Traceless selenocarboxylates for the one-pot synthesis of amides and derivatives

Article abstract of DOI:10.1016/j.tet.2020.131834

We have recently reported a one-pot procedure for glycosyl amides synthesis using selenocarboxylate as traceless reagent. Herein, we present a further application of selenocarboxylate-azide reaction for amide bond formation on a broader range of substrates, including heterocyclic systems and fatty acid. This method proved to be highly efficient for the synthesis of primary and secondary amides, sulfonamides, imides, phosphoramide and also carbamate.

Full text of DOI:10.1016/j.tet.2020.131834

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Traceless Selenocarboxylates for the One-Pot Synthesis of Amides and Derivatives
Luana Silva, Alisson R. Rosário, Bianca M. Machado, Diogo S. Lüdtke
PII:
S0040-4020(20)31082-6
https://doi.org/10.1016/j.tet.2020.131834
TET 131834
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 October 2020
Revised Date: 28 November 2020
Accepted Date: 30 November 2020
Please cite this article as: Silva L, Rosário AR, Machado BM, Lüdtke DS, Traceless Selenocarboxylates
for the One-Pot Synthesis of Amides and Derivatives, Tetrahedron, https://doi.org/10.1016/
j.tet.2020.131834.
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Graphical Abstract:

Traceless Selenocarboxylates for the One-Pot Synthesis of Amides and Derivatives
Luana Silva, Alisson R. Rosário, Bianca M. Machado and Diogo S. Lüdtke*
Instituto de Química, Universidade Federal do Rio Grande do Sul, UFRGS, Av. Bento
Gonçalves 9500, 91501-970, Porto Alegre, RS, Brazil.
email: dsludtke@iq.ufrgs.br
Phone: +55 51 3308 9637
Abstract: We have recently reported a one-pot procedure for glycosyl amides
synthesis using selenocarboxylate as traceless reagent. Herein, we present a further
application of selenocarboxylate-azide reaction for amide bond formation on a broader
range of substrates, including heterocyclic systems and fatty acid. This method proved to
be highly efficient for the synthesis of primary and secondary amides, sulfonamides,
imides, phosphoramide and also carbamate.
Keywords: amidation, selenium reagents, traceless
Graphical Abstract:
1

Introduction
The amide bond is a key linker found in biomolecules essential for maintenance of
life, most notably at the backbones of all peptides and proteins.1 Furthermore, this
structural framework imparts significant biological importance, since it is present in many
fine chemicals and drugs, being extensively applied in medicinal chemistry, (bio)polymers,
agrochemicals, natural products and chemical intermediates (Figure 1).2 Due to this
reasons, the construction of amides is hugely important especially in the pharmaceutical
industry, since amide bond-forming reactions are one of the most prevalent
transformations carried out in medicinal chemistry, accounting for 16% of all reactions in
this field.3
Figure 1. Important molecules containing secondary amide structures.
The most common methods for amide bond formation rely on the condensation
between an activated carboxylic acid as the electrophile and a free amine as a nucleophile
through the intermediacy of coupling reagents.4 These methods have been successful for
a variety of amides, but the coupling agents are often toxic and sometimes generate
byproducts, which is not always easily separable from the amide. Moreover, in many
cases free amines cannot be used due to either structural instability or the presence of
2

incompatible functional groups. As an alternative to conventional amide synthesis, highly
innovative approaches have been recently reported5, such as transamidation6, α-ketoacid–
hydroxylamine ligation7, boronic acid-catalyzed amidation8, reaction of Grignard reagents
with isocyanates or N-carboxyanhydrides9, and umpolung reactivity of α-bromo
nitroalkanes10. Amongst the emergent methods, several strategies have used azides
instead of amines as the substrate to form the desired amide bonds.11 Organic azides
have been an attractive nitrogen source since oxidative or basic conditions are not
required, broad tolerance of chemicals, mild and green conditions applies since N2(g) is in
general the by-product.12 Among these, the Staudinger ligation13, hydrative amide
synthesis through alkyne–azide coupling14, thioacid-azide ligation15 and more recently
17, 19
selenocarboxylate-azide amidation16,
stand out. In particular, the reaction of
selenocarboxylates with azides is a more reactive variation of the thioacid-azide ligation,
since the selenide atom is larger and more easily polarizable - thus a better nucleophile
than sulfur.18
In this context, we have reported an expedient methodology for the synthesis of
glycosyl amides that successfully relied on the in situ generation of lithium
selenocarboxylates from Se0/LiEt3BH and activated carboxylic acid derivatives and
subsequent reaction with sugar azides (Scheme 1). This protocol proved very convenient
since it avoided the isolation and handling of reactive and sensitive selenium containing
intermediates, providing to the selenocarboxylate the status of a traceless reagent.19
Building up on the efficiency of this reaction, we have decided to investigate the
applicability of our selenocarboxylate protocol to a broader range of substrates with
different scaffolds. Therefore, herein we reported our results on the synthesis of a variety
3

of amides with structural diversity, including aryl, benzyl, alkyl, sulfonamide,
phosphoramide, imide and carbamate.
Scheme 1. Amide bond formation through Selenocarboxylate-azide reaction
Results and Discussion
We started our studies from conditions previously employed for the amidation of
glycosyl azides from selenocarboxylates.19 Thus, the in situ generation of the reactive
selenocarboxylate, took place with the reduction of elemental selenium with lithium
triethylborohydride,20 to generate a nucleophilic Se2- species that then reacts with an
activated carboxylic acid derivative (e.g. acyl chloride, activated carboxylic acid),
generating in situ the desired selenocarboxylate. To validate our strategy of one-pot amide
4

synthesis from selenocarboxylates, we selected 4-nitrophenyl azide as the standard
starting material, due to its well-known reactivity with selenocarboxylates in amide-bond
forming reactions (Table 1).17, 19 Under these conditions, the desired amide product 1 was
obtained in excellent yield (entry 1). Additional attempts to improve even further the
reaction conditions have been examined. Reducing the number of equivalents of the
selenocarboxylate, unfortunately led to decreased isolated yields (entries 2-4). Lowering
the temperature from 50 oC to room temperature didn’t impact significantly the yield (entry
5). The reaction is also possible starting with toluyl instead of benzoyl chloride and
gratifyingly, the reaction time was also reduced to 16 h (entries 6-7), leading to the amide
2 in excellent yield. Higher reaction temperature led to decomposition of the
selenocarboxylate reagent (entry 8).
Table 1. Standard Conditions and deviations
Entry
Deviation from standard condition
none
Yield (%)a
>95
75
1
2
3
4
5
6
7
8
1 equiv. of selenocarboxylate
0 °C instead of r.t./ 1 equiv. of selenocarboxylate
2 equiv. of selenocarboxylate
75
72
r.t. instead of 50 °C
93
toluyl instead of benzoyl chloride/ r.t. instead of 50 °C
toluyl instead of benzoyl chloride /16 h instead of 48 h
60 °C instead of 50 °C
>95
>95
N.R.b
5

