A microwave-assisted SmI2-catalyzed direct N-alkylation of anilines with alcohols

Article abstract of DOI:10.1021/acs.joc.9b00717

A new protocol for the alkylation of aromatic amines has been described using alcohols in the presence of SmI₂ as a catalyst with the generation of water as the sole byproduct. The reaction proceeds under MW conditions and selectively generates monoalkylated amines. This protocol features a broad substrate scope and good functional-group tolerance with moderate to high yields.

Full text of DOI:10.1021/acs.joc.9b00717

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Note
A Microwave-Assisted SmI2-Catalyzed
Direct N-Alkylation of Anilines with Alcohols
Jitendra Gour, Srikanth Gatadi, Satyaveni Malasala, Madhavi Venkata Yaddanapudi, and Srinivas Nanduri
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00717 • Publication Date (Web): 08 May 2019
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Page 1 of 9
The Journal of Organic Chemistry
A Microwave-Assisted SmI2-Catalyzed Direct N‑Alkylation of
Anilines with Alcohols
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Jitendra Gour,† Srikanth Gatadi,† Satyaveni Malasala,† Madhavi Venkata Yaddanpudi,† and Srinivas
Nanduri*†
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†Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad 500
037, India
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Sustainable C-N bond formation
R1
NH2
SmI2 (3 mol %)
R1
OH
N
H
R
+
R
H2O
31 examples
up to 83% yield
Broad substrate scope
High selectivity
First SmI2 catalysed N-alkylation
ABSTRACT: A new protocol for the alkylation of aromatic amines has been described using alcohols in presence of SmI2 as
catalyst with the generation of water as the sole byproduct. The reaction proceeds under MW conditions and selectively generates
monoalkylated amines. This protocol features broad substrate scope and good functional-group tolerance with moderate to high
yields.
he direct construction of C-N bond is of immense interest
of stabilizing ligands such as PN5P ligand, alanine-triazole
ligand, PNP pincer, pyridine-based PNNH pincer and NHC.6a,
Thus, the there exists a need for developing easily
accessible and inexpensive catalytic systems for
monoalkylation of amines is desirable.
1
Tdue to important application of amine functionality in
10b, 16
pharmaceuticals, agrochemicals, material chemistry and
chemical industry.2 Therefore, development of new selective
and efficient methodologies for the monoalkylation of amine
has gained significant interest in both academic and industrial
communities.
In the last decades, samarium diiodide (SmI2) catalyst has
gained considerable interest due to various useful synthetic
applications in organic chemistry.17a However, the use of SmI2
is limited to reductive manipulations of functional groups and
reductive couplings to make C−C bonds.17 Herein, we are
disclosing a new protocol for monoalkylation of various
amines with alcohols in presence of samarium diiodide
(Scheme 1c). To the best of our knowledge, this is the first
demonstration of monoalkylation of amines with alcohols by
utilizing samarium diiodide (SmI2) as catalyst.
In this direction, several methods have been successfully
developed for the alkylation of amine, which includes the
reactions of amines with alkyl halides,3 reductive alkylation4
and electrophilic amination5 reactions. In particular, the
activation of alcohols under mild conditions for N-alkylation
have been identified as a more suitable methods,6 which are
commonly performed by ruthenium7 or iridium complexes8
and less often by other transition metal complexes.9
Recognizing the potential of this transformation, several
groups have pursued various strategies for the direct
construction of C-N bond.10 In 2011, selective N-mono- and
dialkylation of amines with alcohols by using non-metal-based
acid–base catalysis were successfully achieved by Saito and
co-workers which involves substitution (SN) at the alcohols sp3
carbon atom bearing the hydroxyl group (Scheme 1a).11a
Recently, Kempe11b(Co catalyst), Beller,12 and Milstein13(Mn
pincer complexes) demonstrated the convenient protocol for
alkylation of amines by borrowing-hydrogen or hydrogen-
autotransfer (BH/HA) approach. Base-promoted direct
alkylation of amines with alcohols under transition-metal-free
conditions was reported. However, longer reaction time and
excess of base were necessary.14 More recently, an elegant
example of nickel-catalyzed direct alkylation of amines using
benzyl alcohols was described by Banerjee and co-workers.15a
In 2014, Barta and co-workers reported the first example of a
direct amination of alcohols catalyzed by an iron complex15b
through the borrowing hydrogen strategy (Scheme 1b).
Scheme 1.Various Synthesis Strategies for the N-alkylation
of amines
Previous work
Substitution (SN) Approch
R1 R2
H2O
H
N
N
H
R2
cat. TAPC
a
b
R1
H
HO
140-200 °C
R1 R2
N
R2
2H2O
Hydrogen Borrowing Strategy
R2
N
R2
M
(ligand)
R1
R1
H2O
OH
H2N
H
Base
M = Ir, Ru, Co, Mn, Ni and Fe etc.
