisopropylphenyl)imidazolylidene[1,5-a]pyridines as the catalyst. The ligands are readily
available from commercial chemicals. The reaction shows broad substrate scope and
functional group tolerance. The method is applicable to both aromatic and aliphatic
amines, and a number of secondary and tertiary aromatic amines bearing various
functional groups were obtained in high yields.
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KEYWORDS: palladium • N-heterocyclic carbene • nitroarenes • aniline • denitration •
C-N coupling
Arylamines are a privileged structural scaffold, which frequently occurs in opto-
electronic materials,1 agrochemicals,2 and pharmaceuticals.3 The construction of C-N
bonds via copper-catalyzed Ullmann coupling4 and palladium-catalyzed Buchwald-
Hartwig5 coupling reactions of (pseudo)haloarenes and amines have been the most
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efficient and practical approaches to aromatic amines in modern synthetic chemistry.
Numerous efforts have been made in the development of more efficient ligands including
P-, N-, and O-donors.6 Ethers, esters, and amides have also been studied as economic
and greener electrophilic partners in recent years.7
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Nitroarenes are basic raw chemical materials for pharmaceutical, pesticide, and dye
industry. They are cheap and readily available from nitration of arenes.8 In principle,
nitroarenes are ideal electrophilic partners for the manufacture of valuable aromatic
chemicals through metal-catalyzed cross-coupling reactions. Moreover, many
functionalized haloarenes especially bromo-and iodoarenes have to be prepared through
Sandmeyer-type reactions of anilines originated from nitroarenes. However, in this
context only quite limited success has been made due to the inertness of C-N bond
towards oxidative addition. In 2011, Wu et al reported rhodium-catalyzed C-O coupling of
nitroarenes and phenylboronic acids leading to aromatic ethers.9 Later, the same C-O
coupling reactions was also achieved by using nano copper catalyst.10 These C-O
coupling reactions are generally restricted to electron-deficient nitroarenes. Recently,
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Nakao et al described palladium-catalyzed Suzuki coupling,11 hydrodenitration,12 and
Buchwald-Hartwig amination of nitroarenes.13 The success of such protocols has been
attributed mainly to the use of sophisticated Buchwald biaryl monophosphines
(BrettPhos).14
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Bulky NHC ligands have proved to be useful ligands for palladium-catalyzed
amination of haloarenes.15 The use of bulky NHC ligands in place of BrettPhos is
attractive taking account of their ease of availability and cost benefits.16 We envisioned
that well-designed bulky NHC ligands with strong electron-donating properties would be
able to furnish the activation of C-N bonds of nitroarenes. Most likely, a NHC ligand
geometrically resembling Buchwald-type biphenyl monophosphines would fulfil the
challenging amination of nitroarenes. As a continuation of our NHC chemistry,17 herein
we report palladium-catalyzed denitrative C-N coupling reactions of nitroarenes with
aromatic and aliphatic amines using 5-(2,4,6-triisopropylphenyl) imidazolylidene [1,5-a]
pyridines as the ligands.
Scheme 1. Structural Illustration of the Ligand Precursors.
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1
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L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
: R = R = H, R = Me, n = 0
R3
R1
1
2
3
: R = R = Me, R = H, n = 0
R1
R1
1
2
3
: R = R = R = Me, n = 0
R2
1
2
3
: R = R = Et, R = H, n = 0
N
N
Cl-
1
2
3
N
Cl-
R3
n
: R = R = Et, R = Me, n = 0
N
R3
N
N
-
R2
R2
1
2
3
PF6
: R = R = iPr, R = H, n = 0
iPr
iPr
1
2
3
1
2
3
L12
: R = R = R = Me
: R = R = R = F, n = 0
1
2
3
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L11
: R = R = OMe, R = H, n = 0
Ph
1
2
3
1
2
, R3 = Me
L13
: R = R = R = Me, n = 1
: R = R =
iPr
1
2
3
Ph
: R = R = Me, R = Br, n = 0
The ligand precursors listed in Scheme 1 were prepared according to the general
procedure of imidazolium salts.18 The reaction of 4-nitroanisol and p-toluidine was initially
investigated as the model reaction using 5 mol% Pd(acac)2 as the catalyst in dioxane at
130 C.13 Unfortunately, no denitrative C-N coupling product was detected in the
o
presence of the imidazolium salt (L1) bearing a N-p-tolyl substituent (Table 1, entry 1).
