TBAB-Catalyzed Csp3–N Bond Formation by Coupling Pyridotriazoles with Anilines: A New Route to (2-Pyridyl)alkylamines

Article abstract of DOI:10.1002/ejoc.201801803

A new metal-free procedure allowing Csp³–N bond formation through coupling of pyridotriazoles and weakly nucleophilic anilines has been developed. This sustainable reaction shows high tolerance towards functional groups (ketones, free alcohols) leading to 2-picolylamine derivatives. The key to our success is the use of a catalytic amount of TBAB and water as a co-solvent leading to the formation of pyridylalkylamine derivatives. As this coupling tolerates the presence of Csp²–Br bond on both partners of the reaction, we performed a sequential one-pot reaction between functionalized triazolopyridines and anilines followed by a second coupling with N-tosylhydrazones leading to the formation of Csp³–N and Csp²–Csp² bonds.

Full text of DOI:10.1002/ejoc.201801803

A Journal of
Accepted Article
Title: TBAB Catalyzed Csp3-N Bond Formation by Coupling
Pyridotriazoles with Anilines: A New Route to (2-
Pyridyl)alkylamines
Authors: Diana Lamaa, Hsin-Ping Lin, Tourin Bzeih, Pascal Retailleau,
mouad alami, and Abdallah Hamze
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801803
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801803
Supported by

10.1002/ejoc.201801803
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
TBAB Catalyzed Csp3−N Bond Formation by Coupling
Pyridotriazoles with Anilines: A New Route to (2-
Pyridyl)alkylamines
Diana Lamaa,a Hsin-Ping Lin,a Tourin Bzeih,a Pascal Retailleau,b Mouad Alami,a* and
Abdallah Hamze.a*
Abstract. A new metal-free procedure allowing a Csp3-N As this coupling tolerates the presence of Csp2-Br bond on
bond formation through coupling of pyridotriazoles and both partner of the reaction, this allowed us to perform a
weakly nucleophilic anilines has been developed. This sequential one-pot reaction between functionalized
sustainable reaction shows high tolerance towards functional triazolopyridines and anilines followed by a second coupling
groups (ketones, free alcohols) leading to 2-picolylamines with N-tosylhydrazones leading to the formation of Csp3-N
derivatives. The key to our success is the use of a catalytic and Csp2-Csp2 bonds.
amount of TBAB and water as a co-solvent leading to the
formation of pyridyl-alkylamines derivatives.
Keywords: diazo compounds, metal-free, Csp3-N bond
formation, synthetic methods, nitrogen heterocycles
academic research, as well as for chemical
industries.[6] The most common route for the
preparation of -branched amines is the reductive
amination of imino C=N bonds which are not always
easy to synthesize and have limited stability.[7]
Introduction
Products that contain a Csp3-nitrogen bond constitute
a fascinating group of compounds with a large degree
of structural diversity. Also, nitrogen heterocycles
represent the most significant structural components of
FDA approved drugs. Among them, pyridine nuclei
are ubiquitous scaffolds that occupy a central role in
many therapeutic compounds.[1] Figure 1 shows
representative examples of bioactive molecules
containing (2-Pyridyl)alkylamines motif with various
pharmacological properties.[2,
Introduction of
3]
nitrogen atom into therapeutically active small
molecules led to drastically change in the
physicochemical and biological properties.[4] The
typical example is the ampicillin, which differs from
penicillin G (benzylpenicillin) by the presence of a
benzylic amine. This change permits a broadened
spectrum of activity and increases the acid-stability of
ampicillin in comparison to penicillin G.[5]
Figure 1. (2-Pyridyl)alkylamines-containing bioactive
molecules.
The development of efficient methodologies for Csp3–
N bond formation is of paramount importance for
Therefore, we have recently reported a copper-
catalyzed reaction inducing Csp3−N bond formation
utilizing N-tosylhydrazones as coupling partners
(Scheme 1a).[8]. This methodology works well for
hydrazones derived from acetophenone, but was
totally inefficient for hydrazone derived from 2-
acetylpyridine, as the only isolated product was the
pyridotriazole derivative (Scheme 1b). The formation
of the latter compound can be explained by
intramolecular cyclization of the diazo intermediate
generated in situ on the nitrogen atom of the pyridine
nucleus.
[a]
Diana Lamaa, Dr. Hsin-Ping, Lin, Dr. Tourin Bzeih, Dr. Mouad Alami
and Prof. Dr. Abdallah Hamze
BioCIS, Equipe Labellisée Ligue Contre le Cancer, Univ. Paris-Sud,
CNRS, University Paris-Saclay, 92290, Châtenay-Malabry, France.
E-mail: mouad.alami@u-psud.fr
https://www.biocis.u-psud.fr/?-ALAMI-Mouad-
E-mail: abdallah.hamze@u-psud.fr
https://www.biocis.u-psud.fr/?-HAMZE-Abdallah,78-
Dr. Pascal Retailleau
[b]
Institut de Chimie des Substances Naturelles, UPR 2301, CNRS,
91198, Gif-sur-Yvette, France.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/adsc.201######.
1
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10.1002/ejoc.201801803
European Journal of Organic Chemistry
In recent years, the 1,2,3-triazole ring has emerged as
a new partner of metal-catalyzed cross-coupling
reactions.[9-11] It has been proved that N-fused-triazoles
exist in an equilibrium between their closed and their
opened form.[12] However, the opened form could be
trapped with a metal to form the metallo-carbene,
which plays the role of the reactive species in many
transformations.[11] Consequently, triazolopyridine
moiety has been employed as a precursor of
rhodium,[13] or copper[14] carbenes in a wide range of
organic transformations affording nitrogen-containing
heterocyclic compounds such as imidazopyridines or
indolizine (Scheme 1c).[10] However, metal-free
transformations describing the pyridotriazole’s ring-
opening were barely reported in the literature. In this
context, Adimurthy et al have reported the synthesis of
imidazopyridines derivatives from benzotriazoles and
nitriles in the presence of BF3.OEt2 (Scheme 1c).[15]
Recently, Dong et al investigated the use of other
acidic
conditions
in
the
synthesis
of
Scheme 1. a and c, Metal catalyzed C−N bond formation
through metallo-carbene species. b, In-situ rearrangement of
the triazole from its corresponding N-tosylhydrazone. d,
Metal-free formation of Csp3−N bond from pyridotriazoles
and amines.
pyridopyrroloindolizine starting from azaindoles and
pyridotriazoles.[16]
In connection with our interest in diazo chemistry,[17,
18] we envisaged the use of the emerging, economical,
and eco-friendly metal-free conditions replacing the
expensive and rare metal Rh catalysts in the formation
of Csp3−N bond from pyridotriazole derivatives.
Herein, we wish to report a sustainable and practical
transformation of 1,2,3-pyridotriazole into 2-
picolylamines derivatives using metal-free conditions
(Figure 1d). Highlighted features of this methodology
include (a) easily available pyridotriazole derivatives
from aldehydes, ketone or benzophenones; (b)
transition-metal, and base-free coupling leading to the
formation of C-N bond with the respect of sustainable
approach that limits the use of expensive noble metals;
solvents were used such as toluene, PhF, and DCE (SI
part). Notably, the efficiency of this transformations
was significantly affected by the nature of the base.
Thus, compound 3a was not detected when using a
strong base such as LiOtBu (entry 2). Following these
results, we decided to carry out the coupling in the
absence of base, which improved the reaction
efficiency to provide the desired 2-picolylamine 3a in
31% yield (Table 1, entry 3). Rising the temperature
up to 150 °C increased slightly the yield to 38% (entry
4). The use of tetrabutylammonium bromide (TBAB
0.1 equiv) or H2O (25 equiv) as additives also
enhanced the reaction efficiency (Table 1, entries 5
and 6). Gratifyingly, we found that combining TBAB
and H2O efficiently promoted the reaction and
afforded the desired compound 3a in a good 82% yield
(Table 1, entry 7). To our great surprise, further
investigation of the reaction conditions showed that
the cross-coupling could even take place in metal-free
conditions with a moderate yield of 68% (Table 1,
entry 9). Encouraged by these results, we decided to
optimize the metal-free process. Rising the
temperature up to 165 °C increased the yield to 79%
(Table 1, entry 10). Fine-tuning of the reaction
conditions led us to find that the use of 0.2 equivalent
of TBAB instead of 0.1 equivalent boosted the yield to
92% (Table 1, entry 11). In addition, comparing
different PTCs (cf, entries 12 and 13 vs 11) showed
that the use of TBAB is the optimal for this
transformation. Carrying out the reaction in water
showed a lower yield due to the low solubility of the
reagents in the reaction medium (Table 1, entry 14).
Control experiment demonstrated that the TBAB was
vital for this transformation (cf, entry 15 vs 16), as no
desired product was detected in its absence, and that
addition of water was very important (cf, entry 11 vs
15).
(c)
chemoselectivity
and
functional-group
compatibility; (d) water tolerance; (e) development of
sequential Csp3-N and Csp2-Csp2 bonds formation in a
one-pot manner.
Results and Discussion
To begin, the cross-coupling reaction of pyridotriazole
1a and p-anisidine 2a was chosen as a model to
explore the reaction conditions (Table 1). During this
study, a screening of various reaction parameters
(solvent, temperature, and copper source) was carried
out (for more details, see the Supporting Information
part). Reaction development commenced by
examining commercially available copper(II)
acetylacetonate as thecatalyst source (entries 1-6). The
combination of Cu(acac)2 and K2CO3 as the base in
dioxane at 130 °C led to the formation of the desired
product but in a low 25% yield (Table 1, entry 1).
