Rearrangement of 4-amino-3-halo-pyridines by nucleophilic aromatic substitution

Article abstract of DOI:10.1021/jo4003773

The reaction of 3-halo-4-aminopyridines with acyl chlorides and triethylamine is described. The pyridin-4-yl α-substituted acetamide products were obtained in moderate to high yields. The presented rearrangement reaction, in which the presumed N-acylated intermediate reacts intramolecularly via nucleophilic aromatic substitution, results in a formal two-carbon insertion.

Full text of DOI:10.1021/jo4003773

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Note
Rearrangement of 4-Amino-3-halo-pyridines
by Nucleophilic Aromatic Substitution
Matthäus Getlik, Brian J. Wilson, M. Monzur Morshed, Iain D. G.
Watson, Doris Tang, Pandiaraju Subramanian, and Rima Al-awar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4003773 • Publication Date (Web): 09 May 2013
Downloaded from http://pubs.acs.org on May 11, 2013
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Rearrangement of 4-Amino-3-halo-pyridines by Nucleophilic Aromatic
Substitution
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Matthäus Getlik,† Brian J. Wilson,† M. Monzur Morshed,† Iain D. G. Watson,† Doris Tang,†
Pandiaraju Subramanian,† Rima Al-awar†,‡,*
†Drug Discovery Program, Ontario Institute for Cancer Research, 101 College Street, MaRS
Centre, South Tower, Toronto, Ontario, M5G 0A3, Canada. ‡Department of Pharmacology and
Toxicology, University of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto
ON M5S 1A8
*Rima.Alawar@oicr.on.ca
ABSTRACT
The reaction of 3-halo-4-aminopyridines with acyl chlorides and triethylamine is described. The
pyridin-4-yl α-substituted acetamide products were obtained in moderate to high yields. The
presented rearrangement reaction, in which the presumed N-acylated intermediate reacts
intramolecularly via nucleophilic aromatic substitution, results in a formal two carbon insertion.
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Rearrangements are especially elegant reactions, leading to non-obvious products via
intramolecular bond breakage and formation.1,2 Through atom or atom group migration they can
provide access to complex molecules and are valuable transformations in natural product
synthesis, heterocyclic chemistry, and industrial processes.3-8 The Smiles rearrangement is an
intramolecular nucleophilic substitution in which an aromatic system shifts from one heteroatom
to another via a spirocyclic intermediate. Usually, the nucleophilic heteroatom of phenols or
anilines intramolecularly attacks a second aromatic ring, which is activated by electron
withdrawing substituents ortho or para to the attacked position.9-13
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In the Smiles-Truce rearrangement, an extended variant of the Smiles rearrangement, the
nucleophilic attack is carried out by a carbanion and leads to the formation of a new C-C bond
making it an attractive reaction for synthetic chemists (Scheme 1).2, 12, 14, 15
SCHEME 1. C-C bond forming rearrangements (1) Smiles-Truce rearrangement (2) N-acyl
aminopyridine rearrangement.
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In this study, we wish to report the facile synthesis of pyridin-4-yl α-substituted acetamides. The
rearrangement of in situ generated intermediate B leads to the insertion of a two carbon unit into
the C-N bond of 4-aminopyridine A. We suggest that intramolecular nucleophilic attack by the
enol (B) leads to the breakage of a C-N bond and the formation of a new C-C bond (Scheme 1).
The obtained pyridin-4-yl α-substituted acetamide products (C) constitute synthetically useful
products for the synthesis of functionalized molecules.16,17 The herein described pyridin-4-yl α-
substituted acetamides are synthetically demanding synthons and to our best knowledge have not
been reported previously in the literature.
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In the original attempt to N-acylate 1a, adding triethylamine (7 equiv) and chloro acetyl chloride
(7 equiv) in THF at room temperature, the starting material 1a was consumed overnight and 2-
chloro-2-(3-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl) acetamide 2a was isolated in 79%
yield (Table 1, entry 1). However, the isolated product proved not to be the anticipated N-
acylated compound. Single-crystal X-ray analysis confirmed the formation of the unexpected
rearrangement product 2a (Figure 1).
FIGURE 1. Crystal structure of 2a.
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Motivated by the potential scope and applicability of this reaction, we decided to further
investigate our initial findings. Examination of the reaction conditions found that excess and/or
repeated addition of reactants was crucial for complete turnover of the starting material (not
achieved for every substrate). We propose that triethylamine promotes dehydrohalogenation of
chloro acetyl chloride to generate a ketene in situ - ketenes are known to form under the given
conditions - which subsequently reacts with 1a.18 As reported by Sauer and others,19-21 the high
reactivity of ketenes often leads to dimerization and polymerization byproducts, and could
explain the requirement for an excess of reagents. For strongly exothermic reactions, lowering
the temperature to 0 °C increased the isolated yields. Overall, the reaction appeared to be cleaner
in THF than in CH2Cl2 or toluene and thus became the solvent of choice for further studies.
We subjected various substituted 4-aminopyridines to the optimized conditions and found that
halogen (1a-d) and methyl (1e) substituents in the 3-position were tolerated, whereas
introduction of a nitrile (1f) or methyl acetate group (1g) led to N-acylation or no reaction (Table
1). Interestingly, subjecting N-(2,4-dimethoxybenzyl)-3-fluoropyridin-4-amine (1b) to the
standard reaction conditions resulted in a mixture of the rearranged and the N-acylated products
2b and 3a in a 2.5:1 ratio. However, the same substrate (1b) gave solely the rearranged product
N-(2,4-dimethoxybenzyl)-2-(3-fluoropyridin-4-yl)-2-phenoxyacetamide (2r) when treated with
phenoxyacetyl chloride.
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TABLE 1. Rearrangement of 3-substituted 4-amino-pyridines
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OMe
OMe
Cl
acyl chloride, Et3N
THF, 0 °C or RT
H
3
H
N
R
N
R
4
N
2
N
OMe
O
OMe
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5
1
6
1a-i
2a-e
product
yield
[%]
entry subst.
R
rearranged
N-acylated
1
2
3
4
5
6
7
8
9
3-Cl
3-F
3-Br
3-I
3-Me
3-CN
3-CO2Me
2-Cl
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3a
-
-
-
3b
-
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3d
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12/3
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-
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1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
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2d
2e
-
-
-
-
47
98
2-CN
Electron withdrawing halides in the 3-position seem to enable the nucleophilic attack at the
pyridine’s ipso-carbon (C-4). A comparable activation of an aromatic substrate is observed in the
Smiles rearrangement, where ortho- or para-activating substituents are required in the migrating
aryl moiety.1,2 Despite the electron withdrawing character of nitrile and methyl ester substituents,
decoration of the pyridine with these moieties did not allow substrates 1f and 1g to rearrange.
