A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles

Article abstract of DOI:10.1016/j.tet.2019.130527

A general synthesis of previously unknown semicarbazone-based α-amidoalkylating reagents, 4-(tosylmethyl)semicarbazones, has been developed. The synthesis involved three-component condensation of semicarbazones of aliphatic or aromatic aldehydes with the same or other aldehydes and p-toluenesulfinic acid. The scope and limitations of this reaction were investigated. The compounds obtained were demonstrated to be an efficient α-(4-semicarbazono)alkylating agents. They were reacted with H- (sodium borohydride), O- (sodium methylate), S- (sodium phenylthiolate), N- (pyrrolidine, sodium succinimide), P- (trialkyl phosphites), and C-nucleophiles (sodium diethyl malonate) to give the corresponding products of the tosyl group substitution, 4-substituted semicarbazones, including analogues of nitrofurazone. Among the prepared compounds tested in vitro for antibacterial and antifungal activity, three nitrofuryl-containing semicarbazones exhibited high biological activities with minimum inhibitory concentration (MIC) values of 8–32 μg/mL.

Full text of DOI:10.1016/j.tet.2019.130527

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A general and convenient synthesis of 4-(tosylmethyl)semicarbazones
and their use in amidoalkylation of hydrogen, heteroatom, and carbon
nucleophiles
Anastasia A. Fesenko, Alexander N. Yankov, Anatoly D. Shutalev*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., 119991, Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A general synthesis of previously unknown semicarbazone-based a-amidoalkylating reagents, 4-(tosyl-
Received 11 June 2019
Received in revised form
1 August 2019
Accepted 12 August 2019
Available online xxx
methyl)semicarbazones, has been developed. The synthesis involved three-component condensation of
semicarbazones of aliphatic or aromatic aldehydes with the same or other aldehydes and p-toluene-
sulfinic acid. The scope and limitations of this reaction were investigated. The compounds obtained were
demonstrated to be an efficient a-(4-semicarbazono)alkylating agents. They were reacted with H- (so-
dium borohydride), O- (sodium methylate), S- (sodium phenylthiolate), N- (pyrrolidine, sodium succi-
nimide), P- (trialkyl phosphites), and C-nucleophiles (sodium diethyl malonate) to give the
corresponding products of the tosyl group substitution, 4-substituted semicarbazones, including ana-
logues of nitrofurazone. Among the prepared compounds tested in vitro for antibacterial and antifungal
activity, three nitrofuryl-containing semicarbazones exhibited high biological activities with minimum
Keywords:
Semicarbazones
Three-component condensation
Sulfones
inhibitory concentration (MIC) values of 8e32 mg/mL.
Amidoalkylation
Nucleophiles
Antibacterial and antifungal activity
© 2019 Published by Elsevier Ltd.
1. Introduction
semicarbazide-based amidoalkylating reagents. Synthesis of these
reagents would significantly extend scope of the amidoalkylation
reaction and give unique access to various semicarbazide-
containing compounds which are of great interest due to their
different valuable properties [14]. For example, they exhibit anti-
convulsant [15], antihypertensive [16], antitumor [17], anti-
trypanosomal activity [18], serve as effective ligands in
coordination chemistry [19], and are used in the synthesis of aza-
peptides [14b,d].
Synthesis of the desired amidoalkylating reagents directly from
semicarbazides can not be performed since the basicity and
nucleophilicity of the nitrogen N1 are significantly higher than
those of the amide nitrogen N4 (e.g., pKa ¼ 3.86[20] and
pKa ¼ 0.053[21] for protonated semicarbazide and urea, respec-
tively, in water at 25 ꢀC). Therefore, the nitrogen N1 of semi-
carbazide should be initially protected with an electron-
withdrawing group (e.g., alkylidene, arylidene, or acyl group). In a
preliminary report, we described the first synthesis of
semicarbazide-based amidoalkylating reagents, 4-(tosylmethyl)
semicarbazones (4 examples), involving the condensation of aro-
matic aldehydes with semicarbazones of the same aldehydes and p-
toluenesulfinic acid in EtOH [22]. It would be highly desirable to
examine the scope and limitations of this three-component
a
-Amidoalkylation reaction is a powerful tool of modern organic
synthesis for carbon-carbon or carbon-heteroatom bond formation
(Scheme 1) [1]. The distinguishing features of amidoalkylating re-
agents are higher electrophilicity and wider structural diversity
compared with those of reagents involved in aminoalkylation re-
actions (the Mannich reaction, the Pictet-Spengler reaction, etc.).
Therefore, amidoalkylation has been extensively applied in the
synthesis of various nitrogen-containing acyclic and heterocyclic
compounds including bioactive natural products (e.g., alkaloids [2],
antibiotics [3], toxins [4], vitamins [5]) and pharmaceuticals [6].
Recently, some enantioselective variants of this reaction employing
catalytic amounts of chiral auxiliaries has also been described [7].
Commonly, electrophilic amidoalkylating reagents are based on
carboxamides and carbamates [1]. Their preparation from other
amides, e.g. ureas [8], thioureas [9], guanidines [10], thio- and di-
thiocarbamates [11], amides of various oxoacids of sulfur [12] and
phosphorus [13] has been much less studied. To the best of our
knowledge, there are no reports on preparation and application of
* Corresponding author.,
E-mail addresses: anatshu@gmail.com, shad@ioc.ac.ru (A.D. Shutalev).
https://doi.org/10.1016/j.tet.2019.130527
0040-4020/© 2019 Published by Elsevier Ltd.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

2
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
this coupling.
4-(Tosylmethyl)semicarbazones 4 were synthesized using the
three-component condensation of aldehyde semicarbazones 1 with
aldehydes 2 and p-toluenesulfinic acid (3). First, based on our
previous experience [26], we attempted to prepare sulfone (E)-4a
by the reaction of semicarbazone of benzaldehyde [(E)-1a] with
equimolar amounts of benzaldehyde (2a) and acid 3 in H2O at room
temperature (Scheme 3).
Scheme 1. Some a-amidoalkylating reagents and their reactions with nucleophiles.
However, under the above conditions, the reaction proceeded
very slowly, and after 6 days, the conversion of (E)-1a into (E)-4a
was only 15% (1H NMR data for isolated crude material) (Table 1,
entry 1). A slow reaction rate can be explained by the extremely
poor solubility of (E)-1a in water.
Elevated temperature (entry 1 vs entry 2; entry 6 vs entry 7), use
of excess of 2a and 3 (entry 1 vs entry 3 vs entry 5), and change of
the solvent from water (entry 5) to aqueous ethanol (entries 6, 8, 9)
or 80% aqueous formic acid (entry 10) resulted in an increase in the
level of conversion of (E)-1a. Under optimal conditions, the reaction
proceeded with 100% conversion at room temperature in 95% aq
EtOH for 8 days (Method A) or in 80% aq HCOOH for 24 h (Method
B) to give sulfone (E)-4a in 96 or 74% yield, respectively. In both
cases, the crude product was isolated by filtration of the precipitate
formed after completion of the reaction with >95% purity (1H NMR
data) and was used for amidoalkylation without additional
purification.
condensation depending on structure of starting compounds and
reaction conditions, prepare a representative number of 4-(tosyl-
methyl)semicarbazones, and study in detail their reactivity towards
a large variety of nucleophiles.
Herein we describe preparative synthesis of various 4-(tosyl-
methyl)semicarbazones and their application for the amidoalky-
lation of some H-, O-, S-, N-, P-, and C-nucleophiles to afford the
corresponding 4-substituted semicarbazones including analogues
of 5-nitro-2-furancarboxaldehyde semicarbazone (nitrofurazone)
[23] with potential antimicrobial activity. Results of antibacterial,
antifungal, cytotoxicity, and haemolytic tests of some synthesized
compounds are also reported.
2. Results and discussion
Methods A and B were applied for the preparation of other 4-
(tosylmethyl)semicarbazones 4b-g by the condensation of aromatic
aldehydes 2b-g with semicarbazones of the same aldehydes 1b-g
and sulfinic acid 3 (Scheme 4).
All sulfones 4b-g precipitated from the reaction mixture and
were isolated by filtration in good yields (83e99%) and excellent
purity (>95%) (Table 2, entries 3e13). Generally, the product yields
were higher according to Method A (EtOH, rt, 3e6 days) compared
with Method B (80% aq HCOOH, rt, 24 h). Since nitrofurazone [(E)-
1g] appeared to be practically insoluble in EtOH its condensation
with 5-nitrofurfural (2g) and sulfinic acid 3 under Method A con-
ditions failed to give the target sulfone 4g. When a EtOHeDMF
2.1. Synthesis of 4-(tosylmethyl)semicarbazones
The starting compounds, semicarbazones of aromatic aldehydes
1a-g or aliphatic aldehydes 1h-j, were prepared according to a
known procedure [24] using the reaction of semicarbazide hydro-
chloride with the corresponding aldehyde in the presence of AcONa
in water or aqueous ethanol (Scheme 2).
According to NMR data, semicarbazones of aromatic aldehydes
1a-g and semicarbazone of isobutyric aldehyde (1j) were isolated
as
a single stereoisomer with (E)-configuration, which was
assigned based on previously reported single-crystal X-ray struc-
tural analyses of analogous semicarbazones [25]. In contrast,
depending on the reaction conditions and isolation procedure
semicarbazones of propionic and butyric aldehyde (1h and 1i) were
obtained as mixtures of two stereoisomers in various ratio. To the
best of our knowledge, stereochemistry of these compounds has
not been previously described. Therefore, we assigned configura-
tion of both stereoisomers by the comparison of their 1H NMR
spectra with those of (E)-1j in DMSO‑d6. Chemical shifts of the NH
and NH2 protons (9.76 and 6.11 ppm, respectively) in (E)-1j are
close to those in the major isomers of compounds 1h,i (9.80 and
6.12e6.13 ppm) and strongly differ from those in the minor isomers
(9.29 and 6.28e6.29 ppm). Thus, the major isomers of 1h,i have (E)-
and minor isomers have (Z)-configuration. The additional evidence
of (E)-configuration in the major isomers of compounds 1h,i is a
long-range coupling 4J between the NH and CH protons
(0.6e0.7 Hz), which was also observed for (E)-1j (0.7 Hz), while the
spectra of the minor isomers of semicarbazones 1h,i did not show
Scheme 3. Synthesis of sulfone (E)-4a by the reaction of semicarbazone (E)-1a with
benzaldehyde and sulfinic acid 3.
Table 1
Synthesis of sulfone (E)-4a by the reaction of benzaldehyde semicarbazone [(E)-1a]
with benzaldehyde (2a) and p-toluenesulfinic acid (3).
Entry 1a:2a:3 ratio Solvent
Reaction conditions 4a:1a ratioa
1
2
3
4
5
6
7
8
9
1:1:1
1:1:1
1:1.1:1.1
1:1.1:1.1
1:1.5:1.5
1:1:1
H2O
H2O
H2O
H2O
rt, 6 days
58 ꢀC, 1.5 h
rt, 7 days
70 ꢀC, 7 h
rt, 8 days
rt, 6 days
47 ꢀC, 6.5 h
rt, 5 days
rt, 8 days
15:85
69:31
73:27
67:33
82:18
30:70
24:76
89:11
100:0b
100:0c
H2O
H2OeEtOH, 1:1
H2OeEtOH, 1:1
H2OeEtOH, 1:2
H2OeEtOH, 5:95
1:1:1
1:1.5:1.5
1:1.5:1.5
1:1.1:1.1
10
H2OeHCOOH, 20:80 rt, 24 h
a
According to 1H NMR spectroscopic data of the crude product isolated by
filtration after cooling the reaction mixture to 0 ꢀC.
b
96% isolated yield.
74% isolated yield.
c
Scheme 2. Synthesis of aldehyde semicarbazones 1a-j.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
3
assigned by the comparison of their 1H and 13C NMR spectra with
those of semicarbazones 1h-j in DMSO‑d6. Chemical shifts of the
CH]N proton in the major isomers of 4h-j (7.14e7.18 ppm) are
close to those of (E)-1h-j (7.08e7.16 ppm) and in minor isomers of
4h-j (6.33e6.48 ppm) are close to those of (Z)-1h,i
(6.34e6.37 ppm). A long-range coupling 4J between the NH and CH
protons was observed in the spectra of the major isomers of 4h-j
(0.6e0.7 Hz) and (E)-1h-j (0.6e0.7 Hz), while the spectra of the
minor isomers of 4h-j and (Z)-1h,i did not show this coupling. Close
Scheme 4. Synthesis of sulfones 4a-j by the reaction of semicarbazones (E)-1a-j with
aldehydes 2a-j and sulfinic acid 3.
values of carbon chemical shifts of the a-CH2 group were observed
Table 2
for (E)-1h,i (25.0 and 33.6 ppm) and the major isomer of 4h,i (25.0
and 33.5 ppm), and for (Z)-1h,i (20.1 and 28.5 ppm) and the minor
isomer of 4h,i (20.3 and 28.6 ppm). Thus, the major isomers of 4h-j
have (E)-configuration, and minor isomers of 4h-j have (Z)-
configuration.
We also tried to perform the three-component condensation
using 4-substituted semicarbazones. However, all attempts to
prepare of sulfone 6 by the reaction of semicarbazone 5a with
benzaldehyde (2a) and sulfinic acid 3 under various conditions
failed, and only starting 5a was recovered (see Scheme 5). There-
fore, substitution at the N4 nitrogen of semicarbazones hampers
the condensation presumably due to steric hindrance.
Next, we studied the condensation of various aldehydes with
semicarbazones of other aldehydes and p-toluenesulfinic acid. It
should be noted that this reaction could be complicated by the
formation of trans-semicarbazonation products.
We found that the condensation proceeds smoothly with
aliphatic aldehydes and semicarbazones of aromatic aldehydes
(Scheme 6). The transformation of 1-arylidene-semicarbazides into
1-alkylidene-derivatives does not take place under reaction con-
ditions. It can be explained by a higher thermodynamic stability of
semicarbazones of aromatic aldehydes compared with semi-
carbazones of aliphatic aldehydes due to conjugation effect in the
former ones.
Synthesis of sulfones 4a-j by the reaction of semicarbazones 1a-j with aldehydes 1a-
j and p-toluenesulfinic acid.
Entry
1
2
R
Methoda Time (d) Product Yield (%)b
1
(E)-1a 2a Ph
(E)-1a 2a Ph
A
B
A
B
A
B
A
B
A
B
A
B
B
C
C
C
8
1
6
1
6
1
5
1
5
1
3
1
1
1
1
1
(E)-4a
(E)-4a
(E)-4b
(E)-4b
(E)-4c
(E)-4c
(E)-4d
(E)-4d
(E)-4e
(E)-4e
(E)-4f
(E)-4f
(E)-4g
4hg
96
74
98
91
99
89
94
92
94
88
96
96
83
95
94
87
2c
3
(E)-1b 2b 4-MeC6H4
(E)-1b 2b 4-MeC6H4
(E)-1c 2c 4-MeOC6H4
(E)-1c 2c 4-MeOC6H4
(E)-1d 2d 4-EtC6H4
(E)-1d 2d 4-EtC6H4
(E)-1e 2e 4-i-PrC6H4
(E)-1e 2e 4-i-PrC6H4
(E)-1f 2f 4-t-BuC6H4
(E)-1f 2f 4-t-BuC6H4
(E)-1g 2g 5-NO2-2-furyl
4
5
6
7
8
9
10
11d
12
13
14
15
16
1he
1if
2h Et
2i Pr
4ih
(E)-1j 2j i-Pr
4ji
a
Method A: 95% aq EtOH, 1:2:3 M ratio ¼ 1:1.5:1.5, rt, 3e8 days; Method B: 80%
aq HCOOH, 1:2:3 M ratio ¼ 1:1.25:1.25, rt, 1 day; Method C: H2O, 1:2:3 M ra-
tio ¼ 1.1:1:1, rt, 1 day.
b
Isolated yield.
c
1a:2a:3 M ratio ¼ 1:1.1:1.1.
d
1f:2f:3 M ratio ¼ 1:1.25:1.25.
e
(E)-1h/(Z)-1h ¼ 59:41.
f
(E)-1i/(Z)-1i ¼ 72:28.
g
(E)-4h/(Z)-4h ¼ 90:10.
Thus, semicarbazones of aromatic aldehydes 1a,b,d-g reacted
with aliphatic aldehydes 2h-j (1.25 equiv) and sulfinic acid 3 (1.25
equiv) in 80% aq HCOOH at room temperature for 24 h (Method B)
to give the corresponding sulfones 7a-e,g-o in high yields (71e96%)
(Table 3). Reaction of semicarbazone 1b with butanal (2i) and sul-
finic acid 3 also proceeded in 95% aq EtOH (Method A) affording
sulfone 7d in 96% yield, however, the reaction rate was lower than
in 80% aq HCOOH (Method B) (entry 4 vs entry 5). According to
Method B, sulfone 7f was prepared from semicarbazone 1b, form-
aldehyde (1.05 equiv) and sulfinic acid (1.05 equiv) in 69% yield
(Table 3, entry 7).
h
(E)-4i/(Z)-4i ¼ 90:10.
i
(E)-4j/(Z)-4j ¼ 97:3.
mixture (2:1 v/v) was used for this reaction (rt, 7 days), the only
isolated material was starting (E)-1g. However, sulfone 4g was
prepared according to Method B in 83% yield (entry 13).