To our delight, when L2 bearing a N-2,6-dimethylphenyl substituent, the amination
reaction successfully gave 4-methoxy-N-(p-tolyl)aniline 3aa in 65% yield (Table 1, entry
2). An additional para-methyl of the N-phenyl group favors the coupling, and the reaction
yield was increased to 76% (Table 1, entry 3). When the two ortho 2,6-substituents are
replaced by two ethyl, the yield was sharply increased to 93%. The enhancement effect
of the para-methyl was also observed for the bulkier ligands (Table 1, entry 4 vs 5). Bulkier
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ligand L6 bearing two ortho iPr groups led to a diminished yield (Table 1, entry 6).
Although bulkier ligand is expected to promote the reductive elimination, it disfavors the
oxidative addition of Ar-NO2 bond. Other ligands such as L7 and L8 bearing fluoro and
methoxy substituents at two ortho positions resulted in no or low conversions (Table 1,
entries 7 and 8). The results illustrate that the electronic properties should also be
precisely tuned to balance the requirement of oxidative addition and reductive elimination
processes. The NHC ligand, L5 electronically and sterically fits the denitrative coupling
of nitroarenes, resulting in the best catalyst.
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Table 1. Optimization of reaction conditions.
H
NO2
N
H2N
L5
Pd/ , base
+
130 oC, N2, 24 h
MeO
MeO
Me
Me
1a
2a
3aa
Entry
Ligand
Pd source
Base
Solvent
Yield/%
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4
5
6
7
8
9
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12
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14
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L12
L13
L5
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(OAc)2
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
-
65
76
78
93
74
-
35
33
41
-
<5
<5
70
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L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
Pd2(dba)3
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
K3PO4·3H2O
1,4-dioxane
DMF
toluene
n-heptane
MeCN
MeOH
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
60
-
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K2CO3
78
90
<5
<5
<5
56
-
<5
<5
61
Cs2CO3
KOtBu
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NEt3
DBU
K3PO4
Reaction conditions: 4-nitroanisol (0.3 mmol), p-toluidine (0.45 mmol), solvent (1.5 mL), [Pd] (5 mol%),
HL·Cl (10 mol%), 130 oC, N2, 24 h.
The imidazolium salt L11 bearing no substituent at 5-position showed no activity.
Obviously, these results illustrate that both electronic and steric factors of two N-
substituents are crucial to achieve clean amination of the nitroarene. For comparison, the
commonly employed bulky NHC ligands IMes and IPr* (N,N'-bis(2,6-bis(diphenylmethyl)-
4-methylphenyl)imidazol-2-ylidene) were also explored, and they were found to be not
suitable ligands for the activation of the C-N bond (entries 12 and 13).
Pd(OAc)2 and Pd2(dba)3 are also applied to the amination, but both of them are less
efficient (entries 14 and 15). The influence of solvents was also examined. The C-N
coupling reaction could proceed smoothly in nonpolar and low polar solvents affording
3aa in high yields, and polar solvents are not suitable for the reaction (entries 16-20).
Reduction of nitrobenzene to aniline often occurred in polar solvents. Bases are also
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essential to the reaction, K3PO4·3H2O is the best among the bases examined (entries 21-
26). The palladium-catalyzed amination of haloarenes often requires a strong base such
as KOtBu and NaOtBu et al.19 We speculate that amines coordinated to the LPd(NO2)Ar
species would be more easily deprotonated than their analogous LPd(X)Ar (X = halogen).
