Nickel(II)-NΛNΛO Pincer Type Complex-Catalyzed N-alkylation of Amines with Alcohols via the Hydrogen Autotransfer Reaction

Article abstract of DOI:10.1021/acs.joc.0c00530

A highly sustainable catalytic protocol for the coupling of alcohols and amines for selective monoalkylated amines using Ni(II)-N^ΛN^ΛO pincer type complexes through the borrowing hydrogen methodology is described. An array of Ni(II) catalysts (1-3) was synthesized and characterized by various spectral and analytical methods. Furthermore, the distorted square planar geometry of the complexes (1 and 2) was substantiated with single crystal X-ray diffraction study. The inexpensive nickel-based catalytic methodology displays a broad substrate scope for the N-alkylation of aromatic and heteroaromatic amines using a diverse range of primary alcohols with excellent yields up to 97%. The present approach is environmentally benign, which liberates water as the sole byproduct. A short synthesis of drug intermediates such as mepyramine and chloropyramine illustrates the utility of the present protocol.

Full text of DOI:10.1021/acs.joc.0c00530

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Article
Nickel(II) – N#N#O Pincer Type Complexes Catalyzed N-alkylation
of Amines with Alcohols via Hydrogen Auto Transfer Reaction
Gunasekaran Balamurugan, Rengan Ramesh, and Jan Grzegorz Malecki
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00530 • Publication Date (Web): 08 May 2020
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Page 1 of 11
The Journal of Organic Chemistry
Nickel(II) – NɅNɅO Pincer Type Complexes Catalyzed N-alkylation of Amines
1
2
3
4
5
with Alcohols via Hydrogen Auto Transfer Reaction
Gunasekaran Balamurugan,a Rengan Ramesha* and Jan Grzegorz Maleckib
aCentre for Organometallic Chemistry, School of Chemistry, Bharathidasan University, Tiruchirappalli-620024, Tamilnadu,
6
7
8
9
India. E-mail: ramesh_bdu@yahoo.com.
bDepartment of Crystallography, Institute of Chemistry,University of Silesia,40-006 Katowice, Poland.
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PPh3
O
N
N
Ni
N
X
R
(4 mol%)
X
OH
R
+
N
X
H2O
R'
+
R'
H
H2N
X
KOH, PhCH3, 120 °C, 24 h
R' = H, halogen, -OCH3
R = H, CH3; X = H, N
Sustainable catalyst
low catalyst load
mechanistic evidence
32 substrates, yields up to 97%
ABSTRACT: A highly sustainable catalytic protocol for the coupling of alcohols and amines to selective monoalkylated amines
using Ni(II) NɅNɅO pincer type complexes through borrowing hydrogen methodology is described. An arrayof Ni(II) catalysts (1-
3) was synthesized and characterized by various spectral and analytical methods. Further, the distorted square planar geometry of
the complexes (1 and 2) was substantiated with single crystal X-ray diffraction study. The inexpensive nickel based catalytic
methodology displays a broad substrate scope for the N-alkylation of aromatic and heteroaromatic amines using a diverse range of
primary alcohols with excellent yields up to 97%. The present approach is environmentally benign which liberates water as the sole
by-product. A short synthesis of drugs intermediate such as mepyramine and chloropyramine illustrates the utility of the present
protocol.
H
R2
N
NH2
+
HO
R2
H2O
+
INTRODUCTION
R1
R1
[M] cat./base
MH2
a
O
c
b
x
n
i
Production of chemical compounds or required materials from
available feedstock using transition metal catalysts under
environmentally benign conditions is the emerging field of
catalysis chemistry.1 particularly, the N-alkylation of amine
reactions are of considerable interest due to the valuable
alkylated amine products bearing carbon-nitrogen bonds
which were found to be effective in the field of
pharmaceuticals, material chemistry and agrochemicals (Fig.
1).2 on the basis of their essentiality and utility in many fields
of chemistry, a sequence of synthetic procedures have been
developed to afford the amine products. In this connection,
some classical synthetic routes like nucleophilic substitutions,
buchwald–hartwig, ullmann reactions and hydroaminations
have addressed well for the formation of a variety of amines.
In fact, these methodologies were not successful to provide
desired amines due to the formation of low yield, over
alkylation and by-product salts.3 There is a need by the science
community in the aspect of sustainable synthetic protocol
towards amination reaction with good selectivity, high yield,
and atom economy without harsh reactions condition.
d
o
i
a
t
t
c
i
o
u
n
d
e
R
a
N
R2
R2
-H2O
O
R1
Scheme 1. Borrowing-hydrogen strategy for alcohols amination
reaction.
R
Br-
N+
N
O
N
N
H
H
N
N
N
N
S
N
N
N
Thonzonium bromide
(Antifungal activity)
Methapyrilene
(Anticancer)
MSX-122
(Tumor activity)
H
N
R'
N
N
N
OH
H
N
R
F3C
Me
N
N
N
Cinacalcet
Derivatives of resveratrol
(Antioxidant)
CXCR4
(Antagonists)
(Secondary Hyperparathyroidism)
H
O
N
N
To achieve this goal, the direct coupling of alcohols and
amines catalyzed by transition metals have been successfully
exploited to synthesize selective secondary amines with
greener water as a by-product through borrowing-hydrogen
strategy as depicted in (Scheme 1).4
N
N
H
N
O
N
O
N
O
N
N
H
(N-methyl-D-aspartate receptor antagonists)
(Potent p38 inhibitor)
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Figure 1.Representative examples of biologically active N-
alkylated amines
available less toxic alcohols and elimination of water as the
only by-product.
1
2
3
4
5
6
7
8
9
In this connection, a huge number of reports from precious
metals (Ru, Ir, Rh, and Pd) catalysed alcohol amination
reactions were well documented.5 Alternatively, non-precious
metal (Fe, Co, Mn) complexes were also known as catalysts to
couple the alcohols and amines to provide the desired amine
product in an environmentally benign reaction condition.6
However, the catalysts seeker showed a special interest in
designing and synthesis of novel catalysts as earth-abundant
based non-precious metals to achieve the same catalytic
reactions with extensive substrate scope as well as the yield of
the products, etc.,
RESULTS AND DISCUSSION
Methyl-2-pyrrolyl ketone derived hydrazone ligands with
NɅNɅO donor atoms have been prepared in accordance with
previously described literature with slight modified
procedure.24 The bench-stable Ni(II)-NɅNɅO pincer type
complexes (1-3) were accomplished by the reaction of
NiCl2(PPh3)2 with the prepared ligands in ethanol with an
equivalent of triethylamine under refluxing condition for 12 h
(Scheme 3). All the air and moisture stable complexes are
readily soluble in organic solvents (CH2Cl2, CHCl3, DMSO,
and CH3CN) and were analytically pure as their elemental
analysis data confirmed the proposed molecular formula.
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Previous work
1)
Ru,Rh,Ir,Pd
and
H
Mn, Co, Fe
R
+
NH2
R'
OH
N
R'
+
H2O
(a)
NH
R
2) Ni(N,O)2(7 mol%), KOtBu,
toluene, 130 °C, 24 h
PPh3
N
Ni
NiCl2(PPh3)2
N
3) NiBr2(10 mol%), L1(20 mol%)
KOtBu, toluene, 130 °C, 48 h
O
N
Ethanol, Et3N,
reflux, 12 h
HN
O
N
N
O
N
Ni
N
2)
3)
O
N
Ni
Br
Br
N
N
R
R
1: R = H; 2: R = OCH3; 3: R = Cl
Present work
PPh3
O
N
N
Scheme 3. Synthesis of Ni(II)-NNO pincer type complexes(1-3).
Ni
The FT-IR spectra of the free ligands showed broad bands in
the regions 3218–3255 cm-1 correspond to N-H of pyrrole
moiety. These bands were disappeared upon complexation
indicate the coordination of pyrrole nitrogen to the nickel ion.
The absorption bands around 1610–1642 cm-1 were attributed
to C=N(azomethine) group of the free ligands. After the
complexation, the decrease of azomethine frequency to 1520-
1531 cm-1 revealed that azomethine nitrogen is another one of
the coordinating atoms. Further, the reduction of C=O
frequency from 1539–1568 cm-1 to 1333–1374 cm-1 dictated
the coordination of imidolate oxygen (C-O) to nickel via the
enolization pathway.25 From the FT-IR spectral data, the
formation of the complex as well as their NɅNɅO coordination
pattern of ligand to nickel ion via pyrrole nitrogen, imine
nitrogen and imidolate oxygen were confirmed.
N
(4 mol%)
H
N
R'
+
R'
OH
R
NH2
H2O
(b)
+
R
KOH, PhCH3, 120 °C, 24 h
Scheme 2. Transition metal-catalyzedN-alkylation of amines (a)
and (b)
Hence, low cost and high-natural-abundance nickel would
serve as a sustainable alternative to noble metal complexes
catalysed organic syntheses.7 In general, most of the nickel-
based catalytic reactions have gained
a
significant
achievement in cross-coupling reaction like C-C, C-N bond
formation etc.,8-20 It has also been found that the reported
literatures on nickel catalysed alkylation of amine reaction are
limited. Previously,
a few of them investigated the
heterogeneous Raney nickel systems in alkylation of amine
under borrowing-hydrogen path way.21a-c Yus et al.
synthesized the nickel nanoparticle and used as
heterogeneous-catalyst for alcohol amination reaction.21d-e In
addition, Barta et al. have disclosed the nickel nanoparticle for
monoalkylation of amines under heterogeneous catalytic
condition.21f In contrast, to our knowledge, there are only two
examples of a nickel based homogeneous catalyst to alkylation
of amine reactions. Among them, Adhikari et al. recently
accounted the azo-phenolate ligand coordinated Ni(II)
catalysts for alkylation of amines with a range of primary
alcohols.22b Banerjee et al. have reported in situ generated
nickel complexes containing phenanthroline and phosphine
co-ligands as a catalyst for the N-alkylation of amines with
alcohols to selective secondary amines22a (Scheme 2, a).