This work
SmI
2 (3 mol %),
R1
NH2
KOt-Bu (1 equiv)
OH
H2O
N
+
c
R
H
toluene, 140 °C, MW, 1 h
R
R1
Short reaction time
No special ligands design
Despite these achievements, these methods have
shortcomings due to expensive metal complexes, requirement
Alkylation of N-heterocycles
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The Journal of Organic Chemistry
Page 2 of 9
b
Schlenk tube. Conversion was determined by GC analysis using
As a model system, the SmI2-catalyzed alkylation of aniline
(2a) with benzyl alcohol (1a) was optimized (Table 1). With
the use of 3 mol % of SmI2 catalyst for the reaction of 1a (1.5
mmol) with 2a (1.0 mmol) in presence of KOt-Bu (1.0 mmol)
in toluene at 140 °C, the reaction was slow. Only 38% and
65% conversion of 3a was obtained when the reaction was
carried out for 24 and 36 hours respectively (Table 1, entry 1,
2). Interestingly, when the reaction was performed under
microwave irradiation (Table 1, entry 3), it resulted in
complete conversion of the starting materials to afford 3a in
81% yield after 1 h. Encouraged by these results, we further
investigated other reaction parameters, such as solvent, base,
and substrate ratio (see the Supporting Information). Initially,
solvent screening showed that etherate solvent such as THF
gave a mixture of products 3a and 3a’ in equal ratio (Table S1,
entry 4, SI). Whereas, other solvents such as DMF and
methanol gave inferior results (see Table S1, Supporting
Information). Further, exploring the effect of bases, potassium
tert-butoxide gave best results under MW conditions (Table
S2, SI). Surprisingly, when the reaction was carried out with
sodium hydroxide as base, it yielded 3a in moderate yield and
3a’ as major product (Table 1, entry 4).
1
2
3
4
5
6
7
8
biphenyl as internal standard. The value in parentheses is the yield
of the product 3a.cReaction was performed in microwave at 140
d
e
°C. Reaction was performed in microwave at 150 °C. Reaction
was performed in microwave at 110 °C. f4 Å molecular sieves was
added.
Other inorganic and organic bases proved to be comparatively
inefficient for this transformation (see the Supporting
Information). The reaction failed to obtain the desired product
in absence of a base (Table 1, entries 12).When the reaction
time was reduced to 40 min, the conversion yield of product
decreased to 71% (Table 1, entry 5). When the influence of
temperature was tested; it was found that increase of
temperature (150 °C) did not improve the yield. When the
reaction was carried out at 110 °C, imine 3a’ was formed as a
major product (entries 6-7, Table 1) probably due to the
deceleration of imine reduction. In the presence of 4 Å
molecular sieves, the yields were considerably lower,
signifying that the presence of water increases the rate of
reduction (Table 1, entries 8).18 When the catalyst loading was
reduced to 1.5 mol %, it resulted in decrease of yield of 3a
(Table 1, entry 9). However, no improvement was observed
with higher catalyst loading (Table 1, entries 10). In addition,
reaction provided very less yield in absence of catalyst (Table
1, entries 11).
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Table 1. Optimization of Reaction Conditionsa
H
N
N
conditions
+
NH2
OH
+
With the optimized reaction conditions in hand, we studied
the scope of this new catalytic protocol for the alkylation of
amines with benzylic alcohols (Table 2). Both, electron
donating and electron withdrawing substituents on benzyl
alcohols and anilines are well-tolerated, to achieve the desired
products in good to high yields under MW irradiation. First,
we tested the reactions of benzyl alcohol with various
substituted anilines, and it was observed that functionalities
such as methoxy, methyl, t-butyl and halide as well as
electron-withdrawing substituents on the aryl ring were well
tolerated under the reaction conditions to furnish the
corresponding products in 59−82% yields. As expected, 3-
phenoxyaniline also underwent N-monoalkylation to give the
desired product in 81% yield (3h). In contrast, 4-fluoroaniline
led to lower yield of 3f along with the formation of imine
(12% yield) as a byproduct. Next, substituted anilines were
alkylated with various benzyl alcohols to show the method
variability (Table 2). Again, a notable functional group
tolerance was observed. 4-methoxy benzyl alcohol was found
to be the suitable substrate for the SmI2-catalysed reaction to
afford the corresponding product 3m in 83% yield. The
reaction of benzylic alcohol tethered with electron-
withdrawing groups gave the desired products in lesser yields,
comparatively. Interestingly, 2,4-dichloro-substituted benzyl
alcohol furnished the N-alkylated amine 3p and 3r in 65%
and 70%, yields, respectively. Notably, no cleavage of halogen
atom was observed when halide-substituted alcohols or aniline
were employed.11b Furthermore, the reaction of 4-cyano benzyl
alcohol gave the desired product 3y in less yield (59%) along
with the formation of hydrolysed product (4-cyano to amide,
22% yield) due to the presence of potassium tert-butoxide in
the reaction. The reaction of n-butanol with 4-methoxy aniline
failed to give corresponding product 3s under present reaction
condition. When aliphatic amines (3t-u) were used as the
substrates the reactions yielded inseparable mixtures.
3a'
1a
3a
2a
bconversi
on (%)
catalyst
(mol %)
entr
y
solvent
base
time
3a
3a’
1
SmI2(3)
SmI2(3)
SmI2(3)
SmI2(3)
SmI2(3)
SmI2(3)
SmI2(3)
SmI2(3)
toluene
KOt-Bu
24 h
38
52
2
3c
toluene
KOt-Bu
36 h
1 h
1 h
65
35
0
toluene KOt-Bu
89
(81)
4c
toluene
toluene
toluene
toluene
toluene
toluene
toluene
NaOH
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
31
71
87
27
74
61
89
58
18
0
5c
40
min
6d
7e
1 h
1 h
1 h
1 h
1h
62
13
24
0
8c,f
9c
SmI2
(1.5)
10c
SmI2(5)
11c
12c
-
toluene
toluene
KOt-Bu
1 h
1h
11
0
SmI2(3)
-
0
aReaction conditions: (1.5 mmol) benzyl alcohol,(1.0 mmol)
aniline, (1.0 mmol) base, 3 mL solvent and SmI2 (0.1 M solution
in THF) at 140 °C (oil bath) for 24 and 36 h respectively in a
Considering the importance of alkylation of heterocylclic
amines, we further expanded the scope of this methodology
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The Journal of Organic Chemistry
aminopyridine and
towards
the
alkylation
of
1
2
3
4
5
6
7
8
pyrazolopyrimidine with alcohols under optimized reaction
conditions. 2-aminopyridine successfully transformed into the
intermediates of bioactive drugs chloropyramine (5b) and
mepyramine (5c), extensively used in first generation
antihistamine. To our delight, the pharmaceutically active
pyrazolopyrimidines transformed efficiently into the desired
secondary amines in 59% yield (Table 3, 5e). Furthermore, 2-
indolylmethanol with 2-aminopyridine lead to products 5f in
good yield, while the reaction of unprotected 2-
indolylmethanol with 2-aminopyridine failed to give
corresponding 5g product. Moreover, 2-(benzylamino)-5,7-
dihydro-6H-benzo[b]pyrimido[4,5-d]azepin-6-one
aReaction conditions: 1.0 mmol aniline, 1.5 mmol benzyl alcohol,
1.0 mmol Base, 3 mL solvent.b Reaction yields. Reaction was
performed in microwave at 140 °C for 1 h.cReaction was carried
out with 1.5 mmol of aliphatic alcohol. Reaction was carried out
with 1.0 mmol of aliphatic amines.