Other copper(I) or (II) sources were tested and no
improvement of the yield was observed. In addition,
similar or lower yields were obtained when different
2
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10.1002/ejoc.201801803
European Journal of Organic Chemistry
Table 1. Optimization of the reaction conditions.[a]
(compound 3l-m). Furthermore, bicyclic anilines also
underwent the reaction forming the corresponding
products (compounds 3n-o). Coupling a secondary
aniline constitutes a challenging issue, since the steric
hindrance around the nitrogen center could affect its
reactivity. We were pleased to find that the
methylaniline and the tetrahydroquinoline reacted
smoothly to give the corresponding products in good
yields (compounds 3q-r). Encouraged by these results,
we further examined the substrate scope with respect
to the second partner of the coupling reaction, the
pyridotriazole. To our satisfaction, a variety of
triazoles were used successfully, and the desired
products were obtained in good yield (Table 2). The
structure of the product 3w was confirmed by single
crystal X-ray diffraction.[19] It should be noted that
halides (Br, F) are conserved in the reactions and
provide potential points for further modifications
(compounds 3x-aa). Moreover, pyridotriazoles
bearing different substituents at the C3 poisition
conducted the reaction successfully. Thus, 3-
Entry catalyst solvent base
additive T (oC) t (h) Yield
(%)
1
2
3
4
Cu(acac)2 dioxane K2CO3
Cu(acac)2 dioxane LiOtBu -
Cu(acac)2 dioxane -
Cu(acac)2 dioxane -
-
130 24 25
130 24
130 24 31
150 24 38
-
-
-
5[b] Cu(acac)2 dioxane -
6[c] Cu(acac)2 dioxane -
7[b,c] Cu(acac)2 dioxane -
TBAB 150 24 48
H2O 150 24 46
TBAB +150 24 82
H2O
TBAB +130 24 45
H2O
8 [d,c] Cu(acac)2 dioxane -
9[b,c]
10[b,c]
11[d]
12[d]
13[d]
-
-
-
-
-
dioxane -
dioxane -
dioxane -
dioxane -
dioxane -
TBAB + 150 12 68
H2O
TBAB + 165 12 79
H2O
TBAB +165 12 92
H2O
TBAI + 165 12 65
H2O
methylcarboxylate-pyridotriazole
afforded
the
carboxylic acid derivative (3ac) issued from the ester’s
hydrolysis after 12 h, however reducing the reaction
time to 6h furnished the corresponding ester
compounds in moderate yields (3ad-af). Readily
available 3-phenyl-pyridotriazoles furnished the
corresponding compounds in moderate yield (3ag-ai).
Moreover, we performed the coupling with triazoles
derived from 2-pyridine carboxaldehyde (compounds
3aj-al) showing a further utility of this process.
TBAC + 165 12 59
H2O
14[d]
15[d]
16
-
-
-
-
H2O
-
TBAB 165 12 45
TBAB 165 12 58
dioxane -
dioxane -
dioxane -
H2O
165 12
0
Next, to demonstrate the robustness of this method, we
conducted a gram-scale synthesis of compound 3a in
76% yield (Scheme 2). Moreover, we have
demonstrated the utility of our methodology by
synthesizing 3am (L2-b) from the triazolopyridine 1h
by a single step route with a 71% yield. L2-b is a metal
chelating agent could generate nontoxic amyloid
17[d,e]
TBAB +165 12 60
H2O
[a] Reaction Conditions: substrate (1a, 0.5 mmol), aniline
(2a, 2 equiv), [Cu] catalyst (0.1 equiv), base (2.2 equiv) in
5 mL of dioxane in a sealed tube. [b] TBAB (0.1 equiv) was
used as additive. [c] H2O (25 equiv) was used as additive,
the use of 25 equiv was found to be the optimal. [d] TBAX
(0.2 equiv) and H2O (25 equiv) were used as additives. [e] 1
equivalent of aniline was used.
species and reduce toxicity linked to A oligomers in
20]
vivo.[3,
In addition, we studied the late stage
modification of compound 3al by synthesizing the
amide directly from the corresponding amine using the
conditions reported recently by Das’ group.[21] Thus
compound 3al underwent successfully a visible-light-
mediated metal-free α-oxygenation to afford the amide
3an with a 66% yield (Scheme 2c).
With the optimized conditions in hand, we
investigated the substrate scope using different
pyridotriazoles 1 and a series of anilines 2. As
presented in Table 2, the reaction worked efficiently
affording the coupling products, in good to high yields.
Both electron-donating and electron-withdrawing
groups on the aniline ring underwent reaction to afford
the desired products in good to high yields
(compounds 3a-f, 3h, 3i). Also, the reaction proceeds
successfully with different substituents at various
positions in the anilines (3b, 3e-f, 3j, 3p), including
bulky methoxy group at the ortho position (3c). It is
noteworthy that the coupling tolerates the bromine
substitution on aniline (compound 3k), enabling later
additional derivatizations through metal-catalyzed
cross-coupling. Next, we examined the selectivity
issue (NH vs OH), and the coupling was conducted in
the presence of anilines having a free OH group
(phenol or 2-phenylethanol), interestingly, we
discovered that the reaction showed a high selectivity
leading to an exclusive C-N bond formation
Scheme 2. Applications of the methodology and
transformation. a. Gram-scale reaction of 3a; b. Synthesis of
L2-b, an A oligomers metal-chelator; c. metal-free α
oxygenation of amine 3al to amide.
3
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10.1002/ejoc.201801803
European Journal of Organic Chemistry
[a]
Table 2. Substrate scope of 1,2,3-pyridotriazoles with anilines.
[a] Reaction conditions: substrate (1, 0.5 mmol), aniline (2, 2 equiv), TBAB (0.2 equiv), H2O (25 equiv) in 5 ml of dioxane
in a sealed tube. [b] 1 equiv of TBAB was employed.
Subsequently, based on the results obtained above,
notably, on the fact that the coupling tolerated the
presence of bromine substituent, we were curious to
carry out a new coupling reaction on the compound 3k
in one-pot reaction fashion (Scheme 3). These types of
transformations allow us to access rapidly to complex
structures in attractive ecological and economical
ways. Thus, limiting the waste and time of the
purification of intermediates. Consequently, we
envisaged creating first a Csp3−N bond by reacting
triazolopyridine and 4-bromoaniline (2k), followed by
a new C−C bond by using a compatible Barluenga type
cross-coupling reaction.[22]
Next, we wondered if this one-pot reaction tolerates
the use of bromopyridotriazole 1c as the coupling
partner. Again, we demonstrated the feasibility of the
coupling by synthesizing 2,5-substituted pyridines 5a
and 5b in good overall yields (Scheme 3b).
To gain insight into the reaction mechanism, we
conducted control experiments (Scheme 4a-e). We
examined the reactivity of the TBAB with
pyridotriazole without the addition of the aniline. Thus,
under the standard conditions, the formation of the
1
benzylbromide intermediate 6 was confirmed by H
NMR analysis of the crude reaction mixture.[23]
Addition of para-anisidine to the reaction medium
conducted to the formation of compound 3a. In
addition, benzyl bromide 7 underwent the reaction
with p-anisidine to afford the compound 3ai proving
that benzylbromide intermediate could work with
aniline to give the final product (Scheme 4a-b).
Performing the reaction in the presence of deuterated
The coupling between intermediate 3k and the N-
tosylhydrazone was carried in the presence of
Pd(OAc)2 as the catalyst, the bidentate ligand dppp and
LiOt-Bu as the base.[18] Gratifyingly, The reaction took
place even in the presence of water, and TBAB from
the first step affording the compound 4a in 55 % yield
(Scheme 3a). Remarkably, tosylhydrazones bearing
water afforded the compound D-3d.
A
D-
electron-withdrawing
group
or
heterocycles
incorporation at  position of the amine was observed;
it was also accompanied by an H/D exchange on
aniline’s aromatic ring on ortho position due to the
heating of the anilinium hydrobromide formed in situ
underwent efficiently the reaction affording the
corresponding compound 4b and 4c in acceptable
yields.
4
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10.1002/ejoc.201801803
European Journal of Organic Chemistry
in the presence of D2O (Scheme 4c).[24] These
experiments clearly indicate the important role of
TBAB and water for the reaction progression (cf.
Table 1).
Csp3-N and Csp2-Csp2 bonds affording access to a
molecular diversity.
Pyridotriazole
1
is thermally subjected to
tautomerization giving a diazo-compound A generated
in situ from the pyridotriazole 1 upon heating,[25] which
normally decomposes giving the carbene species.[26]
Scheme 3. Scope of One-Pot, Reaction of triazopyridines
with anilines and N-tosylhydrazones with formation of
Csp3-N and Csp2-Csp2 bonds.[a]
No
cyclopropane
product
(2-(1-methyl-2-(p-
tolyl)cyclopropyl)pyridine) was detected when styrene
was added into the reaction in the presence or absence
of aniline, indicating that no carbene intermediate was
generated during the course of the reaction (Scheme
4d-e). Accordingly, the diazo compound A could react
with water giving rise to the intermediate B. The
electrophilic carbon bearing the diazo was then
attacked by the nucleophilic bromine[27] of the TBAB
forming the benzyl bromide intermediate C and lead
Scheme 4. Control experiments, and proposed mechanism.
Experimental Section
to
the
N2
release
and
formation
of
tetrabutylammonium hydroxide (TBAH). Next,
intermediate C was further attacked by the aniline
affording the coupling product D.
General procedure for the synthesis of -branched
amines.
Finally, D undergoes a deprotonation process in the
presence of TBAH to afford the corresponding
pyridyl-alkylamine 3.
0.5 mmol of pyridyltriazole , 1 mmol of aniline, 0.1 mmol
of TBAB, 12.5 mmol (0.2 ml, 25 equiv) of H2O in 5 ml of
dioxane were placed in a sealed tube under argon. The
mixture was allowed to stir at 165 oC for 12h. After cooled
the solvent was removed under reduced pressure and the
crude mixture was purified on flash column using a gradient
of petroleum ether and ethyl acetate.
Conclusion
4-Methoxy-N-(1-(pyridin-2-yl)ethyl)aniline
(3a)[28]
.