1
In the H NMR spectra, the absence of signals due to -NH
protons of imine nitrogen and pyrrole nitrogen of free ligand
around δH = 9.10-8.00 ppm indicated that ligand underwent
deprotonation during complexation. Also, three different
singlets with low intensity around δH = 6.30-5.00 ppm
correspond to the pyrrole ring protons in the complexes. A
multiplet was observed around δH = 7.70-6.50 ppm due to
aromatic protons of triphenylphosphine and benzhydrazone
ligands of the complexes (1-3).The position of the methyl
protons signal in the complexes is slightly shifted to downfield
in comparison with that of the free ligands, suggesting that the
deshielding of the methyl proton after complexation. Further,
the complex 2 showed a signal at δH = 3.80 ppm as a singlet
due to methoxy proton of the ligand. The 13C NMR spectra
displayed signals around δC = 174 and 158 ppm that
correspond to imine carbon and imidolate carbon of all the
complexes. In addition, a signal appeared around δC = 11 ppm
due to methyl carbon of pyrrole ketone. Thus, the NMR
spectral data of all the complexes confirm the coordination
mode of ligand to Ni(II) ion via the imine nitrogen, pyrrole
nitrogen, and the imidolate oxygen.
In continuation of our previous reports on the catalytic
activity of metal complexes for various coupling reactions,23
herein we report the Ni(II)-NɅNɅO pincer type complexes as
homogeneous catalysts for alcohol amination reaction
(Scheme 2, b). The feature of the present approach merits
attention as it is eco-friendly, due to the use of readily
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Furthest, the ESI-MS was studied to determine the exact
1).The excellent yield of 92% (Table 1, entry 6) obtained in
the test reaction helped us to investigate the catalytic
parameters like solvent, base, and temperature. Therefore, a
number of test reactions were performed by changing the
catalytic parameters, which inferred that PhCH3/KOH at 120
°C was preferred as the best reaction condition. On the basis of
the experimental result, the bases play a key role to activate
the catalyst towards the formation of alkylated amine products
in an effective manner was inferred. As a whole, the
activation of catalyst was found to be effective in the presence
of KOH when compared to other bases (NaOH, NaOCH3,
KOtBu, Cs2CO3, K2CO3, Et3N) exploited in this catalytic
reactions. Further, it has been observed a marginal change in
the yield of the product on increasing the reaction temperature
from 120 °C to 130 °C (Table 1, entries 6 and 7).
1
2
3
4
mass of all the complexes. The ESI-MS spectra showed a
fragment peak of [M+H+CH3OH+Na]+ pattern for complexes
1 and 2 with the m/z = 601.1034, m/z = 631.1147
respectively. In addition, complex 3 displayed a fragment of
[M]+ with m/z = 579.1605.
5
6
7
8
9
The incredible potential of nickel catalysts in a wide spectrum
of coupling reactions motivated us to carry out the N-
alkylation of amines from the coupling of alcohols and
amines.
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60
Table 1. Effect of Solvent, Base and Temperaturea
H2N
Complex 1 (6 mol%)
N
OH
+
H
base, solvent, 80-130°C
O
O
However, a moderate or poor yield was received when the
temperature was lowered (Table 1, entries 12 and 13). The
choice of solvents was also examined, which concluded that
the non-polar solvent progressively enhance the alkylation
process with maximum yield than other solvents employed in
this reaction (Table 1, entries 1–4). Further, poor yield of the
N-alkylated product was obtained under oxygen atmosphere
(Table 1, entries 15). The control experiments revealed that
the catalyst and base were essential for this reaction, and the
reaction was ineffective in the absence of any of them (Table
1, entries 16 and 17).
1a
3a
2a
Entry
1
Solvent
T(°C)
120
100
90
Base
Yield(%)b
t-amyl alcohol
1,4-Dioxane
n-hexane
PhCH3
NaOCH3
NaOCH3
NaOCH3
NaOCH3
NaOCH3
KOH
30
52
46
62
83
92
94
89
80
50
<32
67
40
<10
16
-
2
3
4
110
120
120
130
120
120
120
120
110
80
Table 2. Effect of Substituent of Catalysta
5
PhCH3
H2N
6
PhCH3
OH
N
Complex 1-3 (6 mol%)
+
H
O
KOH, PhCH3 , 120 °C, 24 h
O
7
PhCH3
KOH
1a
3a
2a
Entry
[Ni]complex
Yield (%)b
8
PhCH3
NaOH
KOtBu
Cs2CO3
K2CO3
KOH
1
2
3
1
2
3
92
93
98
9
PhCH3
10
11
12
13
14
15c
16d
17e
PhCH3
PhCH3
aGeneral reaction conditions: Amine (2a, 0.75 mmol), alcohol (1a,
1.5 mmol), complex 1-3 (6 mol%, with respect to amine),
PhCH3
b
KOH(0.5 mmol) and PhCH3 (2 mL) at 120 °C for 24 h. Isolated
yields.
PhCH3
KOH
After the optimization of solvent, base and temperature in the
respective catalytic reactions, next we were interested to
investigate the effect of substituents (R = -H, -OCH3 and -Cl)
of all the catalytic complexes (1-3) under identical catalytic
condition. Utmost all the catalysts (1-3) showed impressive
results in the formation of N-(4-methoxybenzyl)aniline
product (Table 2). However, the experimental results implied
that the catalyst 3 exhibited a relatively higher yield of N-(4-
methoxybenzyl)aniline (98%) as compared to the catalysts (1
and 2), which probably reflects that the presence of an
electron-withdrawing group(-Cl). Hence, complex 3 opted as a
model catalyst to the broad substrate scope using a different set
of amines and alcohols.
PhCH3
120
120
120
120
Et3N
PhCH3
KOH
PhCH3
-
PhCH3
KOH
5
aGeneral reaction conditions: Amine (2a, 0.75 mmol), alcohol (1a,
1.5 mmol), complex 1 (6 mol%, with respect to amine), base(0. 5
mmol), solvent (2 mL), temperature(80-130 °C) for 24 h.
bIsolatedyield. Reaction performed under oxygen condition. No
c
d
base was used. eNo catalyst was used.
In order to initiate the C-N bond forming reaction, the N-
alkylation of 4-methoxybenzyl alcohol with aniline to
respective N-(4-methoxybenzyl)aniline product using 6 mol %
of catalyst 1 was preferred as a benchmark substrate (Table
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Table 3. Effect of Catalyst Loada
Complex 3 (4 mol%)
R''
H2N
R''
R' OH
1
+
+
H2O
R'
N
H
1
KOH, PhCH3, 120°C, 24 h
3
2
2
3
4
H2N
Complex 3 ( mol%)
OH
N
+
H
O
KOH, PhCH3 , 120 °C, 24 h
O
N
H
N
3a
1a
2a
N
H
H
5
6
7
8
O
3b, (94%)
3c, (76%)
3a, (96%)
Entry
Mol% of complex 3
Yield(%)b
1
2
3
4
6
4
2
1
98
96
63
41
N
H
N
H
N
H
9
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
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60
F
3f, (89%)
3e, (84%)
3d, (92%)
O
O
N
H
N
H
N
H
aGeneral reaction conditions: Amine (2a, 0.75 mmol), alcohol
(1a, 1.5 mmol), complex 3 (6.0 – 1.0 mol%), KOH(0.5 mmol) and
PhCH3 (2 mL) at 120 °C for 24 h. bIsolated yields
O
3i, (91%)
3h, (79%)
3g, (96%)
Br
O
Br
Performing the reactions at low catalysts loading to achieve the
desired secondary amine products is the most important factor
in catalysis research. Thereupon, a low catalyst load (6.0 – 1.0
mol%) has been studied under the established reaction
condition (Table 3). Outstandingly, the complex 3 performed
well with 4 mol% to give the desired amine product with 96%
isolated yield. While reduce the catalyst loading from 2 to 1
mol%, there was no appreciable yield in the catalytic reactions.
Based on this result, the N-alkylation of amine formation has
been proceeded profoundly in 4 mol% catalyst in 24 h.
N
H
O
O
O
N
H
N
H
O
3j, (94%)
3l, (93%)
3k, (97%)
O
O
O
N
N
N
H
N
N
H
H
N
3n, (87%)
3m, (89%)
3o, (92%)
aGeneral reaction conditions: Amine (2, 0.75 mmol), alcohol (1,
1.5 mmol), complex 3 (4 mol%, with respect to amine), KOH(0.5
mmol) and PhCH3 (2 mL) at 120 °C for 24 h. bIsolated yields.
The scope of the N‐alkylation reaction was examined under
the optimized reaction condition for various alcohols and
amines (Table 4). It is worth to note that the reaction of
benzyl alcohols bearing the electron-releasing substituents,
4‐methyl, 4‐methoxy and 3-methyl with aniline increase the
yield of N-alkylation process to provide the desired secondary
amines 3a‐3d in 92–96% yields. Indeed, benzyl alcohols
comprising the electron-withdrawing substituents, such as
4‐chloro, and 3‐fluoro were found to be good coupling
partners of amine and gave the selective monoalkylated
products of 3e‐3f in 84–89% yields. Further, 1-naphthalene
methanol readily reacted with aniline and 4-methoxy aniline to
desired 3g and 3h in 79% and 96% yields respectively.
Interestingly, both of the electron-donating derivatives of 4-
methoxybenzyl alcohol and 4-methoxy aniline gave the 3i in
91% yield. Since, piperonyl analogue is the most important
building block in the drug development process.28
It is well known that morpholine moieties are known as
potential heterocyclic building blocks and widely present in
large number of drug molecules.26b,2h So, we have significantly
tuned the current protocol in construction of the 2-
morpholinoethanol with aniline and 4-methoxy aniline which
gave the corresponding amines 3n and 3o in 87% and 92%
yields respectively.
Next, we are interested to explore the wide scope of 2-
aminopyridine/2-aminopyrimidine based mono N-alkylated
amines those also were primarily used as intermediate in
various drug development process (Table 5).26-28 Hence, we
have intensely probed the utility of the catalyst in the coupling
of a sort of alcohols with amines to provide a pharmaceutically
active secondary amine product in excellent yield. More
interestingly, the reaction of 2-aminopyridine with benzyl
alcohol gave the corresponding secondary amines 6a in 94%
of isolated yield. In addition, electron-donating substituent on
amine moiety such as 2-amino-4-methylpyridine was coupled
with benzyl alcohol to the respective 6d in 96%. Further, 2-
aminopyridine with 3-fluorobenzyl alcohol underwent N-
alkylation process smoothly to the desired 6e in 83% yield.
Also, the present catalyst worked well in the coupling of
piperonyl alcohol with amine afforded the 6f in 80% yield.
Furthere, sterically hindered 1-naphthalenemethanol and 9-
anthracenemethanol were reacted with 2-aminopyridine to
provide the respective 6g and 6h in 93% and 95% yields.