Sulfones 4a-g were formed as a single geometrical isomer (1H
NMR spectroscopic data) with (E)-configuration of the C]N double
bond, which was proved by close chemical shifts of the CH]N
proton in starting semicarbazones (E)-1a-g (7.79e7.84 ppm) and in
sulfones 4a-g (7.84e7.90 ppm) in DMSO‑d6.
According to 1H NMR spectroscopic data, sulfones 7a-o were
Aliphatic aldehydes 2h-j also reacted with semicarbazones of
the same aldehydes 1h-j and sulfinic acid 3 to give the corre-
sponding sulfones 4h-j (Table 2). Under optimized conditions, the
condensation completed in H2O with 10% molar excess of 1h-j at
room temperature for 24 h (Method C) to afford compounds 4h-j in
90e95% yields (Table 2, entries 14e16). Unexpectedly, a partial cis/
trans isomerization around the C]N double bond proceeded dur-
ing the reaction. Condensation of (E)-1j with 2j and 3 gave mixture
of (E)- and (Z)-isomers of 4j in a ratio of 97:3 (entry 16), reactions of
1h (E/Z ¼ 59:41) or 1i (E/Z ¼ 72:28) with the corresponding alde-
hydes 2h,i and sulfinic acid 3 resulted in mixtures of (E)- and (Z)-
4h,i in ratio of 90:10 and 89:11, respectively. We suppose that these
products are formed under thermodynamic control conditions,
since an increase in the reaction time up to 48 h had no effect on
isomeric ratio. Presumably, the cis/trans isomerization proceeded
via addition of sulfinic acid 3 to the C]N double bond of 4h-j fol-
lowed by fast elimination.
Scheme 5. Attempt to synthesize sulfone 6 from 4-substituted semicarbazone 5a.
Scheme 6. Synthesis of “mixed” sulfones 7a-r by the reaction of semicarbazones 1a-g
with aldehydes 2b,c,h-k and sulfinic acid 3.
Configuration of both stereoisomers of compounds 4h-j was
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

4
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
Table 3
[31]. The reported syntheses of 4-substituted semicarbazones
include condensation of carbonyl compounds or their derivatives
with 4-substituted semicarbazides [16,18,27,29,30b,32], N-carba-
moylation of hydrazones [17b,31,33], and substitution of group X in
RR1CH ¼ NR2NHC(O)X (where X ¼ NH2, OR', Cl, etc.) under the ac-
tion of amines [16,31,33c,34]. The drawbacks of these methods are
low availability of some starting compounds, multistep syntheses,
harsh reaction conditions, laborious procedures, use of hazardous
reagents, etc.
Synthesis of sulfones 7a-r by the reaction of semicarbazones of aromatic aldehydes
1a-g with aldehydes 2b,c,h-k and p-toluenesulfinic acid.
Entry
1
2
R
R1
Methoda Product Yield (%)b
1
2
3
4
1a 2h Ph
1a 2i Ph
Et
Pr
Et
Pr
Pr
i-Pr
H
Et
Pr
Et
Pr
Et
Pr
B
B
B
A
B
B
B
B
B
B
B
B
B
B
B
B
A
A
7a
7b
7c
7d
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7r
77
88
82
96
86
71
69
81
84
86
83
83
84
91
92
89
95d
96e
1b 2h 4-MeC6H4
1b 2i 4-MeC6H4
1b 2i 4-MeC6H4
1b 2j 4-MeC6H4
1b 2k 4-MeC6H4
1d 2h 4-EtC6H4
1d 2i 4-EtC6H4
1e 2h 4-i-PrC6H4
1e 2i 4-i-PrC6H4
1f 2h 4-t-BuC6H4
1f 2i 4-t-BuC6H4
1g 2h 5-NO2-2-furyl Et
1g 2i 5-NO2-2-furyl Pr
1g 2j 5-NO2-2-furyl i-Pr
1b 2c 4-MeC6H4
1c 2b 4-MeOC6H4
5
6
7c
8
We showed that sulfones (E)-4a-g and 7a-o were smoothly
reduced with NaBH4 (1.1e2.0 equiv.) in EtOH at room temperature
for 1.5 h to give the corresponding 4-substituted semicarbazones
5a-w in good to excellent yields (Scheme 7, Table 4).
9
10
11
12
13
14
15
16
17
18
According to 1H NMR spectroscopic data, semicarbazones 5a-w
were obtained as a single geometric isomer. Since the starting
compounds had (E)-configuration, the same configuration was
assigned to 5a-w.
Thus, we developed a novel general two-step approach to
4-substituted semicarbazones starting from semicarbazones (e.g.,
1a-j) based on preparation of 4-(tosylmethyl)semicarbazones (e.g.,
4a-j and 7a-r) followed by their reduction with NaBH4. This
approach has various advantages over classic syntheses of
4-substituted semicarbazones. For example, following our method
4-MeOC6H4
4-MeC6H4
a
Method A: 95% aq EtOH, 1:2:3 M ratio ¼ 1:1.5:1.5, rt, 7 days; Method B: 80% aq
HCOOH, 1:2:3 M ratio ¼ 1:1.25:1.25, rt, 1 day.
b
Isolated yield.
c
1b:2k:3 M ratio ¼ 1:1.05:1.05.
d
The crude product contained 5 mol% of (E)-4c.
4-propyl-,
4-butyl-,
and
4-isobutylsemicarbazones
of
e
The crude product contained 5 mol% of (E)-4b.
5-nitrofurfural (5u-w) were obtained from readily available
5-nitrofurfural semicarbazone (1g) in 75e77% overall yields (see,
Tables 2e4), while previously reported synthesis of these com-
pounds included condensation (51e65% yields) of 5-nitrofurfural
with the corresponding 4-substituted semicarbazides, which
were prepared in 4 steps starting from nitrourea [27].
Next, 4-(tosylmethyl)semicarbazones 4 and 7 were reacted with
typical O- and S-nucleophiles such as methylate-anion and
phenylthiolate-anion. The reaction of sulfones (E)-4b,c and 7d with
MeONa (1.09e1.10 equiv) smoothly proceeded in MeOH at room
temperature for 3 h to give the corresponding products of the tosyl
group substitution, ethers 8a-c, in excellent yields (Scheme 8,
Table 5, entries 1e3). Similarly, the treatment of sulfones (E)-4b,c
and 7d,f with PhSNa (1.09e1.10 equiv), generated by reaction of
PhSH with NaH, in THF (rt, 3 h) afforded phenylthio derivatives 9a-
d in good to excellent yields (entries 4e7).
Compounds 8a-c and 9a-d are the first representatives of pre-
viously unknown types of 4-substituted semicarbazones. They can
be considered as novel amidoalkylating reagents for organic syn-
thesis, and also as potentially biological active substances. For
example, 4-(hydroxymethyl)nitrofurazone (a close analog of com-
pounds 8) was found to exhibit remarkable trypanocidal activity
[35].
formed as a single geometric isomer with (E)-configuration of the
C]N double bond.
The condensation of aromatic aldehydes with semicarbazones
of other aromatic aldehydes and sulfinic acid 3 gave the expected 4-
(tosylmethyl)semicarbazones 7 along with a small amount of trans-
semicarbazonation products. When semicarbazone of p-methyl-
benzaldehyde (1b) was reacted with p-methoxybenzaldehyde (2c)
and acid 3 in EtOH for 7 days (Method A) a mixture of sulfones 7p
and (E)-4c in a ratio of 95:5 was isolated (Table 3, entry 17). Anal-
ogously, the condensation of semicarbazone of p-methox-
ybenzaldehyde (1c) with p-methybenzaldehyde (2b) and acid 3
under Method A conditions gave a 95:5 mixture of 7r and (E)-4b
(entry 18).
We found that alkylidene group in semicarbazones of aliphatic
aldehydes or ketones was readily replaced by arylidene group
when these semicarbazones were reacted with aromatic aldehydes
and sulfinic acid 3 under various conditions. The treatment of
propanal semicarbazone (1h) (1.1 equiv) with benzaldehyde (2a)
(1.0 equiv) and acid 3 (1.0 equiv) in H2O at room temperature for
24 h gave a mixture of benzaldehyde semicarbazone [(E)-1a], two
“symmetrical” sulfones - (E)-4a and 4h (E/Z ¼ 89:11), and “mixed”
Pyrrolidine and sodium succinimide were chosen as N-nucleo-
philes for amidoalkylation reaction with 4-(tosylmethyl)semi-
carbazones. We found that the treatment of a-aryl sulfones (E)-4b,c
with excess of pyrrolidine (2.17e2.21 equiv) in MeCN at room
temperature for 1.5 h gave the expected aminals 10a,b in 92e95%
yields (Table 5, entries 8 and 10). In contrast, the reaction of a-alkyl
sulfone
-
(E)-1-propylidene-4-[(phenyl)(tosyl)methyl]semi-
carbazide in a ratio of 29:5:21:45, respectively (1H NMR spectro-
scopic data). Equimolar amounts of acetone semicarbazone,
benzaldehyde (2a) and acid 3 reacted in EtOH at room temperature
for 7 h 20 min to afford a 80:20 mixture of benzaldehyde semi-
carbazone [(E)-1a] and sulfone (E)-4a.
sulfone 7d with pyrrolidine (2.96 equiv) in MeCN (rt, 6h) afforded a
mixture of aminal 10c [36] and semicarbazone (E)-1b in a ratio of
15:85 (entry 11). We suppose that the initially formed 10c further
2.2. Amidoalkylation of H-, N-, S-, O-, P-, and C-nucleophiles with
4-(tosylmethyl)semicarbazones
We found that the obtained 4-(tosylmethyl)semicarbazones 4a-
j and 7a-r are efficient reagents for amidoalkylation of various
nucleophiles. We started with the hydride reduction affording
4-substituted semicarbazones. These compounds are of current
interest due to their various biological activities such as antimi-
crobial [27], anticonvulsant [14c,28], anti-HIV [29], anti-
trypanosomal [30], antihypertensive [16], and herbicidal effects
Scheme 7. Synthesis of 4-substituted semicarbazones 5a-w by the reduction of sul-
fones (E)-4a-g and 7a-o with NaBH4.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
5
Table 4
Synthesis of 4-substituted semicarbazones 5a-w by the reduction of sulfones (E)-4a-g and 7a-o with NaBH4 (EtOH, rt, 1.5 h).
Entry
Sulfone
R
R1
Equiv. of NaBH4
Product
Yield (%)a
1
2
3
4
5
6
7
8
(E)-4a
7a
7b
(E)-4b
7c
7d
7e
7f
(E)-4c
(E)-4d
7g
7h
(E)-4e
7i
7j
(E)-4f
7k
Ph
Ph
Ph
Ph
Et
Pr
4-MeC6H4
Et
Pr
i-Pr
1.1
2.0
2.0
1.1
2.0
2.0
2.0
2.0
2.0
1.1
2.0
2.0
1.1
2.0
2.0
1.1
2.0
2.0
1.5
1.5
1.5
1.5
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5r
93
91
93
94
89
89
95
96
94
82
91
88
60
92
81
88
99
100
89
85
84
85
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-EtC6H4
H
9
4-MeOC6H4
4-EtC6H4
Et
Pr
4-i-PrC6H4
Et
Pr
4-t-BuC6H4
Et
Pr
5-NO2-2-furyl
Et
Pr
i-Pr
10
11
12
13
14
15
16
17
18
19
20
21
22
4-EtC6H4
4-EtC6H4
4-i-PrC6H4
4-i-PrC6H4
4-i-PrC6H4
4-t-BuC6H4
4-t-BuC6H4
4-t-BuC6H4
5-NO2-2-furyl
5-NO2-2-furyl
5-NO2-2-furyl
5-NO2-2-furyl
7l
5s
5t
5u
5v
5w
(E)-4g
7m
7n
7o
a
Isolated yield.
Scheme 8. Reactions of (E)-4a-c and 7d,f with O-, S-, N-, P-, and C-nucleophiles.
reacted with excess of pyrrolidine to give (E)-1b as a product of
nucleophilic substitution via an SN1-type pathway. It is noteworthy
that under the same conditions sulfone (E)-4b afforded only aminal
10a in 86% yield (entry 9).
column chromatography to give the pure compounds in 56e84%
yields.
Thus, the amidoalkylation of N-nucleophiles with 4-(tosyl-
methyl)semicarbazones provides a convenient general access to
various semicarbazone aminals. To the best of our knowledge, the
only reported synthesis of these compounds is based on the reac-
tion of some semicarbazones with formaldehyde and secondary
amines [37] affording products in moderate (44e48%) [37a] or not
specified [37b] yields. Some of the obtained aminals demonstrated
pronounced antibacterial activity [37b].
Amidoalkylation of P-nucleophiles (trimethyl phosphite or
triethyl phosphite) with sulfones (E)-4a-c gave the corresponding
products of the Arbuzov transformation, phosphonates 12a-e, in
excellent yields (87e98%) (Table 5, entries 17e21). However, in
contrast to other nucleophiles, the phosphites reacted with sul-
fones (E)-4a-c under more drastic conditions (2.91e3.00 equiv of
Similarly to 10c, compounds 10a,b have a strong tendency to
cleavage of the N4eC bond to produce the corresponding semi-
carbazones (E)-1b,c. For example, these compounds partly
decomposed during crystallization from boiling MeCN to give
mixtures of 10a/(E)-1b and 10b/(E)-1c in ratio of 83:17 and 72:28,
respectively. Slow formation of (E)-1b,c was also observed upon
storage of solid samples of 10a,b in closed vessels at room tem-
perature (2 mol% for 4 days according to 1H NMR data). The above
tendency can be explained by a high stability of the iminium cat-
ions arising from the heterolytic cleavage of the N4eC bond.
Sulfones (E)-4b,c, 7d,f reacted with sodium succinimide
(1.49e1.51 equiv) generated by treatment of succinimide with NaH
in THF at room temperature for 3.5 h to give the corresponding
succinimido-derivatives 11a-d along with some unidentified side
products (ca. 7e14% according to 1H NMR data) (entry 12e15). In
MeCN the reaction between sulfone 7f and sodium succinimide
(1.51 equiv) also proceeded (rt, 3.5 h) to afford compound 11d,
however, the amount of unidentified side products under these
conditions increased compared with THF (ca. 13% in MeCN vs ca. 7%
in THF) (entry 16). Crude 11a-d were purified using silica gel
phosphite, refluxing MeCN,1 h). The rate of the reaction between
alkyl sulfone 7d and P(OMe)3 (2.88 equiv) in refluxing MeCN
significantly decreased compared with -aryl sulfones (E)-4a-c.
a-
a
Thus, after 2.5 h, a mixture of starting material 7d and phosphonate
12f in a ratio of 21:79 was isolated. After 6 h with 4.96 equivalents
of P(OMe)3 in refluxing MeCN reaction was complete to provide
phosphonate 12f in 94% yield (entry 22). It is noteworthy that
sulfone 7f being treated with P(OMe)3 (MeCN, reflux) remained
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

6
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
Table 5
Amidoalkylation of O-, S-, N-, P-, and C-nucleophiles with sulfones (E)-4a-c and 7d,f.
Entry
Sulfone
R
R1
R2
Reaction conditions
Product
Yield (%)a
1
2
3
4
5
6
7
8
(E)-4b
(E)-4c
7d
(E)-4b
(E)-4c
7d
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
4-MeC6H4
4-MeOC6H4
Pr
4-MeC6H4
4-MeOC6H4
Pr
e
MeONa (1.10 equiv), MeOH, rt, 3 h
MeONa (1.10 equiv), MeOH, rt, 3 h
MeONa (1.09 equiv), MeOH, rt, 3 h
PhSH (1.15 equiv), NaH (1.10 equiv), THF, rt, 3 h
PhSH (1.13 equiv), NaH (1.09 equiv), THF, rt, 3 h
PhSH (1.15 equiv), NaH (1.10 equiv), THF, rt, 3 h
PhSH (1.12 equiv), NaH (1.10 equiv), THF, rt, 3 h
Pyrrolidine (2.21 equiv), MeCN, rt, 1.5 h
Pyrrolidine (3.01 equiv), MeCN, rt, 6 h
Pyrrolidine (2.17 equiv), MeCN, rt, 1.5 h
Pyrrolidine (2.96 equiv), MeCN, rt, 6 h
Succinimide (1.56 equiv), NaH (1.50 equiv), THF, rt, 3.5 h
Succinimide (1.56 equiv), NaH (1.49 equiv), THF, rt, 3.5 h
Succinimide (1.56 equiv), NaH (1.49 equiv), THF, rt, 3.5 h
Succinimide (1.56 equiv), NaH (1.51 equiv), THF, rt, 3.5 h
Succinimide (1.53 equiv), NaH (1.51 equiv), MeCN, rt, 3.5 h
P(OMe)3 (2.99 equiv), MeCN, reflux, 1 h
P(OEt)3 (2.96 equiv), MeCN, reflux, 1 h
P(OMe)3 (2.91 equiv), MeCN, reflux, 1 h
P(OEt)3 (2.99 equiv), MeCN, reflux, 1 h
P(OMe)3 (3.00 equiv), MeCN, reflux, 1 h
P(OMe)3 (4.96 equiv), MeCN, reflux, 6 h
P(OMe)3 (2.90 equiv), MeCN, reflux, 1 h
CH2(COOEt)2 (1.26 equiv), NaH (1.25 equiv), MeCN, rt, 8 h
CH2(COOEt)2 (1.20 equiv), NaH (1.20 equiv), MeCN, rt, 8 h
CH2(COOEt)2 (1.19 equiv), NaH (1.20 equiv), MeCN, rt, 8 h
8a
8b
8c
9a
9b
9c
9d
98
97
96
99
96
89
83
95
86
92
e
e
e
e
e
e
7f
H
e
(E)-4b
(E)-4b
(E)-4c
7d
(E)-4b
(E)-4c
7d
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
Pr
H
H
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeOC6H4
Pr
H
Ph
e
10a
10a
10b
10cb
11a
11b
11c
11d
11d
12a
12b
12c
12d
12e
12f
NRc
13a
13b
13c
9
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
e
e
e
84
75
75
e
e
e
7f
7f
e
e
56
98
87
98
96
95
94
e
(E)-4a
(E)-4a
(E)-4b
(E)-4b
(E)-4c
7d
OMe
OEt
OMe
OEt
OMe
OMe
OMe
e
Ph
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeC6H4
Ph
7f
(E)-4a
(E)-4b
(E)-4c
91
94
88
4-MeC6H4
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
e
e
a
Isolated yield.
b
c
Obtained in a mixture with semicarbazone (E)-1b, 10c/(E)-1b ¼ 15:85.