In summary, we have performed a metal-free reaction
between pyridotriazoles, and a wide variety of
commercially available anilines. This new process
catalyzed by TBAB permits the formation of Csp3–N
bond affording a variety of -branched arylamines.
This methodology features a wide substrates scope,
chemoselectivity, functional groups tolerance, and
scalability. Moreover, additional coupling in a one-pot
reaction could be conducted with the formation of
Column chromatography on silica gel afforded 105 mg of
the desired compound 3a as a brown solid (0.46 mmol, yield
92%). m.p. = 73-75 °C. 1H NMR (300 MHz, CDCl3) δ 8.56
(ddd, J = 4.9, 1.8, 1.1 Hz, 1H), 7.59 (td, J = 7.5, 1.8 Hz, 1H),
7.33 (dt, J = 7.5, 1.1 Hz, 1H), 7.12 (ddd, J = 7.5, 4.9, 1.1 Hz,
1H), 6.70 (d, J = 9.0 Hz, 2H), 6.52 (d, J = 9.0 Hz, 2H), 4.54
(q, J = 6.7 Hz, 1H), 3.69 (s, 3H), 1.52 (d, J = 6.7 Hz, 3H).13C
NMR (75 MHz) δ 164.2 (Cq), 152.1 (Cq), 149.3 (CH),
141.4 (Cq), 136.9 (CH), 122.0 (CH), 120.5 (CH), 114.9 (4
CH), 55.8 (OCH3), 55.7 (CH), 23.4 (CH3). IR ( cm-1) 3416,
5
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10.1002/ejoc.201801803
European Journal of Organic Chemistry
3043, 2880, 1613, 1520, 1503, 1478, 1110. HRMS (ESI) for
C14H17N2O [M+H]+: calcd 229.1341, found 229.1336.
N-(1-(Pyridin-2-yl)ethyl)aniline
(3g)[29]
.
Column
chromatography on silica gel afforded 86 mg of the desired
compound 3g as a colorless oil (0.435 mmol, yield 87%). 1H
NMR (300 MHz, CDCl3) δ 8.58 (dd, J = 4.9, 1.7 Hz, 1H),
7.61 (td, J = 7.8, 1.7 Hz, 1H), 7.35 (dd, J = 7.8, 1.1 Hz, 1H),
7.13 (m, 3H), 6.66 (t, J = 7.4, 1H), 6.57 (d, J = 7.4, 2H), 4.63
(q, J = 6.7 Hz, 1H), 4.46 (s, 1H), 1.55 (d, J = 6.7 Hz, 3H).
13C NMR (75 MHz) δ 164.0 (Cq), 149.4 (CH), 147.2 (Cq),
137.0 (CH), 129.3 (2CH), 122.1 (CH), 120.4 (CH), 117.5
(CH), 113.5 (2CH), 54.9, 23.34. IR ( cm-1) 3407, 3051,
2869, 1603, 1570, 1503, 1473. HRMS (ESI) for C13H15N2
[M+H]+: calcd 199.1235, found 199.1238.
3-Methoxy-N-(1-(pyridin-2-yl)ethyl)aniline
(3b).
Column chromatography on silica gel afforded 88 mg of the
desired compound 3b as a brown solid (0.385 mmol, yield
77%). m.p. = 70-72 °C. 1H NMR (300 MHz, CDCl3) δ 8.57
(ddd, J = 4.7, 1.7, 1.0 Hz, 1H), 7.61 (td, J = 7.7, 1.7 Hz, 1H),
7.34 (dt, J = 7.7, 1.0 Hz, 1H), 7.14 (ddd, J =7.7, 4.7, 1.0 Hz,
1H), 7.02 (t, J = 8.1 Hz, 1H), 6.26 – 6.16 (m, 2H), 6.12 (t, J
= 2.3 Hz, 1H), 4.61 (q, J = 6.7 Hz, 1H), 4.50 (s, 1H), 3.70
(s, 3H), 1.54 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 163.9 (Cq), 160.8 (C), 149.4 (CH), 148.6 (Cq), 137.0 (CH),
130.0 (CH), 122.1 (CH), 120.5 (CH), 106.6 (CH), 102.8
(CH), 99.5 (CH), 55.1 (CH), 54.8 (OCH3), 23.3 (CH3). IR
( cm-1) 3421, 3050, 2867, 1625, 1543, 1501, 1460, 1180.
HRMS (ESI) for C14H17N2O[M+H]+: calcd 229.1341, found
229.1335.
4-Fluoro-N-(1-(pyridin-2-yl)ethyl)aniline (3h). Column
chromatography on silica gel afforded 81 mg of the desired
1
compound 3h as colorless oil (0.375 mmol, yield 75%). H
NMR (300 MHz, CDCl3) δ 8.55 (dt, J = 4.8, 1.2 Hz, 1H),
7.60 (td, J = 7.7, 1.2 Hz, 1H), 7.31 (dd, J = 7.6, 1.2 Hz, 1H),
7.14 (ddt, J = 7.6, 4.8, 1.2 Hz, 1H), 6.86 – 6.71 (m, 2H), 6.55
– 6.41 (m, 2H), 4.54 (q, J = 6.7 Hz, 1H), 4.36 (s, 1H), 1.52
(d, J = 6.7 Hz, 3H). 13C NMR (75 MHz) δ 163.8 (Cq), 155.9
(Cq, d, J = 234.9 Hz), 149.5 (CH), 143.6 (Cq), 137.0 (CH),
122.2 (CH), 120.5 (CH), 115.7 (CH, d, J = 22.3 Hz), 114.4
(CH, d, J = 7.3 Hz), 55.5 (CH), 23.3 (CH3). 19F NMR (376
MHz, CDCl3) δ -130.58. IR ( cm-1) 3422, 3058, 2898,
1601, 1578, 1501, 1474. HRMS (ESI) for C13H14N2F
[M+H]+: calcd 217.1141, found 217.1143.
2-Methoxy-N-(1-(pyridin-2-yl)ethyl)aniline (3c). Column
chromatography on silica gel afforded 97 mg of the desired
compound 3c as a light brown oil (0.425 mmol, yield 85%).
1H NMR (300 MHz, CDCl3) δ 8.58 (dd, J = 4.9, 1.6 Hz, 1H),
7.59 (td, J = 7.7, 1.8 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.13
(ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 6.76 (td, J = 6.7, 5.6, 1.5 Hz,
1H), 6.70 (dd, J = 7.7, 1.5 Hz, 1H), 6.62 (td, J = 7.7, 1.6 Hz,
1H), 6.36 (dd, J = 7.7, 1.6 Hz, 1H), 4.87 (s, 1H), 4.61 (q, J
= 6.8 Hz, 1H), 3.89 (s, 3H), 1.59 (d, J = 6.8 Hz, 3H). 13
C
NMR (75 MHz, CDCl3) δ 164.5(Cq), 149.3(CH), 146.8(Cq), 1-(4-((1-(Pyridin-2-yl)ethyl)amino)phenyl)ethan-1-one
137.1(Cq), 136.9(CH), 121.9(CH), 121.2(CH), 120.1(CH),
116.6(CH), 111.0(CH), 109.4(CH), 55.5(OCH3), 54.9 (CH),
(3i). Column chromatography on silica gel afforded 86 mg
of the desired compound 3i as a light brown solid (0.36
23.4 (CH3). IR ( cm-1) 3420, 3013, 2876, 1599, 1540, 1507, mmol, yield 72%). m.p. = 120-122 °C. 1H NMR (300 MHz,
1486, 1190. HRMS (ESI) for C14H17N2O [M+H]+: calcd
229.1341, found 229.1342.
CDCl3) δ 8.58 (d, J = 4.8, 1.7 Hz, 1H), 7.77 (d, J = 8.7 Hz,
2H), 7.64 (td, J = 7.6, 1.7 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H),
7.18 (dd, J = 7.6, 4.8 Hz, 1H), 6.55 (d, J = 8.7 Hz, 2H), 5.20
(d, J = 6.5 Hz, 1H), 4.71 (p, J = 6.5 Hz, 1H), 2.46 (s, 3H),
1.57 (d, J = 6.5 Hz, 3H).13C NMR (75 MHz, CDCl3) δ 196.5
(C=O), 162.6 (Cq), 151.1 (Cq), 149.5 (CH), 137.10 (CH),
130.9 (2 CH), 126.9 (Cq), 122.4 (CH), 120.5 (CH), 112.2
(2CH), 54.1 (CH), 26.1 (CH3), 23.0 (CH3). IR ( cm-1) 3325,
2971, 1652, 1599, 1528, 1474, 1277. HRMS (ESI) for
C15H17N2O [M+H]+: calcd 241.1341, found 241.1332.
4-Methyl-N-(1-(pyridin-2-yl)ethyl)aniline (3d). Column
chromatography on silica gel afforded 74 mg of the desired
compound 3d as a colerless oil (0.35 mmol, yield 70%). 1H
NMR (300 MHz, CDCl3) δ 8.62 – 8.52 (m, 1H), 7.60 (tt, J
= 7.8, 1.3 Hz, 1H), 7.35 (dt, J = 7.8, 1.1 Hz, 1H), 7.13 (ddt,
J = 7.2, 4.9, 1.1 Hz, 1H), 6.93 (d, J = 8.1 Hz, 2H), 6.49 (d,
J = 8.1 Hz, 2H), 4.60 (q, J = 6.7 Hz, 1H), 4.32 (s, 1H), 2.20
(s, 3H), 1.54 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 164.2 (Cq), 149.3(CH), 144.9 (Cq), 136.9(CH), 129.7
(2CH), 126.6 (Cq), 122.0 (CH), 120.4 (CH), 113.7 (2CH),
55.1 (CH), 23.3 (CH3), 20.4 (CH). IR ( cm-1) 3421, 3061,
2891, 1603, 1555, 1502, 1488. HRMS (ESI) for C14H17N2
[M+H]+: calcd 213.1392, found 213.1388.