d
To establish the synthetic utility of present protocol, we
performed an intramolecular cyclization of 1,2-
phenylenediamine with benzyl alcohol. Fascinatingly, the
reaction proceeded smoothly to afford benzimidazole in 52%
yield (Scheme 2).
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successfully converted to corresponding alkylated product
(5h) in 48% yield. Notably, this method is highly selective for
N-monoalkylated products and no dialkylation of amines was
observed. Application of this methodology with anilines
having amide, carbonyl, ester functionalities, and secondary
benzylic alcohols was not successful (see Table S5 in the
Supporting Information).
Scheme 2. Direct Synthesis of Benzimidazole
H
SmI2 (3 mol %),
KOt-Bu, Toluene
N
NH2
NH2
HO
N
MW, 140 °C, 1 h
6a, 52%
Table3: Alkylation of heteroaromatic amines with various
primary alcoholsa,b
To demonstrate the practicality of this SmI2-Catalyzed
reaction, we carried out gram-scale synthesis of products 5b
under the optimal reaction. The reaction proceeded smoothly
and afforded the desired products 5b in 71% yield, suggesting
that the large-scale synthesis of monoalkylation of amines
might be possible (see scheme S5 in the Supporting
Information for detail).
SmI2 (3 mol %),
KOt-Bu, Toluene
Ar(Het)
Ar(Het)
R'
OH
R'
N
H2
N
H
MW, 140 °C, 1 h
3
5a-i
4
N
H
N
N
H
N
N
H
N
Table2: Alkylation of aniline derivatives with various
primary alcoholsa,b
Cl
5a
5b
, 77%
, 78%
5c
, 73%
HN
NH2
R1
SmI2 (3 mol %),
KOt-Bu, Toluene
OH
N
H
R
R
N
R1
N
MW, 140 °C, 1 h
N
1
3a-t
NH
N
2
N
H
N
O
N
N
Cl
H
Br
O
5f
67%
5d
, 78%
c5e
, 59%
N
N
H
N
H
N
H
H
3b
, 82%
3c
, 77%
3a
, 81%
3d
, 80%
NH
HN
N
N
N
N
H
F
Cl
H
N
O
N
N
H
N
N
H
O
H
H
5g,
0%
c, d5h
, 48%
3h
, 81%
3e
, 82%
3g
, 76%
3f
, 68%
aReaction conditions: 1.0 mmol aniline, 1.5 mmol benzyl alcohol,
F
Br
b
c
1.0 mmol Base, 3 mL solvent. Reaction yields. Reaction at 140
°C for 1.5 h. dDioxane used as a solvent.
N
H
N
H
N
H
N
H
3l
, 77%
3k
, 78%
3i
3j
, 80%
, 78%
Scheme 3. Reaction of tert-Butyl Alcohol or Phenol with
Aniline
Cl
Cl
Cl
H
N
O
SmI2 (3 mol %),
KOt-Bu, Toluene
N
N
N
H
H
HO
H2N
H
48
OH
O
Cl
or
No Reaction
49
50
51
52
MW, 140 °C, 1 h
3m
, 83%
3n
, 72%
3o
, 78%
3p
, 65%
Cl
Cl
H
N
H
N
N
N
H
N
H
O
Cl
O
To gain insight into the reaction mechanism, the reactions of
tert-butanol and phenol were studied with aniline under the
optimized reaction conditions. No products were formed,
which suggests the pathway involves initial alcohol
53
d3u
d3t
, 0%
3q
c3s
, 0%
, 77%
HN
, 0%
3r
, 70%
54
55
56
57
58
59
60
CN
H
H
N
N
CF3
NO2
N
H
N
N
H
NO2
3x
, 72%
3w
, 69%
3z
3y
,61%
, 59%
3v
, 73%
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dehydrogenation, condensation and the imine reduction
Microwave Irradiation Experiments. Microwave irradiation
experiments were conducted in a Monowave 300 single-mode
microwave reactor.20 SiC10 Silicon Carbide reaction vessels
(10 mL) or reusable Pyrex vials (30 mL) are utilized for
conducting the reactions.
(Scheme 3).19a
1
2
3
4
5
6
7
8
Further, we studied the reaction of 4-OMe benzyl alcohol
with 3-amino pyridine in presence of SmI2 catalyst and KOt-
Bu (Scheme S1). 4-anisaldehyde was found to be formed after
10 min (detected by NMR) which further reacted with 3-
amino pyridine to give the desired products (Scheme S2).