Hence, we have used the present catalyst to synthesis of
piperonyl scaffolds based amines. Proficiently, we achieved
the desired amines (4-methoxy aniline and 4-bromo aniline)
attached with piperonyl moiety yielded 3j and 3k in 94% and
97% yields respectively. More interestingly, the catalyst
performed well in the reaction of sterically hindered 9-
anthracenemethanol with 4-bromo aniline gave 3i in 93%
yield. Further, we have investigated the some of heterocyclic
alcohols like 2-pyridinemethanol, 2-morpholinoethanol. The
2-pyridinemethanol smoothly alkylated with aniline and gave
the product 3m in 89% yield.
Table 4. N-alkylation of Various Aromatic amines with
Alcoholsa,b
It is worth to mention that the current catalytic strategy is
more useful to the synthesis of drug intermediates such as
mepyramine 6b and chloropyramine 6c with the yield of 95%
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and 85% respectively from the coupling of 4-methoxybenzyl for secondary alcohols in the catalytic reactions and are not
1
2
3
4
5
6
7
8
alcohol and 4-chlorobenzyl alcohol with the 2-
aminopyridine.29a-b
successful.
At this point, we are very much interested to compare the
efficiency of present Ni(II)-NɅNɅO catalyst with structurally
related Ni(II) catalysts. In this regard, Adhikari et al. recently
accounted the azo-phenolate ligand coordinated Ni(II)
catalysts in N-alkylation of amines with a range of primary
alcohols using 7 mol% of catalyst in 24 h at 130°C.22b
Similarly, Banerjee et al. reported the alcohol amination
reaction using 10 mol% of in situ generated Ni(II) catalyst in
48 h at 130°C.22a Therefore, the present Ni(II) pincer type
complexes worked well with 4 mol% of catalyst load at 120°C
in 24 h for effectively couple the alcohol and amine to
produce the monoalkylated amine product with an excellent
yield of 97% than the existing methodology.
Table 5. N-alkylation of Various Heteroaromatic Amines with
Alcoholsa,b
Complex 3 (4 mol%)
R''
H2N R''
5
H2O
R'
N
H
+
R' OH
4
+
KOH, PhCH3, 120°C, 24 h
6
9
N
N
N
N
N
H
N
H
H
10
11
12
13
14
15
16
17
18
19
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21
22
23
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60
Cl
O
6b, (95%)
6c, (85%)
6a, (94%)
O
N
N
N
H
N
H
N
H
N
O
Further,wehave
carried
out
a
sequence
of
F
controlexperiments under different conditions (Scheme 4) in
6f, (80%)
6d, (96%)
6e, (83%)
order to get more insight into the reaction mechanism.
N
(a) Dehydrogenation of alcohol
N
N
N
N
H
N
N
H
H
O
OH
Complex 3 (4 mol%)
O
KOH, PhCH3, 120 °C, 24 h
O
6h, (95%)
6i, (89%)
1a' = 90%
1a
6g, (93%)
(b) Formation of imine
N
N
N
N
N
N
N
N
N
H2N
O
+
H
H
H
N
KOH
O
O
PhCH3 , 120 °C
O
2a
1a'
3a'= 70%
6k, (95%)
N
6l, (91%)
6j, (93%)
(c) Hydrogenation of imine
N
N
Complex 3 (4 mol%)
O
O
N
H
N
N
N
N
H
N
N
+
N
H
H
KOH, PhCH3 , 120 °C, 15 h
(i)
N
3a'
Cl
O
O
O
3a' = 60%
3a = 30%
6m, (92%)
6n, (85%)
6o, (96%)
+
N
Complex 3 (4 mol%)
OH
O
N
H
N
N
H
N
O
KOH, PhCH3 , 120 °C, 24 h
(ii)
N
N
O
1a
H
3a = 83%
6q, (86%)
6p, (94%)
(d) Reaction of aniline with tert-Butyl alcohol or phenol
aGeneral reaction conditions: Amine (5, 0.75 mmol), alcohol (4,
1.5 mmol), complex 3 (4 mol%, with respect to amine), KOH(0.5
mmol) and PhCH3 (2 mL) at 120oC for 24 h. bIsolated yields.
OH
H2N
Complex 3 (4 mol%)
No product formation
+
or
KOH, PhCH3, 120 °C, 24 h
OH
2a
Pyrimidine based amines are considered to be a privileged
scaffold and have given a significant contribution in the fields
of bioorganic and medicinal chemistry.2g-h,29 But, only few
reports were investigated on the synthesis of pyrimidine based
N-alkylated amine moieties under the borrowing-hydrogen
catalytic condition.30 Furthest, we continued our investigation
and tuned the Ni(II)-NɅNɅO complex 3 to catalyse the 2-
aminopyrimidine with a range of benzyl alcohol derivatives
led to selective mono alkylated amine products in appreciable
yields (Table 5). More impressively, the benzyl alcohols
Scheme 4. Control experiments
The reaction of 4-methoxybenzyl alcohol 1a in absence of
amine 2a under standard reaction condition yielded the
corresponding aldehyde 1a’ (1a’ Fig. S76, page no. S44,
Supporting Information) which dictated that the formation
of
4-methoxybenzaldehyde
1a’
occurs
through
dehydrogenation of alcohol pathway. Further, the reaction of
4-methoxybenzaldehyde 1a’ and amine 2a yielded imine
intermediate 3a’ (Fig. S77, page no. S44, Supporting
Information). In addition, the reaction of 4-methoxybenzyl
alcohol 1a with imine 3a’ under standard condition in 15 h
afforded N-alkylated product 3a in 30% yield and 60% of
unreactive imine 3a’ was observed in the reaction mixture
(Fig. S78, page no. S45, Supporting Information).
Significantly, the excellent yield of N-alkylated product 3a
achieved when the reaction time extended to 24 h. Hence that,
the formed imine intermediate underwent hydrogen
autotransfer reaction yielded to desired N-alkylated product
was proved.
comprising
electron-donating
substituents,
such
as
4‐methylbenzyl alcohol, 3-methylbenzyl alcohol, 4-
methoxybenzyl alcohol and unsubstituted benzyl alcohol were
readily alkylated with 2-aminopyrimidine to the selective
mono-alkylated products 6i‐6l with the isolated yields of 89–
95%. Further, reducible 4-chlorobenzyl alcohol also readily
underwent N-alkylation with aminopyrimidine to the desired
6n of 85% yield. In addition, sterically hindered 1-
naphthalenemethanol and 9-anthracenemethanol were
alkylated with 2-aminopyrimidine to give the respective 6o
and 6p in 96% and 94% yields. More interestingly, 2-
morpholinoethanol easily alkylated with 2-aminopyridine to
provide the desired 6q in 86% yield. Attempts were also taken
A plausible catalytic mechanism has been proposed for the C-
N
bond forming reaction based on our experimental
observation which is further supported by literature reports22
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The Journal of Organic Chemistry
Page 6 of 11
(Scheme 5). Initially, alcohol is coordinated to nickel in to selective monoalkylated products by using nickel
1
2
3
4
5
6
7
8
presence of KOH base to form Ni-alkoxide (A) with the
release of PPh3. This active species (A) subsequently
underwent β-hydride elimination to release aldehyde with the
formation of Ni-hydride (B). Then the aldehyde coupled with
amine to form an imine which is inserted to nickel to form
(C). The reduction of imine with metal hydride leads to the
formation of (D).This species (D) further reacts with alcohol
and delivered the alkylated amine product, thereby
regeneration of Ni-alkoxide (A) for next catalytic cycle.
Further, we have deeply probed the reaction mechanism to
isolate the Ni-hydride intermediate and that was not
successful. Indeed, the most of the literatures reported that
isolation of Ni-hydride species from the reaction mixture was
unsuccessful due to its unstable nature.22 To further establish
the N-alkylation process via borrowing hydrogen stategy, we
conducted a control experiment involving the alkylation of
aniline with tert-butyl alcohol or phenol under the optimized
condition (Scheme 4d). It has been observed that no coupled
products were obtained, which supports the borrowing
hydrogen mechanism for the present nickel-catalyzed N-
alkylation via alcohol dehydrogenation reaction using
benzylalcohol. Hence, we believe the formation of amine
products via borrowing hydrogen strategy as evidenced from
our control experiments31 and the previous reports.22,32
complexeswith 85-97% isolated yields. Further, the greener
hydrogen auto transfer path way of the catalytic reaction was
evidenced by mechanistic investigation.
EXPERIMENTAL SECTION
Materials and Methods
9
NiCl2(PPh3)2,
Methyl-2-pyrrolyl
ketone,
10
11
12
13
14
15
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17
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21
22
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59
60
benzhydrazide derivatives, and CDCl3 were purchased from
Aldrich and were used as received. Solvents were freshly
distilled before use following the standard procedures.33 The
benzhydrazone ligands were prepared as described in the
literature.24 Melting points were recorded in the Boetius micro
heating table and are uncorrected. The C, H and N analyses
were performed on a Vario EL III CHNS elemental analyser at
the Sophisticated Test and Instrumentation Centre (STIC),
Cochin University, Cochin. The FT-IR spectra of the
complexes were recorded with KBr pellets using a Perkin-
Elmer 597 spectrophotometer in the range 4000–400 cm-1. The
NMR spectra were recorded on
a Bruker 400 MHz
spectrometer in CDCl3 solvent using TMS as an internal
standard. The HRMS(ESI) was recorded for all the complexes
in methanol solution with Micro mass Thermo scientific LTQ
XL mass spectrometer.
PPh3
O
N
N
Ni
X-ray crystallography
N
The single crystals have been grown for complexes 1 and 2 by
slow evaporation of ethanol solvent at room temperature. The
molecular structures of the complex 1 and 2 were resolved by
single crystal X-ray diffraction. The thermal ellipsoid view of
complexes,selected bond lengths, bond angles and detailed
description of crystal structures are provided (S8-S9, Table 1
and 2, see Supporting Information). Hence, the observed
bond lengths and bond angles of the present complex are
consistent with the reported nickel complexes.25 Bruker
SMART APEX II four-circle diffractometer with
monochromated Mo-Kα radiation (λ = 0.71073 Å) was used to
collect the X-ray intensity data at room temperature. The
absorption corrections were performed by a multi-scan method
using SADABS software. The unit cell parameters were
determined by the method of difference vectors using
reflections scanned from three different zones of the reciprocal
lattice. The intensity data were measured using ω and ϕ scan
with a frame width of 0.5ο. Frame integration and data
reduction were performed using the Bruker SAINT-Plus
(Version 7.06a)34 software Corrections were made for Lorentz
and polarization effects. The crystal structures were solved
and refined using Olex2,35 SHELXS and SHELXL36 programs.