Although soluble organic bases are recently found to show enhancement effect,20
however, we found that organic bases favor the reduction of nitroarene to aniline other
than denitrative coupling. Finally, the optimized conditions were established to be 5 mol%
Pd(acac)2 and 10 mol% L5 in dioxane using K3PO4·3H2O as the base.
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Table 2. Scope of nitroarenes.
NO2
HN
Me
H2N
L5
Pd/ , base
+
130 oC, N2, 24 h
Me
R
R
1
2a
3
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Nitroarenes
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6
H
N
H
N
H
N
H
N
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Me
Me
Me
Me
Me
Me
Me
MeO
3aa
Me
Me
3ab
, 87%
3ac
, 93%
, 99%
3ad
, 90%
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Ph
H
N
H
N
H
N
H
N
Me
Me
Me
Me
Ph
Me
3ae
, 82%
3af,
99%
3ag
, 99%
3ah
, 99%
H
N
H
H
N
H
N
N
R
Me
OMe
Me
Ph
Me
R
R=4-MeOPh
3aj
R=Morpholinyl
3al
3ak
3ai
, 54%
, 58%
, 98%
, 56%
H
N
H
H
N
H
N
N
Me
Me
Me
F
F3C
Me
EtO2C
O
3ap
3an
, 57%
3am
, 63%
3ao
, 27%
, 72%
Me
NO2
H
H
N
H
N
N
HN
Me
Me
Me
NO2
3ar,
CO2Me
3as
3aq
, 58%
, 86%
50%
3at,
98%
Nitroheteroarenes
Me
Me
H
N
H
N
Me
HN
HN
N
N
Me
N
Me
N
H
Me
N
OMe
N
3ay
3ax
, 56%
3au
, 86%
, 48%
3aw
, 55%
3av
, 88%
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Reaction conditions: 1 (0.6 mmol), p-toluidine (1.5 equiv.), dioxane (3 mL), Pd(acac)2 (5 mol%), HL5·Cl
(10 mol%), K3PO4·3H2O (3.0 equiv.), 130 oC, N2, 24 h.
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Under the optimized conditions, we explored the scope of nitroarenes through their
reactions with p-toluidine, and the results are listed in Table 2. Various nitroarenes
bearing methyl and phenyl at o-, m-, and p-positions worked well, affording diarylamines
3aa-3ai in nearly quantitative yields. Even sterically hindered 1,3-dimethyl-2-nitrobenzene
could be transformed to 3ae in 82% yield. For comparison, Pd/Brettphos are not able to
catalyse the coupling of ortho-substituted nitroarenes. Unsaturated substituent such as
alkynyl is compatible, and 3aj was afforded in 56% yield. Nitroarenes bearing strong
electron-donating groups such as methoxy and amino gave the target products 3ak and
3al in good yields. The C-F bond in 4-nitro-1-fluorobenzene is tolerant giving the
corresponding fluoro-containing diarylamine in good yield. Unfortunately, nitroarenes
bearing chloro- and bromo functionalities were not successful because Ar-Cl and Ar-Br
are more reactive than Ar-NO2 bond with the Pd/NHC catalyst. In such cases,
diarylamines containing a nitro group were generally obtained in excellent yields. Electro-
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withdrawing substituents such as ester, trifluoromethyl, acetyl, and nitro groups are well
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compatible, and the corresponding secondary amines 3an-3as were obtained in good
yields. In the cases of 1,2- and 1,3-dinitrobenzene, no double coupling products were
observed. It should be mentioned that 1,4-dintrobenzene is unreactive under the
optimized conditions, and only trace amount of the reduced product was observed. The
coupling of nitrobenzaldehyde derivatives also failed, and in such case only imine was
detected. Nitronaphthalene is a good coupling partner giving naphthalen-1-amine 3at in
a quantitative yield. The coupling reaction is also applied to N-heterocyclic compounds.