Based on the above experiment and control experiments
(scheme S4), we propose the plausible reaction pathway as
depicted in Scheme 4. In the presence of SmI2 catalyst and
KOt-Bu, dehydrogenation of primary alcohol gives the
corresponding aldehyde, which subsequently reacts with the
amine to form the imine intermediate. Further, SmI2 catalyzed
reduction of the imine intermediate gives the desired amine
product. With the observations made and literature
precedence19, we propose that the active species of Sm to be
Sm (III). The formation of Sm (III)-H is reported.19e Further,
microwave reaction conditions might be favouring
hydrogenation due to the high pressure created in the vial,
promoting partially a better redistribution of H2 which can be
seen from table 1, entries 1-3. The stepwise details for this N-
alkylation protocol still remain an area for further
experimental and computational investigations. Further
extensions and deeper mechanistic insights of the reactions are
in progress.
General procedure for alkylation of amines. Amines (1.0
mmol), alcohols (1.5 mmol), KOt-Bu (1.0 mmol, 110 mg) and
SmI2 0.1 M solution in THF (3 mol %, 0.3 mL in inert condition)
were added in a 10 mL monowave vial (SiC10) followed by
toluene (2 mL). The vessel was subsequently placed in the
microwave cavity and irradiated for 1 h at 140 °C. The reaction
mixture was cooled to room temperature and 5.0 mL of ethyl
acetate was added and concentrated in vacuo. The residue was
purified by column chromatography using a gradient pentane/
Et2O (eluent system) to afford the pure products.
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N-benzylaniline (3a): Yield: 81% (148 mg); colourless oil;
1H NMR (500 MHz, CDCl3) δ 7.36 – 7.28 (m, 4H), 7.27– 7.22
(m, 1H), 7.14 (t, J = 6.8 Hz, 2H), 6.70 (t, J = 7.3 Hz, 1H), 6.59 (d,
J = 7.9 Hz, 2H), 4.27 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ
148.2, 139.6, 129.4, 128.7, 127.6, 127.3, 117.7, 113.0, 48.4
;
HRMS (ESI): calcd for C13H14N [M + H]+ 184.1126, found:
184.1117.
N-benzyl-4-bromoaniline (3b): Yield: 82% (214 mg);
colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.36 – 7.32 (m,
4H), 7.30 – 7.26 (m, 1H), 7.26 – 7.22 (m, 2H), 6.54 – 6.48 (m,
2H), 4.29 (brs, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 146.8,
138.7, 132.0, 129.3, 128.7, 127.5, 114.6, 109.4, 48.4; HRMS
(ESI): calcd for C13H13BrN [M + H]+ 262.0231, found:
262.0230.
Scheme 4. Plausible reaction mechanism for SmI2-
Catalyzed N-monoalkylation of amines
R1
SmI
KOt-Bu
2 (3 mol %),
NH2
H2
O
N
H
OH
R
+
R
toluene, 140 °C, MW, 1 h
R1
Reduction
N-benzyl-3-chloroaniline (3c): Yield: 77% (164 mg);
colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.33 (brs, 4H), 7.31
– 7.25 (m, 1H), 7.05 (t, J = 8.0 Hz, 1H), 6.69 – 6.65 (m, 1H), 6.61
(t, J = 2.1 Hz, 1H), 6.50 – 6.46 (m, 1H), 4.29 (s, 2H). 13C{1H}
NMR (125 MHz, CDCl3) δ 148.3, 138.1, 135.1, 130.3, 128.8,
127.7, 127.6, 118.3, 113.4, 111.9, 48.7; HRMS (ESI): calcd for
C13H13ClN [M + H]+ 218.0737, found: 218.0729.
Dehydrogenation
R1
Condensation
N
O
R
R
In summary, we have reported the first example of
SmI2 catalyzed selective and direct N-alkylation of amines
with alcohols. The reaction tolerates a wide range of
functional groups and allows the synthesis of alkylated
heterocyclic amines. The developed protocol provides an
interesting strategy for sustainable C-N bond synthesis.
N-benzyl-4-methoxyaniline (3d): Yield: 80% (170 mg);
colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.39 – 7.35 (m,
2H), 7.34 – 7.30 (m, 2H), 7.28 – 7.24 (m, 1H), 6.80 – 6.75 (m,
2H), 6.71 – 6.64 (m, 2H), 4.28 (s, 2H), 3.73 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3) δ 153.1, 140.7, 138.5, 128.6, 128.0,
127.4, 115.4, 114.9, 55.8, 50.1; HRMS (ESI): calcd for
C14H16NO [M + H]+ 214.1232, found: 214.1226.
EXPERIMENTAL SECTION
N-benzyl-4-(tert-butyl)aniline (3e): Yield: 82% (196 mg);
o
1
brown solid; m.p. 49–50 C; H NMR (500 MHz, CDCl3) 7.38
(dd, J = 7.9, 1.0 Hz, 2H), 7.35 – 7.31 (m, 2H), 7.29 – 7.26 (m,
1H), 7.23 – 7.20 (m, 2H), 6.69 – 6.65 (m, 2H), 4.30 (s, 2H), 1.27
(s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 144.5, 141.6, 138.8,
128.6, 127.9, 127.4, 126.1, 113.6, 49.4, 33.9, 31.5; HRMS (ESI):
calcd for C17H22N [M + H]+ 240.1752, found: 240.1739.
1
General Information. H and 13C NMR spectra were recorded
in CDCl3 or DMSO–d6 on a 500 MHz and 125 MHz spectrometer
respectively, using tetramethylsilane as the internal standard. Spin
multiplicities were described as s (singlet), d (doublet), dd (double
douplet), t (triplet), and m (multiplet). Coupling constant (J)
values were expressed in hertz (Hz). High-resolution mass spectra
(HRMS) were recorded on ESI-QTOF mass spectrometer. All the
melting points were recorded on micromelting point apparatus
and are uncorrected. Thin layer chromatography (TLC) was
performed on MERCK precoated silica gel 60F-254 (0.5 mm)
aluminum plates. TLC spot visualization was achieved under UV
light. Column chromatography was performed using silica gel
100-200.