Cl
R'
KOH
-H2O
-
O K+
HO
R'
PPh3
H
N
R'
K
R''
O
N
R'
Ni
N
O
R'
OH
N
K
R'
O
H
Cl
R''N
Ni
N
N
(A)
K
R'
H
N
O
Ni
N
O
N
N
R'' NH2
(D)
Cl
(B)
Cl
N
R'
K
R''
N
N
H
R'
Ni
N
R''
O
N
(C)
Cl
Synthetic procedure for Ni(II) complexes(1-3)
NiCl2(PPh3)2 (65.41 mg, 0.1 mmol), Methyl-2-pyrrolyl ketone
derived benzhydrazone ligands (R = H, OCH3 and Cl) (22-30
mg, 0.1mmol) and triethylamine(1 equiv.) as a base were
dissolved in 15 ml of ethanol and taken in a round neck
flask(50 ml) and stirred at refluxing condition for 12 h.
Further, the formation of complex was identified with thin
layer chromatographic technique. Then, the solvent volume
was reduced to 5 ml under reduced pressure and the addition
Scheme 5. Plausible mechanism for N-alkylation of amine
reaction
CONCLUSIONS
In conclusion, three Ni(II)-NɅNɅO pincer type complexes
were demonstrated as effective catalysts for synthesis of
biologically important monoalkylated amines. A diverse range
of primary alcohols was coupled with different sets of amines
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The Journal of Organic Chemistry
of 10 ml pet. ether in the reaction mixture to form a brown into a 100 mL oven dried schlenk tube under an atmosphere of
1
2
3
4
5
6
7
8
precipitate and filtered and dried in a vacuum.
N2 and was heated at 120 °C (oil bath) for 24 h. The progress
of N-alkylation was monitored with thin layer
chromatography. After the reaction was completed, the
reaction mixture was cooled to room temperature. Then, 60 ml
of ethyl acetate was added and dried under vacuum and
resulting residue purified with column chromatography over
silica gel (60–120 mesh) with pet.ether/EtOAc (80:20) mixture
as eluent to give 3a (1.9 g, 80%).
Characterization of the complexes (1-3)
Complex 1. Yield: 40 mg, 73.23%.
Mp:293°C (with
decomposition). Anal.Calcd. For C31H26N3OPNi (546.2248 g mol-
1): C, 68.16; H, 4.80; N, 7.69. Found: C, 68.20; H, 4.71; N, 7.61.
9
Characterization of the catalyzed products
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
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50
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59
60
FT-IR (KBr, cm-1): 1539 (s), 1337 (m), 1573 (s). H NMR (400
N-(4-methoxybenzyl)aniline (3a):22a yellow oil, yield 96% (153
MHz, CDCl3): δ (ppm) = 7.75-7.20(m, 20H, aromatic), 6.31(s,
1H, pyrrole-H), 5.57(s, 1H, pyrrole-H), 5.09(s, 1H, pyrrole-H),
2.42(s, 3H, pyrrole-CH3), 13C{1H}NMR (100 MHz, CDCl3): δ
(ppm)=11.85,109.2,114.0,127.6,128.2,128.6,129.8,130.8,131.4,13
4.7,136.7,144.4,158.8,174.8. HRMS (ESI) m/z: [M + H + CH3OH
+ Na]+ Calcd. for C31H26N3NiOPNa,CH4O,H 601.1405; Found
601.1034.
1
mg); H NMR (400 MHz, CDCl3): δ (ppm) = 7.24(d, 2H, J = 8.8
Hz), 7.13(t, 2H, J = 9.2 Hz ), 6.84(d, 2H, J = 8.8 Hz), 6.68(s, 1H),
6.59(d, 2H, J = 7.6 Hz), 4.19(s, 2H), 3.92(s, 1H), 3.74(s, 3H).
13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 158.9,148.3, 131.5,
129.3, 128.9, 117.5, 114.1, 112.9, 55.4, 47.9.
N-(4-methylbenzyl)aniline (3b):22a yellow oil, yield 94% (139
1
Complex 2. Yield: 50 mg, 79.11%. Mp:301°C (with
decomposition). Anal.Calcd. For C32H28N3NiO2P (576.2508 g
mol-1): C, 66.70; H, 4.90; N, 7.29. Found: C, 66.62; H, 4.64; N,
mg); H NMR (400 MHz, CDCl3): δ (ppm) =7.24(t, 2H, J = 8
Hz), 7.19-7.14(m, 4H), 6.71(s, 1H), 6.63(d, 2H, J = 8 Hz), 4.27(s,
2H), 3.99(s, 1H), 2.34(s, 3H).13C{1H}NMR (100 MHz, CDCl3): δ
(ppm) = 148.3, 136.9, 136.4, 129.4, 127.6, 117.5, 112.9, 48.1,
21.2.
7.32. FT-IR (KBr, cm-1): 1535 (s), 1338 (m), 1577 (s). H NMR
1
(400 MHz, CDCl3): δ (ppm) = 7.78 (s, 6H, aromatic), 7.73-7.53
(m, 11H, aromatic), 6.70(d, 2H, J = 8.8 Hz, aromatic), 6.32(d, 1H,
J = 3.2 Hz, pyrrole-H), 5.57(t,1H, J = 2.2 Hz, pyrrole-H),
5.09(s,1H, pyrrole-H), 3.77(s, 3H, -OCH3), 2.41(s, 3H, pyrrole-
CH3). 13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 11.8, 55.2,
109.0, 113.0, 113.6, 124.0, 128.6, 129.9, 130.9, 134.7, 136.5,
144.5, 158.1, 161.0, 174.8. HRMS (ESI) m/z: [M + H + CH3OH
+ Na]+ Calcd.for C32H28N3NiO2PNa,CH4O,H 631.1511; Found
631.1134.
N-(3-methylbenzyl)aniline (3c): yellow oil, yield 76% (112 mg);
1H NMR (400 MHz, CDCl3): δ (ppm) = 7.36-7.07(m, 6H), 6.73-
6.62(m, 3H), 4.27(s, 2H), 3.99(s, 1H), 2.34(s, 3H). 13C{1H}NMR
(100 MHz, CDCl3): δ (ppm) = 148.3, 139.4, 138.4, 129.3, 129.1,
128.6, 128.4, 128.1, 124.7, 117.6, 112.9, 48.4, 21.5.
N-benzylaniline (3d):22a yellow oil, yield 92% (126 mg); 1H NMR
(400 MHz, CDCl3): δ (ppm) = 7.37-7.15(m, 7H), 6.73-6.62(m,
3H), 4.31(s, 2H), 4.02(s, 1H). 13C{1H}NMR (100 MHz, CDCl3): δ
(ppm) = 148.2, 139.5, 129.3, 128.7, 127.6, 127.3, 117.6, 112.9,
48.4.
Complex 3. Yield: 45 mg, 77.50%. Mp:315°C (with
decomposition). Anal.Calcd. For C31H25N3ClNiOP (580.6699 g
mol-1): C, 64.12; H, 4.34; N, 7.24. Found: C, 64.01; H, 4.10; N,
7.30. FT-IR (KBr, cm-1): 1538 (s), 1347 (m), 1598 (s). H NMR
1
N-(3-fluorobenzyl)aniline (3e): yellow oil, yield 84% (125 mg);
1H NMR (400 MHz, CDCl3): δ (ppm) = 7.67-6.99(m, 7H), 6.97-
6.60(m, 2H), 4.34(s, 2H), 4.12(s, 1H). 13C{1H}NMR (100 MHz,
CDCl3): δ (ppm) = 147.8, 130.2, 129.3, 122.8, 117.8, 114.3,
114.2,114.1, 114.0, 113.9, 112.9, 47.8.
(400 MHz, CDCl3): δ (ppm) = 7.79 (d, 6H, J = 8 Hz, aromatic),
7.53-7.45 (m, 11H, aromatic), 7.15(d, 2H, J = 8 Hz, aromatic)
6.35(s, 1H, pyrrole-H ), 5.58(s, 1H, pyrrole-H), 5.11(s, 1H,
pyrrole-H), 2.40(s, 3H, pyrrole-CH3).13C{1H}NMR (100 MHz,
CDCl3): δ (ppm)
= 11.7, 109.4, 114.3, 127.8, 128.6, 129.5,
130.0, 130.9, 134.6, 135.7, 136.9, 144.4, 159.1, 173.3. HRMS
(ESI) m/z: [M]+ Calcd. for C31H25N3ClNiOP 579.0777; Found
579.1605).
N-(4-chlorobenzyl)aniline (3f):22a yellow oil, yield 89% (145
mg); H NMR (400 MHz, CDCl3): δ (ppm) = 7.33-7.23(m, 5H),
7.15(t, 2H, J = 8 Hz), 6.70(t, 1H, J = 6.8Hz), 6.61-6.55(m, 2H),
4.25(s, 2H), 4.01(s, 1H). 13C{1H}NMR (100 MHz, CDCl3): δ
(ppm) = 147.9, 138.1, 132.9, 129.4, 129.4, 128.8, 128.8, 128.7,
127.6, 117.9, 113.0, 112.9, 47.7.
1
Catalytic procedure for N-alkylation of amine reactions
Alcohols (1.5 mmol), amines (0.75 mmol), catalyst 3 (4 mol%
with respect to amine), KOH (0.5 mmol) and PhCH3 (2 ml)
were transferred into a 10 mL oven dried schlenk tube under
an atmosphere of N2 and was heated at 120 °C (oil bath) for 24
h. The progress of N-alkylation was monitored with thin layer
chromatography. After the reaction was completed, the
reaction mixture was cooled to room temperature and 4 ml of
ethyl acetate was added and dried under vacuum and resulting
residue purified with column chromatography over silica gel
(60–120 mesh) with pet.ether/EtOAc (80:20) mixture as
eluent.
N-(naphthalene-1-ylmethyl)aniline (3g):22a white solid, yield
1
96% (168 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.06(t,
1H, J = 4.6 Hz), 7.90-7.87(m, 1H), 7.80(d, 1H, J = 8 Hz), 7.54-
7.49(m, 3H),7.41(t, 1H, J = 8 Hz), 7.22-7.18(m, 2H), 6.74 (t, 1H,
J = 7.6 Hz), 6.68(d, 2H, J = 8 Hz), 4.72(s, 2H), 3.98(s, 1H).
