Nickel-Catalyzed Phosphine Free Direct N-Alkylation of Amides with Alcohols

Article abstract of DOI:10.1021/acs.joc.7b03215

Herein, we developed an operational simple, practical, and selective Ni-catalyzed synthesis of secondary amides. Application of renewable alcohols, earth-abundant and nonprecious nickel catalyst facilitates the transformations, releasing water as byproduct. The catalytic system is tolerant to a variety of functional groups including nitrile, allylic ether, and alkene and could be extended to the synthesis of bis-amide, antiemetic drug Tigan, and dopamine D2 receptor antagonist Itopride. Preliminary mechanistic studies revealed the participation of a benzylic C-H bond in the rate-determining step.

Full text of DOI:10.1021/acs.joc.7b03215

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Note
Nickel Catalyzed Phosphine Free Direct N-alkylation of Amides with Alcohols
Jagadish Das, and Debasis Banerjee
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03215 • Publication Date (Web): 14 Feb 2018
Downloaded from http://pubs.acs.org on February 15, 2018
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Nickel Catalyzed Phosphine Free Direct N-alkylation of Amides
with Alcohols
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Jagadish Das and Debasis Banerjee*
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Department of Chemistry, Indian Institute of Technology Roorkee, Roorkeeꢀ247667, Uttarakhand, India
*
Supporting Information
ABSTRACT:
Sustainable Catalysis
Ni
O
O
R1
OH
R1
N
R2
H2N
R2
H
H2O
Drug Synthesis
O
Relatively mild conditions
Broad substrate scope
Drug synthesis
R
N
N
H
R1
O
41 examples
up to 92% yield
R = R1= OMe; Tigan
R1
R = H; R1= OMe; Itopride
Herein, we developed an operational simple, practical and selective Niꢀcatalyzed synthesis of
secondary amides. Application of renewable alcohols, earthꢀabundant and nonꢀprecious nickel
catalyst facilitates the transformations, releasing water as by product. The catalytic system is
tolerant to variety of functional groups including nitrile, allylic ether and alkene and could be
extended to the synthesis of bisꢀamide, antiemetic drug Tigan and dopamine D2 receptor
antagonist Itopride. Preliminary mechanistic studies, revealed the participation of benzylic CꢀH
bond in the rateꢀdetermining step.
Transition metalꢀcatalyzed efficient and selective synthesis of amide CꢀN bond represents a key
challenge and most commonly used in chemical transformations in the synthesis of
pharmaceuticals, peptides, and in natural products (Figure 1).1 In this direction, sustainable and
atomꢀeconomic technology for amide synthesis, which minimize the waste generation is
recognized by the ACS Pharmaceutical Roundtable as one of the important area where
significant method development is most desirable.2
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Figure 1: Selected examples of important pharmaceuticals with amide functionalities
Traditionally, laboratory scale synthesis of amides rely on the condensation of carboxylic
acids or their derivatives (such as, acid chlorides, anhydrides and esters) with amines.3 In
addition, aryl and alkenyl halides were also employed for Nꢀalkylation of amide.4 Unfortunately,
in spite of broader applications, these methodologies inevitably generates stoichiometric
equivalent of waste and involves multiꢀstep synthesis (Scheme 1a).5
Notably, the direct application of an alcohol would represent a promising alternative to the
above processes.5d Alcohols are highly abundant renewable feedstocks, low cost, nonꢀtoxic and
easy to handle. However, strong binding and poor leaving ability of hydroxyl group makes it
inferior substrate class for such transformations and required harsh reaction conditions.
Nevertheless, in terms of sustainability, metal catalyzed borrowing hydrogen or hydrogen autoꢀ
transfer (BH/HA) approach renders an elegant technology for formal CꢀN bond forming
reactions.6 This catalytic method involves a tandem dehydrogenation of alcohol to an
electrophilic aldehyde followed by condensation with an amide. Advantageously, the newly
formed C=N bond get hydrogenated by metalꢀhydride to the Nꢀalkylated amide and water is
formed as sole byproduct. Over the past decades, BH/HA strategy for Nꢀalkylation of amines
using alcohols has been well documented (Scheme 1b).6
On the other hand, Nꢀalkylation of primary amides are quite limited, because of poor
nucleophilicity compare to amines and often required higher catalyst loadings or higher reaction
temperature. In this direction, notable breakthrough by the group of Watanabe,7a and Jenner,7b for
Nꢀalkylation of amide with alcohols using Ruꢀcatalyst at 180o Cꢀ210o C is worth mentioning.
Later, precious metalꢀcatalysts, such as, Irꢀ7, Ruꢀ8a and Au/Pd,9b in combination with expensive
phosphine or highly reactive Nꢀheterocyclic carbene ligands for amidation of alcohols were
developed.
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Scheme 1: Approaches for synthesis of amides: (a) Conventional methods for amide synthesis;
(b) Precious metalꢀcatalyzed Nꢀalkylation of amides with alcohols; (c) Nickelꢀcatalyzed
amidation of alcohols.
To explore the scope of earthꢀabundant baseꢀmetalꢀcatalysts, we became interested in the
nickelꢀcatalyzed amidation of alcohols with primary amide. High natural abundance and
inexpensive nature associated with nickel would serve an attractive sustainable alternative to
palladiumꢀcatalysts.10 To the best of our knowledge, till date no nickel catalyzed general
methodology for amidation of primary alcohols is known.11,12 Herein, for the first time we
developed an inexpensive nickel catalyst system in combination with nitrogen ligands that
enables selective monoꢀalkylation of a variety of amides with primary alcohols (Scheme 1c).13
Notably, optimized protocol could be applied in the presence of nitrile, allylic and alkene
moieties as reducible functional groups. The key features of the methodology provide a general
synthesis of bisꢀamide, and drug molecules Tigan and Itopride.