a Isolated yields. Reaction performed at room temperature in THF. N.R. = No reaction.
b Decomposition of selenocarboxylate
With the optimized reaction conditions in hands, the scope of this one-pot method
was evaluated with a wide range of azides derivatives. In order to develop the
methodology, expand the number of examples and evaluate possible steric and electronic
effects, a variety of azides were subjected to amidation with selenocarboxylates in optimal
reaction conditions. The evaluation of azides and acyl chlorides derivatives are presented
in Scheme 2.
Under the standard conditions, a variety of aromatic azides bearing electron-
withdrawing groups, in ortho, meta and para positions, such as nitro (-NO2, 1, 2, 3 and 20),
cyano (-CN, 7, 18, 21 and 33), bromine (-Br, 4 and 5), iodine (-I, 6), trifluoromethyl (-CF3, 8
and 9), reacted with selenocarboxylates to afford the corresponding amides in excellent
yields. These results are consistent with our previous reports19 wherein aromatic deficient-
azides are highly reactive reaction partners with selenocarboxylates due the ability of
stabilization the negative charge on nitrogen during the transition state, similarly as
proposed for thiocarboxylates.15c, d For electron-rich aromatic azides, that are less reactive,
(10-14), also good results were obtained. Even methoxy substituents have been well
tolerated, gave good yields for the products bearing this strongly electron-donating group
in ortho, meta and para positions. The electron-donating group methyl in ortho position,
gave the amide 13 in a lower yield but with most of the starting azide recovered.
Surprisingly, the azide bearing both nitro and methoxy substitute did not furnished the
amide (35) with the starting material azide recovered. Sterically hindered aryl groups (14)
also gave the desired amide in quantitative yield.
6

Scheme 2. Reaction scope from acyl chlorides derivatives.
R2
N3
i. LiEt3BH, THF
5 min, r.t
O
O
(1 equiv.)
16 h, r.t
R2
+ N2 + Se0
R1
N
R1
Se
ii. acyl chloride
30 min, r.t
H
(4 equiv.)
Aromatic Amides
O2N
O2N
Br
Br
O
O
O
O
O
N
H
N
H
N
H
N
O2N
N
H
H
5 >95%
1
4
>95%
>95%
2
3
>95%
94%
CF3
I
NC
O
O
O
O
O
N
H
N
N
H
F3C
N
H
F3C
N
H
H
OMe
10
6 >95%
77%
7
8
9
>95%
90%
75%
MeO
O
O
O
O
O
O
N
H
MeO
N
H
N
N
H
O
H
N
H
13
34%
11
12
14
15
72%
>95%
>95%
O
>95%
Alkyl-Containing Amides
O2N
Benzyl-Containing Amides
O
NC
NC
O
Br
O
O
O
N
H
N
N
N
N
N
6
H
H
H
H
H
5
Br
16
17
18 >95%
19
65%
20
74%
21 >95%
>95%
>95%
Heterocycle-Containing Amides
HO
N
O
S
O
O
S
O
N
O
O
N
N
N
N
N
O
H
H
O
N
O
H
N
N
H
N
H
N
N
N
H
22
23
25 >95%
40%
92%
MeO
24 >95%
26 >95%
27
58%
Miscelaneous
Limitation Scope
MeO
O
O
O
O
O
O
N
EtO
S
S
N
N
N
O
H
O
H
H
H
O
NO2
28
>95%
29
76%
36
N.R.
35 N.R.
O
O
O
O
O
O
O
HO
N
H
N
N
N
MeO
H
H
H
O
38
37
N.R.
30
31
N.R.
62%
85%
O
NC
O
O
O
O
O
OEt
Si
H2N
O
Si
EtO
P
N
H
N
N
H
O
N
H
O
H
OEt
39
40
N.R.
N.R.
34 82%
32
>95%
33
72%
Amides substituted by heterocycles (22-27) such as pyridine (22), thiazole (23),
benzothiazole (24), benzoxazole (25), pyrimidine (26) and quinine (27) could be accessed
7

from the corresponding azide. Moreover, amides functionalized with heterocycles are
important from medicinal chemistry point-of-view, an amide bearing a pyrimidine moiety
was prepared in quantitative yield (26). This heterocyclic compound, known as Biginelli
adducts, presents a wide range of biological activity, such as antibacterial, antiviral, anti-
inflammatory and especially anticancer, and also interesting photophysical properties.21
Furthermore, benzazoles-derived amides, fluorescent molecules that belong to a class of
compounds commonly used as fluorophores with potential applications as fluorescent
probes and optical sensors, were also obtained (24 and 25) in excellent yields.22 This
amidation method was also applied to the modification of quinine, an alkaloid that has
been extensively researched due to its potent antimalarial activity and role in catalysis.23
The quinine moiety was successfully transferred from the starting azide to the final amide
27.
Surprisingly, when p-phenol azide was submitted to amidation, a different product was
obtained instead of the expected amide, with a free OH group. A second reaction took
place at the hydroxyl and an amide functionalized with an ester was isolated in 72% yield
(Scheme 3, 15). Attempts to reduce the amount of the selenocarboxylate to achieve
selectivity resulted in the same product, in lower yields.
Scheme 3.
8

Apart from amides, other carbonyl derivatives were accessed from the
corresponding azide, as sulfonamides (28 and 29), imides (30 and 31), phosphoramide
(32) and carbamate (33). Worth to point out that the expansion of the methodology for the
synthesis of this class of carbonyl compounds represents an important advance since
several compounds bearing these functional group have pronounced pharmacological
activities.24 Benzylic azides were effective partners in reaction with selenocarboxylates,
providing amides 16 and 17 in quantitative yields. These results are a positive aspect of
our method, since previous reports from the literature indicate that aliphatic azides are not
reactive substrates to react with selenocarboxylates to provide amides.17 Alkyl azides were
less efficient. An alkyl derivative was obtained in moderate yields (19). However, when
alkyl azides containing carbonyl substituents were tested, the products were not obtained
(36, 37 and 38). Neither when azides containing organosilicon groups were used (39 and
40).
Furthermore, different commercial acyl chlorides were explored for generation of
selenocarboxylate in situ, starting from elemental selenium. Besides aromatic (1-17, 19,
22-28, 30-32, 34), benzyl (18 and 29) and alkyl (20 and 21 ) selenocarboxylates have also
been successfully employed in this amidation reaction. Additional functional group
tolerance was observed for the use iso-butylchloroformate as the amidation substrate.
When exposed to our reaction conditions, carbamate 33 was isolated in very good yield.
Notably, the mildness of the reaction can be seen by the tolerance of a cyano group at the
azide reactant, which remains untouched in the final product. Also worth to point out is the
possibility of obtaining a primary amide simply by using sodium azide as ammonia
equivalent (Scheme 4). The reaction with the selenocarboxylate occurred smoothly and,
gratifyingly the desired primary amide was isolated yield of 82% yield (34, Scheme 4).
9