No reaction.
intact (entry 23).
N(4) double bond compared with that in the C]N(1) double bond.
Because of low basicity [42] phosphites can not participate in
the amidoalkylation via the E1cB-AdN pathway. If the trans-
formation proceeded via SN2 mechanism the rate of the reaction
Compounds 12a-f represent a novel type of derivatives of
a-
aminophoshonic acids which are currently of great interest due to
their pronounced biological activities [38], e.g. antibacterial [39],
anticancer [40], and enzyme inhibition properties [41].
We found that sulfones (E)-4a-c readily reacted with sodium
diethyl malonate (1.19e1.25 equiv) generated by treatment of
diethyl malonate with NaH in MeCN at room temperature for 8 h to
give compounds 13a-c in excellent yields (88e94%) (entries
24e26).
We suppose that the pathway of the reaction of 4-(tosylmethyl)
semicarbazones 4 and 7 with nucleophiles with relatively strong
basicity (NaBH4, MeONa, PhSNa, sodium succinimide, sodium
diethyl malonate, and pyrrolidine) differs from that with weakly
basic phosphites. In the first case, the reaction proceeds through an
E1cB-type elimination of p-toluenesulfinic acid to give N-acyli-
mines B followed by addition of nucleophile to the C]N(4) double
bond (Scheme 9). Selectivity of the addition to intermediate B can
be explained by higher electrophilicity of carbon atom in the C]
between P(OMe)3 and
higher compared with
a
-unsubstituted sulfone 7f would be much
a-alkyl sulfone 7d (Table 5, entry 22 vs entry
23). However,
a-unsubstituted sulfone 7f did not react with
P(OMe)3, therefore, SN2 mechanism can be excluded. We suppose
that the amidoalkylation of phosphites proceeds via SN1 mecha-
nism with the formation of N-acyliminium cations D, which is
supported by a higher rate of the reaction between phosphites and
a-aryl sulfones (E)-4a-c compared with
a-alkyl sulfone 7d (entries
17e21 vs entry 22).
2.3. Antibacterial activity, antifungal activity, and cytotoxicity of
some semicarbazones
Eleven compounds prepared [(E)-4g, 5t-w, 7f, 9a,d, and 12a,d,f]
were tested at the University of Queensland (Australia) for anti-
bacterial activity against one Gram-positive strain (Staphylococcus
aureus), four Gram-negative strains (Escherichia coli, Klebsiella
pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa)
and for antifungal activity against two strains of yeasts (Candida
albicans, Cryptococcus neoformans var. grubii). The minimum
inhibitory concentration (MIC) assay was performed by a broth
microdilution plate based method [43] following the CLSI guide-
lines [44], identifying the lowest concentration at which >80% in-
hibition of the bacteria or fungi has been detected. Among the
compounds tested, four nitrofuryl-containing semicarbazones [(E)-
4g, 5t-v] exhibited significant biological activities (Table 6).
Compounds (E)-4g, 5u,v showed potent antifungal activity
against C. albicans and C. neoformans with MIC values of 8e32
mL. Compound (E)-4g also possessed high antibacterial activity
against Gram-positive S. aureus (MIC 8e16 g/mL), Gram-negative
E. coli and A. baumannii (MIC 8e16 g/mL), and compound 5u
exhibited good antibacterial activity against Gram-positive
mg/
m
m
Scheme 9. Plausible pathways for amidoalkylation of anionic nucleophiles with 4-
(tosylmethyl)semicarbazones 4 and 7.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
7
Table 6
Selected data on antibacterial and antifungal activity, cytotoxicity and haemolytic activity of semicarbazones (E)-4g, 5t-v.a
Organism name (Description; Strain)
(E)-4g
MIC (
5t
5u
5v
m
g/mL)b/Dmax (%)c
S. aureus (MRSA; ATCC 43300)
E. coli (FDA control; ATCC 25922)
16/97.0; 8/95.1
8/99.0; 8/98.3
>32/39.3; >32/59.9
>32/49.2; >32/51.1
>32/14.2; >32/31.8
>32/36.2; >32/49.6
>32/3.8; >32/9.7
16/89.2; 16/94.8
>32/30.6; >32/32.1
>32/30.7; >32/35.4
>32/24.7; >32/4.4
>32/2.9; >32/6.8
16/100.8; 16/99.5
16/98.5; 32/81.9
>32/75.2; >32/79.6
>32/10.5; >32/11.5
>32/27.6; >32/29.6
>32/16.2; >32/9.3
>32/ꢁ1.9; >32/3.6
16/101.6; 32/101.0
16/84.2; 16/99.3
K. pneumoniae (MDR; ATCC 700603)
A. baumannii (Type strain; ATCC 19606)
P. aeruginosa (Type strain; ATCC 27853)
C. albicans (CLSI reference; ATCC 90028)
C. neoformans var. grubii (Type strain; H99, ATCC 208821)
>32/64.9; >32/68.3
16/96.4; 16/97.0
>32/4.7; >32/9.7
16/100.0; 32/100.9
8/91.7; >32/75.3
>32/26.2; >32/40.8
>32/18.8; >32/20.8
CC50
11.0/93.1; 11.6/93.8
HC10
g/mL)e/Dmax (%)c
>32/4.5; >32/5.9
(m
g/mL)d/Dmax (%)c
Human embryonic kidney cells (HEK-293; ATCC CRL-1573)
>32/111.5; >32/84.1
>32/1.0; >32/2.2
21.6/84.2; >32/75.7
>32/10.5; >32/11.0
>32/18.0; >32/9.4
>32/3.7; >32/5.5
(m
Human red blood cells (RBC)
a
All screening was performed as two replica (n ¼ 2), with both replicas on different assay plates, but from single plating and performed in a single screening experiment
(microbial incubation). Each individual value is reported in the table.
b
MIC - Minimum Inhibitory Concentration.
Dmax - the highest percentage inhibition response for all concentrations tested.
CC50 - Concentration at 50% cytotoxicity.
HC10 - Concentration at 10% haemolytic activity.
c
d
e
S. aureus (MIC 16
m
g/mL).
sources were distilled prior to use. Petroleum ether had a distilla-
tion range 40e70 ꢀC. Anhydrous THF, MeOH, and petroleum ether
were obtained according to the standard procedures. Sodium hy-
dride (60% suspension in mineral oil) was washed thoroughly with
anhydrous petroleum ether and dried in vacuum before use.
Granular NaBH4 (10e40 mesh) was used in the reactions. p-Tol-
uenesulfinic acid was synthesized by treatment of a saturated
aqueous solution of sodium p-toluenesulfinate [47] with hydro-
chloric acid at 0 ꢀC, dried over P2O5, and stored at ꢁ18 ꢀC. All other
reagents were purchased from commercial sources and used
without additional purification. FTIR spectra were recorded using a
Bruker Alpha-T spectrophotometer in KBr (for 13a) and a Bruker
Vector 22 spectrophotometer in Nujol (for all other compounds).
Band characteristics in the IR spectra are defined as very strong (vs),
strong (s), medium (m), weak (w), shoulder (sh), and broad (br).
NMR spectra (solutions in DMSO‑d6) were acquired using a Bruker
DPX-300 spectrometer at 300.13 (1H) and 75.48 (13C) MHz. 1H NMR
chemical shifts are referenced to the residual proton signal in
DMSO‑d6 (2.50 ppm). In 13C NMR spectra, central signal of DMSO‑d6
(39.50 ppm) was used as a reference. Multiplicities are reported as
singlet (s), doublet (d), triplet (t), quartet (q), and some combina-
tions of these, multiplet (m). Selective 1He1H decoupling and
DEPT-135 experiments were used to aid in the assignment of 1H
and 13C NMR signals. Elemental analyses (CHN) were performed
using a Thermo Finnigan Flash EA1112 apparatus. High-resolution
mass spectra (HRMS) were obtained using a Bruker mikrOTOF II
focus spectrometer (ESI, solutions in MeCN). Thin-layer chroma-
tography was performed on silica gel plates Kieselgel 60 F254
(Merck) in CHCl3/MeOH (9:1, v/v). Spots were visualized with UV
Cytotoxicity (against HEK-293) and haemolytic activity (against
human RBC) of compounds (E)-4g, 5t-v obtained as previously
described in the literature [43b,45,46] are presented in Table 6.
These data show moderate cytotoxicity and low haemolytic activity
of the compounds.
3. Conclusions
A
general synthesis of 4-(tosylmethyl)semicarbazones of
aliphatic and aromatic aldehydes based on three-component
condensation of the corresponding semicarbazones with various
aldehydes and p-toluenesulfinic acid has been developed. The
scope and limitations of this condensation were investigated. Un-
der optimal conditions, the target compounds can be obtained in
high yields from aliphatic or aromatic aldehydes and semi-
carbazones of aromatic aldehydes, and from aliphatic aldehydes
and semicarbazones of aliphatic aldehydes. The obtained com-
pounds represent a novel type of
a-amidoalkylating reagents,
which makes it possible to easily introduce a (4-semicarbazono)
methyl moiety into various nucleophilic substrates. The synthetic
utility of these reagents has been demonstrated by their reactions
with H- (sodium borohydride), O- (sodium methylate), S- (sodium
phenylthiolate), N- (pyrrolidine, sodium succinimide), P- (trialkyl
phosphites), and C-nucleophiles (sodium diethyl malonate)
affording the corresponding products of the tosyl group substitu-
tion, 4-substituted semicarbazones, in particular,
ones. We believe that this research provides a valuable extension of
the classic -amidoalkylation reaction. Among the prepared com-
a-functionalized
a
light.
Column
chromatography
was
performed
with
pounds tested in vitro for antibacterial and antifungal activity, three
nitrofuryl-containing semicarbazones (E)-4g, 5u,v exhibited high
biological activities, particularly compound (E)-4g was active
against S. aureus, E. coli, A. baumannii, C. albicans, and C. neoformans
MachereyeNagel silica gel 60 (0.063e0.200 mm). All yields refer to
isolated, spectroscopically and TLC pure material. The color of the
solids is white if not otherwise mentioned. Under optimized con-
ditions, the crude sulfones 4a-j and 7a-r were obtained in analyt-
ically pure form. As a rule, crystallization of these products did not
increase their purity.
(MIC 8e32
mg/mL), compound 5u was active against S. aureus,
C. albicans, and C. neoformans (MIC 16e32
mg/mL), and compound
5v was active against C. albicans and C. neoformans (MIC 16e32 mg/
mL).
4.2. Synthesis of 4-(tosylmethyl)semicarbazones 4a-j and 7a-r
4. Experimental section
4.2.1. (E)-1-Benzylidene-4-[(phenyl)(tosyl)methyl]semicarbazide
[(E)-4a]
4.1. General methods
Method A: To a stirred solution of benzaldehyde (2a) (14.78 g,
139.28 mmol) in EtOH (50 mL) were added p-toluenesulfinic acid
All solvents and liquid reagents purchased from commercial
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

8
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
(21.76 g, 139.31 mmol) and EtOH (50 mL), and the resulting mixture
was stirred at room temperature for 10 min. To the obtained solu-
tion semicarbazone of benzaldehyde [(E)-1a] (15.17 g, 92.95 mmol)
and EtOH (50 mL) were added, and the reaction mixture was stirred
at room temperature for 192 h. Then the suspension was cooled
(ꢁ18 ꢀC), the precipitate was filtered, washed with cold (ꢁ18 ꢀC)
EtOH (75 mL), ice-cold H2O (6 ꢂ 75 mL), petroleum ether
(2 ꢂ 75 mL), and dried to give sulfone (E)-4a (36.33 g, 96%). Mp
150.5 ꢀC (decomp, MeCNeAcOEt, 2.5:1 v/v); IR (Nujol) nmax 3362
(s), 3188 (br m), 3088 (br m) (NH), 3066 (w), 3037 (w) (CHarom),
1680 (vs) (amide-I), 1600 (m) (C]N), 1519 (s) (amide-II), 1498 (sh)
4.2.3. (E)-1-(4-Methoxybenzylidene)-4-[(4-methoxyphenyl)(tosyl)
methyl]semicarbazide [(E)-4c]
Method A: Sulfone (E)-4c (57.56 g, 99%) was prepared from
4-methoxybenzaldehyde (2c) (25.40 g, 186.56 mmol), p-toluene-
sulfinic acid (29.15 g, 186.61 mmol) and semicarbazone of
4-methoxylbenzaldehyde [(E)-1c] (24.03 g, 124.74 mmol) in EtOH
(200 mL) (rt, 144 h) as described for compound (E)-4a in Method A.
The crude product was obtained in analytically pure form. Crys-
tallization from boiling solvents (EtOH or MeCN) led to partial
decomposition of sulfone (E)-4c. Precipitation from DMF solution
by the addition of water had no effect on purity of sulfone (E)-4c.
Mp 159e159.5 ꢀC (decomp); IR (Nujol) nmax 3398 (m), 3344 (w),
3205 (br m), 3180 (sh), 3118 (br m) (NH), 3074 (w), 3030 (w)
(CHarom), 1687 (vs) (amide-I), 1607 (s) (C]N), 1578 (w) (CCarom),
(CCarom), 1312 (m), 1148 (s) (SO2), 813 (m), 762 (m), 700 (s) (CHarom
)
cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
;
d
10.75 (br s, 1H, NHeN),
7.90 (s, 1H, CH]N), 7.75e7.80 (m, 2H, ArH), 7.69e7.75 (m, 2H, ArH),
7.72 (d, 3J ¼ 10.9 Hz, 1H, NH, signals partly overlap with signals of
aromatic protons), 7.58e7.65 (m, 2H, ArH), 7.42e7.51 (m, 6H, ArH),
7.37e7.42 (m, 2H, ArH), 6.34 (d, 3J ¼ 10.9 Hz, 1H, CHeN), 2.39 (s, 3H,
1508 (s) (amide-II), 1313 (s) (SO2), 1252 (s) (
n
CeO), 1142 (s) (SO2),
1H NMR
d 10.57 (br s, 1H, NHeN), 7.84 (s, 1H, CH]
1029 (m) (CeO), 841 (m), 812 (m) (CHarom) cmꢁ1
;
(300.13 MHz, DMSO‑d6)
CH3 in Ts); 13C NMR (75.48 MHz, DMSO‑d6)
d
153.5 (C]O),144.8 (C),
N), 7.67e7.73 (m, 4H, ArH), 7.58 (d, 3J ¼ 10.9 Hz, 1H, NH), 7.49e7.55
(m, 2H, ArH), 7.36e7.42 (m, 2H, ArH), 6.96e7.06 (m, 4H, ArH), 6.25
(d, 3J ¼ 10.9 Hz, 1H, CHeN), 3.81 (s, 3H, OCH3), 3.78 (s, 3H, OCH3),
141.9 (CH]N),134.1 (C),133.8 (C),130.9 (C),129.7 (CH), 129.6 (2CH),
129.4 (CH), 129.3 (2CH), 129.1 (2CH), 128.8 (2CH), 128.4 (2CH), 126.9
(2CH), 72.6 (CHeN), 21.2 (CH3). Anal. Calcd for C22H21N3O3S: C,
64.85; H, 5.19; N, 10.31. Found: C, 64.74; H, 5.28; N, 10.24.
Method B: To a stirred solution of benzaldehyde (2a) (0.310 g,
2.92 mmol) in 80% formic acid (1 mL) were added p-toluenesulfinic
acid (0.456 g, 2.92 mmol) and 80% formic acid (1 mL), and the
resulting mixture was stirred at room temperature for 15 min. To
the obtained suspension semicarbazone of benzaldehyde [(E)-1a]
(0.433 g, 2.65 mmol) and 80% formic acid (3.3 mL) were added, and
the reaction mixture was stirred at room temperature for 24 h.
Then the suspension was cooled, the precipitate was filtered,
washed with cold EtOH, ice-cold H2O, petroleum ether, and dried to
give sulfone (E)-4a (0.803 g, 74%).
2.39 (s, 3H, CH3 in Ts); 13C NMR (75.48 MHz, DMSO‑d6)
d 160.5 (C),
160.1 (C), 153.5 (C]O), 144.6 (C), 141.7 (CH]N), 133.9 (C), 130.6
(2CH), 129.6 (2CH), 129.0 (2CH), 128.4 (2CH), 126.7 (C), 122.7 (C),
114.3 (2CH), 113.8 (2CH), 72.1 (CHeN), 55.3 (OCH3), 55.2 (OCH3),
21.1 (CH3). Anal. Calcd for C24H25N3O5S: C, 61.66; H, 5.39; N, 8.99.