3-Nitropyridines could couple with p-toluidine giving 3au and 3av in 48% and 88% yields,
respectively. Similarly, 5-nitroquinoline and 5-nitroisoquinoline are suitable substrates,
and their corresponding coupling products 3aw and 3ax were obtained in 55% and 86%
yields, respectively. However, under the same conditions the coupling of 8-nitroquinoline
was not successful. The above results illustrate that electron-deficient nitroarenes
generally disfavor the denitrative C-N coupling reactions. The present Pd/NHC catalyst are
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more efficient for both electron-rich and electron-deficient nitroarenes than previously reported
Pd/Brettphos11 under similar conditions, which can be ascribed to the smaller activation barrier
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for the oxidative addition of Ar-NO2 to (NHC)Pd(0) than that of (BrettPhos)Pd(0).16d In
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addition, NHCs are better to resist oxidation than phosphine ligands, and thus low loading of the
NHC ligand was allowed.
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We next explored the scope of primary and secondary anilines bearing different
functional groups. Various electron-rich, electron-poor, ortho-substituted, and heteroaryl
amines were cross-coupled successfully with 1-nitronaphthalene, and the results were
summarized in Table 3. Generally, mono- and dialkyl-substituted anilines are good
coupling partners, and their corresponding diarylamnies 4aa-4ad were isolated in nearly
quantitative yields. The coupling reaction showed obvious steric effect for 2,6-
disubstituted anilines. The transformation involving 2,6-diethylaniline proceeded
efficiently giving their corresponding secondary amines 4ae and 4af in 70 and 80% yields,
respectively, but the more hindered 2,6-diisopropylaniline was less reactive. Thus, the
reaction of 1-nitronaphthalene and 2,6-diisopropylaniline afforded 4ag in only 63% yield.
The electron-rich anilines bearing methoxy, phenoxy, and amino groups at ortho or para-
positions are quite active giving the desired products 4ah-4aj in up to 94% yields.
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However, unprotected 4-aminophenol gave a complicated mixture. Interestingly, 3,4-
difluoroaniline was afforded in 97% with two fluoro unreacted. Again, haloanilines are not
compatible since Ar-X (X = Cl, Br, and I) bonds are more reactive than Ar-NO2.
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Palladium-catalyzed denitrative coupling is also applied to anilines bearing electron-
withdrawing substituents such as ester, acetyl, cyanide, and CF3 to give 4am-4at. The
yields of the coupling products are dependent upon the substitution positions. For
example, under the same conditions the reaction of ethyl 4-aminobenzoate and
nitronaphthalene afforded 4aq in 93% yield, whereas methyl 2-aminobenzoate gave 4ao
in only 32% yield. Generally, the electron-deficient anilines are less reactive probably due
to reduced coordination abilities to palladium center of the amines. We next explored the
possibility of secondary aromatic amines, and found both N-methyl and N-ethylaniline
could successfully couple with 1-nitronaphthalene furnishing tertiary amines 4au and 4av
in 71% and 28% yields, respectively. Cyclic indoline is a good secondary nucleophilic
amination reagent. The influence of steric hindrance is also remarkable for the coupling
reactions of 1,3-dimethyl-2-nitrobenzene and 2-nitrobiphenyl with 2,6-dimethylaniline and
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2,6-diethylaniline. The yields of 4ax-4bb vary depending upon the bulkiness of the
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A variety of aliphatic chain and cyclic, primary and secondary amines were further
studied. n-Butylamine, n-hexylamine, and benzylamine were successfully N-arylated with
1-nitronaphthalene in almost quantitative yields. Cyclic primary amine such as
cyclohexylamine was transformed to N-cyclohexylnaphthalen-1-amine 4bg in up to 98%
yield. In addition, the coupling reaction was amenable to pyrrolidine, piperidine,
morpholine, and azepane, which are pharmaceutically important building blocks, to give
the products 4bh-4bm in high yields. It should be noted that Ph2NH and Et2NH are not
reactive, and thus the secondary amines listed in Tables 2 and 3 were selectively
obtained. Obviously, the Pd/NHC catalyst is more suitable for the coupling of primary
aromatic and aliphatic amines. In contrast, Ph2NH is able to couple with various
nitroarenes delivering triarylamines in good yields when Pd/Brettphos was employed
under similar conditions.13 Probably, the pocket-shaped imidazolylidene [1,5-a] pyridine
ligands would inhibit the coordination of diarylamine.