1-(3-((1-(Pyridin-2-yl)ethyl)amino)phenyl)ethan-1-one
(3j). Column chromatography on silica gel afforded 83 mg
of the desired compound 3j as a light brown solid (0.345
1
mmol, yield 69%). m.p. = 63-65 °C. H NMR (300 MHz,
CDCl3) δ 8.63 – 8.50 (m, 1H), 7.62 (td, J = 7.6, 1.6 Hz, 1H),
7.32 (dd, J = 7.9, 1.1 Hz, 1H), 7.25 – 7.10 (m, 4H), 6.74
(ddd, J = 7.4, 2.3, 1.2 Hz, 1H), 4.89 – 4.55 (m, 2H), 2.50 (d,
J = 0.8 Hz, 3H), 1.55 (d, J = 6.5 Hz, 3H).13C NMR (75 MHz,
CDCl3) δ 198.6(Cq), 163.2(Cq), 149.4(CH), 147.4(Cq),
138.1(Cq), 136.9(CH), 129.4(CH), 122.2(CH), 120.6(C),
118.1(CH), 117.7(CH), 112.6(CH), 54.5(CH), 26.7(CH3),
23.1(CH3). IR ( cm-1) 3330, 2954, 1663, 1598, 1524, 1482,
1270. HRMS (ESI) for C15H17N2O[M+H]+: calcd 241.1341,
found 241.1347.
3,5-Dimethoxy-N-(1-(pyridin-2-yl)ethyl)aniline
(3e).
Column chromatography on silica gel afforded 95 mg of the
desired compound 3e as a brown solid (0.37 mmol, yield
74%). m.p. = 83-85 °C. 1H NMR (300 MHz, CDCl3) δ 8.56
(ddd, J = 4.8, 1.9, 1.0 Hz, 1H), 7.61 (tt, J = 7.6, 1.4 Hz, 1H),
7.33 (dt, J = 7.9, 1.1 Hz, 1H), 7.13 (ddt, J = 7.3, 4.9, 1.2 Hz,
1H), 5.83 (t, J = 2.1 Hz, 1H), 5.76 (d, J = 2.2 Hz, 2H), 4.60
(q, J = 6.8 Hz, 1H), 4.52 (s, 1H), 3.68 (s, 6H), 1.53 (d, J =
6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 163.8(Cq),
161.7(Cq), 149.4(CH), 149.1(Cq), 136.9(CH), 122.1(CH),
120.5(CH), 92.4(2CH), 90.1(CH), 55.2(2OCH3), 54.7(CH),
4-Bromo-N-(1-(pyridin-2-yl)ethyl)aniline (3k). Column
chromatography on silica gel afforded 97 mg of the desired
23.2(CH3). IR ( cm-1) 3413, 3032, 2890, 1602, 1524, 1498, compound 3k as a colorless oil(0.35 mmol, yield 70%). H
1
1440, 1199. HRMS (ESI) for C15H19N2O2 [M+H]+: calcd
259.1447, found 259.1454.
NMR (300 MHz, CDCl3) δ 8.57 (dd, J = 4.6, 1.2 Hz, 1H),
7.62 (td, J = 7.7, 1.2 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.22
– 7.12 (m, 3H), 6.44 (d, J = 8.3 Hz, 2H), 4.56 (q, J = 6.8 Hz,
1H), 1.53 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3)
δ 163.4 (C), 149.5 (CH), 146.2 (C), 137.0 (CH), 132.0
(2CH), 122.3 (CH), 120.5 (CH), 115.1 (2CH), 109.1 (C),
54.8 (CH), 23.2 (CH3). IR ( cm-1) 3300, 2969, 1593, 1571,
1498, 1434.HRMS (ESI) for C13H14N2Br [M+H]+: calcd
277.0340, found 277.0333.
3,4,5-Trimethoxy-N-(1-(pyridin-2-yl)ethyl)aniline (3f).
Column chromatography on silica gel afforded 119 mg of
the desired compound 3f as a brown oil (0.415 mmol, yield
1
83%). H NMR (300 MHz, CDCl3) δ 8.62 – 8.51 (m, 1H),
7.64 (td, J = 7.6, 1.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.16
(dd, J = 7.5, 4.9 Hz, 1H), 5.80 (s, 2H), 4.58 (q, J = 6.7 Hz,
1H), 3.72 (s, 9H), 1.54 (d, J = 6.7 Hz, 3H).13C NMR (75
MHz, CDCl3) δ 164.2 (Cq), 153.9 (Cq), 149.3(CH), 144.0
(Cq), 137.1 (CH), 122.2 (CH), 120.5 (CH), 91.2 (2CH), 61.2
(CH3), 56.0(2 CH3), 55.4 (CH), 23.32 (CH3). IR ( cm-1)
3422, 3080, 2912, 1624, 1509, 1489, 1430, 1187. HRMS
(ESI) for C16H21N2O3 [M+H]+: calcd 289.1552, found
289.1553.
4-((1-(Pyridin-2-yl)ethyl)amino)phenol (3l). Column
chromatography on silica gel afforded 63 mg of the desired
compound 3l as a black solid (0.295 mmol, yield 59%). m.p.
1
= 139-141 °C. H NMR (300 MHz, Acetone-d6) δ 8.58 –
8.45 (m, 1H), 7.73 – 7.59 (m, 1H), 7.41 (d, J = 7.9 Hz, 1H),
7.24 – 7.09 (m, 1H), 6.56 (d, J = 8.5 Hz, 2H), 6.45 (d, J =
8.5 Hz, 2H), 4.50 (q, J = 6.8 Hz, 1H), 1.45 (d, J = 6.7 Hz,
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801803
European Journal of Organic Chemistry
3H). 13C NMR (75 MHz, Acetone-d6) δ 149.8 (CH), 148.8
(Cq), 142.0 (2Cq), 137.3 (CH), 122.5 (CH), 120.9 (CH),
116.4 (CH), 115.4 (CH), 56.3 (CH), 23.3 (CH3). IR ( cm-
1) 3402, 2974, 1584, 1562, 1495, 1420. HRMS (ESI) for
C13H15N2O [M+H]+: calcd 215.1184, found 215.1180.
4.9 Hz, 1H), 6.87 – 6.79 (m, 2H), 6.72 (ddd, J = 8.3, 6.7, 1.1
Hz, 1H), 5.13 (q, J = 6.9 Hz, 1H), 2.80 (s, 3H), 1.63 (d, J =
6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 162.5(Cq),
150.1(Cq), 149.2(CH), 136.6(CH), 129.3(2CH), 121.9(CH),
121.6(2CH), 116.9(CH), 113.2 (CH), 59.1(CH), 32.4(CH3),
16.3(CH3). IR ( cm-1) 3064, 2878, 1589, 1555, 1506, 1487.
HRMS (ESI) for C14H17N2 [M+H]+: calcd 213.1392, found
213.1397.
2-(4-((1-(Pyridin-2-yl)ethyl)amino)phenyl)ethan-1-ol
(3m). Column chromatography on silica gel afforded 94 mg
of the desired compound 3m as a brown solid (0.39 mmol,
yield 78%). m.p. = 93-95 °C. 1H NMR (300 MHz, Acetone-
d6) δ 8.52 (d, J = 3.8 Hz, 1H), 7.67 (td, J = 7.7, 1.7 Hz, 1H),
7.42 (d, J = 7.8 Hz, 1H), 7.18 (dd, J = 7.3, 4.8 Hz, 1H), 6.89
(d, J = 8.3 Hz, 2H), 6.50 (d, J = 8.4 Hz, 2H), 5.32 (d, J = 5.2
Hz, 1H), 4.62 – 4.53 (m, 1H), 3.62 (dt, J = 12.6, 6.4 Hz, 2H),
3.48 (t, J = 5.4 Hz, 1H), 2.61 (t, J = 7.2 Hz, 2H), 1.48 (d, J
= 6.8 Hz, 3H). 13C NMR (75 MHz, Acetone-d6) δ 165.9
(Cq), 150.0 (CH), 147.2 (Cq), 137.5 (CH), 130.3 (2CH),
128.2 (Cq), 122.7 (CH), 120.9 (CH), 114.1 (2CH), 64.5
(CH2), 55.7 (CH), 39.6 (CH2), 23.3 (CH3). HRMS (ESI) for
C15H19N2O [M+H]+: calcd 243.1497, found 243.1492.
1-(1-(Pyridin-2-yl)ethyl)-1,2,3,4-tetrahydroquinoline
(3r)[30]. Column chromatography on silica gel afforded 89
mg of the desired compound 3r as a colorless oil (0.375
mmol, yield 75%). 1H NMR (300 MHz, , CDCl3) δ 8.61 (d,
J = 5.0 Hz, 1H), 7.60 (td, J = 7.6, 1.8 Hz, 1H), 7.30 (d, J =
7.9 Hz, 1H), 7.15 (dd, J = 7.6, 5.0 Hz, 1H), 7.00 (t, J = 7.6
Hz, 2H), 6.60 (q, J = 7.8, 7.3 Hz, 2H), 5.12 (q, J = 7.0 Hz,
1H), 3.34 (ddd, J = 12.3, 8.3, 4.2 Hz, 1H), 3.19 (dt, J = 11.2,
5.0 Hz, 1H), 2.80 (t, J = 6.5 Hz, 2H), 1.94 (tq, J = 12.9, 7.6,
5.8 Hz, 2H), 1.68 (d, J = 7.0 Hz, 3H).13C NMR (75 MHz,
CDCl3) δ 162.7 (C), 149.3 (CH), 145.5 (C), 136.6 (CH),
129.3 (CH), 127.2 (CH), 123.1 (C), 121.9 (CH), 121.4 (CH),
115.9 (CH), 111.1 (CH), 57.7 (CH), 43.4 (CH2), 28.6 (CH2),
22.6 (CH2), 16.2 (CH3). IR ( cm-1) 3052, 2912, 1579,
1502, 1499, 1487. HRMS (ESI) for C16H19N2 [M+H]+: calcd
238.1548, found 239.1543.