Found: C, 61.50; H, 5.57; N, 9.22.
Method B: Sulfone (E)-4c (0.992 g, 89%) was prepared from
4-methoxybenzaldehyde (2c) (0.404 g, 2.97 mmol), p-toluene-
sulfinic acid (0.464 g, 2.97 mmol) and semicarbazone of
4-methoxylbenzaldehyde [(E)-1c] (0.459 g, 2.38 mmol) in 80% for-
mic acid (3.6 mL) (rt, 24 h) as described for compound (E)-4a in
Method B.
4.2.2. (E)-1-(4-Methylbenzylidene)-4-[(4-methylphenyl)(tosyl)
methyl]semicarbazide [(E)-4b)]
4.2.4. (E)-1-(4-Ethylbenzylidene)-4-[(4-ethylphenyl)(tosyl)methyl]
semicarbazide [(E)-4d]
Method A: Sulfone (E)-4d (5.188 g, 94%) was prepared from
4-ethylbenzaldehyde (2d) (2.397 g, 17.86 mmol), p-toluenesulfinic
Method A: Sulfone (E)-4b (51.46 g, 98%) was prepared from
4-methylbenzaldehyde (2b) (21.74 g, 180.94 mmol), p-toluene-
sulfinic acid (28.27 g, 180.97 mmol) and semicarbazone of
4-methylbenzaldehyde [(E)-1b] (21.37 g, 120.60 mmol) in EtOH
(193 mL) (rt, 144 h) as described for compound (E)-4a in Method A.
The crude product was obtained in analytically pure form. Crys-
tallization from boiling solvents (EtOH or MeCN) led to partial
decomposition of sulfone (E)-4b. Precipitation from DMF solution
by the addition of water failed to give pure substance. Mp
156.5e157 ꢀC (decomp); IR (Nujol) nmax 3408 (s), 3347 (w), 3197 (br
s), 3100 (br s) (NH), 3054 (w), 3026 (w) (CHarom), 1685 (vs) (amide-
I), 1614 (m) (C]N), 1595 (m), 1580 (w) (CCarom), 1521 (s), 1508 (s)
acid
(2.796 g,
17.90 mmol)
and
semicarbazone
of
4-ethylbenzaldehyde [(E)-1d] (2.278 g, 11.91 mmol) in EtOH
(24 mL) (rt, 120 h) as described for compound (E)-4a in Method A.
The crude product was obtained in analytically pure form. Mp
153.5e154 ꢀC (decomp); IR (Nujol) nmax 3398 (s), 3200 (br s), 3106
(br s) (NH), 3050 (w), 3022 (w) (CHarom), 1687 (vs) (amide-I),
1614 (m) (C]N), 1595 (m), 1577 (w) (CCarom), 1521 (s), 1508 (s)
(amide-II), 1320 (s), 1145 (s) (SO2), 833 (m), 815 (m) (CHarom) cmꢁ1
;
1H NMR (300.13 MHz, DMSO‑d6)
d
10.64 (br s, 1H, NHeN),
(amide-II), 1321 (s), 1146 (s) (SO2), 819 (m), 808 (m) (CHarom) cmꢁ1
1H NMR (300.13 MHz, DMSO‑d6)
10.64 (br s, 1H, NHeN), 7.86 (s,
;
7.86 (s, 1H, CH]N), 7.69e7.74 (m, 2H, ArH), 7.64e7.69 (m, 2H, ArH),
7.61 (d, 3J ¼ 10.9 Hz, 1H, NH), 7.47e7.53 (m, 2H, ArH), 7.36e7.42 (m,
2H, ArH), 7.26e7.34 (m, 4H, ArH), 6.27 (d, 3J ¼ 10.9 Hz, 1H, CHeN),
2.65 (q, 3J ¼ 7.6 Hz, 2H, CH2 in Et), 2.64 (q, 3J ¼ 7.6 Hz, 2H, CH2 in Et),
2.39 (s, 3H, CH3 in Ts), 1.21 (t, 3J ¼ 7.6 Hz, 3H, CH3 in Et), 1.19 (t,
d
1H, CH]N), 7.68e7.73 (m, 2H, ArH), 7.62e7.67 (m, 2H, ArH), 7.62 (d,
3J ¼ 10.9 Hz, 1H, NH), 7.45e7.50 (m, 2H, ArH), 7.36e7.42 (m, 2H,
ArH), 7.22e7.31 (m, 4H, ArH), 6.27 (d, 3J ¼ 10.9 Hz, 1H, CHeN), 2.39
(s, 3H, CH3 in Ts), 2.35 (s, 3H, CH3), 2.34 (s, 3H, CH3); 13C NMR
3J ¼ 7.6 Hz, 3H, CH3 in Et); 13C NMR (75.48 MHz, DMSO‑d6)
d 153.4
(75.48 MHz, DMSO‑d6)
d
153.4 (C]O), 144.7 (C), 142.0 (CH]N),
(C]O), 145.7 (C), 145.2 (C), 144.7 (C), 141.9 (CH]N), 133.9 (C), 131.6
(C), 129.6 (2CH), 129.2 (2CH), 129.0 (2CH), 128.20 (2CH), 128.16 (C),
127.7 (2CH), 126.9 (2CH), 72.3 (CHeN), 28.1 (CH2), 27.9 (CH2), 21.1
(CH3 in Ts), 15.5 (CH3 in Et), 15.4 (CH3 in Et). Anal. Calcd for
139.4 (C), 138.9 (C), 133.8 (C), 131.4 (C), 129.6 (2CH), 129.4 (2CH),
129.1 (2CH), 129.0 (2CH), 128.9 (2CH), 127.9 (C), 126.8 (2CH), 72.4
(CHeN), 21.1 (CH3), 21.0 (CH3), 20.8 (CH3). Anal. Calcd for
C
24H25N3O3S: C, 66.19; H, 5.79; N, 9.65. Found: C, 65.95; H, 5.67; N,
9.93.
Method B: Sulfone (E)-4b (1.078 g, 91%) was prepared
C
26H29N3O3S: C, 67.36; H, 6.31; N, 9.06. Found: C, 67.27; H, 6.56; N,
9.09.
Method B: Sulfone (E)-4d (1.051 g, 92%) was prepared from
4-ethylbenzaldehyde (2d) (0.415 g, 3.09 mmol), p-toluenesulfinic
acid (0.483 g, 3.09 mmol) and semicarbazone of
from 4-methylbenzaldehyde (2b) (0.410 g, 3.41 mmol), p-toluene-
sulfinic acid (0.533 g, 3.41 mmol) and semicarbazone of
4-methylbenzaldehyde [(E)-1b] (0.484 g, 2.73 mmol) in 80% formic
acid (4.1 mL) (rt, 24 h) as described for compound (E)-4a in
Method B.
4-ethylbenzaldehyde [(E)-1d] (0.473 g, 2.47 mmol) in 80% formic
acid (3.7 mL) (rt, 24 h) as described for compound (E)-4a in Method
B.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
9
4.2.5. (E)-1-(4-Isopropylbenzylidene)-4-[(4-isopropylphenyl)(tosyl)
methyl]semicarbazide [(E)-4e]
mixture was stirred at room temperature for 15 min. To the ob-
tained solution semicarbazone of 5-nitrofurfural [(E)-1g] (0.504 g,
2.54 mmol) and 80% formic acid (5.4 mL) were added, and the re-
action mixture was stirred at room temperature for 24 h. The sus-
pension was cooled, the precipitate was filtered, washed with cold
EtOH, ice-cold H2O, petroleum ether, and dried to give sulfone (E)-
4g (1.009 g, 83%) as a yellow solid. The crude product was obtained
in analytically pure form. Mp 135.5e136 ꢀC (decomp); IR (Nujol)
nmax 3397 (s), 3156 (m), 3135 (s), 3093 (br s) (NH), 1693 (vs) (amide-
I), 1592 (s), 1578 (m), 1537 (s), 1510 (s), 1498 (vs) (C]N, amide-II,
NO2, CCarom), 1353 (vs), 1341 (vs) (NO2), 1140 (s) (SO2), 813 (s)
Method A: Sulfone (E)-4e (6.035 g, 94%) was prepared from
4-isopropylbenzaldehyde (2e) (2.912 g, 19.65 mmol), p-toluene-
sulfinic acid (3.073 g, 19.67 mmol) and semicarbazone of
4-isopropylbenzaldehyde [(E)-1e] (2.688 g, 13.10 mmol) in EtOH
(16.4 mL) (rt, 120 h) as described for compound (E)-4a in Method A.
The crude product was obtained in analytically pure form. Mp
150e150.5 ꢀC (decomp); IR (Nujol) nmax 3392 (m), 3198 (br s), 3096
(br s) (NH), 3052 (w), 3023 (w) (CHarom), 1690 (vs) (amide-I), 1614
(m) (C]N), 1595 (m), 1577 (w) (CCarom), 1505 (s) (amide-II), 1320
(s), 1146 (s) (SO2), 829 (m), 815 (m) (CHarom) cmꢁ1
;
1H NMR
(CHarom in Ts) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 11.23 (br s,
(300.13 MHz, DMSO‑d6) 10.66 (s, 1H, NHeN), 7.86 (s, 1H, CH]N),
d
1H, NHeN), 8.03 (d, 3J ¼ 10.5 Hz, 1H, NH), 7.90 (s, 1H, CH]N), 7.82
(d, 3J ¼ 4.0 Hz, 1H, H-4 in furan moiety), 7.71e7.77 (m, 2H, ArH), 7.74
(d, 3J ¼ 3.8 Hz, 1H, H-4 in furan moiety), 7.43e7.49 (m, 2H, ArH),
7.28 (d, 3J ¼ 4.0 Hz, 1H, H-3 in furan moiety), 7.20 (d, 3J ¼ 3.8 Hz, 1H,
H-3 in furan moiety), 6.65 (d, 3J ¼ 10.5 Hz, 1H, CHeN), 2.41 (s, 3H,
7.70e7.76 (m, 2H, ArH), 7.64e7.69 (m, 2H, ArH), 7.62 (d, 3J ¼ 10.9 Hz,
1H, NH), 7.49e7.55 (m, 2H, ArH), 7.29e7.42 (m, 6H, ArH), 6.27 (d,
3J ¼ 10.9 Hz, 1H, CHeN), 2.85e3.01 (m, 2H, 2 ꢂ CH in i-Pr), 2.39 (s,
3H, CH3 in Ts), 1.23 (d, 3J ¼ 6.9 Hz, 6H, 2 ꢂ CH3 in i-Pr), 1.22 (d,
3J ¼ 6.9 Hz, 6H, 2 ꢂ CH3 in i-Pr); 13C NMR (75.48 MHz, DMSO‑d6)
CH3); 13C NMR (75.48 MHz, DMSO‑d6)
d 152.8 (C]O), 152.0 (C),
d
153.4 (C]O), 150.3 (C), 149.8 (C), 144.7 (C), 141.9 (CH]N), 133.9
151.8 (C), 151.7 (C), 148.0 (C), 145.7 (C), 132.8 (C), 130.8 (CH]N),
130.0 (2CH), 129.2 (2CH), 116.1 (CH), 114.9 (CH), 114.3 (CH), 113.6
(CH), 67.8 (CHeN), 21.2 (CH3). Anal. Calcd for C18H15N5O9S: C, 45.29;
H, 3.17; N, 14.67. Found: C, 45.44; H, 3.19; N, 14.70.
(C), 131.8 (C), 129.6 (2CH), 129.3 (2CH), 129.1 (2CH), 128.3 (C), 126.9
(2CH), 126.8 (2CH), 126.3 (2CH), 72.3 (CHeN), 33.4 (CH in i-Pr), 33.2
(CH in i-Pr), 23.78 (CH3 in i-Pr), 23.75 (CH3 in i-Pr), 23.7 (2 ꢂ CH3 in
i-Pr), 21.2 (CH3 in Ts). Anal. Calcd for C28H33N3O3S: C, 68.40; H, 6.77;
N, 8.55. Found: C, 68.31; H, 7.01; N, 8.58.
4.2.8. 1-Propylidene-4-(1-tosylprop-1-yl)semicarbazide (4h)
Method B: Sulfone (E)-4e (0.947 g, 88%) was prepared from
4-isopropylbenzaldehyde (2e) (0.405 g, 2.73 mmol), p-toluene-
sulfinic acid (0.428 g, 2.74 mmol) and semicarbazone of
4-isopropylbenzaldehyde [(E)-1e] (0.449 g, 2.19 mmol) in 80% for-
mic acid (3.3 mL) (rt, 24 h) as described for compound (E)-4a in
Method B.
To a solution of propanal (2h) (0.205 g, 3.53 mmol) in cold H2O
(2 mL) were added p-toluenesulfinic acid (0.551 g, 3.53 mmol) and
water (3 mL), and the resulting mixture was stirred at room tem-
perature for 15 min. To the obtained suspension semicarbazone of
propanal (1h) (0.446 g, 3.87 mmol) [a 59:41 mixture of (E)- and (Z)-
isomers] and water (2 mL) were added. The reaction mixture was
stirred for 24 h and cooled (0 ꢀC). The precipitate was filtered,
washed with ice-cold H2O, petroleum ether, and dried to give sul-
fone 4h (1.043 g, 95%) as a mixture of (E)- and (Z)-isomers in a ratio
of 90:10. After crystallization from CHCl3/petroleum ether the
4.2.6. (E)-1-(4-tert-Butylbenzylidene)-4-[(4-tert-
butylphenyl)(tosyl)methyl]semicarbazide [(E)-4f]
Method A: Sulfone (E)-4f (22.76 g, 96%) was prepared from 4-
tert-butylbenzaldehyde (2f) (9.29 g, 57.26 mmol), p-toluenesulfinic
acid (8.97 g, 57.39 mmol) and semicarbazone of 4-tert-butylben-
zaldehyde [(E)-1f] (10.05 g, 45.82 mmol) in EtOH (90 mL) (rt, 72 h)
as described for compound (E)-4a. The crude product was obtained
in analytically pure form. Mp 160e160.5 ꢀC (decomp); IR (Nujol)
nmax 3398 (m), 3194 (br m), 3102 (br m) (NH), 3060 (w), 3036 (w)
(CHarom), 1693 (vs) (amide-I), 1615 (m) (C]N), 1596 (w), 1576 (w)
(CCarom), 1522 (s), 1509 (s) (amide-II), 1318 (s), 1149 (s) (SO2), 833
isomeric ratio did not change. Mp 130e130.5 ꢀC (decomp, CHCl3
-
petroleum ether, 1:1 v/v); IR (Nujol) nmax 3327 (s), 3195 (br s), 3096
(br s) (NH), 3062 (w) (CHarom), 1682 (vs) (amide-I),1633 (m) (C]N),
1597 (m) (CCarom), 1520 (vs) (amide-II), 1314 (s), 1144 (vs) (SO2), 808
(m) (CHarom) cmꢁ1
DMSO‑d6)
;
1H NMR spectrum of (E)-4h (300.13 MHz,
10.12 (s, 1H, NHeN), 7.65e7.70 (m, 2H, ArH), 7.37e7.43
d
(m, 2H, ArH), 7.18 (t, 3J ¼ 5.1 Hz, 1H, CH]N), 6.83 (d, 3J ¼ 10.5 Hz,
1H, NH), 4.95 (ddd, 3J ¼ 11.0, 3J ¼ 10.5, 3J ¼ 3.5 Hz, 1H, CHeN), 2.39
(s, 3H, CH3 in Ts), 2.16e2.26 (m, 2H, CH2 in Et), 1.96e2.10 (m, 1H, HA
in CHAHBCH3), 1.67e1.83 (m, 1H, HB in CHAHBCH3), 1.03 (t,
3J ¼ 7.5 Hz, 3H, CH3 in Et), 0.91 (t, 3J ¼ 7.3 Hz, 3H, CH3 in Et); 1H NMR
(m), 812 (m) (CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
;
d
10.66 (br s, 1H, NHeN), 7.86 (s, 1H, CH]N), 7.71e7.77 (m, 2H,
ArH), 7.64e7.70 (m, 2H, ArH), 7.60 (d, 3J ¼ 10.9 Hz, 1H, NH),
7.44e7.56 (m, 6H, ArH), 7.37e7.43 (m, 2H, ArH), 6.26 (d,
3J ¼ 10.9 Hz,1H, CHeN), 2.39 (s, 3H, CH3 in Ts),1.31 (s, 9H, 3 ꢂ CH3 in
t-Bu), 1.30 (s, 9H, 3 ꢂ CH3 in t-Bu); 13C NMR (75.48 MHz, DMSO‑d6)
spectrum of (Z)-4h (300.13 MHz, DMSO‑d6)
d 9.63 (s, 1H, NHeN),
7.13 (d, 3J ¼ 10.4 Hz, 1H, NH), 6.46 (t, 3J ¼ 5.4 Hz, 1H, CH]N), 4.96
(ddd, 3J ¼ 11.0, 3J ¼ 10.4, 3J ¼ 3.4 Hz, 1H, CHeN), signals of other
protons overlap with analogous signals of the (E)-isomer; 13C NMR
d
153.3 (C]O), 152.4 (C), 152.0 (C), 144.7 (C), 141.7 (CH]N), 134.0
(C), 131.4 (C), 129.6 (2CH), 129.0 (2CH), 128.9 (2CH), 127.9 (C), 126.6
(2CH), 125.6 (2CH), 125.2 (2CH), 72.1 (CHeN), 34.5 (Cquat in t-Bu),
34.4 (Cquat in t-Bu), 31.0 (3 ꢂ CH3 in t-Bu), 30.9 (3 ꢂ CH3 in t-Bu),
21.1 (CH3). Anal. Calcd for C30H37N3O3S: C, 69.33; H, 7.18; N, 8.09.