Scheme 4. Synthesis of a primary amide.
Next, to prove that the reaction is not limited to the use of acyl chlorides as the
precursors for the selenocarboxylates, we have decided to explore the scope for the use of
carboxylic acids as the source of selenocarboxylate, in a one-pot 4-step amidation
reaction. Carboxylic acids are interesting starting material since less harmful that the acyl
chlorides, are widely available, affordable, and present in a number of pharmaceuticals
and medicinally relevant molecules.25
To evaluate the suitability of the use of carboxylic acids as the starting substrate, we
selected the more reactive electron-deficient aromatic azides as the reaction partners.
Therefore, the starting carboxylic acid material was first activated as a mixed anhydride26
by reaction with N-methylmorpholine (NMM) and ethyl chloroformate. After full
consumption of the carboxylic acid, reaction with freshly prepared Li2Se took place,
resulting in the corresponding selenocarboxylate, which can be used directly for the
amidation reaction. Introduction of the azide to the reaction mixture resulted in evolution on
N2 and precipitation of elemental selenium indicating the completion of the reaction. The 4-
step sequence occurs without isolation of any intermediates and only stable, easy-to-
handle materials have been manipulated. All reactive intermediates are generated in situ
and their handling avoided. In addition, by-products formed, Se and N2, are harmless and
removed by simple filtration. A variety of carboxylic acid were successfully employed in
generation of selenocarboxylate furnishing amides bearing both aryl (Scheme 5, 41-47)
and alkyl (49-54) moieties. Functional group tolerance was also observed in aromatic
10

selenocarboxylates such as chloro (41 and 42), methoxy (43-45), iodine (46),
trifluoromethyl (47), and only the carboxylic acid bearing both bromide and methoxy
groups did not furnished the desired amide (48).
The reaction of the aliphatic selenocarboxylates (Scheme 5, 49-54) gave
comparable yields to aromatic selenocarboxylates. Amidation worked well when 4-
phenylbutiric (49 and 50), sterically hindered pivalic (51), α,β-unsaturated tiglic (52),
ibuprofen (53) and oleic acids have been used (54). Worth pointing out is the 4-step
amidation was successfully applied to the modification of ibuprofen, which is a well-known
anti-inflammatory drug,27 to give an amide derivative in up to >95% yield. In addition, a
fatty acid derivative from oleic acid was also obtained in a good 48% yield, which is a slight
decrease compared to smaller alkyl substrates, likely due to solubility issues. These two
examples highlight the potential utility of this method in medicinal chemistry.
Scheme 4. Reaction scope from carboxylic acid derivatives.
11

Next, the scope was further investigated in carbohydrate chemistry. The amidation
method was successfully employed in N-glycosylation/modifying carbohydrates, using
sugar-derived azides possessing a pyranosyl and furanosyl scaffold and carboxylic acids
from biomolecules as starting materials for selenocarboxylate generation (Scheme 6).
Amides derived from two different sugars have been studied. The glycosyl amide 55 was
synthesized by reacting selenocarboxylate derived from fatty acid/estearic acid with and a
glucosyl-derived azide in 50% yield. An amino acid derivative was also tested under the
amidation conditions, and N-Boc-phenylalanine was used, followed by a ribose-derived
azide as reaction partner, furnishing the expected amide 56 in 65% yield. Glycosyl amides
are an important connection found in nature (e.g. glycopeptides, lipopolysaccharides),
known for possessing a wide range of bioactivities and are important scaffolds on
glycobiology studies.28 These examples highlight the potential of the methodology in
carbohydrate chemistry/ biomolecules amidation.
Scheme 5. Glycosyl amides synthesis by azide-selenocarboxylate amidation
A) N-glycosyl amidation starting from fatty acid
OAc
O
AcO
AcO
N3
i. NMM
ii. ClCOOEt
O
AcO
OAc
O
(1 equiv.)
O
Se
+ N2 + Se0
O
16
AcO
AcO
iii. Li2Se
THF, r.t
NH
55 50%
OH
THF
16 h, r.t
(4 equiv.)
AcO
B) N-glycosyl amidation starting from amino acid
O
N3
OMe
O
O
O
O
O
O
N
i. NMM
ii. ClCOOEt
OMe
H
(1 equiv.)
HN
OH
Boc
Se
Boc
O
+ N2 + Se0
O
HN
HN
iii. Li2Se
THF, r.t
THF
16 h, r.t
Boc
(4 equiv.)
56 65%
12

Conclusions
In summary, a broad scope of 49 amides were prepared in up >95% yield for a wide
range of substrates, in alkyl, aryl, and heterocyclic derivatives and displaying broad
functional group tolerance at both reaction partners. Our one-pot procedure proved to be
very efficient across a range of different acyl chlorides and carboxylic acids used as the
selenocarboxylate precursors, including amino acid and fatty acid in mild reaction
conditions. Selenocarboxylates were easily obtained in situ by reacting mixed anhydrides
with Li2Se, starting from elemental selenium and avoiding handling and isolating any
intermediate, rendering to the selenocarboxylate the status of a traceless reagent.
Generally, it weren’t observed electronic and steric effects that exert much influence in
reaction yield, once the amidation was successfully applied in a broad range of functional
groups from both azides and selenocarboxylates reaction partners. However, a certain
limitation was observed with the alkyl carbonyl compounds. In addition,
selenocarboxylates formed from carboxylic acids presented slightly lower yields than from
acyl chlorides. It is important to notice that selenocarboxylate-azide amidation were more
effective when electron-deficient azides were employed but the improvement with less
reactive azides, such as benzylic substrates, since other protocols in literature did not
react at all to furnish amide with selenocarboxylate.
Experimental Section
1
General Information. H, 13C, 19F, 31P NMR spectra were recorded on a 400 MHz
spectrometer (for 1H NMR) at room temperature, using a 5-mm internal diameter probe in
chloroform (CDCl3), methanol (CD3OD) or dimethyl sulfoxide (DMSO-d6). ESI-QTOF-MS
measurements were performed in the positive ion mode (m/z 50-2000 range). IR spectra
13

were obtained on an FTIR-ATR instrument. Melting points were measured optical
microscope apparatus and are uncorrected. Optical rotation were obtained in polarimeter
o
at 20 C, unless otherwise noted. Flash column chromatography was performed using
Silica Gel (230-400 mesh) following the methods described by Still29 with the indicated
solvent system. Thin layer chromatography (TLC) was performed using supported silica
gel GF254, 0.25 mm thickness, and visualization of the compounds was accomplished
with UV light (254 nm) or vanillin. Lithium triethylborohydride was used as a 1M THF
commercial solution. Elemental selenium (-100 mesh) was dried in oven (80 oC) overnight
prior to use. Applied azides are known compounds and were prepared according to
literature procedures.30
General procedure for amidation using acyl chloride. Under an argon
atmosphere, lithium triethylborohydride (2.0 mmol, 8 equiv.) was added over selenium
powder (1.0 mmol, 4 equiv.) forming Li2Se as a white solution. THF (3 mL) was added into
the mixture and after 5 min stirring, the acyl chloride (1.0 mmol, 4 equiv.) was then added
dropwise and the orange/yellow clear solution formed was stirred at room temperature for
30 min. After this time, the azide (0.25 mmol,1 equiv.) was added. The reaction was
allowed to stir at room temperature for up to 16 h. After consumption of the starting azide,
as shown by TLC or selenium powder precipitated, the reaction mixture was quenched
with aqueous saturated NaCl (20 mL) and extracted with AcOEt (3x15 mL). The combined
organic layers were dried with MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by flash column chromatography eluting with a mixture of
hexane/ethyl acetate.
14