N-(1-(Pyridin-2-yl)ethyl)-2,3-dihydro-1H-inden-4-
amine (3n). Column chromatography on silica gel afforded
93 mg of the desired compound 3n as a brown oil (0.39
mmol, yield 78%). 1H NMR (300 MHz, CDCl3) δ 8.55 (dd,
J = 4.9, 1.7 Hz, 1H), 7.57 (td, J = 7.7, 1.8 Hz, 1H), 7.36 –
7.28 (m, 1H), 7.10 (ddt, J = 7.2, 4.9, 1.1 Hz, 1H), 6.91 (t, J
= 7.7 Hz, 1H), 6.59 (d, J = 7.4 Hz, 1H), 6.22 (d, J = 8.0 Hz,
1H), 4.64 (q, J = 6.7 Hz, 1H), 4.23 (s, 1H), 2.89 (t, J = 7.6
Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.10 (p, J = 7.4 Hz, 2H),
1.55 (d, J = 6.7 Hz, 3H).13C NMR (75 MHz, CDCl3) δ
164.0(Cq), 149.2(CH), 144.8(Cq), 143.3(Cq), 136.8(CH),
128.3(Cq), 127.4(CH), 121.9(CH), 120.2(CH), 113.6(CH),
108.4(CH), 54.7(CH), 33.4(CH2), 29.5(CH2), 24.5(CH2),
23.3(CH3). IR ( cm-1) 3340, 3072, 2891, 1603, 1559 1501,
1466. HRMS (ESI) for C16H19N2 [M+H]+: calcd 239.1548,
found 239.1541.
4-(1-(pyridin-2-yl)ethyl)morpholine
(3t).
Column
chromatography on silica gel afforded 34 mg of the desired
compound 3s as a light yellow oil (0.175 mmol, yield 35%).
1H NMR (300 MHz, MeOD) δ 8.51 (d, J = 4.9 Hz, 1H), 7.85
(t, J = 7.7 Hz, 1H), 7.60 – 7.51 (m, 1H), 7.38 – 7.27 (m, 1H),
3.71 (t, J= 4.7 Hz, 4H) 3.55 (q, J = 6.8 Hz, 1H), 2.67 – 2.53
(m, 2H), 2.46-2.33 (m, 2H), 1.42 (d, J = 6.7 Hz, 3H). 13
C
NMR (75 MHz, MeOD).δ 158.26 (C), 149.5 (CH),
138.8(CH), 123.9(CH), 123.7(CH), 67.9 (2CH2), 67.7(CH),
52.3(2CH2), 18.7(CH3). IR ( cm-1) 3152, 3066, 2888, 1560,
1505, 1488, 1201. HRMS (ESI) for C11H17N2O [M+H]+:
calcd 193.1341, found 193.1338.
N-(1-(Pyridin-2-yl)ethyl)-2,3-
dihydrobenzo[b][1,4]dioxin-6-amine
(3o).
Column
N-benzyl-1-(pyridin-2-yl)ethan-1-amine (3u).[31] Column
chromatography on silica gel afforded 104 mg of the desired
compound 3o as brown solid (0.41 mmol, yield 82%). m.p.
= 96-98 °C. 1H NMR (300 MHz, CDCl3) δ 8.56 (dd, J = 5.0,
1.8 Hz, 1H), 7.60 (td, J = 7.7, 1.8 Hz, 1H), 7.32 (d, J = 7.7
Hz, 1H), 7.12 (dd, J = 7.7, 5.0 Hz, 1H), 6.63 (d, J = 9.4 Hz,
1H), 6.14 – 6.08 (m, 2H), 4.50 (q, J = 6.7 Hz, 1H), 4.20 –
4.08 (m, 4H), 1.50 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 164.1 (Cq), 149.4 (CH) , 144.0 (Cq), 142.2 (Cq),
136.9 (CH), 135.7 (Cq), 122.0 (CH), 120.5 (CH), 117.6
(CH), 107.4 (CH), 102.3 (CH), 64.8 (CH2), 64.2 (CH2), 55.5
(CH), 23.3 (CH3). IR ( cm-1) 3325, 2970, 2869, 1592,
1506, 1453, 1217. HRMS (ESI) for C15H17N2O2 [M+H]+:
calcd 257.1290, found 257.1282.
chromatography on silica gel afforded 42 mg of the desired
1
compound 3t as a colorless oil (0.2 mmol, yield 40%). H
NMR (300 MHz, , CDCl3) δ 8.58 (d, J = 4.9 Hz, 1H), 7.66
(dt, J = 7.4, 1.2, 1H), 7.37 – 7.28 (m, 5H), 7.25 – 7.13 (m,
2H), 3.93 (q, J = 6.7 Hz, 1H), 3.65 (s, 2H), 1.41 (d, J = 6.7
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 159.4 (C),
149.4(CH), 140.5 (C), 136.7(CH), 128.5(2CH), 128.3(2CH),
127.0(CH), 122.1(CH), 121.4(CH), 58.8(CH), 51.8(CH2),
23.0(CH3). IR ( cm-1) 3389, 3140, 3012, 2915, 1600, 1545,
1469. HRMS (ESI) for C14H17N2 [M+H]+: calcd 213.1392,
found 213.1388.
N-(1-(5-Methylpyridin-2-yl)ethyl)aniline (3v). Column
chromatography on silica gel afforded 82 mg of the desired
compound 3v as a light brown solid (0.385 mmol, yield
77%). m.p. = 80-82 °C. 1H NMR (300 MHz, , CDCl3) δ 8.40
(d, J = 2.2 Hz, 1H), 7.41 (dd, J = 8.0, 2.2 Hz, 1H), 7.24 (d,
J = 8.0 Hz, 1H), 7.11 (t, J = 7.7 Hz, 2H), 6.65 (t, J = 7.7 Hz,
1H), 6.56 (d, J = 7.7 Hz, 2H), 4.59 (q, J = 6.7 Hz, 1H), 4.43
(s, 1H), 2.30 (s, 3H), 1.53 (d, J = 6.7 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 161.1 (C), 149.7 (CH), 147.3 (C), 137.5
(CH), 131.4 (C), 129.2 (2CH), 119.9 (CH), 117.4 (CH),
113.5 (2CH), 54.5 (CH), 23.4 (CH3), 18.2 (CH3). ). IR
( cm-1) 3361, 3010, 2915, 1605, 1556, 1466. HRMS (ESI)
for C14H17N2 [M+H]+: calcd 213.1392, found 213.1390.
2-Fluoro-4-methoxy-N-(1-(pyridin-2-yl)ethyl)aniline
(3p). Column chromatography on silica gel afforded 85 mg
of the desired compound 3p as a light brown solid (0.345
mmol, yield 69%). m.p. = 113-115 °C. 1H NMR (300 MHz,
CDCl3) δ 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 7.62 (td, J = 7.7,
1.7 Hz, 1H), 7.31 (dd, J = 7.7, 1.0 Hz, 1H), 7.15 (ddd, J =
7.7, 4.9, 1.0 Hz, 1H), 6.75 (t, J = 9.1 Hz, 1H), 6.36 (dd, J =
13.4, 2.6 Hz, 1H), 6.25 (ddd, J = 8.9, 2.6, 1.2 Hz, 1H), 4.51
(q, J = 6.7 Hz, 1H), 4.30 (s,1H), 3.76 (s, 3H), 1.52 (d, J =
6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 163.63 (C),
153.53 (d, J = 243.6 Hz, C ), 149.48 (CH), 142.38 (d, J =
9.2 Hz, C), 139.51 (d, J = 11.1 Hz, C), 122.21, 120.51,
115.97 (d, J = 2.8 Hz, CH), 108.73 (d, J = 2.6 Hz, CH),
102.62 (d, J = 22.0 Hz, CH), 57.59 (OCH3), 55.41 (CH),
23.26 (CH3). 19F NMR (376 MHz, CDCl3) δ -136.12. IR
( cm-1) 3358, 3020, 2914, 1588, 1543, 1504, 1462, 1180.
HRMS (ESI) for C14H16N2OF [M+H]+: calcd 247.1247,
found 247.1251.
4-Methoxy-N-(1-(5-methylpyridin-2-yl)ethyl)aniline
(3w). Column chromatography on silica gel afforded 97 mg
of the desired compound 3w as a light yellow solid (0.4
mmol, yield 80%). m.p. = 111-113°C. 1H NMR (300 MHz, ,
CDCl3) δ 8.38 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 7.8, 1.8 Hz,
1H), 7.22 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 8.9 Hz, 2H), 6.52
(d, J = 8.9 Hz, 2H), 4.51 (q, J = 6.7 Hz, 1H), 4.15 (s, 1H),
3.69 (s, 3H), 2.29 (s, 3H), 1.50 (d, J = 6.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 161.3 (Cq), 152.1 (Cq), 149.7 (CH),
141.5 (Cq), 137.5 (CH), 131.4 (Cq), 120.0 (CH), 114.9
(4CH), 55.8 (OCH3), 55.4 (CH), 23.4 (CH3), 18.2 (CH3). IR
( cm-1) 3340, 3000, 2926, 1602, 1511, 1442, 1295. HRMS
N-Methyl-N-(1-(pyridin-2-yl)ethyl)aniline (3q). Column
chromatography on silica gel afforded 85 mg of the desired
1
compound 3q as a colorless oil (0.4 mmol, yield 80%). H
NMR (300 MHz, CDCl3) δ 8.62 – 8.57 (m, 1H), 7.59 (td, J
= 7.7, 1.9 Hz, 1H), 7.29 – 7.18 (m, 3H), 7.14 (dd, J = 7.5,
7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801803
European Journal of Organic Chemistry
(ESI) for C15H19N2O [M+H]+: calcd 243.1497, found
243.1488.