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Table 1: Optimization for standard conditionsa
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Entry Catalyst
Ligand Solvent
3a(%)b,c
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1
NiCl2
NiBr2
Ni(acac)2
NiCl2.dme
Ni(cod)2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
ꢀ
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
L1
L1
L1
ꢀ
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
15
75
60
58
7
2
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6
1
7
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12
0
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16c
17c,d
18c,e
19c,f
20c,g
21c,h
45
65
22
Dioxane 30
DMA
0
DMF
0
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
98(83)
70
45
0
NiBr2
NiBr2
R
20
0
L1
R
R
P
R
N
N
N
N
R
N
N
R
R
R = H; L3, 7%
R = Me; L4, 12%
R = Ph; L6, 45%
R = Cy; L7, 65%
L5, 0%
R = H; L1, 98%
R = Me; L2, 1%
a Unless specified, the reaction was carried out with 1a (0.25 mmol), 2a (1.0 mmol), Niꢀcat. (10
mol %), ligand (20 mol %), K3PO4 (0.5 mmol), solvent (2.0 mL), Schenk tube under nitrogen
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b
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atmosphere, 120 ºC in oil bath, 24 h. Conversion was determined by GCꢀMS or HꢀNMR yield
using diphenylmethane as an internal standard (isolated yield in parenthesis, average yield of two
runs). cReaction was performed at 130 ºC. d5 mol % NiBr2 and 10 mol % L1 was used. e2.5 mol
% NiBr2 and 5 mol % L1 was used. fNo catalyst was used. gNo ligand was used. hNo K3PO4 was
used.
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In a recent report, we established an inexpensive Niꢀcatalyst system for efficient and selective
monoꢀalkylation of anilines with alcohols.14 Further to explore the direct amidation of alcohols,
initially we anticipated two key challenges: (i) the efficiency of the Niꢀcatalyst to obtain alcohol
dehydrogenation and (ii) the ability of the in situ formed Niꢀhydride species for imide
hydrogenation.
To realize this goal, five different nickel complexes having oxidation state of Ni(0) and Ni(II)
were assayed for their efficiency to catalyze the model reaction of benzamide 1a and benzyl
alcohol 2a (Table 1, entries 1ꢀ5). Notably, we observed that, a combination of 10 mol% NiBr2, 20
mol% 1,10ꢀphenthroline L1 and 0.5 mmol of K3PO4 at 120 °C in toluene resulted Nꢀalkylated
amide 3a with 75% selectivity in GCꢀMS analysis of the crude reaction mixture. Further to
improve the product yield, a variety of nitrogen ligands L2-L7 having variable electronic nature
were employed and exhibited moderate to poor selectivity of 3a (Table 1, entries 6ꢀ11). The
product conversion suppressed significantly, when xylene and 1,4ꢀdioxane were used as solvent
instead of toluene (Table 1, entries 12ꢀ13). Moreover, the application of polar solvents, such as,
N,Nꢀdimethylacetamide (DMA) and N,Nꢀdimethylꢀformamide (DMF) did not result any desired
product (Table 1, entries 14ꢀ15). To our delight, under identical conditions we observed 83%
isolated yield of 3a at 130 °C (Table 1, entries 2 and 16). As expected, lower catalyst loading
suppressed the product conversion and no Nꢀalkylated product was observed in absence of
catalyst (Table 1, entries 17ꢀ19). Control experiments in absence of ligand and base resulted poor
or no product conversion (Table 1, entries 20ꢀ21 and SI Table S1ꢀS7).
Next, under optimal conditions an in situ NMR study was performed using tolueneꢀd8 at 100
°C and monitor the progress of the reaction. The product formation profile allows the detection
of 1a, benzaldehyde, imide and 3a, all possible reaction intermediates, which are in strong
agreement of the hydrogen borrowing methodology under nickel catalysis (SI, Scheme S1).
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Scheme 2: Scope of primary alcohols. Reaction conditions: Unless specified, the reaction was
carried out with 1a (0.25 mmol), 2 (1.0 mmol), NiBr2 (10 mol%), Phen (20 mol%), K3PO4 (0.5
mmol), 130 °C in toluene (2.0 mL). atꢀBuONa was used. bGCꢀMS yield.
After having identified the optimized conditions, the scope and efficiency of the nickelꢀ
catalyzed amidation of alcohols were studied (Scheme 2). Electron donating substituents on
benzyl alcohols are well tolerated and furnished 62ꢀ84% yield of Nꢀalkylated amides (Scheme 2,
3b-3e). Benzyl alcohols having multiple electron donating substituent furnished lower product
yields (Scheme 2, 3f-3h and 3j-3l). Further, naphthalene methanol and pꢀfluoroꢀbenzyl alcohol
gave the desired product with excellent isolated yield, 81ꢀ82% respectively (Scheme 2, 3m and
3n). Gratifyingly, 2ꢀpyridenemethanol, decanol and renewable terpenoid intermediate citronellol
were also used for Nꢀalkylation under optimized reaction conditions (Scheme 2, 3o-3q). Notably,
chemoꢀselective transformation of unsaturated alcohol citronellol and nitrile substituted benzyl
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alcohol represents a rare instance, otherwise difficult using preciousꢀmetal catalysts (Scheme 2,
3i and 3q).6aꢀc
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Scheme 3: Scope of amides. Reaction conditions: Unless specified, the reaction was carried out
with 1a (0.25 mmol), 2 (1.0 mmol), NiBr2. (10 mol %), Phen (20 mol %), K3PO4 (0.5 mmol),
a
b1
130 °C in toluene (2.0 mL). tꢀBuONa was used. HꢀNMR yield using diphenylmethane as an
internal standard.