Surprisingly, methyl-substitution in the 3-position yielded the rearranged product.
The para-position of the ring nitrogen with respect to the reactive centre proved to be essential
for the reaction, since moving the heteroatom to another position in the ring did not allow the
substrates 5-bromo-2-chloro-N-(2,4-dimethoxybenzyl)pyridin-3-amine and 3-chloro-N-(2,4-
dimethoxybenzyl)pyridin-2-amine to undergo rearrangement. In addition to the importance of
the substituents in the 3-position, the pyridine nitrogen further withdraws electron density from
the aromatic ring and thus increases the electrophilicity of the reacting ipso-carbon.
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Substitution in the 2-position (1h and 1i) led to N-acylated products (3c-d). No substitution of
the pyridine ring (N-(2,4-dimethoxybenzyl)pyridin-4-amine) gave an unstable product that could
not be isolated. Multiple substituents on the pyridine core were not tolerated as substrates for this
reaction (methyl 3-chloro-4-((2,4-dimethoxybenzyl)amino)picolinate and (3-chloro-4-((2,4-
dimethoxybenzyl)amino)pyridin-2-yl)methanol). We then turned our attention to the amino-
substituent and explored its influence on the rearrangement reaction (Table 2). Although this
position appeared to accept a wide range of substituents from benzylic (1a, 1j-n), and aromatic
(1o) to aliphatic (1p-q) residues (Table 2), the 2,4-dimethoxybenzyl group afforded the best
yield.
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TABLE 2. Influence of the nitrogen-substituent on the rearrangement
entry
subst.
R
product
yield [%]
1
2
1a
1j
2a
2f
79
63
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4
1k
1l
2g
2h
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34
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2k
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2l
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2m
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To further illustrate the synthetic value of this method, we investigated the applicability of
various acyl chlorides. A focused set was employed for the generation of mono- or disubstituted
ketenes which all afforded the rearranged product in excellent yields ranging from 79 to 97%
(Table 3). Only introduction of a second substituent at the α-carbon led to a slightly lower yield
of 63% for 2n. The methyl substituent probably sterically hinders the nucleophilic attack on the
pyridine’s γ-carbon. When acetyl chloride or bromo acetyl bromide were used as acylating
agents, no product could be isolated, although consumption of the starting material was
observed.
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TABLE 3. Various acyl halides employed in the rearrangement
acyl
chloride
entry
product
R
yield [%]
1
2
Cl
79
63
2a
2n
Cl, Me
3
4
5
OMe
OPh
OBn
97
92
83
2o
2p
2q
For the presented rearrangement reaction the following mechanism is proposed (Scheme 2). First
the ketene, which is formed in situ by dehydrohalogenation of an acyl chloride with
triethylamine, is attacked on its electrophilic carbon by the amine nitrogen of substrate D to form
the intermediate E. Then, intramolecular π-orbital interaction between the enolate α-carbon and
the pyridine ipso-carbon results in the formation of the four-membered spiro-β-lactam transition
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state F. Finally, rearomatization of the pyridine leads to breakage of the weaker C-N bond of the
spiro-β-lactam and results in formation of the pyridin-4-yl α-substituted acetamide G. The
nucleophilic attack on the pyridine γ-carbon by the enol is possibly facilitated by ortho
substitution with an electron withdrawing halide. Moreover, the electronegative nitrogen of the
pyridine ring lowers the energy of the π-system’s LUMO and increases the electrophilicity of the
γ-position.3-8 This effect could be enhanced by either catalytic acylation (excess of acyl chloride)
or protonation (via the trialkylammonium salts resulting from the ketene formation, that can act
as Brønsted acid catalysts)18 of the pyridine nitrogen atom. This might further decrease the
electron density of the aromatic ring, and ultimately lead to a higher susceptibility of the γ-
carbon towards a nucleophile. A phenyl analogue of the pyridine precursor 1a, N-benzyl-2-
chloro-4-nitroaniline, whose γ-carbon is highly activated through strongly electron withdrawing
ortho-chloro and para-nitro substituents, does not undergo the rearrangement under the applied
standard reaction conditions.
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SCHEME 2. Proposed mechanism for the rearrangement of 4-amino-3-halo-pyridines
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Anand and co-workers have recently reported a [2+2] cycloaddition of cyclohexanone imines
and ketenes leading to the formation of spiro-β-lactams.22 The corresponding analogs cannot be
isolated from our rearrangement reactions since rearomatization of the pyridine ring induces
cleavage of the C-N bond and leads to the open structure. However, the formation of these
spirocyclic-β-lactams by an analogous pathway provides further evidence for the inclusion of
transition state F in our proposed mechanism.23
In summary, we have described the rearrangement of 3-halo-4-amino-pyridines when treated
with triethylamine and acyl chlorides, to yield pyridin-4-yl-acetamides. The mild reaction
conditions and the simple workup allow a straightforward and scalable synthesis (on a multi-
gram-scale 2a was obtained in 50% yield) of pyridin-4-yl α-substituted acetamides. These
molecules represent promising precursor molecules for the synthesis of branched aryl
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acetamides, which might be employed in future biological screening campaigns and are yet to be
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exploited structures.
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EXPERIMENTAL SECTION
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1
General information. NMR spectra were recorded on a 500 MHz spectrometer (500 MHz H,
125 MHz 13C) at 25 °C. Chemical shifts are reported in ppm (δ) referenced to the NMR solvent,
coupling constants (J) in Hz.24 Flash column chromatography was performed on silica gel (60 Å
mesh). High-resolution mass spectrometry (HRMS) was conducted using a quadrupole-time-of-
flight (QTOF) hybrid mass spectrometer system coupled with an ultra-performance liquid
chromatography (UPLC) system. Microwave reactions were carried out in the microwave reactor
Biotage Initiator Eight (single-mode reactor, temperature control via IR).
General procedure A for the synthesis of 2,4-dimethoxybenzyl-pyridin-4-amines. The
reductive aminations were conducted according to literature using the corresponding
aminopyridine (1 equiv), benzaldehyde (3 equiv), acetic acid (3 equiv), sodium
triacetoxyborohydride (3 equiv), and C2H4Cl2 (20 mL).25,26 Some reactions required refluxing at
80 °C. The crude product was purified by silica gel flash chromatography (1-8 % MeOH/CH2Cl2
or 10-80 % EtOAc/Hexanes).
General procedure B for the synthesis of 2,4-dimethoxybenzyl-pyridin-4-amines. The
copper-catalyzed amination of aryl halides was conducted according to literature.27 Alternatively,
some products were obtained through irradiation in a microwave reactor at 100 °C for 60 min at
the absorption level “High”. The crude product was purified by silica gel flash chromatography
(1-8 % MeOH/CH2Cl2 or 10-80 % EtOAc/Hexanes).