Found: C, 69.12; H, 7.14; N, 8.27.
Method B: Sulfone (E)-4f (0.997 g, 96%) was prepared from 4-
tert-butylbenzaldehyde (2f) (0.407 g, 2.51 mmol), p-toluenesulfinic
acid (0.392 g, 2.51 mmol) and semicarbazone of 4-tert-butylben-
zaldehyde [(E)-1f] (0.440 g, 2.01 mmol) in 80% formic acid (3 mL)
(rt, 24 h) as described for compound (E)-4a in Method B.
spectrum of (E)-4h (75.48 MHz, DMSO‑d6) d 154.3 (C]O), 146.3
(CH]N), 144.4 (C), 134.1 (C), 129.5 (2CH), 128.9 (2CH), 71.2 (CHeN),
25.0 (CH2), 21.1 (CH3 in Ts), 20.0 (CH2), 10.7 (CH3 in Et), 9.94 (CH3 in
Et); 13C NMR spectrum of (Z)-4h (75.48 MHz, DMSO‑d6)
d 154.8 (C]
O), 146.4 (CH]N), 144.3 (C), 134.2 (C), 71.3 (CHeN), 20.3 (CH2), 19.9
(CH2), 10.2 (CH3 in Et), 9.92 (CH3 in Et), signals of other carbons
overlap with analogous signals of the (E)-isomer. Anal. Calcd for
C14H21N3O3S: C, 54.00; H, 6.80; N, 13.49. Found: C, 53.99; H, 7.00; N,
13.73.
4.2.9. 1-Butylidene-4-(1-tosylbut-1-yl)semicarbazide (4i)
4.2.7. (E)-1-[(5-Nitro-2-furyl)methylene]-4-[(5-nitro-
2-furyl)(tosyl)methyl]semicarbazide [(E)-4g]
To a stirred solution of 5-nitrofurfural (2g) (0.449 g, 3.18 mmol)
in 80% formic acid (3.5 mL) were added p-toluenesulfinic acid
(0.497 g, 3.18 mmol) and 80% formic acid (3.5 mL), and the resulting
Sulfone 4i (8.535 g, 94%) as a mixture of (E)- and (Z)-isomers in a
ratio of 89:11 was prepared from butanal (2i) (1.938 g, 26.88 mmol),
p-toluenesulfinic acid (4.206 g, 26.93 mmol) and semicarbazone of
butanal (1i) (3.820 g, 29.58 mmol) [a 72:28 mixture of (E)- and (Z)-
isomers] in water (54 mL) (rt, 24 h) as described for compound 4h.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

10
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
After crystallization from CHCl3/petroleum ether the isomeric ratio
did not change. Mp 133.5e134 ꢀC (decomp, CHCl3 - petroleum
ether, 1:1 v/v); IR (Nujol) nmax 3331 (s), 3192 (br s), 3094 (br s) (NH),
3068 (w) (CHarom), 1684 (s) (amide-I), 1631 (m) (C]N), 1597 (m)
(CCarom), 1523 (s) (amide-II), 1295 (m), 1141 (s) (SO2), 808 (m)
(CHarom) cmꢁ1; 1H NMR spectrum of (E)-4i (300.13 MHz, DMSO‑d6)
EtOH, ice-cold H2O, petroleum ether, and dried to give sulfone 7a
(0.952 g, 77%). The crude product was obtained in analytically pure
form. Mp 140.5e141 ꢀC (decomp); IR (Nujol) nmax 3354 (s), 3201 (br
m), 3085 (br s) (NH), 3027 (w) (CHarom), 1686 (vs) (amide-I), 1610
(m) (C]N), 1599 (m), 1575 (w) (CCarom), 1523 (s) (amide-II), 1499
(w) (CCarom), 1308 (s), 1130 (s) (SO2), 809 (m), 753 (m), 689 (m)
d
10.13 (s, 1H, NHeN), 7.64e7.69 (m, 2H, ArH), 7.37e7.42 (m, 2H,
(CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
; d 10.61 (s, 1H,
ArH), 7.14 (dt, 3J ¼ 5.5, 4J ¼ 0.6 Hz, 1H, CH]N), 6.90 (d, 3J ¼ 10.5 Hz,
1H, NH), 5.02 (ddd, 3J ¼ 11.2, 3J ¼ 10.5, 3J ¼ 3.4 Hz, 1H, CHeN), 2.39
(s, 3H, CH3 in Ts), 2.13e2.31 (m, 2H, CH2 in Pr), 1.72e1.98 (m, 2H,
CH2 in Pr), 1.17e1.55 (m, 4H, CH2 in Pr), 0.92 (t, 3J ¼ 7.3 Hz, 3H, CH3
in Pr), 0.85 (t, 3J ¼ 7.4 Hz, 3H, CH3 in Pr); 1H NMR spectrum of (Z)-4i
NHeN), 7.85 (s, 1H, CH]N), 7.74e7.80 (m, 2H, ArH), 7.67e7.72 (m,
2H, ArH), 7.36e7.47 (m, 6H, NH and ArH), 5.00 (ddd, 3J ¼ 11.1,
3J ¼ 10.3, 3J ¼ 3.5 Hz, 1H, CHeN), 2.39 (s, 3H, CH3 in Ts), 2.00e2.13
(m, 1H, HA in CHAHBCH3), 1.81e1.97 (m, 1H, HB in CHAHBCH3), 0.93
(t, 3J ¼ 7.3 Hz, 3H, CH3 in Et); 13C NMR (75.48 MHz, DMSO‑d6)
(300.13 MHz, DMSO‑d6)
d
9.65 (s, 1H, NHeN), 7.17 (d, 3J ¼ 10.4 Hz,
d 154.5 (C]O), 144.4 (C), 141.0 (CH]N), 134.4 (C), 134.1 (C), 129.6
1H, NH), 6.48 (t, 3J ¼ 5.6 Hz, 1H, CH]N), signals of other protons
(2CH), 129.4 (CH), 129.0 (2CH), 128.6 (2CH), 126.9 (2CH), 71.8
(CHeN), 21.1 (CH3 in Ts),19.7 (CH2 in Et),10.2 (CH3 in Et). Anal. Calcd
for C18H21N3O3S: C, 60.15; H, 5.89; N, 11.69. Found: C, 60.12; H, 6.03;
N, 11.73.
overlap with analogous signals of the (E)-isomer; 13C NMR spec-
trum of (E)-4i (75.48 MHz, DMSO‑d6) d 154.1 (C]O), 145.2 (CH]N),
144.31 (C), 134.0 (C), 129.5 (2CH), 128.9 (2CH), 69.5 (CHeN), 33.5
(CH2), 28.1 (CH2), 21.0 (CH3 in Ts), 19.4 (CH2), 18.2 (CH2), 13.4 (CH3 in
Pr), 13.1 (CH3 in Pr); 13C NMR spectrum of (Z)-4i (75.48 MHz,
DMSO‑d6)
d
145.1 (CH]N), 144.28 (C), 134.1 (C), 69.6 (CHeN), 28.6
4.2.12. (E)-1-Benzylidene-4-(1-tosylbut-1-yl)semicarbazide (7b)
Sulfone 7b (1.085 g, 88%) was prepared from butanal (2i)
(0.299 g, 4.15 mmol), p-toluenesulfinic acid (0.647 g, 4.14 mmol)
and semicarbazone of benzaldehyde [(E)-1a] (0.541 g, 3.32 mmol)
in 80% formic acid (5 mL) (rt, 24 h) as described for compound 7a.
The crude product was obtained in analytically pure form. Mp
142e142.5 ꢀC (decomp); IR (Nujol) nmax 3339 (s), 3193 (br m), 3084
(br s) (NH), 3026 (w) (CHarom), 1682 (vs) (amide-I), 1610 (m) (C]
N), 1600 (m), 1575 (w) (CCarom), 1526 (s) (amide-II), 1495 (w)
(CCarom), 1307 (s), 1129 (s) (SO2), 809 (m), 755 (m), 688 (m)
(CH2), 28.0 (CH2), 18.8 (CH2), 13.5 (CH3 in Pr), signals of other car-
bons are hidden by noise or overlap with analogous signals of the
(E)-isomer. Anal. Calcd for C16H25N3O3S: C, 56.61; H, 7.42; N, 12.38.
Found: C, 56.88; H, 7.52; N, 12.36.
4.2.10. 1-Isobutylidene-4-(2-methyl-1-tosylprop-1-yl)
semicarbazide (4j)
Sulfone 4j (1.712 g, 90%) as a mixture of (E)- and (Z)-isomers in a
ratio of 97:3 was prepared from isobutyric aldehyde (2j) (0.406 g,
5.64 mmol), p-toluenesulfinic acid (0.900 g, 5.76 mmol) and semi-
carbazone of isobutyric aldehyde [(E)-1j] (0.801 g, 6.20 mmol) in
water (11.3 mL) (rt, 24 h) as described for compound 4h. After
crystallization from CHCl3/petroleum ether the isomeric ratio did
not change. Mp 108e109.5 ꢀC (decomp, CHCl3 - petroleum ether,
1:9 v/v); IR (Nujol) nmax 3368 (s), 3190 (br s), 3093 (br s) (NH), 1688
(s) (amide-I), 1634 (m) (C]N), 1597 (m) (CCarom), 1507 (s) (amide-
(CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
; d 10.60 (s, 1H,
NHeN), 7.84 (s, 1H, CH]N), 7.74e7.80 (m, 2H, ArH), 7.67e7.72 (m,
2H, ArH), 7.36e7.47 (m, 6H, ArH and NH), 5.08 (ddd, 3J ¼ 10.3,
3J ¼ 8.9, 3J ¼ 5.8 Hz, 1H, CHeN), 2.39 (s, 3H, CH3 in Ts), 1.85e2.01
(m, 2H, CH2 in Pr), 1.20e1.53 (m, 2H, CH2 in Pr), 0.88 (t, 3J ¼ 7.4 Hz,
3H, CH3 in Pr); 13C NMR (75.48 MHz, DMSO‑d6)
d 154.4 (C]O),
144.4 (C), 141.0 (CH]N), 134.4 (C), 134.1 (C), 129.6 (2CH), 129.4
(CH), 129.0 (2CH), 128.6 (2CH), 126.9 (2CH), 70.1 (CHeN), 27.8
(CH2), 21.1 (CH3 in Ts), 18.4 (CH2), 13.2 (CH3 in Pr). Anal. Calcd for
II), 1327 (s), 1144 (s) (SO2), 810 (m) (CHarom) cmꢁ1
trum of (E)-4j (300.13 MHz, DMSO‑d6) 10.14 (s, 1H, NHeN),
;
1H NMR spec-
d
7.66e7.71 (m, 2H, ArH), 7.36e7.42 (m, 2H, ArH), 7.14 (dd, 3J ¼ 4.7,
4J ¼ 0.7 Hz, 1H, CH]N), 6.69 (d, 3J ¼ 11.1 Hz, 1H, NH), 4.91 (dd,
3J ¼ 11.1, 3J ¼ 3.9 Hz, 1H, CHeN), 2.58 (doublet of septet, 3J ¼ 6.8,
3J ¼ 3.9 Hz, 1H, CH in i-Pr), 2.47 (doublet of septet, 3J ¼ 6.9,
3J ¼ 4.7 Hz, 1H, CH in i-Pr), 2.39 (s, 3H, CH3 in Ts), 1.053 (d,
3J ¼ 6.9 Hz, 3H, CH3 in i-Pr), 1.050 (d, 3J ¼ 6.9 Hz, 3H, CH3 in i-Pr),
1.00 (d, 3J ¼ 6.8 Hz, 3H, CH3 in i-Pr), 0.97 (d, 3J ¼ 6.8 Hz, 3H, CH3 in i-
C19H23N3O3S: C, 61.10; H, 6.21; N, 11.25. Found: C, 60.91; H, 6.37; N,
11.32.
4.2.13. (E)-1-(4-Methylbenzylidene)-4-(1-tosylprop-1-yl)
semicarbazide (7c)
Sulfone 7с (0.951 g, 82%) was prepared from propanal (2h)
(0.225 g, 3.87 mmol), p-toluenesulfinic acid (0.604 g, 3.87 mmol)
and semicarbazone of 4-methylbenzaldehyde [(E)-1b] (0.548 g,
3.09 mmol) in 80% formic acid (4.6 mL) (rt, 24 h) as described for
compound 7a. The crude product was obtained in analytically pure
form. Mp 143e144 ꢀC (decomp); IR (Nujol) nmax 3341 (s), 3199 (br
m), 3191 (br m), 3085 (br s) (NH), 3021 (w) (CHarom), 1682 (s)
(amide-I), 1611 (m) (C]N), 1598 (m) (CCarom), 1528 (sh), 1522 (s)
(amide-II), 1492 (m) (CCarom), 1308 (s), 1130 (s) (SO2), 809 (m)
Pr); 1H NMR spectrum of (Z)-4j (300.13 MHz, DMSO‑d6)
d 9.72 (s,
1H, NHeN), 6.94 (d, 3J ¼ 11.1 Hz, 1H, NH), 6.33 (d, 3J ¼ 7.8 Hz, 1H,
CH]N), 4.94 (dd, 3J ¼ 11.1, 3J ¼ 4.0 Hz,1H, CHeN), 2.82 (m,1H, CH in
i-Pr), signals of other protons overlap with analogous signals of the
(E)-isomer; 13C NMR spectrum of (E)-4j (75.48 MHz, DMSO‑d6)
d
154.0 (C]O), 150.0 (CH]N), 144.4 (C), 135.0 (C), 129.5 (2CH),
128.5 (2CH), 73.0 (CHeN), 30.5 (CH in i-Pr), 26.7 (CH in i-Pr), 21.0
(CH3 in Ts), 20.3 (CH3 in i-Pr), 19.45 (CH3 in i-Pr), 19.38 (CH3 in i-Pr),
16.7 (CH3 in i-Pr). Anal. Calcd for C16H25N3O3S: C, 56.61; H, 7.42; N,
12.38. Found: C, 56.62; H, 7.61; N, 12.22.
(CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
; d 10.52 (s, 1H,
NHeN), 7.81 (s, 1H, CH]N), 7.63e7.72 (m, 4H, ArH), 7.36e7.42 (m,
2H, ArH), 7.35 (d, 3J ¼ 10.4 Hz, 1H, NH), 7.21e7.27 (m, 2H, ArH), 5.00
(ddd, 3J ¼ 11.0, 3J ¼ 10.4, 3J ¼ 3.5 Hz, 1H, CHeN), 2.39 (s, 3H, CH3 in
Ts), 2.34 (s, 3H, CH3 in CH3C6H4), 1.99e2.13 (m, 1H, HA in
CHAHBCH3), 1.81e1.96 (m, 1H, HB in CHAHBCH3), 0.93 (t, 3J ¼ 7.3 Hz,
4.2.11. (E)-1-Benzylidene-4-(1-tosylprop-1-yl)semicarbazide (7a)
To the solution of propanal (2h) (0.250 g, 4.30 mmol) in cold 80%
formic acid (1 mL) were added p-toluenesulfinic acid (0.671 g,
4.30 mmol) and 80% formic acid (1 mL), and the obtained mixture
was stirred at room temperature for 15 min. To the obtained sus-
pension semicarbazone of benzaldehyde [(E)-1a] (0.561 g,
3.44 mmol) and 80% formic acid (3.2 mL) were added, and the re-
action mixture was stirred at room temperature for 24 h. The sus-
pension was cooled, the precipitate was filtered, washed with cold
3H, CH3 in Et); 13C NMR (75.48 MHz, DMSO‑d6)
d 154.5 (C]O),144.4
(C), 141.1 (CH]N), 139.1 (C), 134.2 (C), 131.7 (C), 129.6 (2CH), 129.2
(2CH), 129.0 (2CH), 126.9 (2CH), 71.8 (CHeN), 21.1 (CH3 in Ts), 21.0
(CH3 in CH3C6H4), 19.7 (CH2 in Et), 10.2 (CH3 in Et). Anal. Calcd for
C19H23N3O3S: C, 61.10; H, 6.21; N, 11.25. Found: C, 61.11; H, 6.19; N,
11.41.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
11
4.2.14. (E)-1-(4-Methylbenzylidene)-4-(1-tosylbut-1-yl)
semicarbazide (7d)
formic acid (10 mL) were added, the reaction mixture was stirred at
room temperature for 24 h, and then H2O (25 mL) was added. The
obtained suspension was cooled, the precipitate was filtered,
washed with cold EtOH, ice-cold H2O, petroleum ether, and dried to
give sulfone 7f (4.188 g, 69%). Mp 189e189.5 ꢀC (decomp, MeCN); IR
(Nujol) nmax 3380 (s), 3201 (br m), 3180 (br m), 3085 (br m) (NH),
3029 (w) (CHarom), 1682 (s) (amide-I), 1613 (m) (C]N), 1600 (m)
(CCarom), 1527 (s), 1514 (s) (amide-II), 1280 (s), 1144 (s) (SO2), 812
Method A: To a solution of butanal (2i) (1.545 g, 21.43 mmol) in
cold EtOH (5 mL) were added p-toluenesulfinic acid (3.347 g,
21.43 mmol) and EtOH (5 mL), and the resulting solution was stir-
red at room temperature for 15 min. Then semicarbazone of
4-methylbenzaldehyde [(E)-1b] (2.531 g, 14.28 mmol) and EtOH
(8 mL) were added, and the reaction mixture was stirred at room
temperature for 168 h. The obtained suspension was cooled, the
precipitate was filtered, washed with cold EtOH, ice-cold H2O, pe-
troleum ether, and dried to give sulfone 7d (5.315 g, 96%). The crude
product was obtained in analytically pure form. Mp 141.5e142 ꢀC
(decomp, acetone); IR (Nujol) nmax 3343 (s), 3191 (br m), 3083 (br s)
(NH), 3024 (w) (CHarom), 1680 (s) (amide-I), 1613 (m) (C]N), 1601
(m) (CCarom), 1529 (s), 1523 (s) (amide-II), 1294 (s), 1128 (s) (SO2),
(m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 10.61 (s, 1H,
NHeN), 7.87 (t, 3J ¼ 6.9 Hz, 1H, NH), 7.81 (s, 1H, CH]N), 7.69e7.75
(m, 2H, ArH), 7.59e7.65 (m, 2H, ArH), 7.39e7.45 (m, 2H, ArH),
7.19e7.25 (m, 2H, ArH), 4.68 (d, 3J ¼ 6.9 Hz, 2H, NCH2), 2.40 (s, 3H,
CH3), 2.33 (s, 3H, CH3); 13C NMR (75.48 MHz, DMSO‑d6)