Next, selective monoꢀalkylation of various benzamides were demonstrated using optimum
catalytic conditions (Scheme 3). Benzamides bearing electron rich functionalities, such as,
methyl, ethyl, isopropyl and methoxy groups are well tolerated and furnished the desired
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products in moderate to excellent isolated yield (Scheme 3, 4a-4h and 4j). It is to be noted that,
electron poor pꢀfluorobenzamide resulted 72% yield of the Nꢀalkylated amide (Scheme 3, 4i).
Importantly, the application of nicotinamide was studied with benzyl alcohol as well as with 2ꢀ
pyridenemethanol and furnished the corresponding pharmaceutically active nicotinamide
derivatives 4m-4n (Scheme 3). Gratifyingly, more challenging, acetamide yielded the desired
products in 34ꢀ45% respectively (Scheme 3, 4o-4p). The catalytic protocol is highly selective for
primary amides and the application of secondary amide derivatives under the optimized
conditions resulted poor product conversions (Scheme 3, 4q-4t).
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Scheme 4. Amidation with 1,4ꢀphenylenedimethanol
Scheme 5. Synthetic application. tꢀBuONa (0.5 mmol) was used.
After having demonstrated the scope of the amidation protocol, we were interested to explore the
application of 1,4ꢀphenylenedimethanol with benzamides. Notably, the resulted multiꢀfunctional
amides 5aꢀ5c were obtained in 25ꢀ50% yield (Scheme 4).1ꢀ2 Further, to explore the synthetic
potential of the catalytic protocol, an attempt were established in one step synthesis of antiemetic
drug Tigan,15a as well as dopamine D2 receptor antagonist, Itopride (Scheme 5).15b To our
delight, the resulted drugs were obtained in good isolated yields. It is noteworthy to mention that,
the catalytic protocol is tolerant to nitrogen heterocycles, allylic ethers, nitrile and alkene,
including chloride and alkoxy moieties. Unfortunately, under identical conditions, reducible
functional moieties, such as, nitro, carboxylic acids, esters and alkynes were not successful.
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However, bromo and iodo substituted benzamides resulted only poor product conversions (SI,
Table S8).
This results encouraged us to gain more insight about the preliminary mechanistic
investigation of the process. To understand the bifunctional nature of the nickel catalyst, an in
situ NMRꢀstudy was performed and revealed that, proposed amidation of alcohols composed of a
multiꢀstep BH/HA technique (SI Scheme S1). Nevertheless, to confirm the participation of the
putative Niꢀintermediate species, the Cat.A was prepared,16a and used in catalytic as well as in
stoichiometric equiv. in the model reaction. The desired product 3a was obtained in good isolated
yields (Scheme 6a). Nevertheless, the application of defined complex, Ni(phen)2Br2 diminished
the catalytic activity. Therefore, under standard condition addition of any extra ligand L1 to the
defined complex Cat.A, resulted only poor product conversion (SI Scheme S7).
In addition, an attempt was made to prepare and detect the NiꢀH species of Cat.A in combination
with 2a. The in situ NMR studies at ꢀ75 °C was not successful and we observed benzaldehyde
formation (SI Scheme S5).
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Scheme 6. Mechanic investigation: atꢀBuONa was used.
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The experimental results evident that, the NiꢀH species of Cat.A is highly unstable to identify
even at low temperature (SI, Scheme S8). Gratifyingly, we choose electron rich triꢀcyclohexyl
phosphine L7 as ligand (Table 1), the defined complex NiBr2(PCy3)2 and the Niꢀhydride species
(PCy3)2NiBrH, Cat.B1-H were readily prepared.16b,c Next, the Cat.B1-H was employed in
stoichiometric equiv. with imide 3a’ under optimized conditions. To our delight, 3a was obtained
in 40% yield (Scheme 6b). This experimental findings are in agreement for the participation of
NiꢀH species. In addition, a competition experiment between benzyl alcohol 2a and 4ꢀmethoxy
benzyl alcohol 2f were performed and revealed that, for electron rich substituent amidation
occurred at higher rates (SI, Scheme S6).
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Further, amidation reaction of 1a with 2a-d1 was studied and the product distribution analysis
using 1HꢀNMR indicated the formation of 3a-d1 and 3a along with 47% deuterium incorporation
at the benzylic position of 3a-d1 (Scheme 6c and SI Scheme S2). Notably, to gain more insight
about the kinetic isotope effect (KIE), an intermolecular competition reaction of 2a and 2a-d2
with 1a were studied under the standard catalytic conditions and the observed product ratio on
1
the basis of HꢀNMR as well as HRMS analysis witnessed kCHH/kCDD = 2.70. These deuterated
experimental evidences are in strong agreement with the literature observation of D/H exchange
and the microꢀreversible transformation of BH/HA process (Scheme 6d and SI Schemes S2 –
S4).17a These experimental findings evident the involvement of the benzylic CꢀH bond cleavage
in the rate determining step (Scheme 6d).17b
In conclusion, we developed an efficient and selective direct amidation of primary alcohols
using earthꢀabundant and nonꢀprecious Niꢀcatalyst. The transformation could efficiently be
performed in the presence of reducible functional moieties, such as, nitrile, allylic ether and
alkenes. As a special highlights, we have demonstrated the synthesis of bisꢀamides, antiemetic
drug Tigan 6a, and dopamine D2 receptor antagonist, Itopride 6b. Preliminary mechanistic
investigation evident the participation of NiꢀH species. The kinetic isotope effect (KIE) studies
revealed the involvement of the benzylic CꢀH bond in the rateꢀ determining step.