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General procedure C for the rearrangement reaction of pyridin-4-amines. A 5 mL reaction
vial was charged with the corresponding secondary pyridin-4-amine (0.25 mmol), TEA (3
equiv), and THF (2 mL). Then, the corresponding acyl chloride was added dropwise (the more
exothermic reactions required cooling to 0 °C), and the reaction mixture was stirred at rt. If
LCMS indicated incomplete reaction, TEA (5 equiv) and the acyl chloride (2 equiv) were added
in intervals of 1h twice and the reaction mixture was stirred over night before it was diluted with
EtOAc and saturated NaHCO3 (aq.). The aqueous layer was extracted with EtOAc (3x), and the
combined organic layers were concentrated and purified by silica gel flash chromatography (1-
8 % MeOH/CH2Cl2 or 10-80 % EtOAc/Hexanes).
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3-chloro-N-(2,4-dimethoxybenzyl)pyridin-4-amine (1a). A; yellow oil (9.47 g, 83%). 1H NMR
(500 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.97 (d, J = 5.6 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.73 (t, J
= 6.1 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.48-6.45 (m, 2H), 4.32 (d, J = 6.2 Hz, 2H), 3.84 (s, 3H),
3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 159.7, 157.7, 148.9, 148.2, 147.5, 128.0, 117.7,
115.7, 106.2, 104.6, 98.4, 55.4, 55.1, 39.9. HRMS (ESI+-QTOF) m/z calcd for C14H16ClN2O2
([M+H]+): 279.0900, found: 279.0892.
1
N-(2,4-dimethoxybenzyl)-3-fluoropyridin-4-amine (1b). A; colourless oil (0.452 g, 37%). H
NMR (500 MHz, DMSO-d6) δ 8.08 (d, J = 3.8 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.06 (d, J = 8.4
Hz, 1H), 6.91 (t, J = 6.2 Hz, 1H), 6.57 (d, J = 2.3 Hz, 1H), 6.52-6.45 (m, 2H), 4.26 (d, J = 6.2
Hz, 2H), 3.83 (s, 3H), 3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ159.7, 157.7, 148.6 (1JC-F
= 245 Hz), 146.2 (4JC-F = 4.4 Hz), 142.0 (3JC-F = 9.9 Hz), 134.7 (4JC-F = 19 Hz), 128.2, 118.0,
106.7, 104.5, 98.3, 55.4, 55.1, 39.6. HRMS (ESI+-QTOF) m/z calcd for C14H16FN2O2 ([M+H]+):
263.1196, found: 263.1187.
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3-bromo-N-(2,4-dimethoxybenzyl)pyridin-4-amine (1c). A; colourless oil (0.491 g, 50%). H
NMR (500 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H),
6.58 (d, J = 2.4 Hz, 1H), 6.51 (t, J = 6.1 Hz, 1H), 6.48-6.44 (m, 2H), 4.32 (d, J = 6.2 Hz, 2H),
3.84 (s, 3H), 3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 159.8, 157.7, 150.2, 149.8, 148.7,
128.1, 117.6, 106.6, 104.6, 98.4, 55.5, 55.1, 40.2. HRMS (ESI+-QTOF) m/z calcd for
C14H16BrN2O2 ([M+H]+): 323.0395, found: 323.0396.
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N-(2,4-dimethoxybenzyl)-3-iodopyridin-4-amine (1d). A; colourless oil (427 mg, 51%). H
NMR (500 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.97 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H),
6.58 (d, J = 4.2 Hz, 1H), 6.46 (dd, J = 2.4, 8.3 Hz, 1H), 6.40 (d, J = 5.7 Hz, 1H), 6.11 (t, J = 6.0
Hz, 1H), 4.33 (d, J = 6.1 Hz, 2H), 3.84 (s, 3H), 3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ
159.8, 157.8, 155.9, 152.2, 149.0, 128.3, 117.6, 106.2, 104.5, 98.4, 83.3, 55.5, 55.1, 40.6. HRMS
(ESI+-QTOF) m/z calcd for C14H16IN2O2 ([M+H]+): 371.0257, found: 371.0241.
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N-(2,4-dimethoxybenzyl)-3-methylpyridin-4-amine (1e). A; colourless oil (1.28 g, 25%). H
NMR (500 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.87 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.57 (d, J =
2.4 Hz, 1H), 6.50 (dd, J = 2.4, 8.4 Hz, 1H), 6.26-6.21 (m, 2H), 4.27 (d, J = 6.1 Hz, 2H), 3.84 (s,
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3H), 3.72 (s, 3H), 2.08 (s, 3H); C NMR (125 MHz, DMSO-d6) δ 159.5, 157.6, 151.5, 148.7,
147.9, 127.9, 118.4, 116.7, 104.4, 104.2, 98.3, 55.4, 55.1, 14.4. HRMS (ESI+-QTOF) m/z calcd
for C15H19N2O2 ([M+H]+): 259.1447, found: 259.1437.
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4-((2,4-dimethoxybenzyl)amino)nicotinonitrile (1f). B; white solid (328 mg, 32%). H NMR
(500 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.17 (d, J = 6.3 Hz, 1H), 7.71 (t, J = 5.8 Hz, 1H), 7.07 (d, J
= 8.3 Hz, 1H), 6.60-6.58 (m, 2H), 6.48 (dd, J = 2.4, 8.3 Hz, 1H), 4.37 (d, J = 6.4 Hz, 2H), 3.83
(s, 3H), 3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 159.9, 157.7, 154.3, 152.7, 150.9, 128.3,
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117.0, 116.1, 106.2, 104.7, 98.4, 92.7, 55.5, 55.2, 40.2. HRMS (ESI+-QTOF) m/z calcd for
C15H16N3O2 ([M+H]+): 270.1243, found: 270.1230.
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Methyl 4-((2,4-dimethoxybenzyl)amino)nicotinate (1g). A; white solid (596 mg, 20%). H
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NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.49 (bs, 1H), 8.19 (d, J = 6.3 Hz, 1H), 7.71 (d, J =
8.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 6.4 Hz, 1H), 6.48 (dd, J = 2.3, 8.3 Hz, 1H),
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4.40 (d, J = 5.9 Hz, 2H), 3.83 (s, 6H), 3.73 (s, 3H); C NMR (125 MHz, DMSO-d6) δ 167.1,
160.2, 158.0, 154.2, 150.5, 150.3, 129.2, 117.2, 106.8, 106.7, 104.6, 98.6, 55.5, 55.2, 51.9, 40.7.
HRMS (ESI+-QTOF) m/z calcd for C16H19N2O4 ([M+H]+): 303.1345, found: 303.1331.