13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 148.3, 134.4, 133.9,
131.6, 129.4, 128.8, 128.2, 126.4, 126.1, 125.9, 125.6, 123.7,
117.6, 112.8, 46.5.
4-methoxy-N-(naphthalene-1-ylmethyl)aniline (3h):37 white solid,
1
yield 79% (155 mg); H NMR (400 MHz, CDCl3): δ (ppm) =
Catalytic procedure for large-scale reaction
8.09-8.06(m, 1H), 7.90-7.88(m, 2H), 7.80(d, 1H, J = 8.4 Hz),
7.53-7.50(m, 3H), 7.42(t, 1H, J = 7.6 Hz), 6.80(d, 2H, J = 8.8 Hz),
6.67(d, 2H, J = 9.2 Hz), 4.68(s, 2H), 3.75(s, 4H). 13C{1H}NMR
(100 MHz, CDCl3): δ (ppm) = 152.2, 142.7, 134.7, 133.9, 131.6,
4-methoxybenzyl alcohol (1a, 3.1g, 22.5 mmol), aniline (2a,
1.0 g, 11.2 mmol), catalyst 3 (60 mol% with respect to amine),
KOH (0.4 g, 7.5 mmol) and PhCH3 (30 ml) were transferred
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Page 8 of 11
128.8, 128.2, 126.3, 126.1, 125.9, 125.6, 123.7, 115.0, 114.0,
55.9, 47.3.
N-(4-chlorobenzyl)pyridin-2-amine (6c):22a white solid, yield
85% (140 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.11(s,
1
1
1H), 7.42-7.29(m, 4H), 6.60(t, 1H, J = 5.2 Hz), 6.35(d, 1H, J = 8.4
Hz), 4.91(s, 1H), 4.49(d, 2H, J = 5.6 Hz). 13C{1H}NMR (100
MHz, CDCl3): δ (ppm) = 158.4, 148.2, 137.8, 137.5, 132.9,
128.7, 128.6, 127.4, 113.4, 106.9, 45.5.
2
3
4
5
6
7
8
9
4-methoxy-N-(4-methoxybenzyl)aniline (3i):38 white solid, yield
91% (165 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 7.28(t,
2H, J = 8.8 Hz), 6.87(d, 2H, J = 8.4 Hz), 6.77(d, 2H, J = 8.8 Hz),
6.60(d, 2H, J = 8.8 Hz), 4.20(s, 2H), 3.80(s, 4H), 3.74(s, 3H).
13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 158.8, 152.2, 142.6,
131.7, 128.9, 114.9, 114.2, 114.0, 55.8, 55.3, 48.8.
1
N-benzyl-4-methylpyridin-2-amine (6d):42 white solid, yield 96%
(142 mg); 1H NMR (400 MHz, CDCl3): δ (ppm) = 7.96(d,1H, J =
4.8 Hz), 7.36-7.25(m, 5H), 6.44(d, 1H, J = 4.8 Hz), 6.20(s,1H),
4.89(s,1H), 4.49(s, 2H), 2.21(s, 3H). 13C{1H}NMR (100 MHz,
CDCl3): δ (ppm) = 158.8, 148.6, 147.7, 139.3, 128.6, 127.4,
127.2, 114.8, 107.0, 46.3, 21.2.
N-(benzo[d][dioxal-5-ylmethyl)-4-methoxyaniline (3j):38 white
solid, yield 94% (181 mg); 1H NMR (400 MHz, CDCl3): δ (ppm)
= 6.86-6.75(m,5H), 6.60-6.57(m, 2H), 5.93(s, 2H), 4.18(s, 2H),
3.74(s, 4H). 13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 152.2,
147.9, 146.7, 142.4, 133.7, 120.6, 114.9, 114.2, 108.3, 108.1,
101.0, 55.8, 49.1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(3-fluorobenzyl)pyridin-2-amine (6e) : white solid, yield 83%
1
(126 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.09(s, 1H),
7.42-7.37(m,1H), 7.30-7.24(m, 1H), 7.10(dd,2H, J = 7.6, 9.6 Hz ),
6.96-6.91(m,1H), 6.60(dd,1H, J = 5.2, 5.2 Hz ), 6.36(d, 1H, J =
8.4 Hz), 5.14(s, 1H), 4.50(d, J = 4.8 Hz). 13C{1H}NMR (100
MHz, CDCl3): δ (ppm) = 164.3, 161.8, 158.4, 148.0, 142.1,
142.0, 137.6, 130.1, 130.0, 122.7, 114.2, 114.1, 114.0, 113.9,
113.4, 106.9, 45.7.
N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-bromoaniline (3k):39 white
solid, yield 97% (222 mg); 1H NMR (400 MHz, CDCl3): δ (ppm)
= 7.24(t, 2H, J = 7 Hz), 6.82-6.76(m, 3H), 6.48(d, 2H, J = 8.8
Hz), 5.94(s, 2H), 4.19(s, 2H), 4.04(s, 1H). 13C{1H}NMR (100
MHz, CDCl3): δ (ppm) = 148.0, 147.0, 146.9, 132.8, 132.0,
120.6, 114.5, 109.2, 108.4, 107.9, 101.1, 48.1.
N-(benzo[d][1,3]dioxol-5-ylmethyl)pyridin-2-amine (6f) : white
solid, yield 80% (137 mg); 1H NMR (400 MHz, CDCl3): δ (ppm)
= 8.09(d, 1H, J = 4 Hz), 7.42-7.38(m, 1H), 6.85-6.75(m,3H),
6.58(t, 1H, J = 5.2 Hz), 6.36(d, 1H, J = 8.4 Hz), 5.93(s, 2H),
4.96(s, 1H), 4.39(d, 2H, J = 5.2 Hz). 13C{1H}NMR (100 MHz,
CDCl3): δ (ppm) = 158.5, 148.1, 147.9, 146.7, 137.5, 133.3,
120.5, 113.2, 108.3, 108.0, 106.8, 101.0, 46.1.
N-(anthracen-9-ylmethyl)-4-bromoaniline (3l): white solid, yield
1
93% (252 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.44(s,
1H), 8.38(d, 3H, J = 8.4 Hz), 8.01(d, 3H, J = 8.4 Hz), 7.56-
7.52(m, 3H), 7.47(t, 3H, J = 7.6 Hz), 5.63(s, 3H). 13C{1H}NMR
(100 MHz, CDCl3): δ (ppm) = 131.6, 131.0, 130.2, 129.1, 128.4,
126.5, 125.1, 123.9, 57.4.
N-(pyridine-2-ylmethyl)aniline (3m):22a yellow oil, yield 89%
(123 mg); 1H NMR (400 MHz, CDCl3): δ (ppm) = 8.49(d, 1H, J =
4.4 Hz), 7.55-7.51(m, 1H), 7.23(d, 1H, J = 7.6 Hz), 7.12-7.06(m,
3H), 6.65-6.56(m, 3H), 4.70(s, 1H), 4.36(s, 2H). 13C{1H}NMR
(100 MHz, CDCl3): δ (ppm) = 158.6, 149.2, 147.9, 136.7, 129.3,
122.1, 121.6, 117.6, 113.1, 49.3.
N-(naphthalene-1-ylmethyl)pyridin-2-amine (6g):43 white solid,
1
yield 93% (164 mg); H NMR (400 MHz, CDCl3): δ (ppm) =
8.14(s, 1H), 8.06(d, 1H, J = 8.8 Hz),7.87(t, 1H, J = 6 Hz), 7.79(d,
1H, J = 8 Hz), 7.50 (q, 3H, J = 3.2 Hz), 7.40(q, 2H, J = 7.6 Hz),
6.60(t, 1H, J = 5.6 Hz), 6.38(d, 1H, J = 8.4 Hz), 4.93(s, 3H).
13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 158.5, 148.1, 137.5,
134.2, 133.9, 131.5, 128.8, 128.2, 126.4, 125.9, 125.8, 125.5,
123.5, 113.1, 107.2, 44.3 .
N-(2-morpholinoethyl)aniline (3n):40 yellow oil, yield 87% (134
1
mg); H NMR (400 MHz, CDCl3): δ (ppm) = 7.12(t, 2H, J = 7.2
Hz), 6.65-6.55(m, 3H), 4.23(s, 1H), 3.64(t, 4H, J = 4.8 Hz),
3.08(t, 2H, J = 5.6 Hz), 2.54 (t, 2H, J = 6Hz), 2.39(d, 4H, J = 3.6
Hz). 13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 148.5, 129.3,
117.4, 112.9, 67.0, 57.2, 53.4, 39.9.
N-(anthracen-9-ylmethyl)pyridin-2-amine (6h) : white solid, yield
1
95% (203 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.48(s,
1H), 8.33(d, 2H, J = 8.8 Hz), 8.25(d, 1H, J = 4.4 Hz), 8.04(d, 2H,
J = 8 Hz), 7.54-7.43(m, 5H), 6.66(t, 1H, J = 5.6 Hz), 6.45(d, 1H, J
= 8 Hz), 5.44(d, 2H, J = 4.4 Hz), 4.52(s, 1H).13C{1H}NMR (100
MHz, CDCl3): δ (ppm) = 158.4, 148.2, 137.3, 131.5, 130.4,
129.5, 129.1, 127.9, 126.4, 125.1, 124.2, 113.1, 107.9, 38.7.
4-methoxy-N-(2-morpholinoethyl)aniline (3o):41 yellow oil, yield
1
92% (162 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 6.79(d,
2H, J = 8.8 Hz), 6.61(d, 2H, J = 8.8 Hz), 3.74(s, 3H), 3.71(t, 4H, J
= 4.4 Hz), 3.12(t, 2H, J = 6 Hz), 2.62(t, 2H, J = 6 Hz), 2.46(t, 4H,J
= 4.4 Hz). 13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 152.2,
142.8, 114.9, 114.3, 67.0, 57.3, 55.9, 53.4,41.0.
N-benzylpyrimidin-2-amine (6i):30b white solid, yield 89% (123
1
mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.27(s, 2H), 7.37-
7.26(m, 5H), 6.55(t, 1H, J = 4.8 Hz), 5.69(s, 1H), 4.65(d, 2H, J =
5.6 Hz). 13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 162.3,
158.1, 139.0, 128.6, 127.4, 127.2, 110.9, 45.4.