d: 154.4
(C]O), 144.4 (C), 140.9 (CH]N), 139.1 (C), 135.2 (C), 131.7 (C), 129.7
(2CH), 129.2 (2CH), 128.5 (2CH), 126.8 (2CH), 61.9 (NCH2), 21.1
(CH3), 21.0 (CH3). Anal. Calcd for C17H19N3O3S: C, 59.11; H, 5.54; N,
12.17. Found: C, 59.06; H, 5.71; N, 12.28.
810 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 10.51 (s,
1H, NHeN), 7.81 (s, 1H, CH]N), 7.62e7.72 (m, 4H, ArH), 7.36e7.42
(m, 2H, ArH), 7.35 (d, 3J ¼ 10.4 Hz, 1H, NH), 7.21e7.27 (m, 2H, ArH),
5.08 (ddd, 3J ¼ 10.4, 3J ¼ 9.5, 3J ¼ 5.2 Hz, 1H, CHeN), 2.39 (s, 3H, CH3
in Ts), 2.34 (s, 3H, CH3 in CH3C6H4), 1.84e2.02 (m, 2H, CH2 in Pr),
4.2.17. (E)-1-(4-Ethylbenzylidene)-4-(1-tosylprop-1-yl)
semicarbazide (7g)
1.20e1.53 (m, 2H, CH2 in Pr), 0.88 (t, 3J ¼ 7.3 Hz, 3H, CH3 in Pr); 13
C
Sulfone 7g (0.987 g, 81%) was prepared from propanal (2h)
(0.228 g, 3.93 mmol), p-toluenesulfinic acid (0.612 g, 3.92 mmol)
and semicarbazone of 4-ethylbenzaldehyde [(E)-1d] (0.599 g,
3.13 mmol) in 80% formic acid (5.2 mL) (rt, 24 h) as described for
compound 7a. The crude product was obtained in analytically pure
form. Mp 139e139.5 ꢀC (decomp); IR (Nujol) nmax 3350 (s), 3187 (br
s), 3083 (br s) (NH), 1682 (vs) (amide-I), 1614 (m) (C]N), 1599 (m)
(CCarom), 1525 (s), 1517 (s) (amide-II), 1494 (w) (CCarom), 1312 (s),
NMR (75.48 MHz, DMSO‑d6)
d 154.4 (C]O), 144.3 (C), 141.1 (CH]
N), 139.1 (C), 134.1 (C), 131.7 (C), 129.6 (2CH), 129.2 (2CH), 129.0
(2CH), 126.9 (2CH), 70.1 (CHeN), 27.9 (CH2 in Pr), 21.1 (CH3 in Ts),
21.0 (CH3 in CH3C6H4), 18.4 (CH2 in Pr), 13.2 (CH3 in Pr). Anal. Calcd
for C20H25N3O3S: C, 61.99; H, 6.50; N,10.84. Found: C, 61.89; H, 6.70;
N, 10.94.
Method B: Sulfone 7d (0.920 g, 86%) was prepared from butanal
(2i) (0.250 g, 3.47 mmol), p-toluenesulfinic acid (0.542 g,
3.47 mmol) and semicarbazone of 4-methylbenzaldehyde [(E)-1b]
(0.491 g, 2.77 mmol) in 80% formic acid (5.5 mL) (rt, 24 h) as
described for compound 7a.
1129 (s) (SO2), 826 (m), 810 (m) (CHarom
(300.13 MHz, DMSO‑d6) 10.54 (s, 1H, NHeN), 7.82 (s, 1H, CH]N),
) ;
cmꢁ1 1H NMR
d
7.65e7.72 (m, 4H, ArH), 7.36e7.42 (m, 2H, ArH), 7.34 (d, 3J ¼ 10.4 Hz,
1H, NH), 7.24e7.29 (m, 2H, ArH), 5.00 (ddd, 3J ¼ 11.1, 3J ¼ 10.4,
3J ¼ 3.4 Hz, 1H, CHeN), 2.64 (q, 3J ¼ 7.6 Hz, 2H, CH2 in C2H5C6H4),
2.39 (s, 3H, CH3 in Ts),1.99e2.13 (m,1H, HA in CHAHBCH3),1.80e1.97
(m, 1H, HB in CHAHBCH3), 1.19 (t, 3J ¼ 7.6 Hz, 3H, CH3 in C2H5C6H4),
0.93 (t, 3J ¼ 7.3 Hz, 3H, CH3 in Et); 13C NMR (75.48 MHz, DMSO‑d6)
4.2.15. (E)-1-(4-Methylbenzylidene)-4-[(2-methyl-1-tosyl)prop-
1-yl]semicarbazide (7e)
Sulfone 7e (0.766 g, 71%) was prepared from isobutyric aldehyde
(2j) (0.251 g, 3.48 mmol), p-toluenesulfinic acid (0.544 g,
3.48 mmol) and semicarbazone of 4-methylbenzaldehyde [(E)-1b]
(0.494 g, 2.79 mmol) in 80% formic acid (3.5 mL) (rt, 24 h) as
described for compound 7a. The crude product was obtained in
analytically pure form. Mp 133e133.5 ꢀC (decomp); IR (Nujol) nmax
3394 (s), 3186 (br s), 3098 (br s), 3087 (br s) (NH), 1682 (s) (amide-
I), 1613 (m) (C]N), 1595 (m) (CCarom), 1526 (s) (amide-II), 1312 (s),
d
154.5 (C]O), 145.4 (C), 144.4 (C), 141.1 (CH]N), 134.1 (C), 131.9
(C), 129.6 (2CH), 129.0 (2CH), 128.0 (2CH), 127.0 (2CH), 71.8 (CHeN),
28.1 (CH2 in C2H5C6H4), 21.1 (CH3 in Ts), 19.8 (CH2 in Et),15.5 (CH3 in
C2H5C6H4), 10.2 (CH3 in Et). Anal. Calcd for C20H25N3O3S: C, 61.99;
H, 6.50; N, 10.84. Found: C, 61.90; H, 6.53; N, 10.84.
4.2.18. (E)-1-(4-Ethylbenzylidene)-4-(1-tosylbut-1-yl)
semicarbazide (7h)
1148 (s) (SO2), 815 (s) (CHarom) cmꢁ1
;
1H NMR (300.13 MHz,
DMSO‑d6) 10.56 (s, 1H, NHeN), 7.82 (s, 1H, CH]N), 7.68e7.73 (m,
d
Sulfone 7h (0.989 g, 84%) was prepared from butanal (2i)
(0.265 g, 3.68 mmol), p-toluenesulfinic acid (0.575 g, 3.68 mmol)
and semicarbazone of 4-ethylbenzaldehyde [(E)-1d] (0.563 g,
2.94 mmol) in 80% formic acid (4.4 mL) (rt, 24 h) as described for
compound 7a. The crude product was obtained in analytically pure
form. Mp 140e140.5 ꢀC (decomp); IR (Nujol) nmax 3343 (s), 3332 (s),
3190 (br m), 3084 (br s) (NH), 1678 (vs) (amide-I), 1615 (m) (C]N),
1600 (m) (CCarom), 1529 (s) (amide-II), 1493 (w) (CCarom), 1294 (s),
2H, ArH), 7.56e7.61 (m, 2H, ArH), 7.34e7.40 (m, 2H, ArH), 7.23e7.29
(m, 2H, ArH), 7.06 (d, 3J ¼ 11.0 Hz, 1H, NH), 4.96 (dd, 1H, 3J ¼ 11.0,
3J ¼ 5.0 Hz, CHeN), 2.54e2.70 (m, 1H, CH in i-Pr), 2.36 (s, 3H, CH3 in
Ts), 2.34 (s, 3H, CH3 in CH3C6H4),1.05 (d, 3J ¼ 6.8 Hz, 3H, CH3 in i-Pr),
1.03 (d, 3J ¼ 6.8 Hz, 3H, CH3 in i-Pr); 13C NMR (75.48 MHz, DMSO‑d6)
d
154.1 (C]O), 144.4 (C), 141.5 (CH]N), 139.4 (C), 135.1 (C), 131.5
(C), 129.6 (2CH), 129.4 (2CH), 128.6 (2CH), 126.6 (2CH), 73.7
(CHeN), 26.9 (CH in i-Pr), 21.1 (CH3 in Ts), 21.0 (CH3 in CH3C6H4),
20.4 (CH3 in i-Pr), 17.5 (CH3 in i-Pr). Anal. Calcd for C20H25N3O3S: C,
61.99; H, 6.50; N, 10.84. Found: C, 62.10; H, 6.57; N, 11.03.
1128 (s) (SO2), 826 (m), 809 (m) (CHarom
(300.13 MHz, DMSO‑d6) 10.53 (s, 1H, NHeN), 7.81 (s, 1H, CH]N),
) ;
cmꢁ1 1H NMR
d
7.65e7.72 (m, 4H, ArH), 7.36e7.41 (m, 2H, ArH), 7.37 (d, 3J ¼ 10.3 Hz,
1H, NH), 7.24e7.29 (m, 2H, ArH), 5.08 (ddd, 3J ¼ 10.3, 3J ¼ 9.4,
3J ¼ 5.3 Hz, 1H, CHeN), 2.64 (q, 3J ¼ 7.6 Hz, 2H, CH2 in C2H5C6H4),
2.39 (s, 3H, CH3 in Ts), 1.84e2.01 (m, 2H, CH2 in Pr), 1.20e1.53 (m,
2H, CH2 in Pr), 1.19 (t, 3J ¼ 7.6 Hz, 3H, CH3 in C2H5C6H4), 0.87 (t,
4.2.16. (E)-1-(4-Methylbenzylidene)-4-(tosylmethyl)semicarbazide
(7f)
A suspension of paraformaldehyde (0.553 g, 18.42 mmol) in 80%
formic acid (10 mL) was heated at 65 ꢀC (bath temperature) under
stirring until the clear solution formed, and cooled to room tem-
perature. Then p-toluenesulfinic acid (2.879 g,18.43 mmol) and 80%
formic acid (6 mL) were added, and the mixture was stirred at room
temperature for 15 min. To the resulting solution semicarbazone of
4-methylbenzaldehyde [(E)-1b] (3.110 g, 17.55 mmol) and 80%
3J ¼ 7.3 Hz, 3H, CH3 in Pr); 13C NMR (75.48 MHz, DMSO‑d6)
d 154.4
(C]O), 145.4 (C), 144.4 (C), 141.1 (CH]N), 134.1 (C), 131.9 (C), 129.6
(2CH),129.0 (2CH), 128.0 (2CH),127.0 (2CH), 70.1 (CHeN), 28.1 (CH2
in C2H5C6H4), 27.8 (CH2 in Pr), 21.1 (CH3 in Ts), 18.4 (CH2 in Pr), 15.5
(CH3 in C2H5C6H4), 13.2 (CH3 in Pr). Anal. Calcd for C21H27N3O3S: C,
62.82; H, 6.78; N, 10.47. Found: C, 62.78; H, 6.83; N, 10.48.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

12
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
4.2.19. (E)-1-(4-Isopropylbenzylidene)-4-(1-tosylprop-1-yl)
semicarbazide (7i)
Bu), 0.94 (t, 3J ¼ 7.3 Hz, 3H, CH3 in Et); 13C NMR (75.48 MHz,
DMSO‑d6)
d 154.5 (C]O), 152.2 (C), 144.4 (C), 140.9 (CH]N), 134.1
Sulfone 7i (0.991 g, 86%) was prepared from propanal (2h)
(0.207 g, 3.56 mmol), p-toluenesulfinic acid (0.558 g, 3.57 mmol)
and semicarbazone of 4-isopropylbenzaldehyde [(E)-1e] (0.587 g,
2.86 mmol) in 80% formic acid (4.3 mL) (rt, 24 h) as described for
compound 7a. The crude product was obtained in analytically pure
form. Mp 142e142.5 ꢀC (decomp); IR (Nujol) nmax 3355 (s), 3199 (br
m), 3083 (br s) (NH), 3026 (w) (CHarom), 1685 (vs) (amide-I), 1614
(m) (C]N), 1598 (m) (CCarom), 1526 (s), 1518 (s) (amide-II), 1308 (s),
(C), 131.7 (C), 129.6 (2CH), 129.0 (2CH), 126.7 (2CH), 125.4 (2CH),
71.7 (CHeN), 34.5 (Cquat in t-Bu), 31.0 (3 ꢂ CH3 in t-Bu), 21.1 (CH3 in
Ts), 19.8 (CH2 in Et), 10.2 (CH3 in Et). Anal. Calcd for C22H29N3O3S: C,
63.59; H, 7.03; N, 10.11. Found: C, 63.60; H, 7.16; N, 10.06.
4.2.22. (E)-1-(4-tert-Butylbenzylidene)-4-(1-tosylbut-1-yl)
semicarbazide (7l)
Sulfone 7l (0.982 g, 84%) was prepared from butanal (2i)
(0.244 g, 3.38 mmol), p-toluenesulfinic acid (0.529 g, 3.39 mmol)
and semicarbazone of 4-tert-butylbenzaldehyde [(E)-1f] (0.594 g,
2.71 mmol) in 80% formic acid (4.1 mL) (rt, 24 h) as described for
compound 7a. The crude product was obtained in analytically pure
form. Mp 139.5e140 ꢀC (decomp); IR (Nujol) nmax 3383 (s), 3200 (br
m), 3094 (br s) (NH), 3023 (w) (CHarom), 1694 (vs) (amide-I), 1613
(m) (C]N), 1597 (m) (CCarom), 1522 (sh), 1510 (s) (amide-II), 1319
1129 (s) (SO2), 824 (m), 812 (m) (CHarom
(300.13 MHz, DMSO‑d6) 10.54 (s, 1H, NHeN), 7.82 (s, 1H, CH]N),
) ;
cmꢁ1 1H NMR
d
7.65e7.72 (m, 4H, ArH), 7.36e7.42 (m, 2H, ArH), 7.33 (d, 3J ¼ 10.2 Hz,
1H, NH), 7.27e7.32 (m, 2H, ArH), 5.00 (ddd, 3J ¼ 11.2, 3J ¼ 10.2,
3J ¼ 3.5 Hz, 1H, CHeN), 2.92 (septet, 3J ¼ 6.9 Hz, 1H, CH in i-Pr), 2.39
(s, 3H, CH3 in Ts), 2.00e2.13 (m, 1H, HA in CHAHBCH3), 1.80e1.96 (m,
1H, HB in CHAHBCH3), 1.22 (d, 3J ¼ 6.9 Hz, 6H, two CH3 in i-Pr), 0.93
(t, 3J ¼ 7.3 Hz, 3H, CH3 in Et); 13C NMR (75.48 MHz, DMSO‑d6)
;
(s), 1132 (s) (SO2), 818 (m) (CHarom) cmꢁ1 1H NMR (300.13 MHz,
d
154.5 (C]O), 150.0 (C), 144.4 (C), 141.1 (CH]N), 134.1 (C), 132.1
DMSO‑d6) 10.55 (s, 1H, NHeN), 7.81 (s, 1H, CH]N), 7.65e7.72 (m,
d
(C), 129.6 (2CH), 129.0 (2CH), 127.0 (2CH), 126.5 (2CH), 71.7 (CHeN),
33.3 (CH in i-Pr), 23.72 (CH3 in i-Pr), 23.71 (CH3 in i-Pr), 21.1 (CH3 in
Ts), 19.8 (CH2 in Et), 10.2 (CH3 in Et). Anal. Calcd for C21H27N3O3S: C,
62.82; H, 6.78; N, 10.47. Found: C, 62.83; H, 6.85; N, 10.52.