2-chloro-N-(2,4-dimethoxybenzyl)pyridin-4-amine (1h). A; pale yellow oil (0.631 g, 55%).
1H NMR (500 MHz, DMSO-d6) δ 7.78 (d, J = 5.9 Hz, 1H), 7.19 (t, J = 5.5 Hz, 1H), 7.11 (d, J =
8.3 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.51-6.48 (m, 3H), 4.16 (d, J = 5.8 Hz, 2H), 3.81 (s, 3H),
3.74 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 160.0, 158.0, 155.9, 150.9, 148.8, 129.1, 117.8,
107.3, 105.1, 104.5, 98.4, 55.4, 55.2, 40.1. HRMS (ESI+-QTOF) m/z calcd for C14H16ClN2O2
([M+H]+): 279.0900, found: 279.0893.
4-((2,4-dimethoxybenzyl)amino)picolinonitrile (1i). B; colourless crystals (504 mg, 26%); mp
119-121 ºC. 1H NMR (500 MHz, DMSO-d6) δ 8.09 (d, J = 5.9 Hz, 1H), 7.38 (t, J = 5.6 Hz, 1H),
7.13 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.72 (bs, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.49
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(dd, J = 2.4, 8.3 Hz, 1H), 4.19 (d, J = 5.6 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H); C NMR (125
MHz, DMSO-d6) δ 160.1, 158.1, 153.9, 150.5, 132.7, 129.3, 126.3, 122.0, 118.2, 117.4, 104.5,
98.5, 55.4, 55.2, 40.1. HRMS m/z (ESI+-QTOF) calcd for C15H16N3O2 ([M+H]+): 270.1243,
found: 270.1231.
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3-chloro-N-(2,4,6-trimethoxybenzyl)pyridin-4-amine (1j). A; white solid (81 mg, 3 %). H
NMR (500 MHz, DMSO-d6) δ 8.15-8.07 (m, 2H), 6.83 (d, J = 5.5 Hz, 1H), 6.26 (s, 2H), 5.69 (t,
J = 5.8 Hz, 1H), 4.30 (d, J = 6.0 Hz, 2H), 3.83 (s, 6H), 3.77 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 160.8, 158.9, 148.7, 148.4, 147.5, 115.7, 106.1, 105.5, 91.0, 55.9, 55.3, 35.0.
HRMS (ESI+-QTOF) m/z calcd for C15H18ClN2O3 ([M+H]+): 309.1006, found: 309.1013.
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3-chloro-N-(2-methoxybenzyl)pyridin-4-amine (1k). A; white solid (1.32 g, 55 %). H NMR
(500 MHz, DMSO-d6) δ 8.21 (s, 1H), 8.00 (d, J = 5.6 Hz, 1H), 7.27 (m, 1H), 7.13 (dd, J = 7.4,
1.3 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.92 (td, J = 7.4, 0.6 Hz, 1H), 6.87 (t, J = 6.1 Hz, 1H), 6.47
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(d, J = 5.7 Hz, 1H), 4.45 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H); C NMR (125 MHz, DMSO-d6) δ
157.6, 149.9, 149.2, 148.5, 129.1, 127.9, 126.5, 121.2, 116.6, 111.6, 107.1, 56.3, 41.1. HRMS
(ESI+-QTOF) m/z calcd for C13H14ClN2O ([M+H]+): 249.0795, found: 249.0791.
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3-chloro-N-(4-nitrobenzyl)pyridin-4-amine (1l). A; off-white solid (53 mg, 3 %). H NMR
(500 MHz, DMSO-d6) δ 8.22-8.20 (m, 3H), 7.97 (d, J = 5.6 Hz, 1H), 7.59 (d, J = 8.7 Hz, 2H),
7.26 (t, J = 6.1 Hz, 1H), 6.48 (d, J = 5.5 Hz, 1H), 4.61 (d, J = 6.3 Hz, 2H); 13C NMR (125 MHz,
DMSO-d6) δ 148.7, 148.3, 147.8, 147.0, 146.6, 127.9, 123.6, 115.9, 106.3, 44.6. HRMS (ESI+-
QTOF) m/z calcd for C12H11ClN3O2 ([M+H]+): 264.0540, found: 264.0533.
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3-chloro-N-(4-chlorobenzyl)pyridin-4-amine (1m). A; white solid (328 mg, 15%). H NMR
(500 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.96 (dd, J = 0.5, 5.7 Hz, 1H), 7.40-7.33 (m, 4H), 7.13 (t,
J = 6.3 Hz, 1H), 6.49 (d, J = 5.6 Hz, 1H), 4.45 (d, J = 6.3 Hz, 2H); 13C NMR (125 MHz,
DMSO-d6) δ 148.8, 148.2, 147.7, 137.8, 131.4, 128.7, 128.4, 115.8, 106.3, 44.3. HRMS (ESI+-
QTOF) m/z calcd for C12H11Cl2N2 ([M+H]+): 253.0289, found: 253.0299.
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N-benzyl-3-chloropyridin-4-amine (1n). A; white solid (422 mg, 22%). H NMR (500 MHz,
DMSO-d6) δ 8.15 (s, 1H), 7.95 (d, J = 5.6 Hz, 1H), 7.32 (d, J = 4.4 Hz, 4H), 7.21-7.25 (m, 1H),
7.09 (t, J = 6.3 Hz, 1H), 6.50 (d, J = 5.6 Hz, 1H), 4.46 (d, J = 6.3 Hz, 2H); 13C NMR (125 MHz,
DMSO-d6) δ 149.0, 148.2, 147.6, 138.7, 128.4, 126.9, 126.7, 115.7, 106.4, 45.0. HRMS (ESI+-
QTOF) m/z calcd for C12H12ClN2 ([M+H]+): 219.0689, found: 219.0691.
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3-chloro-N-propylpyridin-4-amine (1p). A; yellow oil (740 mg, 53%). H NMR (500 MHz,
DMSO-d6) δ 8.16 (s, 1H), 8.03 (d, J = 5.6 Hz, 1H), 6.63 (d, J = 5.6 Hz, 1H), 6.30 (t, J = 5.6 Hz,
1H), 3.17-313 (m, 2H), 1.58-1.51 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 149.0, 148.3, 147.6, 115.5, 105.7, 48.4, 21.4, 11.1. HRMS (ESI+-QTOF) m/z calcd
for C8H12ClN2 ([M+H]+): 171.0689, found: 171.0678.