149.5 (CH), 148.4 (C), 138.7 (CH), 137.2 (C), 129.9 (2CH),
123.5 (CH), 118.1 (CH), 113.9 (2CH), 66.0 (CH3).IR (film)
3376, 2998, 2977, 1582, 1567, 1530, 1444.HRMS (ESI) for
C13H13N2O2[M+H]+: calcd 229.0977, found 229.0969.
N-(1-(5-Bromopyridin-2-yl)ethyl)aniline (3x). Column
chromatography on silica gel afforded 115 mg of the desired
compound 3x as an yellow oil (0.415 mmol, yield 83%). 1H
NMR (300 MHz, CDCl3) δ 8.63 (d, J = 2.4 Hz, 1H), 7.73
(dd, J = 8.4, 2.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.12 (t, J
= 7.6 Hz, 1H), 6.69 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 7.6 Hz,
Methyl 2-(phenylamino)-2-(pyridin-2-yl)acetate (3ad).
Column chromatography on silica gel afforded 59 mg of the
desired compound 3ad as a yellow oil (0.245 mmol, yield
49%).1H NMR (300 MHz, CDCl3) δ 8.63 (dt, J = 4.9, 1.8,
1.0 Hz, 1H), 7.68 (td, J = 7.7, 1.8 Hz, 1H), 7.49 (d, J = 8.1
Hz, 1H), 7.28 – 7.20 (m, 1H), 7.15 (t, J = 8.0 Hz, 2H), 6.73
(t, J = 7.8 Hz, 1H), 6.65 (d, J = 7.7 Hz, 2H), 5.43 (s, 1H),
5.28 (s, 1H), 3.73 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
171.9 (CO), 156.4(C), 149.6(CH), 146.1 (C), 137.2 (CH),
129.4 (2CH), 123.3 (CH), 122.1 (CH), 118.4 (CH), 113.6
(2CH), 62.4 (CH), 52.9 (OCH3). IR (film) 3249, 2988, 2976,
1720, 1572, 1567, 1535, 1440. HRMS (ESI) for
C14H15N2O2[M+H]+: calcd 243.1134, found 243.1139.
1H), 4.58 (q, J = 6.8 Hz, 1H), 1.54 (d, J = 6.8 Hz, 3H). 13
C
NMR (75 MHz, CDCl3) δ 162.9 (C), 150.5 (CH), 147.0 (C),
139.5 (CH), 129.4 (2CH), 121.8 (CH), 118.8 (C), 117.9
(CH), 113.6 (2CH), 54.6 (CH), 23.3 (CH3). IR ( cm-1)
3322, 3076, 2899, 1607, 1577, 1498. .HRMS (ESI) for
C13H14N2Br [M+H]+: calcd 277.0340, found 277.0348.
N-(1-(5-Bromopyridin-2-yl)ethyl)-4-methoxyaniline (3y).
Column chromatography on silica gel afforded 124 mg of
the desired compound 3y as a yellow oil (0.405 mmol, yield
1
81%). H NMR (300 MHz, CDCl3) δ 8.61 (d, J = 2.3 Hz,
Methyl
2-((4-methoxyphenyl)amino)-2-(pyridin-2-
1H), 7.71 (dt, J = 8.3, 2.3 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H),
6.71 (d, J = 8.9 Hz, 2H), 6.50 (d, J = 8.9 Hz, 2H), 4.50 (q, J
= 6.7 Hz, 1H), 3.70 (s, 3H), 1.51 (d, J = 6.7 Hz, 3H).13C
NMR (75 MHz, CDCl3) δ 163.1 (C), 152.4 (C), 150.5 (CH),
141.1 (C), 139.5 (CH), 121.9 (CH), 118.8 (C), 114.9 (4CH),
55.8 (OCH3), 55.4 (CH), 23.3 (CH3). IR ( cm-1) 3401,
3055, 2901, 1602, 1589, 1533, 1484. 1276. HRMS (ESI) for
C14H16N2OBr [M+H]+: calcd 307.0446, found 307.0443.
yl)acetate (3ae). Column chromatography on silica gel
afforded 69 mg of the desired compound 3ae as a light
1
yellow oil (0.255 mmol, yield 51%). H NMR (300 MHz,
CDCl3) δ 8.61 (dt, J = 5.0, 1.9, 1.0 Hz, 1H), 7.67 (td, J = 7.7,
1.7 Hz, 1H), 7.47 (dt, J = 7.8, 1.1 Hz, 1H), 7.22 (ddt, J = 7.1,
4.8, 1.1 Hz, 1H), 6.74 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 8.9
Hz, 2H), 5.21 (s, 1H), 5.14 (s, 1H), 3.71 (s, 6H). 13C NMR
(75 MHz, CDCl3) δ 172.0 (CO), 156.6 (C), 152.8 (C), 149.6
(CH), 140.2 (C), 137.1 (CH), 123.2 (CH), 122.2 (CH), 115.0
(4CH), 63.3 (CH), 55.7 (OCH3), 52.8 (OCH3). IR (film)
3236, 2990, 2976, 1722, 1569, 1550, 1535, 1449. HRMS
(ESI) for C15H17N2O3[M+H]+: calcd 273.1239, found
273.1245.
N-(1-(5-Bromopyridin-2-yl)ethyl)-4-fluoroaniline (3z).
Column chromatography on silica gel afforded 110 mg of
the desired compound 3z as a colorless oil (0.375 mmol,
yield 75%). 1H NMR (300 MHz , CDCl3) δ 8.56 (d, J = 4.8
Hz, 1H), 7.61 (td, J = 7.7, 1.8 Hz, 1H), 7.36 – 7.31 (m, 2H),
7.23 (m, 2H), 7.14 (dd, J = 7.5, 5.0 Hz, 1H), 4.53 (q, J = 7.1
Hz, 1H), 1.71 (d, J = 7.0 Hz, 3H). 13C NMR (75 MHz,
Methyl
2-((4-fluorophenyl)amino)-2-(pyridin-2-
yl)acetate (3af). Column chromatography on silica gel
CDCl3) δ 164.2 (C), 156.29 (C, d, J = 234.9 Hz), 149.8 (CH), afforded 52 mg of the desired compound 3af as a yellow oil
143.9 (2C), 122.6 (CH), 120.8 (CH), 116.09 (CH, d, J = 22.3
(0.2 mmol, yield 40%). 1H NMR (300 MHz, CDCl3) δ 8.62
(d, J = 4.9 Hz, 1H), 7.68 (td, J = 7.5, 1.5 Hz, 1H), 7.46 (dd,
Hz), 114.81 (CH, d, J = 7.3 Hz), 55.8 (CH), 23.7 (CH3). 19
F
NMR (376 MHz, CDCl3) δ -127.57. IR ( cm-1) 3371, 3103, J = 8.0, 1.1 Hz, 1H), 7.30 – 7.21 (m, 1H), 6.91 – 6.80 (m,
2945,
1609,
1525,
1503.
HRMS
(ESI) for
2H), 6.64 – 6.52 (m, 2H), 5.33 (d, J = 7.2 Hz, 1H), 5.21 (d,
J = 7.1 Hz, 1H), 3.72 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
171.8 (CO), 156.4 (d, J = 236.3 Hz), 156.1 (C), 149.6 (CH),
142.5 (C), 137.2 (CH), 123.4 (CH), 122.2 (CH), 115.90 (d,
J = 22.5 Hz), 114.63 (d, J = 7.4 Hz), 62.9 (CH), 52.9
(OCH3). 19F NMR (188 MHz, CDCl3) δ -126.98. IR (film)
3256, 2991, 2975, 1725, 1601, 1567, 1544, 1451. HRMS
(ESI) for C14H14N2O2F[M+H]+: calcd 261.1039, found
261.1036.
C13H13N2BrF [M+H]+: calcd 295.0246, found 295.0238.
N-(1-(6-bromopyridin-2-yl)ethyl)-4-methoxyaniline
(3aa). Column chromatography on silica gel afforded 132
mg of the desired compound 3aa as a colorless oil (0.43
mmol, yield 86%). 1H NMR (300 MHz, CDCl3) δ 7.44 (td,
J = 7.9, 0.8 Hz, 1H), 7.35 – 7.28 (m, 2H), 6.71 (d, J = 9.0
Hz, 2H), 6.49 (d, J = 9.2 Hz, 2H), 4.51 (q, J = 6.7 Hz, 1H),
4.01 (s, 1H), 3.70 (s, 3H), 1.52 (d, J = 6.8 Hz, 3H).13C NMR
(75 MHz, CDCl3) δ 166.4 (C), 152.4 (C), 141.8 (C), 141.1
(C), 139.2 (CH), 126.3 (CH), 119.1 (CH), 115.0 (2CH),
114.9 (2CH), 55.8 (OCH3), 55.5 (CH), 23.3 (CH3). IR
(film) 3390, 2973, 2922, 1582, 1554, 1514, 1436, 1235. .
HRMS (ESI) for C14H16N2OBr [M+H]+: calcd 307.0446,
found 307.0449.
N-(Phenyl(pyridin-2-yl)methyl)aniline (3ag)[32]. Column
chromatography on silica gel afforded 49 mg of the desired
compound 3ag as a colorless oil (0.19 mmol, yield 38%). 1H
NMR (300 MHz, CDCl3) δ 8.64 (d, J = 4.2 Hz, 1H), 7.67
(td, J = 7.7, 1.9 Hz, 1H), 7.53 – 7.47 (m, 2H), 7.44 – 7.32
(m, 3H), 7.30 (d, J = 7.1 Hz, 1H), 7.24 – 7.12 (m, 3H), 6.77
– 6.64 (m, 3H), 5.63 (d, J = 4.6 Hz, 1H), 5.50 (d, J = 4.7 Hz,
1H). 13C NMR (75 MHz, CDCl3) δ 161.0(Cq), 149.3(CH),
147.1(Cq), 142.6(Cq), 136.9(CH), 129.2(CH), 128.9(CH),
127.6(CH), 127.5(CH), 122.3(CH), 122.0(CH), 117.6(CH),
113.7(CH), 63.4(CH). IR ( cm-1) 3398, 3061, 2888, 1606,
1599, 1576, 1533, 1498, 1474. HRMS (ESI) for C18H17N2
[M+H]+: calcd 261.1392, found 261.1394.