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■ EXPERIMENTAL SECTION
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General Experimental Details: All solvents and reagents were used, as received from the
suppliers. TLC was performed on Merck Kiesel gel 60, F254 plates with the layer thickness of
0.25 mm. Column chromatography was performed on silica gel (100ꢀ200 mesh) using a gradient
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1
of ethyl acetate and hexane as mobile phase. H NMR spectral data were collected at, 400
MHz(JEOL), and 13C NMR were recorded at 100 MHz. H NMR spectral data are given as
1
chemical shifts in ppm followed by multiplicity (sꢀ singlet; dꢀ doublet; tꢀ triplet; qꢀ quartet; mꢀ
multiples), number of protons and coupling constants. 13C NMR chemical shifts are expressed in
ppm. Highꢀresolution mass spectra (HRMS) were obtained on a Brüker micro TOFꢀQ II mass
spectrometer (ESIꢀMS). GCꢀMS were recorded using PerkinꢀElmer Mass Spectrometer. Melting
points were recorded using OptiꢀMelt MPA100.
General Procedure for nickel-catalyzed amidation of alcohols: In a 20 mL oven dried
Schlenk tube amide (0.25 mmol), base (0.5 mmol), ligand (20 mol %), NiBr2 (10 mol %) and
alcohols (1.0 mmol) were added followed by toluene 2 mL under an atmosphere of N2 and heated
at 130 °C for 24ꢀ48 h. The reaction mixture was cooled to room temperature and 3.0 mL of ethyl
acetate was added and concentrated in vacuo. The residue was purified by column
chromatography using a gradient of hexane and ethyl acetate (eluent system) to afford the pure
products.
N-Benzylbenzamide (3a)18a: The title compound was isolated as a white solid using silicaꢀgel
column chromatography eluting with ethyl acetate/ hexane (1:4), (0.044g, Yield: 83%); 1H
NMR (400 MHz, CDCl3) δ 7.79 (d, J = 6.9 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.8 Hz,
13
2H), 7.32ꢀ7.35 (m, 4H), 7.26ꢀ7.32 (m, 1H), 6.58 (br s, 1H), 4.63 (d, J = 5.5 Hz, 2H); C NMR
(100 MHz, CDCl3) δ 167.5, 138.3, 134.5, 131.6, 128.9, 128.7, 128.0, 127.7, 127.1, 44.2.
N-(4-Methylbenzyl)benzamide (3b)18b: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.035g, Yield:
62%); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 6.7 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.33 (t, J
= 7.3 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 7.9 Hz, 2H), 6.34 (br s, 1H), 4.52 (d, J = 5.5
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Hz, 2H), 2.27 (s, 3H); C NMR (100 MHz, CDCl3) δ 167.4, 137.5, 135.2, 134.5, 131.6, 129.6,
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128.7, 128.1, 127.0, 44.0, 21.2.
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N-(4-Ethylbenzyl)benzamide (3c): The title compound was isolated as a white solid using
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silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.050g, Yield:
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84%); mp 101ꢀ102 °C; H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.3
Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 6.42 (br s,
1H), 4.62 (d, J = 5.6 Hz, 2H), 2.65 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 167.4, 143.9, 135.5, 134.5, 131.6, 128.7, 128.4, 128.1, 127.1, 44.0, 28.6, 15.8.
HRMS (ESIꢀTOF) m/z: [M+Na]+ Calcd for C16H17NONa 262.1202; Found 262.1209.
N-(4-Isopropylbenzyl)benzamide (3d)18b: The title compound was isolated as a white solid
using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.051g, Yield:
1
80%); H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.5 Hz, 2H), 7.42 (t, J=7.3Hz, 1H), 7.35 (t,
J=7.6Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 7.15 (d, J=7.9 Hz, 2H), 6.31 (br s, 1H), 4.54 (d, J=5.5Hz,
13
2H), 2.89ꢀ2.78 (m, 1H), 1.17 (d, J=6.7 Hz, 6H); C NMR (100 MHz, CDCl3) δ 167.4, 148.5,
135.5, 134.5, 131.6, 128.7, 128.2, 127.0, 126.9, 44.1, 33.9, 24.1. HRMS (ESIꢀTOF) m/z:
[M+Na]+ Calcd for C17H19NONa 276.1359; Found 276.1353.
N-(2-Methylbenzyl)benzamide (3e)19b: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.043g, Yield:
76%); 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.9 Hz, 2H), 7.41 (t, J = 7.0 Hz, 1H), 7.33 (t, J
= 7.6 Hz, 2H), 7.22 (d, J = 6.7 Hz, 1H), 7.12 (q, J = 6.9 Hz, 3H), 6.22 (br, s, 1H), 4.55 (d, J = 5.5
13
Hz, 2H), 2.29 (s, 3H); C NMR (100 MHz, CDCl3) δ 167.3, 136.7, 135.8, 134.4, 131.6, 130.7,
128.8, 128.7, 128.0, 127.0, 126.4, 42.5, 19.2.