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N-(but-3-en-1-yl)-3-chloropyridin-4-amine (1q). B; yellow oil (128 mg, 32%). H NMR
(500 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.05 (d, J = 5.7 Hz, 1H), 6.68 (d, J = 5.7 Hz, 1H), 6.23 (t,
J = 5.6 Hz, 1H), 5.87-5.75 (m, 1H), 5.13-5.08 (m, 1H), 5.06-5.03 (m, 1H), 3.27 (q, J = 6.1,
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6.9 Hz, 2H), 2.34-2.29 (m, 2H); C NMR (125 MHz, DMSO-d6) δ 148.8, 148.3, 147.6, 135.7,
116.7, 115.6, 105.8, 41.0, 32.5. HRMS (ESI+-QTOF) m/z calcd for C9H12ClN2 ([M+H]+):
183.0689, found: 183.0681.
2-chloro-2-(3-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl)acetamide (2a). C; white solid
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(3.8 g, 79 %); mp 145-147 ºC. H NMR (500 MHz, DMSO-d6) δ 8.87 (t, J = 5.7 Hz, 1H), 8.68
(s, 1H), 8.61 (d, J = 5.1 Hz, 1H), 7.70 (d, J = 5.1 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.55 (d, J =
2.4 Hz, 1H), 6.49 (dd, J = 2.4, 8.3 Hz, 1H), 5.92 (s, 1H), 4.27-4.18 (m, 2H), 3.76 (s, 3H), 3.74 (s,
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3H); C NMR (125 MHz, DMSO-d6) δ 164.8, 160.0, 157.8, 149.1, 148.6, 142.9, 130.0, 129.2,
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124.2, 117.8, 104.3, 98.3, 55.4, 55.2, 54.8, 37.9. HRMS (ESI+-QTOF) m/z calcd for
C16H17Cl2N2O3 ([M+H]+): 355.0616, found: 355.0600.
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2-chloro-N-(2,4-dimethoxybenzyl)-2-(3-fluoropyridin-4-yl)acetamide (2b). C; purification by
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preparative HPLC (5-95 % MeCN/H2O, 15 min); white solid (8 mg, 12 %); mp 119-122 ºC. H
NMR (500 MHz, CDCl3) δ 8.50 (d, J = 1.4 Hz, 1H), 8.44 (d, J = 5.0 Hz, 1H), 7.37-7.36 (m, 2H),
7.19 (d, J = 8.1 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.45 (dd, J = 2.5, 8.1 Hz, 1H), 5.56 (s, 1H),
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4.50-4.41 (m, 2H), 3.87 (s, 3H), 3.82 (s, 3H); C NMR (125 MHz, CDCl3) δ 164.66, 161.18,
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158.90, 157.22 (d, JC-F = 259.5 Hz, 1C), 145.45 (d, JC-F = 5.4 Hz, 1C), 138.0 (d, JC-F = 24.5
Hz, 1C), 134.7 (d, 3JC-F = 10.9 Hz, 1C), 130.9, 124.0, 117.7, 104.3, 99.0, 55.7, 55.6, 52.9 (d, 3JC-
= 1.8 Hz, 1C), 40.4. HRMS (ESI+-QTOF) m/z calcd for C16H17ClFN2O3 ([M+H]+): 339.0912,
F
found: 339.0905.
2-(3-bromopyridin-4-yl)-2-chloro-N-(2,4-dimethoxybenzyl)acetamide
(2c).
C;
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recrystallization (CH2Cl2/Hexanes); off-white solid (59 mg, 84 %); mp 155-157 ºC. H NMR
(500 MHz, DMSO-d6) δ 8.90 (d, J = 5.6 Hz, 1H), 8.78 (s, 1H), 8.62 (d, J = 5.2 Hz, 1H), 7.69 (d,
J = 4.9 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.48 (dd, J = 2.4, 8.3 Hz, 1H),
5.84 (s, 1H), 4.27-4.18 (m, 2H), 3.76 (s, 3H), 3.74 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.7,
160.0, 157.8, 151.7, 149.0, 144.5, 129.2, 124.6, 121.1, 117.8, 104.3, 98.3, 57.1, 55.4, 55.2, 37.9.
HRMS (ESI+-QTOF) m/z calcd for C16H17BrClN2O3 ([M+H]+): 399.0111, found: 399.0103.
2-chloro-N-(2,4-dimethoxybenzyl)-2-(3-iodopyridin-4-yl)acetamide (2d). C; recrystallization
(MeOH); off-white solid (24 mg, 29 %); mp 158-160 ºC. 1H NMR (500 MHz, DMSO-d6) δ 8.94
(s, 1H), 8.92 (t, J = 5.5 Hz, 1H), 8.58 (d, J = 5.0 Hz, 1H), 7.64 (d, J = 5.0 Hz, 1H), 7.11 (d, J =
8.3 Hz, 1H), 6.55 (d, J = 2.5 Hz, 1H), 6.48 (dd, J = 2.4, 6.0 Hz, 1H), 5.66 (s, 1H), 4.27-4.18 (m,
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2H), 3.76 (s, 3H), 3.74 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 164.8, 159.9, 157.8, 157.4, 149.2,
147.7, 129.2, 124.4, 117.8, 104.3, 99.1, 98.3, 61.4, 55.4, 55.2, 37.8. HRMS (ESI+-QTOF) m/z
calcd for C16H17IClN2O3 ([M+H]+): 446.9972, found: 446.9974.
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2-chloro-N-(2,4-dimethoxybenzyl)-2-(3-methylpyridin-4-yl)acetamide (2e). C; clear oil (12
mg, 10 %). 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, J = 5.5 Hz, 1H), 8.44 (d, J = 5.1 Hz, 1H),
8.42 (s, 1H), 7.48 (d, J = 5.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 2.1 Hz, 1H), 6.47
(dd, J = 2.1, 8.3 Hz, 1H), 5.79 (s, 1H), 4.25-4.16 (m, 2H), 3.75 (s, 3H), 3.73 (s, 3H), 2.31 (s, 3H);
13C NMR (125 MHz, DMSO-d6) δ 166.0, 160.5, 158.4, 151.4, 148.2, 144.2, 131.6, 129.8, 122.5,
118.4, 104.8, 98.8, 56.1, 55.9, 55.7, 38.4, 15.9. HRMS (ESI+-QTOF) m/z calcd for
C17H20ClN2O3 ([M+H]+): 335.1162, found: 335.1150.
2-chloro-2-(3-chloropyridin-4-yl)-N-(2,4,6-trimethoxybenzyl)acetamide (2f). C; off-white
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solid (19 mg, 63 %). H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H),
8.37 (t, J = 4.6 Hz, 1H), 7.70 (d, J = 5.1 Hz, 1H), 6.24 (s, 2H), 5.85 (s, 1H), 4.29-4.18 (m, 2H),
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3.78 (s, 3H), 3.75 (s, 6H); C NMR (125 MHz, DMSO-d6) δ 164.2, 160.8, 159.1, 149.1, 148.5,
143.0, 130.1, 124.1, 104.8, 90.7, 55.7, 55.3, 54.7, 32.2. HRMS (ESI+-QTOF) m/z calcd for
C17H19Cl2N2O4 ([M+H]+): 385.0722, found: 385.0720.