N-(4-nitrophenyl)-benzamide (1)
Yellow solid (0.060 g, >95%). CAS Registry Number 3393-96-2. Rf = 0.5 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.83 (s, 1H), 8.28 (d, J = 9.3
Hz, 2H), 8.09 (d, J = 9.3 Hz, 2H), 8.00 (d, J = 7.1 Hz, 2H), 7.68 – 7.55 (m, 3H).13C NMR
(101 MHz, DMSO-d6): δ (ppm) 166.7, 146.0, 142.9, 134.7, 132.6, 129.0, 128.4, 125.2,
120.2.
4-methyl-N-(4-nitrophenyl)-benzamide (2)
Yellow solid (0.063 g, >95%). CAS Registry Number 33667-88-8. Rf = 0.5 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.71 (s, 1H), 8.25 (d, J = 9.3
Hz, 2H), 8.06 (d, J = 9.3 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 2.39 (s,
13
3H). C NMR (101 MHz, DMSO-d6): δ (ppm) 166.5, 146.1, 142.8, 131.8, 129.8, 129.5,
128.4, 125.2, 120.2, 21.5.
4-methyl-N-(3-nitrophenyl)-benzamide (3)
Yellow solid (0.060 g, 94%). m.p.: 118 – 120 °C. Rf = 0.5 (30% ethyl acetate/n-hexane).
1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.61 (s, 1H), 8.82 (t, J = 2.2 Hz, 1H), 8.21 (ddd, J
= 8.2, 2.2, 1.0 Hz, 1H), 7.96 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.65
(t, J = 8.2 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 2.40 (s, 3H).13C NMR (101 MHz, DMSO-d6): δ
(ppm) 166.3, 148.3, 142.6, 140.9, 131.7, 130.4, 129.4, 128.2, 126.5, 118.4, 114.7, 21.52.
IR (νmax, cm-1): 3378, 2960, 1665, 1528, 1353, 1260, 1018, 949, 743. HRMS (ESI+): m/z,
calcd for C14H13N2O3 [M+H]+ 257.0926, found 257.0926.
N-(4-bromophenyl)-benzamide (4)
15

White solid (0.135 g, >95%). CAS Registry Number 7702-38-7. Rf = 0.3 (10% ethyl
acetate/n-hexane). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.38 (s, 1H), 7.96 (d, J = 7.4
13
Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.63 – 7.47 (m, 5H). C NMR (101 MHz, DMSO-d6) δ
(ppm) 166.1, 139.0, 135.2, 132.1, 131.9, 128.8, 128.1, 122.7, 115.8.
4-methyl-N-(4-bromophenyl)-benzamide (5)
White solid (0.069 g, 95%). CAS Registry Number 158525-82-7. Rf = 0.3 (10% ethyl
acetate/n-hexane). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.27 (s, 1H), 7.87 (d, J = 8.2
Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 2.38 (s,
13
3H). C NMR (101 MHz, DMSO-d6): δ (ppm) 165.9, 142.2, 139.1, 132.2, 131.8, 129.4,
128.2, 122.6, 115.6, 21.5.
N-(2-iodophenyl)-4-methyl-benzamide (6)
White solid (0.150 g, >95%). CAS Registry Number 349089-26-5. Rf = 0.5 (30% ethyl
1
acetate/n-hexane). H NMR (400 MHz, CDCl3): δ (ppm) 8.43 (dd, J = 8.0, 1.5 Hz, 1H),
8.26 (br, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.78 (dd, J = 8.0, 1.5 Hz, 1H), 7.40 – 7.34 (m, 1H),
13
7.29 (d, J = 8.4 Hz, 2H), 6.85 (ddd, J = 8.0, 7.5, 1.5 Hz, 1H), 2.41 (s, 3H). C NMR (101
MHz, CDCl3): δ (ppm) 165.1, 142.6, 138.6, 138.2, 131.5, 129.5, 129.2, 127.0, 125.8,
121.6, 90.2, 21.4.
N-(4-cyanophenyl)-4-methyl-benzamide (7)
White solid (0.062 g, 90%). m.p.: 211 – 213 °C. Rf = 0.5 (10% ethyl acetate/n-hexane). 1H
NMR (400 MHz, DMSO-d6): δ (ppm) 10.54 (s, 1H), 8.00 (d, J = 9.0 Hz, 2H), 7.88 (d, J =
8.2 Hz, 2H), 7.80 (d, J = 9.0 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 2.38 (s, 3H). 13C NMR (101
16

MHz, DMSO-d6): δ (ppm) 166.4, 144.0, 142.6, 133.5, 131.9, 129.4, 128.3, 120.6, 119.5,
105.6, 21.5. IR (νmax, cm-1): 3378, 2980, 2170, 1734, 1374, 1233, 1038, 622. HRMS
(ESI+): m/z, calcd for C15H13N2O [M+H]+ 237.1028, found 237.1021.
4-methyl-N-[3-(trifluoromethyl)phenyl]-benzamide (8)
1
White solid (0.046 g, 75%). m.p.: 98 – 100 °C. Rf = 0.4 (10% ethyl acetate/n-hexane). H
NMR (400 MHz, DMSO-d6): δ (ppm) 10.46 (s, 1H), 8.26 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H),
7.91 (d, J = 8.0 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0
Hz, 2H), 2.39 (s, 3H).13C NMR (101 MHz, DMSO-d6): δ (ppm) 166.2, 142.4, 140.5, 132.0,
130.2, 129.8 (q, J = 31.3 Hz), 129.4, 128.2, 124.7 (q, J = 273.7 Hz), 124.1, 120.2 (q, J =
4.0 Hz), 116.7 (q, J = 4.0 Hz), 21.4. 19F NMR (376 MHz, DMSO-d): δ (ppm) -61.3. IR (νmax
,
cm-1): 3297, 2932, 1654, 1540, 1448, 1327, 1128, 801, 702. HRMS (ESI+): m/z, calcd for
C15H13F3NO [M+H]+ 280.0949, 280.0946.
N-[3,5-bis(trifluoromethyl)phenyl]-4-methyl- benzamide (9)
White solid (0.064 g, >95%). CAS Registry Number 424812-38-4. Rf = 0.3 (10% ethyl
1
acetate/n-hexane). H NMR (400 MHz, CDCl3): δ (ppm) 8.09 (s, 3H), 7.70 (d, J = 8.0 Hz,
13
2H), 7.55 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 2.36 (s, 3H). C NMR (101 MHz, CDCl3): δ
(ppm) 165.9, 143.3, 139.4, 132.3 (q, J = 34.3 Hz), 130.8, 129.6, 127.0, 123.0 (q, J = 272.7
Hz), 119.7 (m), 117.6 (m), 21.5. 19F NMR (376 MHz, CDCl3): δ (ppm) -63.0.
N-(2-methoxyphenyl)-4-methyl-benzamide (10)
White solid (0.047 g, 77%). CAS Registry Number 122589-84-8. Rf = 0.5 (30% ethyl
1
acetate/n-hexane). H NMR (400 MHz, CDCl3): δ (ppm) 8.53 (dd, J = 7.6, 1.6 Hz, 2H),
17