N-benzylpyridin-2-amine (6a):22b white solid, yield 94% (129
1
mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.11(s, 1H), 7.43-
N-(4-methoxybenzyl)pyrimidin-2-amine (6j):30b
white solid,
7.26(m, 6H), 6.60(t, 1H, J = 5.6 Hz), 6.35(d, 1H, J = 8.4 Hz),
4.90(s, 1H), 4.49(d, 2H, J = 5.6 Hz). 13C{1H}NMR (100 MHz,
CDCl3): δ (ppm) = 158.4, 148.1, 137.8, 137.6, 132.9, 128.8,
128.6, 113.5, 106.9, 45.6.
1
yield 93% (149 mg); H NMR (400 MHz, CDCl3): δ (ppm) =
8.25(d, 2H, J = 4Hz), 7.27(t, 2H, J = 8.8 Hz), 6.86(d,2H, J = 8.4
Hz), 6.53(t, 1H, J = 4.8 Hz), 5.67(s, 1H), 4.56(d, 2H, J = 6 Hz),
3.80(s, 3H).13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 162.2,
158.8, 158.0, 131.0, 128.8, 114.0, 110.7, 55.3, 44.9.
N-(4-methoxybenzyl)pyridin-2-amine (6b):22a white solid, yield
1
95% (153 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.11(s,
N-(4-methylbenzyl)pyrimidin-2-amine (6k):30b white solid, yield
1H), 7.39(t, 1H, J = 7.6 Hz), 7.27(d, 2H, J = 8.4 Hz), 6.86(d, 2H, J
= 8.4 Hz), 6.58(s, 1H), 6.38(s, 1H), 4.90(s, 1H), 4.41(s, 2H),
3.79(s, 3H) . 13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 158.8,
158.7, 148.0, 137.4, 131.1, 128.7, 144.0, 113.2, 106.9, 55.3, 45.8.
1
95% (141 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.27(d,
2H, J = 4 Hz), 7.25(d, 2H, J = 8.8 Hz), 7.14(d, 2H, J = 7.6 Hz),
6.54(s, 1H), 5.53(s, 1H), 4.59(d, 2H, J = 5.6 Hz), 2.34(s,
3H).13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 162.3, 158.1,
136.9, 135.9, 129.3, 127.4, 110.8, 45.2, 21.1.
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N-(3-methylbenzyl)pyrimidin-2-amine (6l) : white solid, yield
REFERENCES
1
1
2
3
4
91% (134 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.28(s,
2H), 7.26-7.08(m, 4H),6.55(t, 1H, J = 4.4 Hz),5.60(s, 1H),4.61(d,
2H, J = 5.2 Hz),2.34(s, 3H).13C{1H}NMR (100 MHz, CDCl3): δ
(ppm) = 158.1, 138.9, 138.3, 128.5, 128.2, 128.0, 124.5, 110.8,
45.4, 21.4.
(1) Butters, M.; Catterick, D.; Craig, A.; Curzons, A.; Dale, D.;
Gillmore, A.; Green, S. P.; Marziano, I.; Sherlock, J.-P.; White, W.,
Critical assessment of pharmaceutical processes a rationale for
changing the synthetic route. Chem. Rev. 2006, 106, 3002-3027.
(2) (a)
Froidevaux, V.; Negrell, C.; Caillol, S.; Pascault, J.-P.;
5
6
7
8
Boutevin, B., Biobased amines: from synthesis to polymers; present
and future. Chem. Rev. 2016, 116, 14181-14224. (b) Siddalingappa,
B.; Benson, H. A.; Brown, D. H.; Batty, K. T.; Chen, Y., Stabilization
of resveratrol in blood circulation by conjugation to mPEG and
mPEG-PLA polymers: investigation of conjugate linker and polymer
composition on stability, metabolism, antioxidant activity and
pharmacokinetic profile. Plos one 2015, 10, e0118824. (c) McGuire,
J. L., Pharmaceuticals: classes, therapeutic agents, areas of
application. VchVerlagsgesellschaft Mbh2000. (d) Ricci, A., Amino
group chemistry: from synthesis to the life sciences. John Wiley &
Sons 2008. (e) Torres, P. U., CinacalcetHCl: a novel treatment for
secondary hyperparathyroidism caused by chronic kidney disease. J
Ren Nut. 2006, 16, 253-258. (f) Lijinsky, W.; Reuber, M.; Blackwell,
B., Liver tumors induced in rats by oral administration of the
antihistaminic methapyrilene hydrochloride. Science 1980, 209, 817-
819. (g) Herberich, B.; Cao, G. Q.; Chakrabarti, P. P.; Falsey, J. R.;
Pettus, L.; Rzasa, R. M.; Reed, A. B.; Reichelt, A.; Sham, K.;
Thaman, M.; Wurz, R. P.; Xu, S.; Zhang, D.; Hsieh, F.; Lee, M. R.;
Li, R. V.; Grosfeld, D.; Plant, M. H.; Henkle, B.; Sherman, L.;
Middleton, S.; Wong, L. M.; Tasker, A. S. Discovery of highly
selective and potent p38 inhibitors based on a phthalazine scaffold. J.
Med. Chem., 2008, 51, 6271–6279. (h) Liverton, N. J.; Bednar, R. A.;
Bednar, B.; Butcher, J. W.; Claiborne, C. F.; Claremon, D. A.;
Cunningham, M.; DiLella, A. G.; Gaul, S. L.; Libby, B. E.; Lyle, E.
A.; Lynch, J. J.; McCauley, J. A.; Mosser, S. D.; Nguyen, K. T.;
Stump, G. L.; Sun, H.; Wang, H.; Yergey, J.; Koblan, K. S.
Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2-
ylamino) methyl] piperidine-1-carboxylate, an orally bioavailable,
brain penetrant NR2B selective N-methyl-D-aspartate receptor
antagonist. J. Med. Chem., 2007, 50, 807–819.
N-(benzo[d][1,3]dioxol-5-ylmethyl)pyrimidin-2-amine (6m)
:
1
white solid, yield 92% (157 mg); H NMR (400 MHz, CDCl3): δ
(ppm) =8.28(s, 2H), 6.86-6.75(m, 3H), 6.56(d, 1H, J = 4.4 Hz),
5.94(s, 2H), 5.58(s, 1H), 4.54(d, 2H, J = 5.6 Hz).13C{1H}NMR
(100 MHz, CDCl3): δ (ppm) = 158.1, 147.9, 146.7, 133.0, 120.6,
108.3, 108.1, 101.0, 45.2.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-(4-chlorobenzyl)pyrimidin-2-amine (6n):30b white solid, yield
1
85% (139 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.26(s,
2H), 7.35-7.26(m, 4H), 6.54(t, 1H, J = 4.8 Hz), 5.71(s, 1H),
4.64(d, 2H, J = 6 Hz).13C{1H}NMR (100 MHz, CDCl3): δ (ppm)
= 162.3, 158.1, 139.0, 128.6, 127.5, 127.2, 110.8, 45.4.
N-(naphthalen-1-ylmethyl)pyrimidin-2-amine (6o):44 white solid,
1
yield 96% (168 mg); H NMR (400 MHz, CDCl3): δ (ppm) =
8.21(s, 2H), 8.07(d, 1H, J = 8.8 Hz), 7.88-7.79(m, 2H), 7.69-
7.40(m, 4H), 6.51(s, 1H), 5.89(s, 1H), 5.06(d, 2H, J = 3.6 Hz) .
13C{1H}NMR (100 MHz, CDCl3): δ (ppm) = 162.2, 158.1, 134.2,
133.8, 131.5, 128.7, 128.2, 126.4, 125.8, 125.4, 123.5, 110.8,
43.6.
N-(anthracen-9-ylmethyl)pyrimidin-2-amine (6p): white solid,
1
yield 94% (200 mg); H NMR (400 MHz, CDCl3): δ (ppm) =
8.47(s, 1H), 8.33(t, 4H, J = 8.8 Hz), 8.04(d, 2H, J = 8 Hz), 7.55-
7.47(m, 4H), 6.54(t, 1H,
J
=
4.8 Hz), 5.53(s, 3H).
13C{1H}NMR(100 MHz, CDCl3): δ (ppm) = 162.0, 158.1, 131.5,
130.4, 129.1, 128.0, 126.5, 125.1, 124.1, 110.8, 38.1.
(3) (a) Magano, J.; Dunetz, J. R. Large-scale applications of transition
metal-catalyzed couplings for the synthesis of pharmaceuticals. Chem.
Rev. 2011, 111, 2177-2250. (b) Sperotto, E.; van Klink, G. P.; van
Koten, G.; de Vries, J. G. The mechanism of the modified Ullmann
reaction. Dalton Trans. 2010, 39, 10338-10351. (c) Huang, L.; Arndt,
M.; Gooßen, K. t.; Heydt, H.; Goossen, L. J. Late transition metal-
catalyzed hydroamination and hydroamidation. Chem. Rev. 2015,
115, 2596-2697.
N-(2-morpholinoethyl)pyridin-2-amine (6q):45 yellow oil, yield
1
86% (134 mg); H NMR (400 MHz, CDCl3): δ (ppm) = 8.08(d,
1H, J = 4.4 Hz), 7.43-7.39(m, 1H), 6.57-6.55(m, 1H), 6.40(d, 1H,
J = 8.4 Hz), 5.14(s, 1H), 3.72(t, 4H, J = 4.4 Hz), 3.35(q, 2H, J =
5.2 Hz), 2.62(t, 2H, J = 6 Hz), 2.49(s, 4H). 13C{1H}NMR (100
MHz, CDCl3): δ (ppm) = 158.7, 148.0, 137.4, 112.7, 107.1, 66.9,
57.1, 53.3, 38.1.
(4) (a)
Barta, K.; Ford, P. C., Catalytic conversion of nonfood
ASSOCIATED CONTENT
Supporting Information
woody biomass solids to organic liquids. Acc. chem. Res. 2014, 47,
1503-1512. (b) Pelckmans, M.; Renders, T.; Van de Vyver, S.; Sels,
B. Bio-based amines through sustainable heterogeneous catalysis.
Green Chemistry 2017, 19, 5303-5331.
(5) For selected examples, see: (a) Dang, T. T.; Ramalingam, B.;
Shan, S. P.; Seayad, A. M. An efficient palladium-catalyzed N-
alkylation of amines using primary and secondary alcohols. ACS
Catal. 2013, 3, 2536-2540. (b) Corma, A.; Navas, J.; Sabater, M. J.