N-(4-Methoxybenzyl)benzamide (3f)18b: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:3), (0.053g, Yield:
87%); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 6.8 Hz, 2H), 7.49 (t, J = 7.2 Hz, 1H), 7.42 (t, J
= 7.4 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.38 (br s, 1H), 4.57 (d, J = 6.4
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Hz, 2H), 3.80 (s, 3H); C NMR (100 MHz, CDCl3) δ 167.4, 159.2, 134.5, 131.6, 130.4, 129.4,
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128.6, 127.1, 114.2, 55.4, 43.7.
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N-(3,4,5-Trimethoxybenzyl)benzamide (3g): The title compound was isolated as a white solid
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using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (3:7), (0.040g,
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Yield: 53%); H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.3 Hz, 2H), 7.50 (t, J = 7.3 Hz, 1H),
7.42 (t, J = 7.3 Hz, 2H), 6.68 (br s, 1H), 6.55 (s, 2H), 4.55 (d, J = 6.1 Hz, 2H), 3.82 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 167.5, 153.4, 137.3, 134.4, 134.1, 131.7, 128.7, 127.1, 105.0, 60.9,
56.2, 44.5. HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for C17H20NO4 302.1387; Found 302.1381.
N-(2,3,4-Trimethoxybenzyl)benzamide (3h): The title compound was isolated as a white solid
using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (3:7), (0.032g, Yield:
43%); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.3 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.42 (t, J
= 7.3 Hz, 2H), 7.05 (d, J = 8.5 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 6.59 (br s, 1H), 4.58 (d, J = 6.1
13
Hz, 2H), 3.96 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H); C NMR (100 MHz, CDCl3) δ 167.1, 153.7,
152.1, 142.2, 134.7, 131.5, 128.6, 127.0, 124.3, 123.9, 107.3, 61.2, 60.9, 56.1, 39.8. HRMS
(ESIꢀTOF) m/z: [M+H] + Calcd for C17H20NO4 302.1387; Found 302.1383.
N-(4-Cyanobenzyl)benzamide (3i)19a: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:3), (0.022g, Yield:
37%); 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.2 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.54 (t, J
= 7.3 Hz, 1H), 7.44ꢀ7.47 (m, 4H), 6.60 (br s, 1H), 4.71 (d, J = 6.1 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 167.7, 143.9, 133.9, 132.6, 132.1, 128.8, 128.3, 127.1, 118.8, 111.4, 43.6.
N-(4-Chlorobenzyl)benzamide (3j)18b: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.051g, Yield:
83%); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 6.9 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.47 (t, J
= 7.3 Hz, 1H), 7.37ꢀ7.41 (m, 4H), 6.50 (br s, 1H), 4.65 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 167.4, 143.9, 133.9, 132.6, 132.1, 128.8, 128.3, 127.1, 118.8, 43.6.
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N-(2-Chlorobenzyl)benzamide (3k)18b: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.033g, Yield:
53%); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 2H), 7.29ꢀ7.46 (m, 5H), 7.16ꢀ7.19 (m,
2H), 6.57 (br s, 1H), 4.46 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.4, 135.7,
134.3, 133.8, 131.7, 130.6, 129.7, 129.2, 128.7, 127.3, 127.1, 42.2. HRMS (ESIꢀTOF) m/z:
[M+Na] + Calcd for C14H12ClNONa 268.0500; Found 268.0490.
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N-(2,4-Dichlorobenzyl)benzamide (3l)18b: The title compound was isolated as a white solid
using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane(1:4), (0.034g, Yield:
49%); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.0 Hz, 1H), 7.36ꢀ7.44
(m, 4H), 7.21 (d, J = 8.4 Hz, 1H), 6.72 (br s, 1H), 4.66 (d, J = 5.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 167.6, 134.3, 134.0, 133.9, 133.7, 131.9, 131.2, 129.4, 128.7, 127.5, 127.1, 41.6.
N-(4-Fluorobenzyl)benzamide (3m)18e: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.047g, Yield:
82%); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.3 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.33 (t, J
= 7.3 Hz, 2H), 7.21ꢀ7.24 (m, 2H), 6.93 (d, J = 8.5, 2H), 6.53 (br s, 1H), 4.51 (d, J = 5.5Hz, 2H);
13CꢀNMR (100 MHz, CDCl3) δ 167.5, 162.3 (d, JCꢀF = 246.4 Hz), 134.3, 134.1 (d, JCꢀF = 2.9 Hz),
131.7, 129.6, 128.7, 127.1, 115.7 (d, JCꢀF = 22.1 Hz), 43.4.
N-(Naphthalen-1-ylmethyl)benzamide (3n)18b:The title compound was isolated as a white solid
using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.053g, Yield:
81%); 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J= 9.2 Hz, 1H), 7.77 (d, J = 9.6 Hz, 1H), 7.71 (d, J
= 7.8 Hz, 1H), 7.63 (d, J = 7.3 Hz, 2H), 7.35ꢀ7.43 (m, 3H), 7.28ꢀ7.37 (m, 2H), 7.23 (t, J = 7.6
Hz, 2H), 6.47 (br s, 1H), 4.92 (d, J = 5.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.3, 134.4,
134.0, 133.5, 131.6, 128.9, 128.8, 128.6, 127.1, 126.9, 126.8, 126.1, 125.5, 123.6, 42.4.
N-(Pyridin-2-ylmethyl)benzamide (3o)18c: The title compound was isolated as a yellow solid
using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (2:3), (0.030g, Yield:
1
57%); HꢀNMR (400 MHz, CDCl3) δ 8.49 (d, J = 4.1 Hz, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.59ꢀ
7.63 (m, 2H), 7.35ꢀ7.45 (m, 2H), 7.26 (d, J = 7.8 Hz, 1H), 7.13ꢀ7.19 (m, 1H), 4.69 (d, J = 5.0 Hz,
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2H), 2.29 (br s, 1H); CꢀNMR (100 MHz, CDCl3) δ 167.5, 156.3, 149.0, 137.0, 134.4, 131.6,
+
128.6, 127.2, 122.5, 122.3, 44.8; HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C13H12N2ONa
235.0842; Found 235.0833.