7.78 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.03 (dtd, J = 22.0, 7.6, 1.6 Hz, 2H), 6.89
13
(dd, J = 7.6, 1.6 Hz, 1H), 3.89 (s, 3H), 2.40 (s, 3H). C NMR (101 MHz, CDCl3): δ (ppm)
165.1, 148.0, 142.0, 132.3, 129.3, 127.8, 126.9, 123.6, 121.0, 119.6, 109.8, 55.7, 21.3.
N-(3-methoxyphenyl)-4-methyl-benzamide (11)
White solid (0.133 g, >95%). CAS Registry Number 101078-45-9. Rf = 0.5 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.25 (br, 1H), 7.72 (d, J = 8.2 Hz,
2H), 7.42 (t, J = 2.5 Hz, 1H), 7.22 – 7.09 (m, 4H), 6.66 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 3.74
(s, 3H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 165.9, 159.9, 142.1, 139.2,
131.8, 129.4, 129.1, 127.0, 112.4, 110.2, 105.7, 55.1, 21.3.
N-(4-methoxyphenyl)-4-methyl-benzamide (12)
White solid (0.075 g, >95%). CAS Registry Number 33667-91-3. Rf = 0.5 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.05 (br, 1H), 7.88 (d, J = 8.0
Hz, 2H), 7.70 (d, J = 9.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 3.75 (s,
3H), 2.38 (s, 3H). 13C NMR (101 MHz, DMSO-d6): δ (ppm) 165.3, 155.9, 141.7, 132.8,
132.6, 129.3, 128.0, 122.4, 114.1, 55.6, 21.4.
N-(2-methylphenyl)-4-methyl-benzamide (13)
White solid. (0,020 g, 34%). CAS Registry Number 55577-26-9. Rf = 0.7 (30% ethyl
1
acetate/n-hexane). H NMR (400 MHz, DMSO-d6): δ (ppm) 9.78 (s, 1H), 7.89 (d, J = 8.2
Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.34 – 7.12 (m, 4H), 2.38 (s, 3H), 2.23 (s, 3H). 13C NMR
(101 MHz, DMSO-d6): δ (ppm) 165.5, 141.9, 136.9, 134.1, 132.1, 130.7, 129.3, 128.1,
127.1, 126.4, 126.3, 21.4, 18.3.
18

4-methyl-N-2-naphthalenyl-benzamide (14)
White solid (0.090 g, >95%). CAS Registry Number 84647-12-1. Rf = 0.7 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.30 (d, J = 2.0 Hz, 1H), 8.19 (br,
1H), 7.76 (dd, J = 16.0, 8.0 Hz, 5H), 7.58 (dd, J = 8.5, 2.0 Hz, 1H), 7.46 – 7.35 (m, 2H),
13
7.22 (d, J = 8.5 Hz, 2H), 2.38 (s, 3H). C NMR (101 MHz, CDCl3): δ (ppm) 165.9, 142.3,
135.4, 133.7, 131.9, 130.6, 129.3, 128.6, 127.6, 127.4, 127.0, 126.4, 124.9, 120.2, 117.0,
21.4.
4-methyl-4-[(4-methylbenzoyl)amino]phenyl ester benzoic acid (15)
1
White solid (0.049 g, 56%). Rf = 0.6 (30% ethyl acetate/n-hexane). H NMR (400 MHz,
DMSO-d6): δ (ppm) 10.26 (s, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 7.83
(d, J = 9.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 9.0 Hz,
2H), 2.42 (s, 3H), 2.38 (s, 3H). 13C NMR (101 MHz, DMSO-d6): δ (ppm) 146.7, 144.9,
142.1, 137.4, 132.4, 130.3, 130.0, 129.4, 128.1, 126.7, 122.4, 121.7, 21.7, 21.5.
N-[(4-bromophenyl)methyl]-4-methyl-benzamide (16)
White solid (0.076 g, >95%). m.p.: 151 – 153 °C. Rf = 0.6 (30% ethyl acetate/n-hexane).
1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.99 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H),
7.51 (d, J = 8.2 Hz, 2H), 7.3 – 7.25 (m, 4H), 4.43 (d, J = 6.0 Hz, 2H), 2.35 (s, 3H). 13C
NMR (101 MHz, DMSO-d6): δ (ppm) 166.5, 141.6, 139.7, 131.8, 131.5, 129.9, 129.4,
129.3, 127.7, 120.1, 42.4, 21.4. IR (νmax, cm-1): 3297, 2932, 2848, 1639, 1547, 1479, 1303,
19

1258, 1068, 992, 801, 664. HRMS (ESI+): m/z, calcd for C15H15BrNO [M+H]+ 304.0337,
found 304.0339.
N-[(2-bromophenyl)methyl]-4-methyl-benzamide (17)
White solid (0.080 g, >95%). CAS Registry Number 1306052-87-8. Rf = 0.6 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.68 (d, J = 8.0 Hz, 2H), 7.52 (d, J
= 7.5 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.26 – 7.07 (m, 4H), 6.98 (br, 1H), 4.63 (d, J = 6.0
13
Hz, 2H), 2.36 (s, 3H). C NMR (101 MHz, CDCl3): δ (ppm) 167.3, 141.8, 137.2, 132.6,
131.2, 130.0, 129.0, 128.9, 127.5, 126.9, 123.5, 44.0, 21.3.
N-(4-cyanophenyl)-benzeneacetamide (18)
White solid (0.062 g, >95%). CAS Registry Number 89246-38-8. Rf = 0.4 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.62 (s, 1H), 7.81 (d, J = 9.0
13
Hz, 2H), 7.76 (d, J = 9.0 Hz, 2H), 7.38 – 7.22 (m, 5H), 3.72 (s, 2H). C NMR (101 MHz,
DMSO-d6): δ (ppm) 170.4, 143.8, 135.8, 133.7, 129.6, 128.8, 127.1, 119.58, 119.51,
105.4, 43.8.
4-methyl-N-octyl-benzamide (19)
Colorless oil (0.040 g, 65%). CAS Registry Number 203627-10-5. Rf = 0.8 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.67 (d, J = 8.2 Hz, 2H), 7.20 (d, J
= 8.2 Hz, 2H), 6.44 (br, 1H), 3.41 (q, J = 7.0 Hz, 2H), 2.37 (s, 3H), 1.63 – 1.53 (m, J =
14.8, 7.4 Hz, 2H), 1.46 – 1.07 (m, 10H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ (ppm) 167.6, 141.6, 131.7, 129.0, 126.8, 40.0, 31.7, 29.5, 29.2, 29.1, 26.9, 22.5,
21.3, 14.0.
20