4-methoxy-N-(1-(4-methylpyridin-2-yl)ethyl)aniline
(3ab). Column chromatography on silica gel afforded 102
mg of the desired compound 3ab as a colorless oil (0.42
mmol, yield 84%). 1H NMR (300 MHz, CDCl3) δ 8.41 (d, J
= 5.0 Hz, 1H), 7.15 (s, 1H), 6.95 (d, J = 4.9 Hz, 1H), 6.70
(d, J = 9.0 Hz, 2H), 6.53 (d, J = 9.0 Hz, 2H), 4.50 (q, J = 6.7
Hz, 1H), 3.70 (s, 3H), 2.29 (s, 3H), 1.50 (d, J = 6.7 Hz, 3H).
13C NMR (75 MHz, CDCl3) δ 164.1 (C), 152.1 (C), 149.1
(CH), 148.0 (C), 141.6 (C), 123.1 (CH), 121.3 (CH), 114.9
(4CH), 55.8 (OCH3), 55.7 (CH), 23.3 (CH3), 21.2 (CH3).
IR (film) 3385, 2966, 2929, 1577, 1550, 1517, 1438, 1236.
HRMS (ESI) for C15H19N2O[M+H]+: calcd 243.1497, found
243.1498.
4-Methoxy-N-(phenyl(pyridin-2-yl)methyl)aniline
(3ah)[32]. Column chromatography on silica gel afforded 60
mg of the desired compound 3ah as a yellow oil (0.205
1
mmol, yield 41%). H NMR (300 MHz, CDCl3) δ 8.63 –
8.53 (m, 1H), 7.61 (td, J = 7.8, 1.8 Hz, 1H), 7.45 (d, J = 7.1
Hz, 2H), 7.39 – 7.28 (m, 3H), 7.27 – 7.22 (m, 1H), 7.15 (dd,
J = 7.4, 4.9 Hz, 1H), 6.71 (d, J = 8.9 Hz, 2H), 6.58 (d, J =
8.8 Hz, 2H), 5.51 (s, 1H), 5.13 (s, 1H), 3.70 (s, 2H). 13C
NMR (75 MHz, CDCl3) δ 13C NMR (75 MHz, CDCl3) δ
161.3 (C), 152.2(C), 149.3 (CH), 142.7 (C), 142.4 (CH),
141.4 (C), 136.9 (CH), 128.9 (2CH), 127.6 (CH), 127.5
(2CH), 122.2 (CH), 122.0 (CH), 114.9 (2CH), 114.9 (CH),
64.3 (CH), 55.8 (OCH3). HRMS (ESI) for C19H19N2O
[M+H]+: calcd 291.1497, found 291.1494.
2-(phenylamino)-2-(pyridin-2-yl)acetic
acid(3ac).
Column chromatography on silica gel afforded 52 mg of the
desired compound 3ac as a light yellow oil (0.22 mmol,
1
yield 44%). H NMR (300 MHz, MeOD-d4) δ 8.49 (d, J =
5.0 Hz, 1H), 7.82 – 7.71 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H),
7.30 (t, J = 6.4 Hz, 1H), 7.11 – 6.99 (m, 2H), 6.65 – 6.51 (m,
3H), 4.44 (s, 1H). 13C NMR (75 MHz, MeOD) δ 162.1 (CO),
8
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801803
European Journal of Organic Chemistry
4-Fluoro-N-(phenyl(pyridin-2-yl)methyl)aniline (3ai).
Column chromatography on silica gel afforded 49 mg of the
desired compound 3ai as a yellow oil (0.175 mmol, yield
stirred for 48 h under blue LED irradiation. The resulting
mixture underwent an aqueous workup and was extracted
three times with ethyl acetate. The combined organic layers
were dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. Column chromatography on silica
gel afforded 26 mg of the desired compound 3ak as a light
brown solid (0.12 mmol, yield 66%). m.p. = 103-105 ºC 1H
NMR (300 MHz, CDCl3) δ 10.00 (s, 1H), 8.62 (d, J = 4.8
Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.92 (td, J = 7.7, 1.6 Hz,
1H), 7.75 (dd, J = 9.0, 4.7 Hz, 2H), 7.49 (ddd, J = 7.6, 4.8,
1.3 Hz, 1H), 7.08 (t, J = 8.7 Hz, 2H).13C NMR (75 MHz,
CDCl3) δ 162.0(C), 159.5 (C, d, J = 249.4 Hz), 150.0 (C),
148.1 (CH), 137.8 (CH), 134.3(C), 126.6 (CH), 122.5 (CH),
121.47 (CH, d, J = 7.8 Hz), 115.8 (CH, d, J = 24.4 Hz). 19F
NMR (188 MHz, CDCl3) δ -118.08. HRMS (ESI) for
C12H10N2OF [M+H]+: calcd 217.0777, found 217.0786.
1
35%). H NMR (300 MHz, CDCl3) δ 8.61 (d, J = 4.7 Hz,
1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.47 (dd, J = 7.5, 1.8 Hz,
2H), 7.40 – 7.28 (m, 3H), 7.30 – 7.25 (m, 1H), 7.18 (dd, J =
7.5, 4.9 Hz, 1H), 6.88 – 6.80 (m, 2H), 6.61 – 6.53 (m, 2H),
5.53 (d, J = 3.6 Hz, 1H), 5.44 (s, 1H). 13C NMR (75 MHz,
CDCl3) δ 160.8 (Cq), 155.9.5 (Cq, d, J = 234 Hz),
149.2(CH), 143.5 (Cq), 142.4 (Cq), 136.9 (CH), 129.0
(2CH), 127.7 (CH), 127.4 (2CH), 122.4(CH), 122.0 (CH),
115.66 (CH, d, J = 22.3 Hz), 114.53 (CH, d, J = 7.4 Hz),
63.9 (CH). 19F NMR (188 MHz, CDCl3) δ -128.09. . IR
( cm-1) 3386, 3122, 2919, 1603, 1586, 1520, 1488. HRMS
(ESI) for C18H16N2F [M+H]+: calcd 279.1298, found
279.1298.
N-(Pyridin-2-ylmethyl)aniline
(3aj)[33]
.
Column
4-(1-(4-Methoxyphenyl)vinyl)-N-(1-(pyridin-2-
chromatography on silica gel afforded 73 mg of the desired
compound 3aj as a yellow oil (0.175 mmol, yield 79%). 1H
NMR (300 MHz, CDCl3) δ 8.59 (dd, J = 5.0, 1.6 Hz, 1H),
7.64 (tt, J = 7.7, 1.3 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.23
– 7.14 (m, 3H), 6.73 (td, J = 7.3, 1.3 Hz, 1H), 6.67 (dd, J =
7.4, 1.3 Hz, 2H), 4.47 (s, 2H), 4.31 (s, 1H). 13C NMR (75
MHz, CDCl3) δ 158.6 (C), 149.2 (CH), 147.9 (C), 136.7
(CH), 129.3 (2CH), 122.1 (CH), 121.6 (CH), 117.6 (CH),
113.1 (2CH), 49.3 (CH2). IR ( cm-1) 3330, 3120, 3010,
2920, 1610, 1544, 1477. HRMS (ESI) for C12H13N2
[M+H]+: calcd 185.1079, found 185.1080.
yl)ethyl)aniline (4a). Column chromatography on silica gel
afforded 91 mg of the desired compound 4a as a yellow oil
1
(0.275 mmol, yield 55%). H NMR (300 MHz , CDCl3) δ
8.58 (d, J = 4.8 Hz, 1H), 7.63 (td, J = 7.7, 1.9 Hz, 1H), 7.35
(d, J = 7.9 Hz, 1H), 7.26 (d, J = 8.7 Hz, 2H), 7.19 – 7.08 (m,
3H), 6.84 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 8.6 Hz, 2H), 5.23
(d, J = 1.6 Hz, 1H), 5.15 (d, J = 1.6 Hz, 1H), 4.64 (q, J = 6.6
Hz, 1H), 3.81 (s, 3H), 1.56 (d, J = 6.6 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 163.8(C), 159.2 (C), 149.3 (CH), 146.9
(C), 137.1(CH), 130.9 (C), 129.6 (2CH), 129.2 (2CH),
122.1(CH), 120.5 (CH), 113.5 (2CH), 113.0 (2CH), 110.4
(CH2), 55.4 (OCH3), 54.8 (CH), 23.3 (CH3). IR ( cm-1)
3380, 3110, 2930, 1610, 1519, 1512, 1434, 1247. HRMS
(ESI) for C22H23N2O [M+H]+: calcd 331.1810, found
331.1812.
4-Methoxy-N-(pyridin-2-ylmethyl)aniline
(3ak)[34]
.
Column chromatography on silica gel afforded 80 mg of the
desired compound 3ak as a yellow oil (0.375 mmol, yield
1
75%). H NMR (300 MHz , CDCl3) δ 8.58 (d, J = 4.8 Hz,
1H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H),
7.16 (dd, J = 7.3, 5.3 Hz, 1H), 6.78 (d, J = 8.9 Hz, 2H), 6.63
(d, J = 8.9 Hz, 2H), 4.41 (s, 2H), 3.73 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 158.9(C), 152.3(C), 149.3(CH), 142.2(C),
136.6 (CH), 122.1 (CH), 121.7 (CH), 114.9 (2CH), 114.3
(2CH), 55.8 (CH2), 50.3 (OCH3). IR ( cm-1) 3345 3111,
3009, 2918, 1599, 1533, 1456, 1209. HRMS (ESI) for
C13H15N2O [M+H]+: calcd 215.1184, found 215.1182.