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N-(3,7-dimethyloct-6-en-1-yl)benzamide (3q)20e: The title compound was isolated as a viscous
liquid using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (3:7), (0.029g,
Yield: 45%); 1HꢀNMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.3 Hz, 2H), 8.01 (s, 1H), 7.75 (d, J =
1.8 Hz, 2H), 7.60 (q, J = 4.3 Hz, 1H), 5.09 (t, J = 7.0 Hz, 1H), 2.80ꢀ2.94 (m, 2H), 1.96ꢀ2.02 (m,
2H), 1.66 (s, 3H), 1.59 (s, 3H), 1.38ꢀ1.44 (m, 1H), 1.24ꢀ1.29 (m, 4H), 0.99 (d, J = 6.1 Hz, 3H);
HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for C17H26NO 260.2009; Found 260.2009.
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N-Benzyl-4-methylbenzamide (4a)18b: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.052g, Yield:
1
92%); H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.26ꢀ7.42 (m, 5H), 7.21 (d, J =
13
7.6 Hz, 2H), 6.39 (s, 1H), 4.63 (d, J = 5.5Hz, 2H), 2.38 (s, 3H); C NMR (100 MHz, CDCl3) δ
167.4, 142.1, 138.4, 131.6, 129.3, 128.9, 128.0, 127.7, 127.0, 44.18, 21.5.
N-Benzyl-3-methylbenzamide (4b)19d: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.038g, Yield:
1
68%); H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.55ꢀ7.57 (m, 1H), 7.28ꢀ7.36 (m, 7H), 6.44
13
(br s, 1H), 4.64 (d, J = 5.2 Hz, 2H), 2.38 (s, 3H); C NMR (100 MHz, CDCl3) δ 167.6, 138.6,
138.3, 134.5, 132.4, 128.9, 128.6, 128.0, 127.8, 127.7, 124.0, 44.2, 21.4.
N-Benzyl-3,4-dimethylbenzamide (4c)19c: The title compound was isolated as a white solid
using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.052g, Yield:
1
87%); H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.50 (d, J = 8 Hz, 1H), 7.26ꢀ7.36 (m, 5H),
13
7.17 (d, J = 8 Hz, 1H), 6.37 (br s, 1H), 4.64 (d, J = 5.2 Hz, 2H), 2.29 (s, 6H); C NMR (100
MHz, CDCl3) δ 167.5, 140.7, 138.5, 137.1, 131.9, 129.8, 128.9, 128.3, 128.0, 127.7, 124.4, 44.2,
19.9,19.8.
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N-Benzyl-4-isopropylbenzamide (4d): The title compound was isolated as a white solid using
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silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.034g, Yield:
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54%); mp 117ꢀ118°C; H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 2H), 7.30ꢀ7.35 (m,
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5H), 7.28 (d, J = 8.0 Hz, 2H), 6.41 (br s, 1H), 4.64 (d, J = 6.0 Hz, 2H), 2.91ꢀ2.98 (m, 1H), 1.25
(d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 167.4, 152.9, 138.4, 132.0, 128.9, 128.0,
127.6, 127.2, 126.8, 44.2, 34.2, 23.9. HRMS (ESIꢀTOF) m/z: [M+Na] + Calcd for C17H19NONa
276.1359; Found 276.1356.
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N-Benzyl-4-ethylbenzamide (4e): The title compound was isolated as a white solid using silicaꢀ
gel column chromatography eluting with ethyl acetate/ hexane(1:4), (0.042g, Yield: 70%); mp
112ꢀ113°C; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.4 Hz, 2H), 7.29ꢀ7.38 (m, 5H), 7.25 (d,
J = 8 Hz, 2H), 6.37 (br s, 1H), 4.65 (d, J = 6.0 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6
13
Hz, 3H); C NMR (100 MHz, CDCl3) δ 167.4, 148.3, 138.4, 131.8, 128.9, 128.2, 128.0, 127.7,
+
127.1, 44.2, 28.9, 15.5. HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C16H17NONa 262.1202;
Found 262.1223.
N-Benzyl-4-methoxybenzamide (4f)18b: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane(1:4), (0.036g, Yield: 60%);
1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.8 Hz, 2H), 7.27ꢀ7.35 (m, 5H), 6.90 (d, J = 8.4 Hz,
2H), 6.46 (br s, 1H), 4.61 (d, J = 5.2 Hz, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0,
162.3, 138.5, 128.9, 128.8, 128.0, 127.6, 126.7, 113.8, 55.5, 44.1.
N-Benzyl-3,4-dimethoxybenzamide (4g)21b: The title compound was isolated as a white solid
using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (3:7), (0.052g, Yield:
1
77%); H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 1.8 Hz, 1H), 7.25ꢀ7.33 (m, 6H), 6.81 (d, J =
8.5 Hz, 1H), 6.67 (br s, 1H), 4.61 (d, J = 5.5 Hz, 2H), 3.88 (2s, 6H); 13C NMR (100 MHz,
CDCl3) δ 167.2, 151.8, 149.0, 138.5, 128.8, 127.9, 127.6, 127.0, 119.6, 110.7, 110.3, 56.1, 44.2.