2-chloro-2-(3-chloropyridin-4-yl)-N-(2-methoxybenzyl)acetamide (2g). C; yellow solid (91
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mg, 69 %). H NMR (500 MHz, DMSO-d6) δ 8.96 (m, 1H), 8.68 (s, 1H), 8.61 (d, J = 5.1 Hz,
1H), 7.70 (d, J = 5.1 Hz, 1H), 7.26 (m, 1H), 7.18 (dd, J = 7.4, 1.6 Hz, 1H), 6.99 (d, J = 8.2 Hz,
1H), 6.91 (td, J = 7.4 Hz, 0.9, 1H), 5.95 (s, 1H), 4.30 (m, 2H), 3.75 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 165.0, 156.7, 149.1, 148.6, 142.8, 130.0, 128.4, 128.0, 125.6, 124.2, 120.1, 110.6,
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55.3, 54.9, 38.1. HRMS (ESI+-QTOF) m/z calcd for C15H15Cl2N2O2 ([M+H]+): 325.0511, found:
325.0496.
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2-chloro-2-(3-chloropyridin-4-yl)-N-(4-nitrobenzyl)acetamide (2h). C; white solid (10 mg, 34
%). 1H NMR (500 MHz, DMSO-d6) δ 9.37 (t, J = 5.8 Hz, 1H), 8.70 (s, 1H), 8.62 (d, J = 5.1 Hz,
1H), 8.22 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 5.0 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 6.00 (s, 1H),
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4.49 (d, J = 6.1 Hz, 2H); C NMR (125 MHz, DMSO-d6) δ 165.5, 149.2, 148.7, 146.6, 146.5,
142.8, 130.0, 128.3, 124.3, 123.5, 55.1, 42.4. HRMS (ESI+-QTOF) m/z calcd for C14H12Cl2N3O3
([M+H]+): 340.0256, found: 340.0255.
2-chloro-N-(4-chlorobenzyl)-2-(3-chloropyridin-4-yl)acetamide (2i). C; white solid (43 mg,
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53 %). H NMR (500 MHz, DMSO-d6) δ 9.20 (t, J = 5.8 Hz, 1H), 8.68 (s, 1H), 8.60 (d, J = 5.2
Hz, 1H), 7.67 (d, J = 5.2 Hz, 1H), 7.41-7.38 (m, 2H), 7.30-7.27 (m, 2H), 5.94 (s, 1H), 4.33 (d, J
= 6.1 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 165.2, 149.2, 148.6, 142.8, 137.5, 131.6,
130.0, 129.2, 128.3, 124.3, 55.0, 42.2. HRMS (ESI+-QTOF) m/z calcd for C14H12Cl3N2O
([M+H]+): 329.0015, found: 329.0009.
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N-benzyl-2-chloro-2-(3-chloropyridin-4-yl)acetamide (2j). C; white solid (44 mg, 54 %). H
NMR (500 MHz, DMSO-d6) δ 9.18 (t, J = 5.6 Hz, 1H), 8.68 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H),
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7.69 (d, J = 5.1 Hz, 1H), 7.35-7.24 (m, 5H), 5.94 (s, 1H), 4.35 (d, J = 6.1 Hz, 2H); C NMR
(125 MHz, DMSO-d6) δ 165.5, 150.1, 148.5, 143.6, 137.2, 131.6, 129.1, 128.2, 128.15, 123.8,
56.1, 44.6. HRMS (ESI+-QTOF) m/z calcd for C14H13Cl2N2O ([M+H]+): 295.0394, found:
295.0394.
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2-chloro-2-(3-chloropyridin-4-yl)-N-phenylacetamide (2k). C; white solid (43 mg, 53 %). H
NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.71 (s, 1H), 8.64 (d, J = 5.0 Hz, 1H), 7.77 (d, J =
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5.1 Hz, 1H), 7.60-7.57 (m, 2H), 7.37-7.33 (m, 2H), 7.15-7.11 (m, 1H), 6.06 (s, 1H); C NMR
(125 MHz, DMSO-d6) δ 163.5, 149.1, 148.7, 142.3, 138.0, 130.0, 128.9, 124.4, 124.1, 119.6,
55.7. HRMS (ESI+-QTOF) m/z calcd for C13H11Cl2N2O ([M+H]+): 281.0248, found: 281.0234.
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2-chloro-2-(3-chloropyridin-4-yl)-N-propylacetamide (2l). C; colourless oil (63 mg, 35 %). 1H
NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.65 (d, J = 5.6 Hz, 1H), 8.60 (d, J = 5.0 Hz, 1H),
7.68 (d, J = 5.0 Hz, 1H), 5.84 (s, 1H), 3.09 (q, J = 5.9, 6.7 Hz, 2H), 1.49-1.42 (m, 2H), 0.84 (t, J
= 7.5 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 164.8, 149.1, 148.6, 143.0, 129.2, 124.2, 55.0,
41.0, 20.9, 11.2. HRMS (ESI+-QTOF) m/z calcd for C10H13Cl2N2O ([M+H]+): 247.0405, found:
247.0395.
N-(but-3-en-1-yl)-2-chloro-2-(3-chloropyridin-4-yl)acetamide (2m). C; colourless oil (24 mg,
32 %). 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.66 (t, J = 6.0 Hz, 1H), 8.60 (d, J = 5.0
Hz, 1H), 7.66 (d, J = 5.0 Hz, 1H), 5.84 (s, 1H), 5.80-5.72 (m, 1H), 5.05 (dq, 1.6, 2.0, 17.0 Hz,
1H), 5.02-4.99 (m, 1H), 3.22-3.18 (m, 2H), 2.22-2.19 (m, 2H); 13C NMR (125 MHz, DMSO-d6)
δ 164.9, 149.1, 148.6, 143.0, 136.9, 130.0, 124.2, 116.5, 55.0, 39.7, 33.9. HRMS (ESI+-QTOF)
m/z calcd for C11H13Cl2N2O ([M+H]+): 259.0405, found: 259.0395.
2-chloro-2-(3-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl)propanamide (2n). C; white solid
(99 mg, 63 %). 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 8.38 (t,
J = 5.9 Hz, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H), 6.48
13
(dd, J = 2.3, 8.3 Hz, 1H), 4.24 (m, 2H), 3.77 (s, 3H), 3.74 (s, 3H), 2.13 (s, 3H); C NMR (125
MHz, DMSO-d6) δ 168.3, 159.7, 157.6, 150.1, 148.6, 146.9, 130.2, 128.5, 122.8, 118.3, 104.2,
98.1, 68.8, 55.3, 55.1, 38.0, 28.5. HRMS (ESI+-QTOF) m/z calcd for C17H19Cl2N2O3 ([M+H]+):
369.0773, found: 369.0768.