3-methyl-N-(4-nitrophenyl)-butanamide (20)
Yellow solid (0.041 g, 74%). CAS Registry Number 151860-14-9. Rf = 0.5 (30% ethyl
1
acetate/n-hexane). H NMR (400 MHz, CDCl3): δ (ppm) 8.19 (d, J = 9.2 Hz, 2H), 8.12 (br,
1H), 7.76 (d, J = 9.2 Hz, 2H), 2.31 (d, J = 6.6 Hz, 2H), 2.29 – 2.17 (m, 1H), 1.03 (s, 3H),
1.01 (s, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 171.6, 144.0, 143.2, 124.9, 119.0, 46.8,
26.1, 22.3.
N-(4-cyanophenyl)-heptanamide (21)
1
White solid (0.059 g, >95%). m.p.: 69 - 71 °C. Rf = 0.6 (30% ethyl acetate/n-hexane). H
NMR (400 MHz, CDCl3): δ (ppm) 8.38 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz,
2H), 2.41 (t, J = 8.0 Hz, 2H), 1.71 (quint, J = 8.0 Hz, 2H), 1.40 – 1.24 (m, 6H), 0.87 (t, J =
6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ (ppm) 172.5, 142.4, 133.0, 119.5, 118.9,
106.2, 37.5, 31.3, 28.7, 25.3, 22.3, 13.8. IR (νmax, cm-1): 3239, 3169, 3101, 3039, 2925,
2857, 2222, 1664, 1587, 1527, 1404, 831, 541. HRMS (ESI+): m/z, calcd for C14H19N2O
[M+H]+ 231.1497, found 231.1483.
4-methyl-N-2-pyridinyl-benzamide (22)
1
White solid (0.050 g, 40%). Rf = 0.4 (30% ethyl acetate/n-hexane). RMN H (400 MHz,
CDCl3): δ (ppm) 8.43 (dt, J = 8.4 Hz, 1H), 8.26 (br, 1H), 7.85 (d, J = 8.3 Hz; 2 H), 7.78 (dd,
J = 8.4 Hz, 1.44 Hz; 1H), 7.37 (ddd, J = 7.0, 1.1 Hz, 1H); 7,31-7,29 (m, 2H); 6,85 (td, J =
13
7,8 Hz e 1,7 Hz; 1H); 2,41 (s, 3H). RMN C (101 MHz, CDCl3): δ (ppm) 171,3; 148,5;
144,4; 131,9; 130,1; 129,1; 126,6; 125,4; 116,6; 115,9; 21,7.
21

4-methyl-N-2-thiazolyl-benzamide (23)
White solid (0.050 g, 92%). CAS Registry Number 150175-93-2. Rf = 0.4 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.99 (d, J = 8.0 Hz, 2H), 7.31 (d, J
13
= 8.0 Hz, 2H), 7.18 (d, J = 3.7 Hz, 1H), 6.95 (d, J = 3.7 Hz, 1H), 2.45 (s, 3H). C NMR
(101 MHz, CDCl3): δ (ppm) 165.6, 160.6, 143.4, 136.6, 130.0, 129.4, 128.1, 113.3, 21.6.
N-[4-(2-benzothiazolyl)phenyl]-4-methyl-benzamide (24)
Yellow solid (0.087 g, >95%). m.p.: 252 – 253 °C. Rf = 0.5 (30% ethyl acetate/n-hexane).
1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.48 (s, 1H), 8.16 – 8.07 (m, 3H), 8.06 – 7.99 (m,
3H), 7.91 (d, J = 8.2 Hz, 2H), 7.57 – 7.50 (m, 1H), 7.48 – 7.41 (m, 1H), 7.36 (d, J = 8.2 Hz,
2H), 2.40 (s, 3H). 13C NMR (101 MHz, DMSO-d6): δ (ppm) 167.5, 166.1, 154.1, 142.7,
142.4, 134.8, 132.2, 129.4, 128.3, 128.3, 128.3, 127.0, 125.7, 123.0, 122.7, 120.8, 21.5.
IR (νmax, cm-1): 3372, 3009, 2919, 2854, 1652, 1586, 1520, 1479, 1405, 1306, 961, 821,
747, 713, 614. HRMS (ESI+): m/z, calcd for C21H17N2OS [M+H]+ 345.1062, found
345.1062.
N-[3-(2-benzoxazolyl)-4-hydroxyphenyl]-4-methyl-benzamide (25)
White solid (0.121 g, >95%). m.p.: 260 – 262 °C. Rf = 0.3 (30% ethyl acetate/n-
hexane).1H NMR (400 MHz, DMSO-d6): δ (ppm) 11.04 (s, 1H), 10.28 (s, 1H), 8.64 (d, J =
2.6 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.90 – 7.83 (m, 3H), 7.52 – 7.43 (m, 2H), 7.35 (d, J =
8.0 Hz, 2H), 7.13 (d, J = 8.9 Hz, 1H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO-d6): δ (ppm)
165.6, 162.7, 154.4, 149.3, 142.1, 140.0, 132.3, 129.4, 128.1, 127.1, 126.4, 125.8, 119.7,
119.1, 117.7, 111.5, 110.2, 21.5. IR (νmax, cm-1): 3363, 3031, 2910, 2858, 1653, 1585,
22