Advances in one-pot synthesis through borrowing hydrogen catalysis.
Chem. Rev. 2018, 118, 1410-1459. (c) Guillena, G.; Ramon, D. J.;
Yus, M., Hydrogen autotransfer in the N-alkylation of amines and
related compounds using alcohols and amines as electrophiles. Chem.
Rev. 2009, 110, 1611-1641.
characterization data and figures illustrating HRMS and NMR
spectra
AUTHOR INFORMATION
Corresponding Author
E-mail: ramesh_bdu@yahoo.com.
(6) (a)
Yan, T.; Feringa, B. L.; Barta, K. Iron catalysed direct
ACKNOWLEDGMENTS
alkylation of amines with alcohols. Nat. Commun. 2014, 5, 5602. (b)
Yan, T.; Feringa, B. L.; Barta, K.Benzylamines via iron-catalyzed
direct amination of benzyl alcohols. ACS Catal. 2015, 6, 381-388. (c)
Rösler, S.; Ertl, M.; Irrgang, T.; Kempe, R. Cobalt‐Catalyzed
Alkylation of Aromatic Amines by Alcohols. Angew.Chem.,Int. Ed.
2015, 54, 15046-15050. (d) Elangovan, S.; Neumann, J.; Sortais, J.-
B.; Junge, K.; Darcel, C.; Beller, M. Efficient and selective N-
alkylation of amines with alcohols catalysed by manganese pincer
complexes. Nat. Commun. 2016, 7, 12641.
We thank the Council of Scientific &Industrial Research
(CSIR) for research grant (Scheme No:02(0142)/13/EMR ‐ II)
and senior research fellowship to G.B UGC‐SAP and
DST‐India (FIST programme) are acknowledged for the use of
Bruker 400 MHz NMR and HRMS facilities at the School of
Chemistry, Bharathidasan University. We also thank
CEFIPRA (Scheme No: IFC/5005‐1/2013/1156), India for
GC–MS instrumentation facility.
(7) (a)
Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent
advances in homogeneous nickel catalysis. Nature 2014, 509, 299-
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 11
309. (b) Irrgang, T.; Kempe, R. 3d-Metal catalyzed N-and C-
Sci. Technol. 2015, 5, 1412−1427. (b) Shimizu, K.-i.; Kon, K.;
alkylation reactions via borrowing hydrogen or hydrogen autotransfer.
Chem. Rev. 2018, 119, 2524-2549. (c) Ananikov, V. P. Nickel: the
“spirited horse” of transition metal catalysis. ACS Publications 2015.
(d) Jolly, P. W.; Wilke, G. The OrganicChemistry of Nickel;
Academic Press: New York, 1974. (e) Wilke, G. Contributions to
Organo‐Nickel Chemistry. Angew.Chem., Int. Ed. Engl. 1988, 27,
185-206. (f) Takahashi, T.; Kanno, K.-i., Modern Organonickel
Chemistry. Wiley-VCH Weinheim 2005. (g) Dander, J. E.; Garg, N.
K. Breaking amides using nickel catalysis. ACS Catal. 2017, 7, 1413-
1423.
Onodera, Yamazaki, W.; Kondo, H. J. Heterogeneous Ni Catalyst for
Direct Synthesis of Primary Amines from Alcohols and Ammonia.
ACS Catal. 2013, 3, 112−117. (c) Cui, X.; Dai, X.; Deng, Y.; Shi, F.
Development of a General Non‐Noble Metal Catalyst for the Benign
Amination of Alcohols with Amines and Ammonia. Chem. Eur. J.
2013, 19, 3665−3675. (d) Alonso, F.; Riente, P.; Yus, M. Nickel
Nanoparticles in Hydrogen Transfer Reactions. Acc. Chem. Res. 2011,
44, 379−391. (e) Alonso, F.; Riente, P.; Yus, M. Alcohols for the
α‐Alkylation of Methyl Ketones and Indirect Aza‐Wittig Reaction
Promoted by Nickel Nanoparticles. Eur. J. Org. Chem. 2008, 2008,
4908−4914. (f) Afanasenko, A.; Elangovan, S.; Stuart, M. C.; Bonura,
G.; Frusteri, F.; Barta, K. Efficient nickel-catalysed N-alkylation of
amines with alcohols. Catal. Sci. Technol. 2018, 8, 5498-5505.
(22) (a) Vellakkaran, M.; Singh, K.; Banerjee, D. An Efficient and
Selective Nickel-Catalyzed Direct N-Alkylation of Anilines with
Alcohols. ACS Catal. 2017, 7, 8152-8158. (b) Bains, A. K.; Kundu,
A.; Yadav, S.; Adhikari, D. Borrowing Hydrogen-Mediated N-
Alkylation Reactions by a Well-Defined Homogeneous Nickel
Catalyst. ACS Catal. 2019, 9, 9051−9059.
1
2
3
4
5
6
7
8
9
(8) Yamaguchi, J.; Muto, K.; Itami, K. Recent Progress in
Nickel‐Catalyzed Biaryl Coupling. Eur. J. Org. Chem. 2013, 19-30.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) (a)
Ge, S.; Hartwig, J. F. Highly Reactive, Single‐Component
Nickel Catalyst Precursor for Suzuki–Miyuara Cross‐Coupling of
Heteroaryl Boronic Acids with Heteroaryl Halides. Angew.Chem. Int.
Edn. 2012, 51, 12837-12841. (b) Ramgren, S. D.; Hie, L.; Ye, Y.;
Garg, N. K. Nickel-catalyzed Suzuki–Miyaura couplings in green
solvents. Org. Lett. 2013, 15, 3950-3953.
10) (a) Quasdorf, K. W.; Tian, X.; Garg, N. K. Cross-coupling
reactions of aryl pivalates with boronic acids. J. Am. Chem. Soc.
2008, 130, 14422–14423. (b) Chuit, C.; Feltun, H.; Frajerman, C.;
Roussi, G.; Swierczewski, G. Action des organomagnesienssur les
alcoolsallyliques en presence de complexes du nickel: I.
Synthesed'olefines. J. Organomet. Chem. 1977, 127, 371-384. (c)
Dankwardt, J. W. Nickel‐Catalyzed Cross‐Coupling of Aryl Grignard
Reagents with Aromatic Alkyl Ethers: An Efficient Synthesis of
Unsymmetrical Biaryls. Angew. Chem. Int. Edn. 2004, 43, 2428-2432.
(11) Harris, M. R.; Hanna, L. E.; Greene, M. A.; Moore, C. E.; Jarvo,
E. R. Retention or inversion in stereospecific nickel-catalyzed cross-
coupling of benzyliccarbamates with arylboronic esters: control of
absolute stereochemistry with an achiral catalyst. J. Am. Chem. Soc.
2013, 135, 3303-3306.
(12) (a) Lin, B. L.; Clough, C. R.; Hillhouse, G. L. Interactions of
aziridines with nickel complexes: oxidative-addition and reductive-
elimination reactions that break and make C− N bonds. J. Am. Chem.
Soc. 2002, 124, 2890-2891. (b) Huang, C.-Y.; Doyle, A. G., Nickel-
catalyzed Negishialkylations of styrenylaziridines. J. Am. Chem. Soc.
2012, 134, 9541-9544.
(13) (a) Muto, K.; Yamaguchi, J.; Itami, K. Nickel-catalyzed C–
H/C–O coupling of azoles with phenol derivatives. J. Am. Chem. Soc.
2011, 134, 169-172. (b) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto,
Y.; Chatani, N. Nickel-catalyzed chelation-assisted transformations
involving ortho C–H bond activation: regioselective oxidative
cycloaddition of aromatic amides to alkynes. J. Am. Chem. Soc. 2011,
133, 14952-14955.
(14) (a) Oestreich, M. The Mizoroki-Heck Reaction. John Wiley &
Sons 2009. (b) Cabri, W.; Candiani, I. Recent developments and new
perspectives in the Heck reaction. Acc. Chem. Res. 1995, 28, 2-7.
(15) Montgomery, J. Nickel‐catalyzed reductive cyclizations and
couplings. Angew.Chem. Int. Edn. 2004, 43, 3890-3908.
(16) Blieck, R.; Azizi, M. S.; Mifleur, A.; Roger, M.; Persyn, C.;
Sauthier, M.; Bonin, H. Nickel‐Catalysed Bis‐Allylation of Activated
Nucleophiles with Allyl Alcohol. Eur. J. Org. Chem. 2016, 2016,
1194-1198.
(17) Böing, C.; Franciò, G.; Leitner, W. Nickel catalysed asymmetric
cycloisomerisation of diethyl diallylmalonate. Chem. Commun. 2005,
1456-1458.
(18) Vellakkaran, M.; Das, J.; Bera, S.; Banerjee, D. Nickel-catalysed
alkylation of C(sp3)–H bonds with alcohols: direct access to
functionalised N-heteroaromatics. Chem. Commun. 2018, 54, 12369-
12372.
(19) Ramalingam, B. M.; Ramakrishna, I.; Baidya, M. Nickel-
Catalyzed Direct Alkenylation of Methyl Heteroarenes with Primary
Alcohols. J. Org. Chem. 2019, 84, 9819-9825.
(23) (a) Manikandan, T. S.; Ramesh, R.; Semeril, D. The Tandem C–
H/N–H Activation of N-Methyl Arylamide Catalyzed by Dinuclear
Pd (II) Benzhydrazone Complex:
A
Concise Access to
Phenanthridinone. Organometallics 2018, 38, 319-328. (b) Sundar, S.;
Rengan, R. Direct synthesis of 2, 4, 5-trisubstituted imidazoles from
primary alcohols by diruthenium (II) catalysts under aerobic
conditions. Org. Biomol. chem. 2019, 17, 1402-1409. (c)
Balamurugan, G.; Balaji, S.; Ramesh, R.; Bhuvanesh, N. S. Synthesis
and Structures of Arene Ruthenium (II)–NHC Complexes: Efficient
Catalytic α‐alkylation of ketones via Hydrogen Auto Transfer
Reaction. Appl. Organomet. Chem. 2019, 33, e4696.
(24) Manikandan, T. S.; Ramesh, R.; Shivalingegowda, N.;
Krishnappagowda, L. N. Direct Aerobic Strategy for Synthesis of
Imines via Alcohols and Amines Promoted by Ruthenium (II)
(η6‐p‐cymene) Complexes. ChemistrySelect 2018, 3, 1561-1568.