N-benzyl-4-fluoroaniline (3f): Yield: 68% (135 mg);
colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.30 – 7.24 (m,
4H), 7.22 – 7.17 (m, 1H), 6.83 – 6.76 (m, 2H), 6.53 – 6.45 (m,
2H), 4.20 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 155.1 (d,
JC-F = 235.5 Hz), 143.1, 138.0, 127.6, 126.6, 126.3, 114.7, 114.6,
113.0, 112.9, 48.1; HRMS (ESI): calcd for C13H13FN [M +
H]+ 202.1032, found: 202.1027.
Microwave reactor (make-Anton Paar GmbH).
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N-benzyl-4-chloroaniline (3g): Yield: 76% (161 mg);
N-(4-methylbenzyl)-3-phenoxyaniline (3o): Yield: 78%
(225 mg); colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.33 –
7.27 (m, 2H), 7.24 – 7.20 (m, 2H), 7.15 – 7.05 (m, 4H), 7.03 –
6.97 (m, 2H), 6.43 – 6.39 (m, 1H), 6.36 (dd, J = 8.1, 1.6 Hz, 1H),
6.34 – 6.31 (m, 1H), 4.23 (s, 2H), 2.34 (s, 3H). 13C{1H} NMR
(125 MHz, CDCl3) δ 158.4, 157.2, 149.1, 137.1, 135.6, 130.2,
129.6, 129.3, 127.7, 123.0, 119.0, 108.5, 108.3, 103.8, 48.4, 21.1;
HRMS (ESI): calcd for C20H20NO [M + H]+ 290.1545,
found: 290.1540.
1
2
3
4
5
6
7
8
colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.29 (m,
4H), 7.29 – 7.23 (m, 1H), 7.13 – 7.04 (m, 2H), 6.57 – 6.46 (m,
2H), 4.28 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 146.6,
139.0, 129.1, 128.7, 127.5, 127.4, 122.2, 114.1, 48.4; HRMS
(ESI): calcd for C13H13ClN [M + H]+ 218.0737, found:
218.0727.
N-benzyl-3-phenoxyaniline (3h): Yield: 81% (222 mg); brown
o
solid; m.p. 56–57 C; 1H NMR (500 MHz, CDCl3) δ 7.33 – 7.22
(m, 7H), 7.11 – 7.04 (m, 2H), 7.01 – 6.97 (m, 2H), 6.40 – 6.36 (m,
1H), 6.36 – 6.32 (m, 1H), 6.30 (t, J = 2.2 Hz, 1H), 4.27 (s, 2H).
13C{1H} NMR (125 MHz, CDCl3) δ 158.5, 157.2, 149.5, 139.0,
130.3, 129.6, 128.7, 127.6, 127.4, 123.1, 119.0, 108.2, 108.0,
103.5, 48.4; HRMS (ESI): calcd for C19H18NO [M + H]+
276.1388, found: 276.1364.
4-chloro-N-(2,4-dichlorobenzyl)aniline (3p) Yield: 65%
9
o
(182 mg); brown solid; m.p. 71–72 C
;
1H NMR (500 MHz,
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
CDCl3) 7.32 – 7.27 (m, 3H), 7.13 – 7.07 (m, 2H), 6.56 – 6.50 (m,
1H), 4.28 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 146.0,
137.2, 133.2, 129.1, 128.8, 128.7, 122.8, 114.3, 47.9; HRMS
(ESI): calcd for C13H11Cl3N [M + H]+ 285.9957, found:
285.9946.
2,5-dimethyl-N-(4-methylbenzyl)aniline (3i): Yield: 78% (174
mg); colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.27 (d, J =
7.8 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.94 (d, J = 7.3 Hz, 1H),
6.50 (d, J = 8.8 Hz, 2H), 4.29 (s, 2H), 2.33 (s, 3H), 2.26 (s, 3H),
2.10 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 145.7, 136.9,
136.8, 129.9, 129.3, 127.8, 119.2, 118.1, 111.3, 48.4, 21.5, 21.1,
17.1; HRMS (ESI): calcd for C16H20N [M + H]+ 226.1596,
found: 226.1591.
4-chloro-N-(4-methoxybenzyl)aniline (3q): Yield: 77%
o
(190 mg); brown solid; m.p. 77–78 C
;
1H NMR (500 MHz,
CDCl3) δ 7.25 (d, J = 8.6 Hz, 2H), 7.14 – 7.06 (m, 2H), 6.90 –
6.84 (m, 2H), 6.59 – 6.51 (m, 2H), 4.21 (s, 2H), 3.79 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ 159.0, 146.4, 130.7, 129.1,
128.8, 122.4, 114.2, 114.1, 55.3, 48.1; HRMS (ESI): calcd for
C14H15ClNO [M + H]+ 248.0842, found: 248.0836.
N-(4-methylbenzyl)aniline (3j): Yield: 80% (157 mg);
colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.28 – 7.23 (m,
2H), 7.20 – 7.12 (m, 4H), 6.75 – 6.70 (m, 1H), 6.65 (dd, J = 8.6,
0.9 Hz, 2H), 4.28 (s, 2H), 2.34 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3) δ 147.8, 137.0, 136.0, 129.3, 129.3, 127.6, 117.9, 113.2,
48.4, 21.1; HRMS (ESI): calcd for C14H16N [M + H]+
198.1283, found: 198.1277.