1479, 1404, 1314, 960, 839, 741, 613. HRMS (ESI+): m/z, calcd for C21H17N2O3 [M+H]+
345.1239, found 345.1214.
2-(4-methylbenzamido)-4-methyl-6-phenyl ethyl ester-5-pyrimidinecarboxylic acid (26)
White solid (0.090 g, >95%). m.p.: 180 - 182 °C. Rf = 0.4 (30% ethyl acetate/n-hexane).
1H NMR (400 MHz, CDCl3): δ (ppm) 8.67 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.74 – 7.58 (m,
2H), 7.50 – 7.42 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 2.65 (s, 3H),
13
2.43 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H). C NMR (101 MHz, CDCl3): δ (ppm) 167.6, 167.3,
165.1, 164.7, 156.7, 142.9, 137.3, 131.1, 130.0, 129.2, 128.3, 128.1, 127.4, 121.1, 61.6,
22.6, 21.3, 13.4. IR (νmax, cm-1): 3295, 2985, 1732, 1695, 1582, 1489, 1422, 1257, 1092,
746, 700. HRMS (ESI+): m/z, calcd for C22H21N3O3 [M+H]+ 376.1661, found 376.1666.
N-[(8α,9S)-6'-methoxycinchonan-9-yl]-4-methyl-benzamide (9CI) (27)
White solid (0.1664 g, 58%). [α]D20= - 36.0 °(c 1.000, MeOH). m.p.: 79 – 81 °C. Rf = 0.3
1
(90% ethyl acetate/10% methanol). H NMR (400 MHz, CD3OD): δ (ppm) 8.69 (d, J = 4.8
Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.71 (d,
J = 4.8 Hz, 1H), 7.41 (dd, J = 9.2, 2.6 Hz, 1H), 7.16 (d, J = 8.5 Hz, 2H), 6.13 (br, 1H, CH,
5.94 (ddd, J = 17.4, 10.4, 7.3 Hz, 1H), 5.15 (d, J = 17.2 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H).
4.11 – 4.03 (m, 1H), 4.01 (s, 3H), 3.81 – 3.65 (m, 1H), 3.42 (dd, J = 13.5, 10.3 Hz, 1H),
3.10 (ddd, J = 13.5, 5.5, 2.1 Hz, 1H), 3.06 – 2.96 (m, 1H), 2.58 – 2.47 (m, 1H), 2.29 (s,
3H), 1.88 – 1.73 (m, 4H), 0.99 (dd, J = 13.5, 6.3 Hz, 1H).13C NMR (75 MHz, CD3OD): δ
(ppm) 169.6, 159.9, 148.2, 145.6, 145.1, 143.5, 141.0, 131.9, 131.4, 129.97, 129.93,
128.6, 123.7, 121.3, 116.0, 103.1, 60.0, 56..4, 55.9, 51.1, 42.5, 39.5, 28.4, 27.0, 26.9,
21.4. IR (νmax, cm-1): 3292, 3074, 2932, 2864, 2100, 1735, 1641, 1617, 1503, 1474, 1365,
23

1321, 1237, 1040, 1025, 921, 829. HRMS (ESI+): m/z, calcd for C28H32N3O2 [M+H]+
442.2495, found 442, 2495.
4-methyl-N-[(4-methylphenyl)sulfonyl]-benzamide (28)
White solid (0.110 g, >95%). CAS Registry Number 120336-96-1. Rf = 0.4 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, CDCl3): δ (ppm) 9.52 (br, 1H), 8.04 (d, J = 8.3 Hz,
2H), 7.72 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 2.42 (s,
3H), 2.35 (s, 3H).13C NMR (101 MHz, CDCl3): δ (ppm) 164.4, 145.0, 144.2, 135.5, 129.5,
129.4, 128.5, 128.2, 127.9, 21.6, 21.5.
N-[(4-methylphenyl)sulfonyl]-benzeneacetamide (29)
White solid (0.055 g, 76%). CAS Registry Number 1788-13-2. Rf = 0.4 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, DMSO-d6): δ (ppm) 7.79 (d, J = 8.2 Hz, 2H), 7.39
(d, J = 8.2 Hz, 2H), 7.30 – 7.19 (m, 3H), 7.18 – 7.13 (m, 2H), 3.54 (s, 1H), 2.38 (s, 3H). 13C
NMR (101 MHz, DMSO-d6): δ (ppm) 169.8, 144.7, 136.8, 134.4, 129.9, 129.7, 128.8,
128.0, 127.3, 42.9, 21.5.
N-benzoyl-4-methyl-benzamide (30)
White solid (0.037 g, 62%). CAS Registry Number 58010-65-4. Rf = 0.4 (30% ethyl
1
acetate/n-hexane). H NMR (400 MHz, CDCl3): δ (ppm) 9.18 (br, 1H), 7.85 (dd, J = 8.4,
1.3 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.57 (tt, J = 7.5, 1.3 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H),
13
7.26 (d, J = 8.4 Hz, 2H), 2.40 (s, 3H). C NMR (101 MHz, CDCl3): δ (ppm) 166.6, 166.3,
143.8, 133.3, 132.8, 130.3, 129.4, 128.6, 128.0, 127.9, 21.5.
24

4-methyl-N-(4-methylbenzoyl)-benzamide (31)
White solid (0.054 g, 85%). m.p.: 108 - 110 °C. Rf = 0.5 (30% ethyl acetate/n-hexane). 1H
NMR (400 MHz, CDCl3): δ (ppm) 9.13 (s, 1H), 7.75 (d, J = 8.0 Hz, 4H), 7.26 (d, J = 8.0 Hz,
4H), 2.40 (s, 6H). 13C NMR (101 MHz, CDCl3): δ (ppm) 166.2, 143.8, 130.5, 129.4, 127.9,
21.6. IR (νmax, cm-1): 3249, 2913, 1720, 1612, 1474, 1230, 1115, 824, 733. HRMS (ESI+):
m/z, calcd for C16H16NO2 [M+H]+ 254.1181, found 254.1179.
N-(4-methylbenzoyl)-diphenyl ester phosphoramidic acid (32)
White crystal solid (0.180 g, >95%). CAS Registry Number 1376827-57-4. Rf = 0.3 (30%
ethyl acetate/n-hexane). 1H NMR (400 MHz, CDCl3): δ (ppm) 9.77 (d, J P-H = 10.0 Hz, 1H),
7.87 (d, J = 8.3 Hz, 2H), 7.26 – 7.17 (m, 8H), 7.17 – 7.08 (m, 4H), 2.36 (s, 3H).13C NMR
(101 MHz, CDCl3): δ (ppm) 167.4 (d, J = 3.5 Hz), 150.0 (d, J = 6.7 Hz), 143.5, 129.57,
129.56, 129.0, 125.40 (d, J = 1.4 Hz), 128.46, 120.43 (d, J = 4.8 Hz), 21.4. Decoupled 31P
31
NMR (162 MHz, CDCl3): δ (ppm) -9.02. Coupled P NMR (162 MHz, CDCl3): δ (ppm) -
9.03 (d, J P-H = 10.0 Hz).
N-(4-cyanophenyl)-2-methylpropyl ester carbamic acid (33)
White solid (0.040 g, 72%). m.p.: 110 - 112 °C. Rf = 0.8 (30% ethyl acetate/n-hexane). 1H
NMR (400 MHz, CDCl3): δ (ppm) 7.58 (d, J = 9.0 Hz, 2H), 7.55 (d, J = 9.0 Hz, 2H), 7.36 –
7.21 (m, 1H), 3.97 (d, J = 6.7 Hz, 2H), 2.04 – 1.92 (m, 1H), 0.96 (d, J = 6.7 Hz, 6H). 13C
NMR (101 MHz, CDCl3): δ (ppm) 153.1, 142.4, 133.2, 118.9, 118.1, 105.7, 71.7, 27.7,
18.8. IR (νmax, cm-1): 3343, 2954, 2924, 2870, 2222, 1726, 1589, 1519, 1214, 1054, 818,
543. HRMS (ESI+): m/z, calcd for C12H15N2O2 [M+H]+ 219.1134, found 219.1138.
25