4-(1-(4-((1-(Pyridin-2-
yl)ethyl)amino)phenyl)vinyl)benzonitrile (4b). Column
chromatography on silica gel afforded 98 mg of the desired
1
compound 4b as a yellow oil (0.3 mmol, yield 60%). H
NMR (300 MHz , CDCl3) δ 8.58 (dd, J = 4.8, 1.8 Hz, 1H),
7.68 – 7.55 (m, 3H), 7.41 (d, J = 8.3 Hz, 2H), 7.34 (d, J =
7.9 Hz, 1H), 7.20 – 7.12 (m, 1H), 7.04 (d, J = 8.5 Hz, 2H),
6.53 (d, J = 8.6 Hz, 2H), 5.43 (s, 1H), 5.26 (s, 1H), 4.64 (q,
J = 6.8 Hz, 1H), 1.56 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 163.5 (CN), 149.4 (CH), 148.6 (Cq), 147.3 (Cq),
147.1 (Cq), 137.0 (CH), 132.0 (2 CH), 129.1 (4CH), 122.2
(CH), 120.4 (CH), 119.1 (Cq), 113.7 (CH2), 113.1 (2CH),
111.1 (Cq), 54.7 (CH), 23.2 (CH3). IR ( cm-1) 3386, 3120,
4-Fluoro-N-(pyridin-2-ylmethyl)aniline (3al)[35]. Column
chromatography on silica gel afforded 81 mg of the desired
compound 3al as a white solid (0.4 mmol, yield 80%). m.p.
1
= 64-66 °C. H NMR (300 MHz , CDCl3) δ 8.58 (dd, J =
2927,
1609,
1520,
1470.
HRMS
(ESI) for
4.8, 1.7 Hz, 1H), 7.64 (td, J = 7.7, 1.8 Hz, 1H), 7.31 (d, J =
7.8 Hz, 1H), 7.18 (dd, J = 7.5, 5.0 Hz, 1H), 6.94 – 6.83 (m,
2H), 6.65 – 6.52 (m, 2H), 4.69 (s, 1H), 4.41 (s, 2H). 13C
NMR (75 MHz, CDCl3) δ 158.3(C), 156.05 (C, d, J = 235.0
Hz), 149.3 (CH), 144.4(C), 136.7(CH), 122.3 (CH), 121.7
(CH), 115.78 (CH, d, J = 22.3 Hz), 113.96 (CH, d, J = 7.4
Hz), 50.0 (CH2). 19F NMR (188 MHz, CDCl3) δ -127.99. IR
( cm-1) 3280, 3133, 3003, 2899, 1605, 1587, 1520, 1488.
HRMS (ESI) for C12H14N2F[M+H]+: calcd 203.0985, found
203.0979.
C22H20N3 [M+H]+: calcd 326.1657, found 326.1660.
4-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)vinyl)-N-(1-
(pyridin-2-yl)ethyl)aniline (4c). Column chromatography
on silica gel afforded 98 mg of the desired compound 4c as
a yellow oil (0.275 mmol, yield 55%). 1H NMR (300 MHz,
CDCl3) δ 8.57 (dd, J = 4.0, 0.7 Hz, 1H), 7.62 (td, J = 7.7,
1.3 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.15 – 7.10 (m, 3H),
6.86 (d, J = 1.4 Hz, 1H), 6.84 – 6.77 (m, 2H), 6.51 (d, J =
8.4 Hz, 2H), 5.22 (s, 1H), 5.15 (s, 1H), 4.67 – 4.60 (m, 1H)),
4.24 (s, 4H), 1.55 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 163.9 (Cq), 149.4 (CH), 149.2 (Cq), 146.9 (Cq),
143.2 (Cq), 143.1 (Cq), 137.0 (CH), 135.8 (Cq), 130.6 (Cq),
129.3 (2CH), 122.1 (CH), 121.8 (CH), 120.5 (CH), 117.4
(CH), 116.8 (CH), 113.0 (2CH), 110.7 (CH2), 64.6 (CH2),
64.5 (CH2), 54.8 (CH), 23.3 (CH3). IR ( cm-1) 3378, 3115,
N1,N1-Dimethyl-N4-(pyridin-2-ylmethyl)benzene-1,4-
diamine (3am)[3]. Column chromatography on silica gel
afforded 80 mg of the desired compound 3am as a light
orange oil (0.355 mmol, yield 71%).1H NMR (300 MHz ,
CDCl3) δ 8.57 (d, J = 4.8 Hz, 1H), 7.62 (td, J = 7.7, 1.8 Hz,
1H), 7.35 (d, J = 7.8 Hz, 1H), 7.16 (dd, J = 7.4, 5.0 Hz, 1H),
6.74 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 4.42 (s,
2H), 2.81 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 159.4 (C),
149.2 (CH), 144.3 (C), 140.5 (C), 136.6 (CH), 122.0 (CH),
121.7 (CH), 115.9 (2CH), 114.6 (2CH), 50.5 (CH2), 42.3
(2NCH3). IR ( cm-1) 3351, 3095, 3021, 2887, 1606, 1577,
1502, 1483. HRMS (ESI) for C14H18N3 [M+H]+: calcd
228.1501, found 228.1499.
2929,
1609,
1518,
1472.
HRMS
(ESI) for
C23H23N2O2 [M+H]+: calcd 359.1760, found 359.1761.
4-Methoxy-N-(1-(5-(1-(p-tolyl)vinyl)pyridin-2-
yl)ethyl)aniline (5a). Column chromatography on silica gel
afforded 120 mg of the desired compound 5a as a brown oil
1
(0.35 mmol, yield 70%). H NMR (300 MHz , CDCl3) δ
8.58 (d, J = 2.3 Hz, 1H), 7.55 (dd, J = 8.1, 2.3 Hz, 1H), 7.32
(d, J = 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1
Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H),
5.50 (s, 1H), 5.44 (s, 1H), 4.60 (q, J = 6.7 Hz, 1H), 3.71 (s,
3H), 2.37 (s, 3H), 1.57 (d, J = 6.7 Hz, 3H).13C NMR (75
MHz, CDCl3) δ 163.5 (C), 152.2 (C), 148.8 (CH), 146.8 (C),
141.5 (C), 138.1 (C), 137.7 (C), 136.5 (CH), 135.6 (C),
129.2 (2CH), 128.1 (2CH), 119.8 (CH), 115.0 (4CH), 114.8
N-(4-Fluorophenyl)picolinamide (3an)[36]. A 10 mL flask
was charged with 0.20 mmol of 3al and 0.006 mmol of rose
bengal. After purging the flask with vacuum nitrogen,
oxygen atmosphere was introtuced through an O2 balloon.
Finally dry DMF (0.7 mL) and dry DBN solution (0.3mmol,
1 mol/L in DMF) were added. The resulting mixture was
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801803
European Journal of Organic Chemistry
(CH2), 55.9 (OCH3), 55.5 (CH), 23.4 (CH3), 21.3 (CH3). IR
( cm-1) 3388, 3087, 2861, 1606, 1577, 1521, 1499. 1265.
HRMS (ESI) for C23H25N2O[M+H]+: calcd 345.1967, found
345.1955.
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4-Fluoro-N-(1-(5-(1-(p-tolyl)vinyl)pyridin-2-
yl)ethyl)aniline (5b). Column chromatography on silica gel
afforded 108 mg of the desired compound 5b as a brown oil
1
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(0.325 mmol, yield 65%). H NMR (300 MHz, CDCl3) δ
8.58 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.2, 2.2 Hz, 1H), 7.28
(d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2
Hz, 2H), 6.84 (dd, J = 9.8, 7.6 Hz, 2H), 6.56 – 6.48 (m, 2H),
5.51 (s, 1H), 5.44 (s, 1H), 4.58 (q, J = 6.7 Hz, 1H), 2.37 (s,
3H), 1.56 (d, J = 6.7 Hz, 3H).13C NMR (75 MHz, CDCl3) δ
163.0 (C), 155.9 (d, J = 235.1 Hz, C), 148.9 (CH), 146.7 (C),
143.6 (C), 138.1 (C), 137.7 (C), 136.5 (CH), 135.8 (C),
129.2 (2CH), 128.0 (2CH), 119.8 (CH), 115.7 (d, J = 22.3
Hz, 2CH), 114.9 (CH2), 114.4 (d, J = 7.3 Hz, 2CH), 55.3
(CH), 23.3 (CH3), 21.3 (CH3). 19F NMR (376 MHz, CDCl3)
δ -127.97. IR ( cm-1) 3401, 3015, 2905, 1612, 1587, 1510,
1483. HRMS (ESI) for C22H22N2F [M+H]+: calcd 333.1767,
found 333.1770
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Authors gratefully acknowledge the support of this project by
CNRS, Univ. Paris-Sud, and by La Ligue Contre le Cancer through
an Equipe Labellisée 2014 grant. BioCIS is a member of the
Laboratory of Excellence LERMIT supported by a grant from ANR
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10.1002/ejoc.201801803
European Journal of Organic Chemistry
FULL PAPER
Synthetic Methods
Diana Lamaa, Hsin-Ping Lin,
Tourin Bzeih, Pascal Retailleau,
Mouad Alami,* and Abdallah
Hamze.*
Page No. – Page No.
Text for Table of Contents (about 350 characters)
Metal-Free
Formation
Csp3−N
Bond
Coupling
by
Pyridotriazoles with Anilines: A
New Route to (2-
Pyridyl)alkylamines
Pyridyl-alkylamines derivatives were prepared through a coupling of pyridotriazoles and nucleophilic amines using a catalytic amount of
TBAB and water as a co-solvent. This metal-free coupling features broad functional groups tolerance, allowing the formation of Csp3-N
and Csp2-Csp2 bonds in one pot-fashion affording access to a molecular diversity
12
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