N-(2,4-dichlorobenzyl)aniline (3r): Yield: 70% (175 mg);
brown solid; m.p. 63–64 oC; 1H NMR (500 MHz, CDCl3) δ 7.20
(brs, 3H), 7.11 – 7.03 (m, 2H), 6.68 – 6.61 (m, 1H), 6.54 – 6.49
(m, 2H), 4.20 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 147.7,
138.0, 132.9, 129.3, 128.8, 118.0, 113.1, 47.7; HRMS (ESI):
calcd for C13H12Cl2N [M + H]+ 252.0347, found 252.0314.
N-((1-benzyl-1H-indol-2-yl)methyl)aniline (3v): Yield:
1
4-fluoro-N-(4-methylbenzyl)aniline (3k): Yield: 78% (167
73% (226 mg); brown solid; m.p. 162–163; H NMR (500
1
mg); brown solid; m.p. 73–74 oC; H NMR (500 MHz, CDCl3) δ
MHz, DMSO-d6) δ 7.48 – 7.45 (m, 1H), 7.36 – 7.29 (m, 1H), 7.27
– 7.22 (m, 2H), 7.21 – 7.17 (m, 1H), 7.04 – 6.95 (m, 5H), 6.57
(dd, J = 8.6, 0.9 Hz, 2H), 6.52 – 6.48 (m, 1H), 6.45 (s, 1H), 6.07
(t, J = 5.7 Hz, 1H), 5.48 (s, 2H), 4.32 (d, J = 5.7 Hz, 2H). 13C{1H}
NMR (125 MHz, DMSO-d6) δ 148.9, 139.0, 138.9, 137.8, 129.2,
129.0, 127.8, 127.6, 126.7, 121.4, 120.3, 119.7, 116.6, 112.9,
110.2, 101.3, 46.5, 40.3; HRMS (ESI): calcd for C22H21N2 [M
+ H]+ 313.1705, found: 313.1697.
7.23 (d, J = 7.9 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.90 – 6.81 (m,
2H), 6.60 – 6.51 (m, 2H), 4.22 (s, 2H), 2.33 (s, 3H). 13C{1H}
NMR (125MHz, CDCl3) δ 156.1 (d, JC-F = 235.5 Hz), 155.2,
144.0, 137.1, 135.8, 129.3, 127.6, 115.8, 115.6, 114.2, 114.1,
49.0, 21.1; HRMS (ESI): calcd for C14H15FN [M +
H]+216.1189, found: 216.1183.
4-bromo-N-(4-methylbenzyl)aniline (3l): Yield: 77% (210
mg); colourless solid; m.p. 78-79;
1H NMR (500 MHz, CDCl3)
7.24 – 7.19 (m, 4H), 7.15 (d, J = 7.9 Hz, 2H), 6.54 – 6.43 (m,
2H), 4.23 (s, 2H), 2.33 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3)
δ 147.0, 137.1, 135.7, 132.0, 129.4, 127.5, 114.6, 109.2, 48.1,
21.1; C14H15BrN [M + H]+ 276.0388, found: 276.0383.
N-benzyl-3-nitroaniline (3w): Yield: 69% (158 mg); Orange
o
1
solid; m.p. 102–103 C; H NMR (500 MHz, CDCl3) δ 7.56 (dd,
J = 8.0, 1.7 Hz, 1H), 7.48 (t, J = 2.2 Hz, 1H), 7.36 (brs, 4H), 7.32
– 7.27 (m, 2H), 6.92 (dd, J = 8.1, 2.0 Hz, 1H), 4.39 (s, 2H).
13C{1H} NMR (125 MHz, CDCl3) δ 149.4, 148.2, 137.7, 129.8,
128.9, 127.8, 127.6, 119.2, 112.6, 107.1, 48.4; HRMS (ESI):
calcd for C13H13N2O2 [M + H]+ 229.0977, found: 229.0967.
N-(4-methoxybenzyl)aniline (3m): Yield: 83% (176 mg);
colourless oil; 1H NMR (500 MHz, CDCl3) δ 7.23 – 7.20 (m,
2H), 7.14 – 7.08 (m, 2H), 6.82 – 6.77 (m, 2H), 6.70 (t, J = 7.3 Hz,
1H), 6.63 (d, J = 7.7 Hz, 2H), 4.26 (s, 2H), 3.79 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3) δ 158.0, 145.8, 129.4, 128.3, 128.1,
117.6, 113.0, 112.9, 54.3, 47.5; HRMS (ESI): calcd for
C14H16NO [M + H]+ 214.1232, found: 214.1229.
N-benzyl-3-(trifluoromethyl)aniline (3x): Yield: 72% (180
mg); colourless oil; 1H NMR (500 MHz, DMSO-d6) δ 7.39 –
7.31 (m, 4H), 7.27 – 7.22 (m, 2H), 6.86 (brs, 1H), 6.84 – 6.78 (m,
2H), 4.32 (s, 2H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 149.5,
139.9, 130.3 (q, JC-F = 31.3 Hz), 129.5 (q, JC-F = 293.7 Hz), 128.8,
127.7, 127.3, 126.1, 123.9, 116.0, 112.1 (q, JC-F = 3.8 Hz), 108.6
(q, JC-F = 3.6 Hz), 46.7; HRMS (ESI): calcd for C14H13F3N [M +
H]+ 252.1000, found: 252.0996.