(25) (a) Niu, J.-L.; Hao, X.-Q.; Gong, J.-F.; Song, M.-P. Symmetrical
and unsymmetrical pincer complexes with group 10 metals: Synthesis
via aryl C–H activation and some catalytic applications. Dalton
Trans. 2011, 40, 5135-5150. (b) RajKumar, R.; Ramesh, R. Synthesis,
molecular structure and electrochemical properties of nickel (II)
benzhydrazone complexes: influence of ligand substitution on
DNA/protein interaction, antioxidant activity and cytotoxicity. RSC
Adv. 2015, 5, 101932-101948.
(26) (a) Zhu, X.; Gao, J. J.; Landao-Bassonga, E.; Pavlos, N. J.; Qin,
A.; Steer, J. H.; Zheng, M. H.; Dong, Y.; Cheng, T. S. Thonzonium
bromide inhibits RANKL-induced osteoclast formation and bone
resorption in vitro and prevents LPS-induced bone loss in vivo.
Biochemical pharmacology 2016, 104, 118-130. (b) Huang, H.; Kang,
J. Y. Mitsunobu Reaction Using Basic Amines as Pronucleophiles. J.
Org. Chem. 2017, 82, 6604-6614.
(27) Hayes, M. P.; Soto-Velasquez, M.; Fowler, C. A.; Watts, V. J.;
Roman, D. L. Identification of FDA-Approved Small Molecules
Capable of Disrupting the Calmodulin–Adenylyl Cyclase
8
Interaction through Direct Binding to Calmodulin. ACS Chem.
Neurosci. 2017, 9, 346-357.
(28) Wang, S.; Bao, L.; Song, D.; Wang, J.; Cao, X. Heterocyclic
lactam derivatives containing piperonyl moiety as potential antifungal
agents. Bioorganic & medicinal chemistry letters 2019, 29, 126661.
(29) (a) Vaughan, J. R.; Anderson, G. W.; Clapp, R. C.; Clark, J. H.;
English, J. P.; Howard, K. L.; Marson, H. W.; Sutherland, L. H.;
Denton, J. Antihistamine Agents. IV. Halogenated N, N-dimethyl-N'-
benzyl-N'-(2-pyridyl)-Ethylenediamines. J. Org. Chem. 1949, 14,
228−234. (b) Parsons, M. E.; Ganellin, C. R. Histamine and its
receptors. Br. J. Pharmacol. 2006, 147, S127−S135. (c) DiMauro, E.
F.; Newcomb, J.; Nunes, J. J.; Bemis, J. E.; Boucher, C.; Buchanan, J.
L.; Buckner, W. H.; Cee, V. J.; Chai, L.; Deak, H. L.; Epstein, L. F.;
Faust, T.; Gallant, P.; Geuns-Meyer, S. D.; Gore, A.; Gu, Y.; Henkle,
B.; Hodous, B. L.; Hsieh, F.; Huang, X.; Kim, J. L.; Lee, J. H.;
Martin, M. W.; Masse, C. E.; McGowan, D. C.; Metz, D.; Mohn, D.;
Morgenstern, K. A.; Oliveira-dos-Santos, A.; Patel, V. F.; Powers, D.;
Rose, P. E.; Schneider, S.; Tomlinson, S. A.; Tudor, Y. Y.; Turci, S.
(20) Patel, U. N.; Pandey, D. K.; Gonnade, R. G.; Punji, B. Synthesis
of Quinoline-Based NNN-Pincer Nickel (II) Complexes: A Robust
and Improved Catalyst System for C–H Bond Alkylation of Azoles
with Alkyl Halides. Organometallics 2016, 35, 1785-1793.
(21) (a) Shimizu, K.-i. Heterogeneous catalysis for the direct
synthesis of chemicals by borrowing hydrogen methodology. Catal.
ACS Paragon Plus Environment

Page 11 of 11
The Journal of Organic Chemistry
M.; Welcher, A. A.; White, R. D.; Zhao, H.; Zhu L.; Zhu, X.
(35) Gildea, R. J.; Bourhis, L. J.; Dolomanov, O. V.; Grosse-
Kunstleve, R. W.; Puschmann, H.; Adams, P. D.; Howard, J. A.,
iotbx. cif: a comprehensive CIF toolbox. J. Appl. Cryst. 2011, 44,
1259–1263.
(36) Sheldrick, G. M. A short history of SHELX. Acta Cryst. 2008,
A64, 112–122.
(37) Emayavaramban, B.; Chakraborty, P.; Sundararaju, B.
Cobalt‐Catalyzed Reductive Alkylation of Amines with Carboxylic
Acids. ChemSusChem 2019, 12, 3089-3093.
(38) Peng, Y.; Fan, Y.-H.; Li, S.-Y.; Li, B.; Xue, J.; Deng, Q.-H. Iron-
Catalyzed Nitrene Transfer Reaction of 4-Hydroxystilbenes with Aryl
Azides: Synthesis of Imines via C═ C Bond Cleavage. Org. Lett.
2019, 21, 8389−8394.
(39) Yang, S.-P.; Han, L.-J.; Wang, D.-Q.; Xia, H.-T. 4-Bromo-N-(3,
4-methylenedioxybenzyl) aniline. Acta Cryst. 2007, E63, o4404-
o4404.
(40) Wang, C.; Chen, C.; Han, J.; Zhang, J.; Yao, Y.; Zhao, Y.
Insight into O2‐Promoted Base‐Catalyzed N‐Alkylation of Amines
with Alcohols. Eur. J. Org. Chem. 2015, 2015, 2972-2977.
(41) Harada, T.; Ueda, Y.; Iwai, T.; Sawamura, M. Nickel-catalyzed
amination of aryl fluorides with primary amines. Chem. Commun.
2018, 54, 1718-1721.
(42) Yu, X.-J.; He, H.-Y.; Yang, L.; Fu, H.-Y.; Zheng, X.-L.; Chen,
H.; Li, R.-X. Hemilabile N-heterocyclic carbene (NHC)-nitrogen-
phosphine mediated Ru (II)-catalyzed N-alkylation of aromatic amine
with alcohol efficiently. Catalysis Communications 2017, 95, 54-57.
(43) Li, X.; Li, S.; Li, Q.; Dong, X.; Li, Y.; Yu, X.; Xu, Q. Efficient
and practical catalyst-free-like dehydrative N-alkylation of amines
and sulfinamides with alcohols initiated by aerobic oxidation of
alcohols under air. Tetrahedron 2016, 72, 264-272.
(44) Li, S.; Li, X.; Li, Q.; Yuan, Q.; Shi, X.; Xu, Q. Structure-
dependent tautomerization induced catalyst-free autocatalyzed N-
alkylation of heteroaryl amines with alcohols. Green Chem. 2015, 17,
3260-3265.
Discovery of aminoquinazolines as potent, orally bioavailable
inhibitors of Lck: synthesis, SAR, and in vivo anti-inflammatory
activity. J. Med. Chem.2006, 49, 5671–5686. (d) Cox, C. D.; Breslin,
M. J.; Whitman, D. B.; Schreier, J. D.; McGaughey, G. B.; Bogusky,
M. J.; Roecker, A. J.; Mercer, S. P.; Bednar, R. A.; Lemaire, W.;
Bruno, J. G.; Reiss, D. R.; Harrell, C. M.; Murphy, K. L.; Garson, S.
L.; Doran, S. M.; Prueksaritanont, T.; Anderson, W. B.; Tang, C.;
Roller, S.; Cabalu, T. D.; Cui, D.; Hartman, G. D.; Young, S. D.;
Koblan, K. S.; Winrow, C. J.; Renger J. J.; Coleman, P. J. Discovery
of the dual orexin receptor antagonist [(7 R)-4-(5-chloro-1, 3-
benzoxazol-2-yl)-7-methyl-1, 4-diazepan-1-yl][5-methyl-2-(2 H-1, 2,
3-triazol-2-yl) phenyl] methanone (MK-4305) for the treatment of
insomnia. J. Med. Chem. 2010, 53, 5320–5332. (e) Traquandi, G.;
Ciomei, M.; Ballinari, D.; Casale, E.; Colombo, N.; Croci, V.;
Fiorentini, F.; Isacchi, A.; Longo, A.; Mercurio, C.; Panzeri, A.;
Pastori, W.; Pevarello, P.; Volpi, D.; Roussel, P.; Vulpetti, A.;
Brasca, M. G. Identification of potent pyrazolo [4, 3-h] quinazoline-3-
carboxamides as multi-cyclin-dependent kinase inhibitors. J. Med.
Chem. 2010, 53, 2171–2187.
(30) (a) Li, F.; Chen, L.; Kang, Q.; Cai, J.; Zhu, G. Regioselective N-
alkylation with alcohols for the preparation of 2-(N-
alkylamino)quinazolines and 2-(N-alkylamino)pyrimidines. New J.
Chem. 2013, 37, 624. (b) Ramachandran, R. ; Viswanathamurthi, P.;
Ramkumar, V.; Prakash, G.; Selvamurugan, S.; Malecki, J. G.;
Efficient and versatile catalysis of N-alkylation of heterocyclic
amines with alcohols and one-pot synthesis of 2-aryl substituted
benzazoles with newly designed ruthenium(II) complexes of PNS
thiosemicarbazones. Dalton Trans. 2014, 43, 7889.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(31) Zhang, G.; Yin, Z.; Zheng, S. Cobalt-Catalyzed N-Alkylation of
Amines with Alcohols. Org. Lett. 2016, 18, 300−303.
(32) Rawlings, A. J.; Diorazio, L. J.; Wills, M. C−N Bond Formation
between Alcohols and Amines Using an Iron Cyclopentadienone
Catalyst. Org. Lett. 2015, 17, 1086−1089.
(33) Vogel, A. I. Vogel’s Text book of Practical Organic Chemistry,
Longman, London, 5th ed.;Longman Group UK Limited: London,
1989, p. 395.
(34) Bruker-Nonius, APEX-II and SAINT-Plus, Version 7.06a,
Bruker AXS Inc.: Madison, WI, 2004.
(45) Kaye, I. A.; Kogon, I. C. N-Monosubstituted 2-Aminopyridines,
2-Aminopyrimidines and 2-Aminolepidines. J. Am. Chem. Soc.1951,
73, 5891-5893.
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