N-Benzyl-3,4,5-trimethoxybenzamide (4h): The title compound was isolated as a white solid
using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (2:3), (0.049g, Yield:
65%); mp 140ꢀ141°C; 1H NMR (400 MHz, CDCl3) δ 7.28ꢀ7.37 (m, 5H), 7.02 (s, 2H), 6.41 (br s,
13
1H), 4.64 (d, J = 5.6 Hz, 2H), 3.88ꢀ3.89 (m, 9H); C NMR (100 MHz, CDCl3) δ 167.1, 153.3,
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141.1, 138.3, 129.9, 128.9, 128.0, 127.8, 104.5, 61.0, 56.4, 44.3. HRMS (ESIꢀTOF) m/z:
[M+Na]+ Calcd for C17H19NO4Na 324.1206; Found 324.1201.
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N-Benzyl-4-fluorobenzamide (4i)18b: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.041g, Yield:
72%); 1H NMR (400 MHz, CDCl3) δ 7.78ꢀ7.81 (m, 2H), 7.26ꢀ7.39 (m, 5H), 7.08 (t, J = 8.7 Hz,
2H), 6.56 (br s, 1H), 4.61 (d, J = 5.5Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 166.5, 164.8 (d, JCꢀ
F = 253.0 Hz), 138.2, 130.6, 129.4 (d, JCꢀF = 8.6 Hz), 128.9, 128.0, 127.8, 115.7 (d, JCꢀF = 22.2
Hz), 44.3.
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N-Benzyl-4-chlorobenzamide (4j)18b: The title compound was isolated as a white solid using
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.015g, Yield:
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25%); H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.30ꢀ
13
7.37 (m, 5H), 6.36 (br s, 1H), 4.64 (d, J = 5.2 Hz, 2H); C NMR (100 MHz, CDCl3) δ 166.3,
138.0,137.9,132.8, 129.0,128.5, 128.1, 127.9, 127.0, 44.4.
N-Benzyl-1-naphthamide (4k)18b: The title compound was isolated as a white solid using silicaꢀ
1
gel column chromatography eluting with ethyl acetate/ hexane (1:4), (0.026g, Yield: 40%); H
NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.5 Hz, 1H), 7.85ꢀ7.91 (m, 3H), 7.60ꢀ7.62 (m, 1H),
13
7.52ꢀ7.58 (m, 2H), 7.29ꢀ7.45 (m, 5H), 6.30 (brs, 1H), 4.73 (d, J = 5.5 Hz, 2H); C NMR (100
MHz, CDCl3) δ 169.5, 138.2, 134.4, 133.8, 130.8, 130.3, 128.9, 128.4, 128.0, 127.8, 127.3,
126.5, 125.5, 125.0, 124.8, 44.2.
N-(4-(allyloxy)benzyl)-3,4,5-trimethoxybenzamide (4l): The title compound was isolated as a
white solid using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (2:3),
1
(0.028g, Yield: 31%); mp 142ꢀ143°C; H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.7 Hz, 2H),
7.02 (s, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.48 (br s, 1H), 6.09ꢀ5.99 (m, 1H), 5.41 (dd, J = 17.4, 1.4
13
Hz, 1H), 5.29 (dd, J = 10.5, 1.4 Hz, 1H), 4.56ꢀ4.52 (m, 4H), 3.87 (s, 9H); C NMR (100 MHz,
CDCl3) δ 167.1, 158.2, 153.3, 141.0, 133.2, 130.5, 129.9, 115.3, 114.8, 104.7, 104.2, 68.9, 61.1,
+
56.4, 43.8. HRMS (ESIꢀTOF) m/z: [M+Na]
380.1462.
Calcd for C20H23NO5Na 380.1468; Found
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N-benzylnicotinamide (4m)18c: The title compound was isolated as a colorless liquidusing
silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (3:7), (0.008g, Yield:
23%); 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J = 1.8 Hz, 1H), 8.71 (d, J = 3.1 Hz, 1H), 8.14 (d,
J = 7.9 Hz, 1H), 7.32ꢀ7.40 (m, 6H),6.58 (br s, 1H), 4.66 (d, J = 6.1 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 165.5, 152.5, 147.9, 137.8, 135.4, 130.2, 129.0, 128.0, 127.8, 123.6, 44.4.
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N-(pyridin-2-ylmethyl)nicotinamide (4n)18d: The title compound was isolated as a viscous
yellow oil using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane (7:3),
(0.011g, Yield: 32%); 1H NMR (400 MHz, CDCl3) δ 9.11 (d, J = 1.8 Hz, 1H), 8.73 (dd, J = 4.8,
1.6 Hz, 1H), 8.56 (d, J = 4.9 Hz, 1H), 8.21 (dt, J = 7.9, 1.8 Hz, 1H), 7.89 (s, 1H), 7.71 (td, J =
7.6, 1.4 Hz, 1H), 7.40 (q, J = 4.3 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.23ꢀ7.26 (m, 1H), 4.77 (d, J
13
= 4.9 Hz, 2H); CꢀNMR (100 MHz, CDCl3) δ 165.6, 155.7, 152.2, 149.1, 148.3, 137.1, 135.2,
130.1, 123.6, 122.8, 122.3, 44.7.
N-Benzylacetamide (4o)19e: The title compound was isolated as a white solid using silicaꢀgel
1
column chromatography eluting with ethyl acetate/ hexane (3:7), (0.017g, Yield: 45%); H
NMR (400 MHz, CDCl3) δ 7.48ꢀ7.52 (m, 2H), 7.37ꢀ7.34 (m, 3H), 5.88 (br s, 1H), 4.59 (d, J =
5.5 Hz, 2H), 1.60 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 138.2, 128.9, 127.9, 127.7,
43.9, 29.8.