4H, ArH), 7.41e7.47 (m, 2H, ArH), 7.36e7.41 (m, 2H, ArH), 7.33 (d,
3J ¼ 10.4 Hz, 1H, NH), 5.07 (ddd, 3J ¼ 10.4, 3J ¼ 10.0, 3J ¼ 4.6 Hz, 1H,
CHeN), 2.39 (s, 3H, CH3 in Ts), 1.83e2.03 (m, 2H, CH2 in Pr),
1.20e1.53 (m, 2H, CH2 in Pr, signals partly overlap with signal of the
t-Bu protons),1.30 (s, 9H, CH3 in t-Bu), 0.88 (t, 3J ¼ 7.4 Hz, 3H, CH3 in
4.2.20. (E)-1-(4-Isopropylbenzylidene)-4-(1-tosylbut-1-yl)
semicarbazide (7j)
Pr); 13C NMR (75.48 MHz, DMSO‑d6)
d 154.4 (C]O), 152.2 (C), 144.4
(C), 140.9 (CH]N), 134.0 (C), 131.7 (C), 129.6 (2CH), 129.0 (2CH),
126.7 (2CH), 125.4 (2CH), 70.0 (CHeN), 34.5 (Cquat in t-Bu), 31.0
(3 ꢂ CH3 in t-Bu), 27.8 (CH2 in Pr), 21.1 (CH3 in Ts), 18.4 (CH2 in Pr),
13.2 (CH3 in Pr). Anal. Calcd for C23H31N3O3S: C, 64.31; H, 7.27; N,
9.78. Found: C, 64.37; H, 7.40; N, 9.70.
Sulfone 7j (0.969 g, 83%) was prepared from butanal (2i)
(0.254 g, 3.52 mmol), p-toluenesulfinic acid (0.550 g, 3.52 mmol)
and semicarbazone of 4-isopropylbenzaldehyde [(E)-1e] (0.578 g,
2.82 mmol) in 80% formic acid (4.2 mL) (rt, 24 h) as described for
compound 7a. The crude product was obtained in analytically pure
form. Mp 138e138.5 ꢀC (decomp); IR (Nujol) nmax 3353 (s), 3196 (br
s), 3083 (br s) (NH), 3022 (w) (CHarom), 1681 (vs) (amide-I), 1613
(m) (C]N), 1600 (m) (CCarom), 1525 (s), 1518 (sh) (amide-II), 1495
4.2.23. (E)-1-[(5-Nitro-2-furyl)methylene]-4-(1-tosylprop-1-yl)
semicarbazide (7m)
Sulfone 7m (1.090 g, 91%) as a yellow solid was prepared from
propanal (2h) (0.222 g, 3.82 mmol), p-toluenesulfinic acid (0.596 g,
3.82 mmol) and semicarbazone of 5-nitrofurfural [(E)-1g] (0.605 g,
3.05 mmol) in 80% formic acid (5.3 mL) (rt, 24 h) as described for
compound 7a. The crude product was obtained in analytically pure
form. Mp 163e183 ꢀC (decomp); IR (Nujol) nmax 3341 (s), 3330 (br
s), 3087 (very br s) (NH), 1680 (vs) (amide-I), 1593 (m), 1581 (m),
1541 (s), 1526 (s), 1513 (s) (C]N, amide-II, NO2, CCarom), 1342 (vs)
(NO2), 1317 (s), 1128 (s) (SO2), 809 (m) (CHarom in Ts) cmꢁ1; 1H NMR
(w) (CCarom), 1297 (s), 1128 (s) (SO2), 822 (m), 807 (m) (CHarom
)
cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d
10.53 (s, 1H, NHeN), 7.81
(s, 1H, CH]N), 7.65e7.72 (m, 4H, ArH), 7.36e7.41 (m, 2H, ArH), 7.35
(d, 3J ¼ 10.3 Hz, 1H, NH), 7.27e7.32 (m, 2H, ArH), 5.08 (ddd,
3J ¼ 10.3, 3J ¼ 9.8, 3J ¼ 4.9 Hz, 1H, CHeN), 2.92 (septet, 3J ¼ 6.9 Hz,
1H, CH in i-Pr), 2.39 (s, 3H, CH3 in Ts), 1.84e2.01 (m, 2H, CH2 in Pr),
1.20e1.53 (m, 2H, CH2 in Pr), 1.22 (d, 3J ¼ 6.9 Hz, 6H, two CH3 in i-
Pr), 0.88 (t, 3J ¼ 7.3 Hz, 3H, CH3 in Pr); 13C NMR (75.48 MHz,
DMSO‑d6)
d
154.4 (C]O), 150.0 (C), 144.4 (C), 141.1 (CH]N), 134.1
(300.13 MHz, DMSO‑d6)
d
11.07 (s, 1H, NHeN), 7.83 (d, 3J ¼ 4.0 Hz,
(C), 132.1 (C), 129.6 (2CH), 129.0 (2CH), 127.0 (2CH), 126.5 (2CH),
70.0 (CHeN), 33.3 (CH in i-Pr), 27.8 (CH2 in Pr), 23.73 (CH3 in i-Pr),
23.71 (CH3 in i-Pr), 21.1 (CH3 in Ts), 18.4 (CH2 in Pr), 13.2 (CH3 in Pr).
Anal. Calcd for C22H29N3O3S: C, 63.59; H, 7.03; N, 10.11. Found: C,
63.74; H, 7.22; N, 10.21.
1H, H-4 in furan moiety), 7.81 (s, 1H, CH]N), 7.67e7.72 (m, 2H,
ArH), 7.40e7.45 (m, 2H, ArH), 7.42 (d, 3J ¼ 10.2 Hz, 1H, NH, one of
the signals overlaps with signals of aromatic protons), 7.32 (d,
3J ¼ 4.0 Hz, 1H, H-3 in furan moiety), 4.99 (ddd, 3J ¼ 11.2, 3J ¼ 10.2,
3J ¼ 3.4 Hz, 1H, CHeN), 2.39 (s, 3H, CH3 in Ts), 1.99e2.13 (m, 1H, HA
in CHAHBCH3), 1.74e1.90 (m, 1H, HB in CHAHBCH3), 0.92 (t,
4.2.21. (E)-1-(4-tert-Butylbenzylidene)-4-(1-tosylprop-1-yl)
semicarbazide (7k)
3J ¼ 7.3 Hz, 3H, CH3 in Et); 13C NMR (75.48 MHz, DMSO‑d6)
d 153.9
(C]O), 152.4 (C), 151.5 (C), 144.5 (C), 133.9 (C), 129.7 (2CH), 129.4
(CH]N), 129.0 (2CH), 115.1 (CH), 113.5 (CH), 71.6 (CHeN), 21.1 (CH3
in Ts), 19.8 (CH2 in Et), 10.1 (CH3 in Et). Anal. Calcd for C16H18N4O6S:
C, 48.73; H, 4.60; N, 14.21. Found: C, 48.77; H, 4.71; N, 14.22.
Sulfone 7k (0.997 g, 83%) was prepared from propanal (2h)
(0.210 g, 3.62 mmol), p-toluenesulfinic acid (0.566 g, 3.62 mmol)
and semicarbazone of 4-tert-butylbenzaldehyde [(E)-1f] (0.635 g,
2.90 mmol) in 80% formic acid (4.4 mL) (rt, 24 h) as described for
compound 7a. The crude product was obtained in analytically pure
form. Mp 141e141.5 ꢀC (decomp); IR (Nujol) nmax 3357 (s), 3198 (br
m), 3087 (br s) (NH), 3025 (w) (CHarom), 1685 (vs) (amide-I), 1612
(m) (C]N), 1597 (m) (CCarom), 1528 (s), 1521 (sh) (amide-II), 1493
4.2.24. (E)-1-[(5-Nitro-2-furyl)methylene]-4-(1-tosylbut-1-yl)
semicarbazide (7n)
Sulfone 7n (0.915 g, 92%) as a yellow solid was prepared from
butanal (2i) (0.219 g, 3.04 mmol), p-toluenesulfinic acid (0.473 g,
3.03 mmol) and semicarbazone of 5-nitrofurfural [(E)-1g] (0.480 g,
2.42 mmol) in 80% formic acid (12.8 mL) (rt, 24 h) as described for
compound 7a. The crude product was obtained in analytically pure
form. Mp 182e188 ꢀC (decomp); IR (Nujol) nmax 3345 (s), 3133 (m),
3110 (m), 3087 (br s), 3068 (br m) (NH), 1685 (vs) (amide-I), 1594
(m), 1580 (m), 1541 (s), 1528 (s), 1511 (s), 1495 (w) (C]N, amide-II,
(w) (CCarom), 1309 (s), 1129 (s) (SO2), 824 (m), 812 (m) (CHarom
)
cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d
10.56 (s, 1H, NHeN), 7.82
(s, 1H, CH]N), 7.65e7.72 (m, 4H, ArH), 7.36e7.47 (m, 4H, ArH), 7.31
(d, 3J ¼ 10.4 Hz, 1H, NH), 5.00 (ddd, 3J ¼ 11.0, 3J ¼ 10.4, 3J ¼ 3.5 Hz,
1H, CHeN), 2.39 (s, 3H, CH3 in Ts), 1.99e2.14 (m, 1H, HA in
CHAHBCH3),1.79e1.97 (m,1H, HB in CHAHBCH3),1.30 (s, 9H, CH3 in t-
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
13
NO2, CCarom), 1335 (vs) (NO2), 1315 (s), 1126 (s) (SO2), 810 (m)
(CHarom in Ts) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
11.06 (s, 1H,
toluenesulfinic acid (2.863 g, 18.33 mmol) and semicarbazone of
4-methoxybenzaldehyde [(E)-1c] (2.354 g, 12.18 mmol) in EtOH
(25 mL) (rt, 120 h) as described for (E)-4a in Method A. The isolated
product contained 5 mol% of sulfone (E)-4b that could not be
removed by crystallization from MeCN or washing with hot EtOH.
However, the crude compound gave satisfactory elemental analysis.
d
NHeN), 7.83 (d, 3J ¼ 4.0 Hz, 1H, H-4 in furan moiety), 7.81 (s, 1H,
CH]N), 7.67e7.72 (m, 2H, ArH), 7.44 (d, 3J ¼ 10.1 Hz, 1H, NH, one of
the signals overlaps with signals of aromatic protons), 7.39e7.45
(m, 2H, ArH), 7.32 (d, 3J ¼ 4.0 Hz, 1H, H-3 in furan moiety), 5.06
(ddd, 3J ¼ 11.2, 3J ¼ 10.1, 3J ¼ 3.6 Hz, 1H, CHeN), 2.39 (s, 3H, CH3 in
Ts), 1.78e2.01 (m, 2H, CH2 in Pr), 1.19e1.51 (m, 2H, CH2 in Pr), 0.87
(t, 3J ¼ 7.3 Hz, 3H, CH3 in Pr); 13C NMR (75.48 MHz, DMSO‑d6)
1H NMR (300.13 MHz, DMSO‑d6)
d 10.55 (br s, 1H, NHeN), 7.84 (s,
1H, CH]N), 7.66e7.73 (m, 4H, ArH), 7.57 (d, 3J ¼ 10.9 Hz, 1H, NH),
7.43e7.48 (m, 2H, ArH), 7.36e7.42 (m, 2H, ArH), 7.22e7.28 (m, 2H,
ArH), 7.00e7.06 (m, 2H, ArH), 6.25 (d, 3J ¼ 10.9 Hz, 1H, CHeN), 3.82
(s, 3H, OCH3), 2.39 (s, 3H, CH3 in Ts), 2.34 (s, 3H, CH3); 13C NMR
d
153.8 (C]O), 152.5 (C), 151.5 (C), 144.5 (C), 133.8 (C), 129.7 (2CH),
129.4 (CH]N), 129.0 (2CH), 115.1 (CH), 113.5 (CH), 69.9 (CHeN),
27.9 (CH2 in Pr), 21.1 (CH3 in Ts), 18.3 (CH2 in Pr), 13.2 (CH3 in Pr).
Anal. Calcd for C17H20N4O6S: C, 49.99; H, 4.94; N, 13.72. Found: C,
50.01; H, 5.15; N, 13.71.
(75.48 MHz, DMSO‑d6)
d 160.5 (C), 153.5 (C]O), 144.7 (C), 141.7
(CH]N), 139.0 (C), 133.9 (C), 129.6 (2CH), 129.2 (2CH), 129.1 (2CH),
128.9 (2CH), 128.4 (2CH), 128.0 (C), 126.7 (C), 114.3 (2CH), 72.4
(CHeN), 55.3 (OCH3), 21.2 (CH3 in Ts), 20.9 (CH3). Anal. Calcd for
4.2.25. (E)-4-[(2-Methyl-1-tosyl)prop-1-yl]-1-[(5-nitro-2-furyl)
methylene]semicarbazide (7o)
C24H25N3O4S: C, 63.84; H, 5.58; N, 9.31. Found: C, 63.94; H, 5.49; N,
9.43.
Sulfone 7o (0.905 g, 89%) as a yellow solid was prepared from
isobutyric aldehyde (2j) (0.224 g, 3.11 mmol), p-toluenesulfinic acid
(0.485 g, 3.10 mmol) and semicarbazone of 5-nitrofurfural [(E)-1g]
(0.492 g, 2.48 mmol) in 80% formic acid (3.7 mL) (rt, 24 h) as
described for compound 7a. The crude product was obtained in
analytically pure form. Mp 131e131.5 ꢀC (decomp); IR (Nujol) nmax
3366 (s), 3138 (m), 3106 (br m) (NH), 1685 (vs) (amide-I), 1596 (m),
1581 (m), 1547 (s), 1529 (s), 1513 (s) (C]N, amide-II, NO2, CCarom),
4.3. Reaction of 4-(tosylmethyl)semicarbazones with NaBH4.
Synthesis of semicarbazones 5a-w
4.3.1. (E)-4-Benzyl-1-benzylidenesemicarbazide (5a)
To a mixture of NaBH4 (0.065 g, 1.72 mmol) and sulfone (E)-4a
(0.631 g, 1.55 mmol) was added EtOH (5.4 mL), and the resulting
mixture was stirred at room temperature for 1.5 h. The solvent was
removed under vacuum, the residue was triturated with saturated
aqueous NaHCO3 until crystallization was complete. The obtained
suspension was cooled (0 ꢀC), the precipitate was filtered, washed
with ice-cold H2O, petroleum ether, and dried to give 5a (0.365 g,
93%). Mp 138e139.5 ꢀC (EtOH) [lit [34c]. mp 139 ꢀC (EtOH)]; IR
(Nujol) nmax 3413 (s), 3197 (br m), 3171 (br m), 3084 (br s) (NH),
3028 (m) (CHarom), 1676 (vs) (amide-I), 1608 (m) (C]N), 1584 (w)
(CCarom), 1534 (s) (amide-II), 1496 (m) (CCarom), 756 (s), 698 (m),
1338 (vs) (NO2),1310 (s),1134 (s) (SO2), 811 (m) (CHarom in Ts) cmꢁ1
1H NMR (300.13 MHz, DMSO‑d6)
11.02 (s, 1H, NHeN), 7.83 (s, 1H,
;
d
CH]N), 7.79 (d, 3J ¼ 3.9 Hz, 1H, H-4 in furan moiety), 7.69e7.74 (m,
2H, ArH), 7.37e7.42 (m, 2H, ArH), 7.25 (d, 3J ¼ 3.9 Hz, 1H, H-3 in
furan moiety), 7.13 (d, 3J ¼ 10.9 Hz, 1H, NH), 4.96 (dd, 3J ¼ 10.9,
3J ¼ 4.9 Hz, 1H, CHeN), 2.60 (doublet of septet, 3J ¼ 6.8, 3J ¼ 4.9 Hz,
1H, CH in i-Pr), 2.37 (s, 3H, CH3 in Ts), 1.04 (d, 3J ¼ 6.8 Hz, 3H, CH3 in
i-Pr), 1.02 d, 3J ¼ 6.8 Hz, (3H, CH3 in i-Pr); 13C NMR (75.48 MHz,
DMSO‑d6)
d
153.4 (C]O), 152.0 (C), 151.6 (C), 144.5 (C), 135.0 (C),
692 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 10.45 (s,
129.71 (CH]N), 129.65 (2CH), 128.7 (2CH), 114.9 (CH), 114.0 (CH),
73.6 (CHeN), 26.9 (CH in i-Pr), 21.1 (CH3 in Ts), 20.3 (CH3 in i-Pr),
17.3 (CH3 in i-Pr). Anal. Calcd for C17H20N4O6S: C, 49.99; H, 4.94; N,
13.72. Found: C, 49.96; H, 5.11; N, 13.69.
1H, NHeN), 7.87 (s, 1H, CH]N), 7.71e7.78 (m, 2H, ArH), 7.65 (t,
3J ¼ 6.4 Hz, 1H, NH), 7.18e7.42 (m, 8H, ArH), 4.37 (d, 3J ¼ 6.4 Hz, 2H,
CH2); 13C NMR (75.48 MHz, DMSO‑d6)
d 155.7 (C]O), 140.8 (C),
139.4 (CH]N), 134.7 (C), 129.0 (CH), 128.5 (2CH), 128.1 (2CH), 127.0
(2CH), 126.6 (2CH), 126.5 (CH), 42.5 (CH2). Anal. Calcd for
4.2.26. (E)-4-[(4-Methoxyphenyl)(tosyl)methyl]-1-
C15H15N3O: C, 71.13; H, 5.97; N, 16.59. Found: C, 71.17; H, 6.12; N,
(4-methylbenzylidene)semicarbazide (7p)
16.48.