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2-(3-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl)-2-methoxyacetamide (2o). C; white solid
(194 mg, 97 %). 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.55 (d, J = 4.9 Hz, 1H), 8.47 (t,
J = 6.0 Hz, 1H), 7.46 (d, J = 4.9 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 2.4 Hz, 1H), 6.46
(dd, J = 2.4, 8.3 Hz, 1H), 5.09 (s, 1H), 4.21 (d, J = 6.0 Hz, 2H), 3.77 (s, 3H), 3.74 (s, 3H), 3.34
(s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 167.3, 159.8, 157.7, 149.0, 148.2, 144.2, 130.8,
128.7, 123.3, 118.4, 104.2, 98.2, 79.2, 57.6, 55.3, 55.2, 37.1. HRMS (ESI+-QTOF) m/z calcd for
C17H20ClN2O4 ([M+H]+): 351.1112, found: 351.1096.
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2-(3-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl)-2-phenoxyacetamide (2p). C; off-white
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solid (196 mg, 92 %). H NMR (500 MHz, DMSO-d6) δ 8.81 (t, J = 5.7 Hz, 1H), 8.67 (s, 1H),
8.54 (d, J = 5.0 Hz, 1H), 7.55 (d, J = 5.0 Hz, 1H), 7.29 (t, J = 8.1 Hz, 2H), 6.85-7.05 (m, 4H),
6.53 (d, J = 2.3 Hz, 1H), 6.44 (dd, J = 2.3, 8.3 Hz, 1H), 6.06 (s, 1H), 4.18-4.30 (m, 2H), 3.75 (s,
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3H), 3.73 (s, 3H); C NMR (125 MHz, DMSO-d6) δ166.1, 159.8, 157.7, 156.4, 149.2, 148.3,
143.3, 130.5, 129.6, 128.8, 123.3, 122.0, 118.2, 115.5, 104.2, 98.2, 75.2, 55.4, 55.2, 37.3. HRMS
(ESI+-QTOF) m/z calcd for C22H22ClN2O4 ([M+H]+): 413.1268, found: 413.1263.
2-(benzyloxy)-2-(3-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl)acetamide (2q). C; white
1
solid (159 mg, 83 %). H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.56 (d, J = 4.9 Hz, 1H),
8.49 (t, J = 5.9 Hz, 1H), 7.54 (d, J = 4.9 Hz, 1H), 7.40-7.25 (m, 5H), 7.07 (d, J = 8.5 Hz, 1H),
6.55 (d, J = 2.2 Hz, 1H), 6.46 (dd, J = 2.2 Hz, J = 8.5 Hz, 1H), 5.75 (CH2Cl2), 5.30 (s, 1H), 4.65-
4.50 (m, 2H), 4.26 (m, 2H), 3.76 (s, 3H), 3.74 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 167.3,
159.8, 157.7, 149.0, 148.2, 144.3, 137.1, 130.8, 128.7, 128.3, 128.2, 127.9, 127.9, 127.7, 123.4,
118.5, 104.2, 98.3, 77.2, 71.5, 55.3, 55.2, 37.3. HRMS (ESI+-QTOF) m/z calcd for
C15H15Cl2N2O2 ([M+H]+): 325.0511, found: 325.0496. HRMS m/z calcd for C23H24ClN2O4
([M+H]+): 427.1425, found: 427.1405.
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N-(2,4-dimethoxybenzyl)-2-(3-fluoropyridin-4-yl)-2-phenoxyacetamide (2r). C; preparative
HPLC (5-95 % MeCN/H2O, 15 min); white solid (6 mg, 14 %). 1H NMR (500 MHz, DMSO-d6)
δ 8.76 (t, J = 5.8 Hz, 1H), 8.62 (d, J = 1.4 Hz, 1H), 8.47 (d, J = 5.0 Hz, 1H), 7.60 (t, J = 5.5 Hz,
1H), 7.32-7.28 (m, 2H), 7.03-6.98 (m, 4H), 6.53 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 2.4, 8.3 Hz,
1H), 6.09 (s, 1H), 4.27-4.20 (m, 2H), 3.74 (s, 3H), 3.73 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
δ 166.5, 159.8, 157.6, 156.8 (d, 1JC-F = 257.2 Hz, 1C), 156.4, 146.1 (d, 4JC-F = 5.0 Hz, 1C), 138.0
(d, 2JC-F = 23.7 Hz, 1C), 132.7 (d, 3JC-F = 11.7 Hz, 1C), 129.6, 128.6, 123.1, 122.0, 118.2, 115.6,
104.2, 98.2, 72.5, 55.3, 55.2, 37.2. HRMS (ESI+-QTOF) m/z calcd for C22H22FN2O4 ([M+H]+):
397.1564, found: 397.1545.
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2-chloro-N-(2,4-dimethoxybenzyl)-N-(3-fluoropyridin-4-yl)acetamide (3a). C; 1:2.5 mixture
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of 3a and the rearranged product 2b. The H NMR of the mixture was collected and confirms
identity of 3a, however the product could not be isolated.
2-chloro-N-(3-cyanopyridin-4-yl)-N-(2,4-dimethoxybenzyl)acetamide (3b). C; colourless oil
(14 mg, 14 %). 1H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.47 (d, J = 6.1 Hz, 1H), 7.17 (d,
J = 6.3 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 6.48 (d, J = 8.5 Hz, 1H), 6.32 (dd, J = 8.3, 8.6 Hz, 1H),
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5.53 (s, 2H), 5.43 (s, 2H), 3.92 (s, 3H), 3.74 (s, 3H); C NMR (125 MHz, DMSO-d6) δ 160.6,
159.4, 157.7, 150.0, 145.8, 144.7, 143.1, 128.6, 116.2, 110.4, 109.9, 104.9, 102.9, 98.7, 55.8,
55.6, 40.6. HRMS (ESI+-QTOF) m/z calcd for C17H17ClN3O3 ([M+H]+): 346.0958, found:
346.0946.