N-(4-methoxybenzyl)acetamide (4p)21c: The title compound was obtained as sticky solid
1
eluting with ethyl acetate/ hexane (3:7), (0.015g, Yield: 34%); H NMR (400 MHz, CDCl3) δ
7.18ꢀ6.87 (m, 4H), 6.42 (brs, 1H), 4.38 (d, J = 5.60 Hz, 1H), 3.78 (s, 3H), 2.00 (s, 3H).
N,N'-(1,4-phenylenebis(methylene))dibenzamide (5a)20d: The title compound was isolated as a
white solid using silicaꢀgel column chromatography eluting with ethyl acetate/ hexane(3:7),
1
(0.022g, Yield: 50%); H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.3 Hz, 4H), 7.51 (t, J = 7.3
Hz, 2H), 7.42 (t, J = 7.3 Hz, 4H), 7.33 (d, J = 1.2 Hz, 4H), 6.29 (br s, 2H), 4.67 (d, J = 4.3 Hz,
4H). HRMS (ESIꢀTOF) m/z: [M+Na] + Calcd for C22H20N2O2Na 367.1417; Found 367.1409.
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N,N'-(1,4-phenylenebis(methylene))bis(4-methylbenzamide) (5b)20c: The title compound was
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isolated as a white solid using silicaꢀgel column chromatography eluting with ethyl acetate/
1
hexane (3:7), (0.012g, Yield: 25%); H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.9 Hz, 4H),
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7.33 (d, J = 7.9 Hz, 4H), 7.22 (d, J = 7.9 Hz, 4H), 6.46 (br s, 2H), 4.60 (d, J = 5.5 Hz, 4H), 2.39
13
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(s, 6H); C NMR (100 MHz, CDCl3) δ 166.9, 142.1, 137.8, 133.0, 130.1, 128.4, 127.0, 45.3,
22.7; HRMS (ESIꢀTOF) m/z: [M+Na] + Calcd for C24H24N2O2Na 395.1730; Found 395.1764.
N,N'-(1,4-phenylenebis(methylene))bis(3,4-dimethylbenzamide) (5c): The title compound
was isolated as a white solid using silicaꢀgel column chromatography eluting with ethyl acetate/
hexane (3:7), (0.016g, Yield: 32%); mp 202ꢀ203°C; 1H NMR (400 MHz, CDCl3) δ 7.57 (s, 2H),
7.51ꢀ7.42 (m, 2H), 7.33 (s, 4H), 7.17 (d, J = 7.9 Hz, 2H), 6.41 (br s, 2H), 4.62 (d, J = 5.5 Hz,
4H), 2.29 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 167.6, 140.8, 137.8, 137.1, 131.9, 129.8,
128.4, 128.4, 124.4, 43.8, 19.9, 19.8. HRMS (ESIꢀTOF) m/z: [M+Na] + Calcd for C26H28N2O2Na
423.2043; Found 423.2042.
N-(4-(2-(dimethylamino)ethoxy)benzyl)-3,4,5-trimethoxybenzamide (6a)20a: The title
compound was isolated as a pale yellow solid using silicaꢀgel column chromatography eluting
1
with methanol/ethyl acetate (1:9), (0.078g, Yield: 80%); H NMR (400 MHz, CDCl3) δ 7.27 (d,
J = 8.4 Hz, 2H), 7.03 (s, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.55 (br s, 1H), 4.56 (d, J = 5.6 Hz, 2H),
4.14 (t, J = 5.6 Hz, 2H), 3.88 (s, 9H), 2.92ꢀ2.89 (m, 2H), 2.46 (s, 6H); 13CꢀNMR (100 MHz,
CDCl3) δ 167.1, 158.0, 153.3, 141.0, 130.8, 129.9, 129.5, 114.8, 104.5, 65.2, 61.0, 57.6, 56.4,
45.1, 43.7. HRMS (ESIꢀTOF) m/z: [M+H] + Calcd for C21H29N2O5 389.2071; Found 389.2075.
N-(4-(2-(dimethylamino)ethoxy)benzyl)-3,4-dimethoxybenzamide
(6b)20b:
The
title
compound was isolated as a pale yellow solid using silicaꢀgel column chromatography eluting
1
with methanol/ethyl acetate (1:9), (0.066g, Yield: 74%); H NMR (400 MHz, CDCl3) δ 7.45 (d,
J = 1.8 Hz, 1H), 7.26ꢀ7.30 (m, 3H), 6.89 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.5 Hz, 1H), 6.33 (br s,
1H), 4.57 (d, J = 5.5 Hz, 2H), 4.15 (t, J = 5.5 Hz, 2H), 3.91 (s, 6H), 2.91 (t, J = 4.6 Hz, 2H), 2.46
13
(s, 6H); CꢀNMR (100 MHz, CDCl3) δ 167.0, 158.1, 151.5, 148.8, 131.0, 129.4, 127.4, 119.3,
+
114.8, 110.5, 110.1, 65.1, 57.7, 56.1, 45.1, 43.7. HRMS (ESIꢀTOF) m/z: [M+H] Calcd for
C20H27N2O4 359.1965; Found 359.1956.
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ASSOCIATED CONTENT
Supporting Information
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1H, 13C and HRMS data for selected compounds.
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The Supporting Information is available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: dbane.fcy@iitr.ac.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank SERB, India (funding to D. B., ECR/2015/000600). JD thank IITꢀR for
financial support.
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