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Finally, heteroarylamines such as 3-aminopyridine, 5-aminoquinoline, 3-
aminocarbazole, and 3-aminothiophene derivatives were coupled with 1-
nitronaphthalene successfully in excellent yields.
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Table 3. Scope of amines
R1 R2
NO2
N
R1
R2
L5
Pd/ , base
HN
+
R
R
130 oC, N2, 24 h
1
4
2
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Aromatic amines
Me
5
6
7
8
Me
Et
Me
HN
Me
Me
HN
HN
HN
HN
Me
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4ad
, 97%
4ac
3at,
, 90%
98%
4ab
, 93%
4aa
, 99%
Me
O
OMe
OMe
Et
Et
iPr
Ph
HN
HN
HN
HN
HN
Et
Et
iPr
4ag
, 63%
4ae
4ah
, 87%
4af
, 70%
, 80%
4ai
, 94%
O
F
F
CF3
N
MeOC
HN
F
HN
HN
HN
HN
4ak
, 89%
4am
, 80%
4al
, 97%
4an
4aj
, 59%
, 94%
CN
MeO2C
HN
CO2Et
HN
CN
Me
HN
HN
CO2Me
HN
Me
4ao
4ap
4aq,
, 32%
, 62%
93%
4ar
, 70%
4as
, 82%
CN
CF3
Me Me
Me
Et
N
N
HN
N
H
N
Me Me
4au
4ax
, 60%
, 71%
4aw
4av
, 92%
4at
, 28%
, 87%
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Et
Me
Me Et
N
N
N
H
H
N
H
H
Et
Me
7
Me Et
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4ay
, 21%
4az
, 94%
4bb
, 18%
4ba
, 40%
Aliphatic amines
S
HN
HN
HN
HN
4bd
, 98%
4bc
4be
, 92%
, 97%
4bf
, 91%
N
N
N
HN
HN
4bi
4bj
, 90%
, 96%
4bg
4bh
, 98%
, 86%
O
O
N
N
N
N
4bk
4bl
4bm
, 74%
, 84%
, 56%
Heteroaryl amines
O
N
O
S
N
N
HN
HN
HN
HN
4bo
4bp
, 97%
, 93%
4bn
4bq,
, 87%
76%
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Reaction conditions: 1 (0.6 mmol), 2 (1.5 equiv), dioxane (3 mL), Pd(acac)2 (5 mol%), HL5·Cl (10 mol%),
K3PO4·3H2O (3.0 equiv), 130 oC, N2, 24 h.
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In summary, we have demonstrated that the combination of palladium and the NHC
ligands in situ generated from 5-(2,4,6-triisopropylphenyl)imidazolium[1,5-a]pyridines are
able to catalyze the dinitrative C-N coupling of nitroarenes and amines leading to
diarylamines and N-alkylanilines in good to excellent yields. The ligands are readily
prepared from inexpensive and commercially available starting materials, and the present
protocol shows broad scopes for both electrophilic and nucleophilic partners and wide
functional group tolerance. The coupling reaction proceeded without the need of strong
bases, that expands the scope for base-sensitive substrates. It offers an alternative
practical approach to prepare secondary and tertiary aromatic amines. In addition, the
present work also demonstrates that the potential application of well-designed NHC
ligands with appropriate electronic and steric properties would be expected for the
activation of inert chemical bonds.
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ASSOCIATED CONTENT
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Detailed experimental procedures; characterization data; and copies of 1 H, 19F,
and 13C NMR spectra (PDF).
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AUTHOR INFORMATION
Corresponding Authors
* E-mail: chenwzz@zju.edu.cn.
E-mail: huayuewu@wzu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation (NSF) of China (21572203 and
21472140) and the NSF of Zhejiang Province (LZ16B020001) for financial support.
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