4-methyl-benzamide (34)
White solid (0.028 g, 82%). CAS Registry Number 619-55-6. Rf = 0.2 (30% ethyl acetate/n-
1
hexane). H NMR (400 MHz, DMSO-d6): δ (ppm) 7.90 (br, 1H), 7.79 (d, J = 8.0 Hz, 2H),
13
7.27 (br, 1H), 7.25 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H). C NMR (101 MHz, DMSO-d6): δ
(ppm) 168.2, 141.5, 131.9, 129.2, 127.9, 21.4.
General procedure for amidation using carboxylic acids. Under argon atmosphere, to
a solution of the carboxylic acid (1.0 mmol, 4 equiv.) in THF (3 mL) was added N-
methylmorpholine (1.0 mmol, 4 equiv.). After stirring for 5 minutes at room temperature,
ethyl chloroformate (1.0 mmol, 4 equiv.) was added and stirring was prolonged for
additional 15 minutes. Then, freshly prepared Li2Se (as previous procedure) (1 mmol, 4
equiv.) was quickly added into the obtained mixed anhydride solution using a syringe. After
additional 15 min of stirring, the azide (0.25 mmol, 1 equiv.) was added over the
selenocarboxylate solution. The reaction was carried out at room temperature. The
reaction was allowed to stir at room temperature for up to 16 h. After consumption of the
starting azide, as shown by TLC or selenium powder precipitated, the reaction mixture was
quenched with HCl 10% (3x20 mL), washed with aqueous saturated NaCl (20 mL) and
extracted with AcOEt (3x15 mL). The combined organic layers were dried with MgSO4,
filtered and concentrated under reduced pressure. The crude product was purified by flash
column chromatography eluting with a mixture of hexane/ethyl acetate (90:10).
4-chloro-N-(4-cyanophenyl)-benzamide (41)
White solid (0.065 g, >95%). m.p.: 120 - 123 °C. Rf = 0.5 (30% ethyl acetate/n-hexane). 1H
NMR (400 MHz, DMSO-d6): δ (ppm) 10.71 (s, 1H), 8.02 (d, J = 2.0 Hz, 2H), 7.99 (d, J =
26

2.0 Hz, 2H), 7.83 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H).13C NMR (101 MHz, DMSO-
d6): δ (ppm) 165.5, 143.8, 137.4, 133.6, 133.5, 130.3, 129.0, 120.7, 119.5, 106.0. IR (νmax
,
cm-1): 3247, 2916, 2855, 2211, 1651, 1590, 1505, 1406, 1322, 1260, 991, 831, 731, 539.
HRMS (ESI+): m/z, calcd for C14H10ClN2O [M+H]+ 257.0482, found 257,0481; calcd for
C14H9ClN2ONa [M+Na]+ 279.0301, found 279.0296.
3-chloro-N-(2-cyanophenyl)-benzamide (42)
White solid (0.055 g, 86%). m.p.: 143 - 145 °C. Rf = 0.6 (30% ethyl acetate/n-hexane). 1H
NMR (400 MHz, DMSO-d6): δ (ppm) 10.73 (s, 1H), 8.02 (t, J = 2.0 Hz, 1H), 7.99 (d, J = 8.9
Hz, 2H), 7.94 – 7.91 (m, 1H), 7.84 (d, J = 8.9 Hz, 2H), 7.70 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H),
7.60 (t, J = 8.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6): δ (ppm) 165.1, 143.6, 136.8,
133.7, 133.6, 132.3, 130.9, 128.0, 127.1, 120.7, 119.4, 106.1. IR (νmax, cm-1): 3321, 3083,
2845, 2222, 1684, 1599, 1523, 1407, 1300, 1253, 839, 716, 546. HRMS (ESI+): m/z, calcd
for C14H10ClN2O [M+H]+ 257.0482, found 257.0480.
N-(4-cyanophenyl)-4-methoxy-benzamide (43)
White solid (0.055 g, 88%). CAS Registry Number 134925-97-6. Rf = 0.3 (30% ethyl
1
acetate/n-hexane). H NMR (400 MHz, CDCl3): δ (ppm) 8.27 (s, 1H), 7.84 (d, J = 8.7 Hz,
2H), 7.80 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 3.87 (s,
3H).13C NMR (101 MHz, CDCl3): δ (ppm) 165.5, 162.8, 142.3, 133.1, 129.1, 126.0, 119.8,
118.9, 114.0, 106.8, 55.4.
N-(4-cyanophenyl)-2-methoxy-benzamide (44)
27

White solid (0.045 g, 70%). CAS Registry Number 361464-65-5. Rf = 0.4 (30% ethyl
1
acetate/n-hexane). H NMR (400 MHz, CDCl3): δ (ppm) 10.05 (br, 1H), 8.25 (dd, J = 8.0,
2.0 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.53 (ddd, J = 8.4, 7.3, 2.0
Hz, 1H), 7.17 – 7.11 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 4.07 (s, 3H).13C NMR (101 MHz,
CDCl3): δ (ppm) 163.4, 157.1, 142.3, 133.8, 133.1, 132.4, 121.7, 120.8, 120.0, 118.9,
111.5, 106.6, 56.28.
N-(4-cyanophenyl)-3,5-dimethoxy-benzamide (45)
White solid (0.075 g, >95%). m.p.: 116 – 118 °C. Rf = 0.5 (30% ethyl acetate/n-hexane).
1H NMR (400 MHz, DMSO-d6): δ (ppm) 10.56 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.83 (d, J =
8.8 Hz, 2H), 7.11 (d, J = 2.3 Hz, 2H), 6.76 (t, J = 2.3 Hz, 1H), 3.84 (s, 6H). 13C NMR (101
MHz, DMSO-d6): δ (ppm) 166.1, 160.9, 143.8, 136.8, 133.5, 120.7, 119.5, 106.3, 105.9,
104.1, 56.03. IR (νmax, cm-1): 3318, 2939, 2832, 2219, 1642, 1590, 1513, 1346, 1203,
1150, 1043, 831, 664, 551. HRMS (ESI+): m/z, calcd for C16H15N2O3 [M+H]+ 283.1083,
found 283.1079.
N-(4-cyanophenyl)-2-iodo-benzamide (46)
Light yellow solid (0.057 g, 65%). CAS Registry Number 81654-64-0. Rf = 0.4 (30% ethyl
acetate/n-hexane). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.94 (br, 1H), 7.91 (d, J = 8.0 Hz,
1H), 7.76 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.50 (dd, J = 7.5, 1.6 Hz, 1H), 7.44
(td, J = 7.5, 1.0 Hz, 1H), 7.17 (td, J = 7.5, 1.6 Hz, 1H).13C NMR (101 MHz, DMSO): δ
(ppm) 168.6, 143.6, 142.9, 139.5, 133.8, 131.8, 128.7, 128.6, 120.1, 119.5, 106.0, 94.0.
N-(4-cyanophenyl)-3-(trifluoromethyl)-benzamide (47)
28