2-chloro-N-(2-chloropyridin-4-yl)-N-(2,4-dimethoxybenzyl)acetamide (3c). C; brown oil (33
mg, 47%). 1H NMR (500 MHz, DMSO-d6) δ 8.36 (d, J = 5.4 Hz, 1H), 7.53 (d, J = 1.7 Hz, 1H),
7.34 (dd, J = 1.85, 4.4 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.47 (d, J = 2.2 Hz, 1H), 6.43 (dd, J =
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2.3, 8.5 Hz, 1H), 4.85 (s, 2H), 4.39 (s, 2H), 3.71 (s, 3H), 3.62 (s, 3H); C NMR (125 MHz,
DMSO-d6) δ 165.4, 160.2, 158.0, 151.2, 150.7, 150.5, 130.2, 122.3, 121.5, 115.6, 104.5, 98.3,
55.2, 55.1, 47.3, 42.9. HRMS (ESI+-QTOF) m/z calcd for C16H17Cl2N2O3 ([M+H]+): 355.0616,
found: 355.0618.
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2-chloro-N-(2-cyanopyridin-4-yl)-N-(2,4-dimethoxybenzyl)acetamide (3d). C; off-white solid
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(63 mg, 98 %). H NMR (500 MHz, DMSO-d6) δ 8.69 (d, J = 5.4 Hz, 1H), 8.08 (d, J = 2.1 Hz,
1H), 7.65 (dd, J = 2.1, 5.4 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 6.43 (dd, J
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= 2.4, 8.4 Hz, 1H), 4.88 (s, 2H), 4.44 (s, 2H), 3.71 (s, 3H), 3.61 (s, 3H); C NMR (125 MHz,
DMSO-d6) δ165.5, 160.3, 158.0, 152.2, 149.8, 133.4, 130.3, 127.2, 125.8, 117.1, 115.5, 104.5,
98.3, 55.2, 55.1, 47.4, 43.0. HRMS (ESI+-QTOF) m/z calcd for C17H17ClN3O3 ([M+H]+):
346.0958, found: 346.0955.
ASSOCIATED CONTENT
Supporting information
1
13
Crystallographic data (CIF) for 2a and 2c and H and C NMR spectra for all compounds are
available. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding author
*E-mail: Rima.Alawar@oicr.on.ca
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Dr. A. J. Lough (University of Toronto) is gratefully acknowledged for XRD analysis. We also
would like to thank Dr. Ahmed Aman and Dr. Taira Kiyota for providing analytical chemistry
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support and obtaining the high resolution mass spectra (HRMS) of all synthesized compounds.
We thank the Government of Ontario for funding which is provided through the Ontario Ministry
of Research and Innovation.
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REFERENCES
(1) Moulay, S. Chem. Educ. Res. Prac. 2002, 3, 33.
(2) Snape, T. J. Chem. Soc. Rev. 2008, 37, 2452.
(3) Overman, L. E. Tetrahedron 2009, 65, 6432.
(4) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry; 2 ed.; Pergamon
Press, 2000.
(5) Nowicki, J. Molecules 2000, 5, 1033.
(6) Commarieu, A.; Hoelderich, W.; Laffitte, J. A.; Dupont, M.-P. J. Mol. Catal. A. Chem. 2002,
182–183, 137.
(7) Dahlhoff, G.; Niederer, J. P. M.; Hoelderich, W. F. Catal. Rev. 2001, 43, 381.
(8) Anelli, P. L.; Brocchetta, M.; Cappelletti, E.; Ferraris, A.; Vincenzi, V. The Open Org. Chem.
J. 2009, 3, 35.
(9) Evans, W. J.; Smiles, S. J. Chem. Soc. (Resumed) 1935, 181.
(10) March, J. Advanced Organic Chemistry: Reactions, Mechanisms and Structure; 4 ed.; John
Wiley & Sons: New York, 1992.
(11) Gilman, N. W.; Levitan, P.; Sternbach, L. H. J. Org. Chem. 1973, 38, 373.
(12) Plesniak, K.; Zarecki, A.; Wicha, J. In Sulfur-Mediated Rearrangements II; Schaumann, E.,
Ed.; Springer Berlin Heidelberg: 2007; Vol. 275, p 163.
(13) Tian, X.; Wu, R.-M. ARKIVOC 2011, 118.
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(14) Truce, W. E.; Ray, W. J.; Norman, O. L.; Eickemeyer, D. B. J. Am. Chem. Soc. 1958, 80,
3625.
7
8
9
(15) Mitchell, L. H.; Barvian, N. C. Tetrahedron Letters 2004, 45, 5669.
(16) France, S.; Wack, H.; Taggi, A. E.; Hafez, A. M.; Wagerle, T. R.; Shah, M. H.; Dusich, C.
L.; Lectka, T. J. Am. Chem. Soc. 2004, 126, 4245.
10
11
12
13
14
15
16
17
18
19
20
21
22
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(17) Erian, A. W.; Sherif, M. S.; Gaber, H. M. Molecules 2003, 8, 793.
(18) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc.
2002, 124, 6626.
(19) Staudinger, H. Justus Liebigs Ann. Chem. 1907, 356, 51.
(20) Sauer, J. C. J. Am. Chem. Soc. 1947, 69, 2444.
(21) Paull, D. H.; Weatherwax, A.; Lectka, T. Tetrahedron 2009, 65, 6771.
(22) Anand, N.; Shah, B. A.; Kapoor, M.; Parshad, R.; Sharma, R. L.; Hundal, M. S.; Pannu, A.
P.; Bharatam, P. V.; Taneja, S. C. J. Org. Chem. 2011, 76, 5999.
(23) The work of Anand and co-workers suggests an alternative mechanism, in which the ketene
may react with the tautomeric pyridonimine via a concerted [2+2] cycloaddition to directly form
the 4-membered spirocyclic transition state F, excluding formation of intermediate E. Both
mechanisms represent valid explanations for the discovered reaction and lead to the same
product. However, the concerted mechanism appears to be less likely, since the aminopyridine is
the predominant tautomeric form whereas the pyridonimine that would be required for a
concerted [2+2] cycloaddition is the less favored tautomer.
(24) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A., NMR Chemical Shifts of Common Laboratory
Solvents as Trace Impurities. J. Org. Chem. 1997, 62, (21), 7512-7515.
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(25) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D., Reductive
Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct
and Indirect Reductive Amination Procedures. J. Org. Chem. 1996, 61, (11), 3849-3862.
(26) McLaughlin, M.; Palucki, M.; Davies, I. W., Efficient Access to Azaindoles and Indoles.
Org. Lett. 2006, 8, (15), 3307-3310.
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(27) Liu, Z.-J.; Vors, J.-P.; Gesing, E. R. F.; Bolm, C., Ligand-Free Copper-Catalyzed Amination
of Heteroaryl Halides with Alkyl- and Arylamines. Adv. Synth. Catal. 2010, 352, (18), 3158-
3162.
(28) Laha, J. K., Barolo, S. M.; Rossi, R. A.; Cuny, G. D., Synthesis of Carbolines by
Photostimulated Cyclization of Anilinohalopyridines, J. Org. Chem. 2011, 76, (15), 6421–6425.
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