4-chloro-N-(4-methylbenzyl)aniline (3n): Yield: 72% (163
mg); brown solid; m.p. 68–69 oC; 1H NMR (500 MHz, CDCl3) δ
7.24 – 7.20 (m, 2H), 7.14 (d, J = 7.9 Hz, 2H), 7.12 – 7.07 (m,
2H), 6.57 – 6.52 (m, 2H), 4.24 (s, 2H), 2.33 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3) δ 146.5, 137.1, 135.7, 129.4, 129.1,
127.5, 122.4, 114.2, 48.3, 21.1; HRMS (ESI): calcd for
C14H15ClN [M + H]+ 232.0893, found: 232.0872.
4-((phenylamino)methyl)benzonitrile (3y): Yield: 59 % (123
mg); brown solid; m.p. 87–88 oC; 1H NMR (500 MHz, CDCl3) δ
7.62 – 7.59 (m, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.21 – 7.08 (m,
2H), 6.77 – 6.73 (m, 1H), 6.60 – 6.57 (m, 2H), 4.42 (s, 2H).
13C{1H} NMR (125 MHz, CDCl3) δ 147.2, 145.2, 132.5, 129.4,
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127.8, 118.9, 118.4, 113.2, 111.0, 48.0; HRMS (ESI): calcd for
1
2
3
4
5
6
7
8
C14H13N2 [M + H]+ 209.1079, found: 209.1072.
2-(benzylamino)-5,7-dihydro-6H-benzo[b]pyrimido[4,5-
d]azepin-6-one (5h): Yield: 48% (150 mg); brown solid; m.p.
N-(2-nitrobenzyl)aniline (3z): Yield: 61% (139 mg); Orange
oil; 1H NMR (500 MHz, CDCl3) δ 8.06 (dd, J = 8.2, 1.2 Hz, 1H),
7.67 (d, J = 7.7 Hz, 1H), 7.58 – 7.53 (m, 1H), ), 7.43 – 7.38 (m,
1H), 7.19 – 7.11 (m, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.59 (dd, J =
8.6, 1.0 Hz, 2H), 4.72 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3)
δ 148.3, 147.1, 135.4, 133. 7, 129.9, 129.4, 128.0, 125.2, 118.3,
113.2, 45.9; HRMS (ESI): calcd forC13H13N2O2 [M + H]+
229.0977, found: 229.0963.
231–232;
1H NMR (500 MHz, DMSO-d6) δ 10.14 (brs, 1H), 8.29
(brs, 1H), 8.02 – 7.77 (m, 2H), 7.60 – 7.10 (m, 7H), 4.56 (brs,
2H), 3.26 (brs, 2H). 13C{1H} NMR (125 MHz, DMSO-d6) δ
172.3, 162.4, 157.9, 141.0, 138.4, 131.4, 130.3, 129.6, 128.6,
127.6, 127.0, 124.2, 122.4, 115.9, 44.7, 36.6; HRMS (ESI):
calcd for C19H17N4O [M + H]+ 317.1402, found: 317.1417.
2-phenyl-1H-benzo[d]imidazole (6a): Yield: 52% (100 mg);
9
o
1
brown solid; m.p. 291–292 C; H NMR (500 MHz, DMSO-d6)
δ 12.91 (s, 1H), 8.21 (d, J = 7.4 Hz, 2H), 7.69 (d, J = 6.3 Hz, 1H),
7.59 –7.54 (m, 3H), 7.52 – 7.47 (m, 1H), 7.22 (s, 2H). 13C{1H}
NMR (125 MHz, DMSO) δ 151.7, 144.3, 135.5, 130.7, 130.3,
129.4, 126.9, 123.0, 122.1, 119.3, 111.8; HRMS (ESI): calcd for
C13H11N2 [M + H]+ 195.0922, found: 195.0921.
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-benzylpyridin-2-amine (5a): Yield: 78% (142 mg);
o
1
colourless solid; m.p. 92–93 C; H NMR (500 MHz, CDCl3) δ
8.09 (brs, 1H), 7.42 – 7.31 (m, 5H), 7.29 – 7.24 (m, 1H), 6.61 –
6.56 (m, 1H), 6.37 (d, J = 8.4 Hz, 1H), 4.99 (brs, 1H), 4.50 (d, J =
5.8 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 158.6, 148.1,
139.1, 137.6, 128.7, 127.4, 127.3, 113.2, 106.8, 46.3; HRMS
(ESI): calcd for C12H13N2 [M + H]+ 185.1079, found:
185.1078.
AUTHOR INFORMATION
Corresponding Author
N-(4-chlorobenzyl)pyridin-2-amine (5b): Yield: 77% (166
mg); colorless solid; m.p. 90–92 oC; 1H NMR (500 MHz,
CDCl3) δ 8.08 (d, J = 4.7 Hz, 1H), 7.46 – 7.41 (m, 1H), 7.29 (brs,
4H), 6.62 (t, J = 4.7 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.27 (brs,
1H), 4.49 (d, J = 5.7 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ
157.7, 146.2, 138.6, 137.2, 133.1, 128.8, 128.6, 113.2, 107.4,
45.6; HRMS (ESI): calcd for C12H12ClN2 [M + H]+ 219.0689,
found: 219.0684.
*E-mail: nandurisrini92@gmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful to DoP, Ministry of Chemicals & Fertilizers,
Govt. of India, New Delhi, for the award of NIPER fellowship.
N-(4-chlorobenzyl)pyridin-2-amine (5c): Yield: 73% (145
mg); white solid; m.p. 73–74 oC; 1H NMR (500 MHz, CDCl3) δ
8.08 (d, J = 4.3 Hz, 1H), 7.47 – 7.35 (m, 1H), 7.24 (s, 1H), 7.19 –
7.11 (m, 2H), 6.67 – 6.53 (m, 1H), 6.39 (d, J = 8.4 Hz, 3H), 5.14
(brs, 1H), 4.45 (d, J = 5.5 Hz, 2H), 2.33 (s, 3H). 13C{1H} NMR
(125 MHz, CDCl3) δ 158.4, 147.3, 137.9, 137.0, 135.8, 129.3,
127.3, 113.0, 107.0, 46.1, 21.1; HRMS (ESI): calcd for
C13H15N2 [M + H]+ 199.1235, found: 199.1228.
ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR spectra for the products (PDF).
REFERENCES
N-(4-methoxybenzyl)pyridin-3-amine (5d): Yield: 78% (165
1. (a) Ricci, A., Amino group chemistry: from synthesis to the life
sciences. John Wiley & Sons: 2008. (b) Smith, M. B., J. March
in Advanced Organic Chemistry. John Wiley & Sons, Inc., New
York 2001.
2. (a) Leonard, J.; Blacker, A. J.; Marsden, S. P.; Jones, M. F.;
Mulholland, K. R.; Newton, R., A survey of the borrowing
hydrogen approach to the synthesis of some pharmaceutically
relevant intermediates. Org. Proc. Res. Dev. 2015, 19, 1400-
1410. (b) Lawrence, S. A., Amines: synthesis, properties and
applications. Cambridge University Press: 2004.
o
1
mg); colourless solid; m.p. 142–143 C; H NMR (500 MHz,
CDCl3) δ 8.06 (d, J = 2.6 Hz, 1H), 7.96 (d, J = 3.7 Hz, 1H), 7.31 –
7.23 (m, 4H), 7.06 (dd, J = 8.2, 4.6 Hz, 1H), 6.94 – 6.85 (m, 3H),
4.26 (s, 2H), 3.80 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ
159.1, 144.1, 138.9, 136.2, 130.5, 128.8, 123.7, 118.6, 114.2,
55.3, 47.4; HRMS (ESI): calcd for C13H15N2O [M + H]+
215.1184, found: 215.1183.
N-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine
(5e):
3. (a) Hartwig, J. F., Palladium‐catalyzed amination of aryl halides
and sulfonates. Modern Arene Chemistry 2002, 107-168. (b)
Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.;
Yield: 59% (132 mg); brown solid; m.p. 265–266 oC; 1H NMR
(500 MHz, DMSO-d6) δ 13.42 (brs, 1H), 8.69 (s, 1H), 8.23 (s,
1H), 8.16 (s, 1H), 7.39 – 7.31 (m, 4H), 7.29 – 7.22 (m, 1H), 4.75
(d, J = 5.9 Hz, 2H). 13C{1H} NMR (125 MHz, DMSO-d6) δ 156.7,
156.1, 154.9, 139.8, 132.8, 128.8, 127.9, 127.4, 100.4, 43.6;
HRMS (ESI): calcd for C12H15N5 [M + H]+ 226.1093, found:
226.1086.
Blackmond, D. G.;
Strieter, E. R.; Buchwald, S. L.,
Reevaluation of the mechanism of the amination of aryl halides
catalyzed by BINAP-ligated palladium complexes. J. Am.
Chem.Soc. 2006, 128, 3584-3591. (c) Zhou, W.; Fan, M.; Yin,
J.; Jiang, Y.; Ma, D., CuI/oxalic diamide catalyzed coupling
reaction of (hetero) aryl chlorides and amines. J. Am. Chem. Soc.
2015, 137, 11942-11945.
N-((1-benzyl-1H-indol-2-yl)methyl)pyridin-2-amine (5f):
Yield: 67% (210 mg); brown solid; m.p. 196–197; H NMR
1
4. (a) Gribble, G. W., Sodium borohydride in carboxylic acid
media: a phenomenal reduction system. Chem. Soc. Rev. 1998,
27, 395-404. (b) Olsen, C. A.; Franzyk, H.; Jaroszewski, J. W.,
N-Alkylation reactions and indirect formation of amino
functionalities in solid-phase synthesis. Synthesis 2005, 16,
2631-2653.
(500 MHz, DMSO-d6) δ 8.01 – 7.94 (m, 1H), 7.54 – 7.47 (m, 1H),
7.39 – 7.33 (m, 2H), 7.30 – 7.25 (m, 2H), 7.24 – 7.20 (m, 1H),
7.07 – 7.01 (m, 3H), 7.00 – 6.96 (m, 1H), 6.54 – 6.48 (m, 1H),
6.46 (s, 2H), 5.49 (s, 2H), 4.63 (d, J = 5.6 Hz, 2H). 13C{1H} NMR
(125 MHz, DMSO-d6) δ 158.8, 147.8, 139.5, 138.8, 137.6, 137.1,
129.0, 127.8, 127.5, 126.7, 121.4, 120.3, 119.7, 112.5, 110.3,
108.9, 101.1, 46.5, 37.6; HRMS (ESI): calcd for C21H20N3 [M
+ H]+ 314.1657, found: 314.1645.
5. Fernandez, E.; Brown, J. M., 2 Electrophilic Amination Routes
from Alkenes. Modern Amination Methods 2000, 37-63.
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6. (a) Corma, A.; Navas, J.; Sabater, M. J., Advances in one-pot
compounds using alcohols and amines as electrophiles. Chem.
Rev. 2009, 110, 1611-1641.
synthesis through borrowing hydrogen catalysis. Chem. Rev.
2018, 118, 1410-1459. (b) Shimizu, K.-i., Heterogeneous
catalysis for the direct synthesis of chemicals by borrowing
hydrogen methodology. Catal. Sci. Technol. 2015, 5, 1412-1427.
(c) Wong, C. M.; McBurney, R. T.; Binding, S. C.; Peterson,
M. B.; Gonçales, V. R.; Gooding, J. J.; Messerle, B. A., Iridium
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