Sulfone
7p
(5.047 g,
95%)
was
prepared
from
4-methoxybenzaldehyde (2c) (2.393 g, 17.58 mmol), p-toluene-
sulfinic acid (2.754 g, 17.63 mmol) and semicarbazone of
4-methylbenzaldehyde [(E)-1b] (2.077 g, 11.72 mmol) in EtOH
(23 mL) (rt, 120 h) as described for (E)-4a in Method A. The isolated
product contained 5 mol% of sulfone (E)-4c that could not be
removed by crystallization from MeCN or washing with hot EtOH.
However, the crude compound gave satisfactory elemental analysis.
4.3.2. (E)-1-Benzylidene-4-propylsemicarbazide (5b)
Compound 5b (0.289 g, 91%) was prepared from sulfone 7a
(0.558 g, 1.55 mmol) and NaBH4 (0.118 g, 3.12 mmol) in EtOH
(5.4 mL) (rt, 1.5 h) as described for compound 5a. Mp 139e140 ꢀC
(EtOH) (lit [32b]. mp 136e138 ꢀC); IR (Nujol) nmax 3376 (s), 3176 (s),
3081 (br s) (NH), 1669 (vs) (amide-I), 1604 (m) (C]N), 1554 (s)
(amide-II), 757 (s), 699 (s) (CHarom) cmꢁ1 1H NMR (300.13 MHz,
;
1H NMR (300.13 MHz, DMSO‑d6)
d
10.61 (br s, 1H, NHeN), 7.86 (s,
DMSO‑d6) d 10.31 (s, 1H, NHeN), 7.83 (s, 1H, CH]N), 7.69e7.75 (m,
1H, CH]N), 7.67e7.72 (m, 2H, ArH), 7.61e7.66 (m, 2H, ArH), 7.58 (d,
3J ¼ 10.9 Hz, 1H, NH), 7.48e7.54 (m, 2H, ArH), 7.36e7.41 (m, 2H,
ArH), 7.25e7.30 (m, 2H, ArH), 6.96e7.02 (m, 2H, ArH), 6.25 (d,
3J ¼ 10.9 Hz, 1H, CHeN), 3.79 (s, 3H, OCH3), 2.39 (s, 3H, CH3 in Ts),
2H, ArH), 7.30e7.42 (m, 3H, ArH), 7.03 (br t, 3J ¼ 6.1 Hz, 1H, NH),
3.06e3.14 (m, 2H, NCH2), 1.42e1.55 (m, 2H, CH2), 0.86 (t, 3J ¼ 7.4 Hz,
3H, CH3); 13C NMR (75.48 MHz, DMSO‑d6)
d 155.6 (C]O), 139.1
(CH]N), 134.8 (C), 129.0 (CH), 128.6 (2CH), 126.6 (2CH), 40.8
(NCH2), 23.3 (CH2), 11.3 (CH3). Anal. Calcd for C11H15N3O: C, 64.37;
H, 7.37; N, 20.47. Found: C, 64.23; H, 7.57; N, 20.40.
2.36 (s, 3H, CH3); 13C NMR (75.48 MHz, DMSO‑d6)
d 160.1 (C), 153.4
(C]O), 144.6 (C), 141.9 (CH]N), 139.4 (C), 133.9 (C), 131.4 (C), 130.5
(2CH), 129.5 (2CH), 129.3 (2CH), 129.0 (2CH), 126.7 (2CH), 122.7 (C),
113.7 (2CH), 72.2 (CHeN), 55.2 (OCH3), 21.1 (CH3 in Ts), 21.0 (CH3).
Anal. Calcd for C24H25N3O4S: C, 63.84; H, 5.58; N, 9.31. Found: C,
63.74; H, 5.51; N, 9.56.
4.3.3. (E)-1-Benzylidene-4-butylsemicarbazide (5c)
Compound 5c (0.351 g, 93%) was from sulfone 7b (0.644 g,
1.72 mmol) and NaBH4 (0.131 g, 3.46 mmol) in EtOH (6 mL) (rt,
1.5 h) as described for compound 5a. Mp 166.5e168 ꢀC (EtOH) (lit
[32b]. mp 160e162 ꢀC); IR (Nujol) nmax 3332 (s), 3173 (s), 3084 (s)
(NH), 3025 (w) (CHarom), 1668 (s) (amide-I), 1603 (m) (C]N), 1551
(s) (amide-II), 1503 (m) (CCarom), 758 (s), 696 (s) (CHarom) cmꢁ1; 1H
4.2.27. (E)-1-(4-Methoxybenzylidene)-4-[(4-methylphenyl)(tosyl)
methyl]semicarbazide (7r)
Sulfone
4-methylbenzaldehyde
7r
(5.289 g,
(2b)
96%)
(2.195 g,
was
prepared
18.27 mmol),
from
p-
NMR (300.13 MHz, DMSO‑d6) d 10.31 (s, 1H, NHeN), 7.83 (s, 1H,
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

14
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
CH]N), 7.69e7.75 (m, 2H, ArH), 7.30e7.42 (m, 3H, ArH), 7.01 (br t,
3J ¼ 6.1 Hz, 1H, NH), 3.10e3.18 (m, 2H, NCH2), 1.40e1.52 (m, 2H,
CH2), 1.22e1.36 (m, 2H, CH2), 0.89 (t, 3J ¼ 7.3 Hz, 3H, CH3); 13C NMR
DMSO‑d6) d 10.24 (s, 1H, NHeN), 7.80 (s, 1H, CH]N), 7.58e7.63 (m,
2H, ArH), 7.17e7.22 (m, 2H, ArH), 6.96 (br t, 3J ¼ 6.2 Hz, 1H, NH),
2.96 (dd, 3J ¼ 7.0, 3J ¼ 6.2 Hz, 2H, NCH2), 2.31 (s, 3H, CH3 in
CH3C6H4), 1.78 (triplet of septet, 3J ¼ 7.0, 3J ¼ 6.7 Hz, 1H, CH in i-Bu),
0.86 (d, 3J ¼ 6.7 Hz, 6H, CH3 in i-Bu); 13C NMR (75.48 MHz,
(75.48 MHz, DMSO‑d6)
d 155.6 (C]O), 139.1 (CH]N), 134.8 (C),
129.0 (CH), 128.5 (2CH), 126.6 (2CH), 38.7 (NCH2), 32.2 (CH2), 19.6
(CH2), 13.8 (CH3). Anal. Calcd for C12H17N3O: C, 65.73; H, 7.81; N,
19.16. Found: C, 65.92; H, 7.86; N, 19.26.
DMSO‑d6)
d 155.7 (C]O), 139.2 (CH]N), 138.6 (C), 132.1 (C), 129.2
(2CH), 126.5 (2CH), 46.5 (NCH2), 28.7 (CH in i-Bu), 21.0 (CH3 in
CH3C6H4), 20.1 (two CH3 in i-Bu). Anal. Calcd for C13H19N3O: C,
66.92; H, 8.21; N, 18.01. Found: C, 67.12; H, 8.06; N, 18.08.
4.3.4. (E)-1-(4-Methylbenzylidene)-4-[(4-methylphenyl)methyl]
semicarbazide (5d)
Compound 5d (0.370 g, 94%) was prepared from sulfone (E)-4b
(0.611 g, 1.40 mmol) and NaBH4 (0.058 g, 1.53 mmol) in EtOH (5 mL)
(rt, 1.5 h) as described for compound 5a. Mp 149e150 ꢀC (EtOH); IR
(Nujol) nmax 3421 (s), 3338 (m), 3191 (br s), 3092 (br s) (NH), 3044
(w), 3011 (w) (CHarom), 1680 (vs) (amide-I), 1612 (m) (C]N), 1580
4.3.8. (E)-4-Methyl-1-(4-methylbenzylidene)semicarbazide (5h)
Compound 5h (0.363 g, 96%) was prepared from sulfone 7f
(0.685 g,1.98 mmol) and NaBH4 (0.150 g, 3.96 mmol) in EtOH (7 mL)
(rt, 1.5 h) as described for compound 5a. Mp 194e195.5 ꢀC (EtOH)
[lit [48] 192e193 ꢀC (EtOH)]; IR (Nujol) nmax 3397 (s), 3185 (s), 3114
(br s) (NH), 1671 (vs) (amide-I), 1606 (m) (C]N), 1556 (s), 1515 (m)
(amide-II), 815 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
(w) (CCarom), 1538 (s), 1515 (s) (amide-II), 809 (m), 800 (m) (CHarom
)
cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 10.34 (s, 1H, NHeN), 7.82
(s, 1H, CH]N), 7.60e7.65 (m, 2H, ArH), 7.53 (t, 3J ¼ 6.4 Hz, 1H, NH),
7.16e7.22 (m, 4H, ArH), 7.09e7.14 (m, 2H, ArH), 4.31 (d, 3J ¼ 6.4 Hz,
2H, CH2), 2.31 (s, 3H, CH3), 2.27 (s, 3H, CH3); 13C NMR (75.48 MHz,
d 10.22 (br s, 1H, NHeN), 7.80 (s, 1H, CH]N), 7.58e7.63 (m, 2H,
ArH), 7.17e7.22 (m, 2H, ArH), 6.90 (br q, 3J ¼ 4.7 Hz,1H, NH), 2.70 (d,
3J ¼ 4.7 Hz, 3H, NCH3), 2.31 (s, 3H, CH3 in CH3C6H4); 13C NMR
DMSO‑d6)
d
155.7 (C]O), 139.5 (CH]N), 138.7 (C), 137.8 (C), 135.5
(75.48 MHz, DMSO‑d6) d 156.1 (C]O), 139.2 (CH]N), 138.5 (C),
(C), 132.0 (C), 129.1 (2CH), 128.7 (2CH), 127.1 (2CH), 126.6 (2CH),
42.2 (CH2), 21.0 (CH3), 20.7 (CH3). Anal. Calcd for C17H19N3O: C,
72.57; H, 6.81; N, 14.94. Found: C, 72.46; H, 6.85; N, 14.94.
132.1 (C), 129.1 (2CH), 126.4 (2CH), 26.0 (NCH3), 20.9 (CH3 in
CH3C6H4). Anal. Calcd for C10H13N3O: C, 62.81; H, 6.85; N, 21.97.
Found: C, 62.74; H, 6.89; N, 22.10.
4.3.5. (E)-1-(4-Methylbenzylidene)-4-propylsemicarbazide (5e)
Compound 5e (0.308 g, 89%) was prepared from sulfone 7c
(0.589 g, 1.58 mmol) and NaBH4 (0.119 g, 3.15 mmol) in EtOH
(5.5 mL) (rt, 1.5 h) as described for compound 5a. Mp 168e169.5 ꢀC
(EtOH); IR (Nujol) nmax 3362 (br s), 3173 (s), 3089 (s) (NH), 3021 (w)
(CHarom), 1675 (vs) (amide-I), 1609 (m) (C]N), 1550 (s), 1518 (m)
(amide-II), 817 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
4.3.9. (E)-1-(4-Methoxybenzylidene)-4-[(4-methoxyphenyl)
methyl]semicarbazide (5i)
Compound 5i (0.336 g, 94%) was prepared from sulfone (E)-4c
(0.532 g,1.14 mmol) and NaBH4 (0.086 g, 2.27 mmol) in EtOH (4 mL)
(rt,1.5 h) as described for compound 5a. Mp 132.5e133.5 ꢀC (EtOH);
IR (Nujol) nmax 3435 (m), 3185 (br s), 3112 (br s) (NH), 3032 (w)
(CHarom), 1677 (s), 1649 (m) (amide-I), 1609 (m) (C]N), 1583 (w)
(CCarom), 1530 (s), 1511 (s) (amide-II), 1254 (s), 1031 (m) (CeO), 828
d
10.23 (s, 1H, NHeN), 7.79 (s, 1H, CH]N), 7.58e7.63 (m, 2H, ArH),
7.17e7.22 (m, 2H, ArH), 6.99 (br t, 3J ¼ 6.1 Hz,1H, NH), 3.05e3.14 (m,
2H, NCH2), 2.31 (s, 3H, CH3 in 4-CH3C6H4), 1.42e1.55 (m, 2H, CH2),
0.85 (t, 3J ¼ 7.4 Hz, 3H, CH3 in Pr); 13C NMR (75.48 MHz, DMSO‑d6)
(m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 10.25 (s, 1H,
NHeN), 7.80 (s, 1H, CH]N), 7.64e7.70 (m, 2H, ArH), 7.45 (t,
3J ¼ 6.4 Hz, 1H, NH), 7.20e7.26 (m, 2H, ArH), 6.91e6.97 (m, 2H,
ArH), 6.84e6.90 (m, 2H, ArH), 4.28 (d, 3J ¼ 6.4 Hz, 2H, CH2), 3.78 (s,
3H, OCH3), 3.72 (s, 3H, OCH3); 13C NMR (75.48 MHz, DMSO‑d6)
d
155.6 (C]O),139.2 (CH]N),138.6 (C),132.1 (C),129.2 (2CH),126.5
(2CH), 40.8 (NCH2), 23.3 (CH2), 21.0 (CH3 in 4-CH3C6H4), 11.3 (CH3 in
Pr). Anal. Calcd for C12H17N3O: C, 65.73; H, 7.81; N, 19.16. Found: C,
65.53; H, 7.85; N, 19.20.
d
160.0 (C), 158.0 (C), 155.8 (C]O), 139.3 (CH]N), 132.8 (C), 128.4
(2CH), 128.1 (2CH), 127.4 (C), 114.0 (2CH), 113.5 (2CH), 55.2 (OCH3),
55.0 (OCH3), 41.9 (CH2). Anal. Calcd for C17H19N3O3: C, 65.16; H,
6.11; N, 13.41. Found: C, 65.26; H, 6.10; N, 13.35.
4.3.6. (E)-1-(4-Methylbenzylidene)-4-butylsemicarbazide (5f)
Compound 5f (0.291 g, 89%) was prepared from sulfone 7d
(0.544 g,1.40 mmol) and NaBH4 (0.106 g, 2.80 mmol) in EtOH (5 mL)
(rt, 1.5 h) as described for compound 5a. Mp 126.5e127.5 ꢀC (EtOH);
IR (Nujol) nmax 3386 (s), 3172 (s), 3086 (br s) (NH), 3014 (w)
(CHarom), 1669 (vs) (amide-I), 1608 (m) (C]N), 1552 (s), 1518 (m)
(amide-II), 812 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
4.3.10. (E)-1-(4-Ethylbenzylidene)-4-[(4-ethylphenyl)methyl]
semicarbazide (5j)
Compound 5j (0.329 g, 82%) was prepared from sulfone (E)-4d
(0.603 g, 1.30 mmol) and NaBH4 (0.054 g, 1.43 mmol) in EtOH
(4.5 mL) (rt, 1.5 h) as described for compound 5a. Mp 95e96.5 ꢀC
(MeCN); IR (Nujol) nmax 3421 (s), 3187 (br s), 3087 (br s) (NH), 3047
(w), 3013 (w) (CHarom), 1682 (vs) (amide-I), 1613 (m) (C]N), 1577
d
10.22 (s, 1H, NHeN), 7.79 (s, 1H, CH]N), 7.58e7.63 (m, 2H, ArH),
7.17e7.22 (m, 2H, ArH), 6.96 (br t, 3J ¼ 6.0 Hz,1H, NH), 3.09e3.17 (m,
2H, NCH2), 2.31 (s, 3H, CH3 in 4-CH3C6H4), 1.40e1.51 (m, 2H, CH2),
1.22e1.36 (m, 2H, CH2), 0.89 (t, 3J ¼ 7.3 Hz, 3H, CH3 in Bu); 13C NMR
(w) (CCarom), 1535 (s), 1516 (m) (amide-II), 824 (m) (CHarom) cmꢁ1
;
1H NMR (300.13 MHz, DMSO‑d6)
d 10.32 (s, 1H, NHeN), 7.84 (s, 1H,
(75.48 MHz, DMSO‑d6)
d
155.6 (C]O), 139.2 (CH]N), 138.6 (C),
CH]N), 7.62e7.67 (m, 2H, ArH), 7.49 (br t, 3J ¼ 6.3 Hz, 1H, NH),
7.19e7.25 (m, 4H, ArH), 7.12e7.17 (m, 2H, ArH), 4.32 (d, 3J ¼ 6.3 Hz,
2H, CH2), 2.53e2.65 (m, 4H, CH2 in two Et), 1.18 (t, 3J ¼ 7.6 Hz, 3H,
CH3), 1.15 (t, 3J ¼ 7.6 Hz, 3H, CH3); 13C NMR (75.48 MHz, DMSO‑d6)
132.1 (C), 129.2 (2CH), 126.5 (2CH), 38.7 (NCH2), 32.2 (CH2), 21.0
(CH3 in 4-CH3C6H4), 19.6 (CH2), 13.8 (CH3 in Bu). Anal. Calcd for
C
13H19N3O: C, 66.92; H, 8.21; N, 18.01. Found: C, 66.81; H, 7.79; N,
17.95.
d 155.7 (C]O), 144.9 (C), 141.9 (C), 139.5 (CH]N), 138.0 (C), 132.2
(C), 127.9 (2CH), 127.5 (2CH), 127.1 (2CH), 126.6 (2CH), 42.2 (NCH2),
28.0 (CH2 in Et), 27.8 (CH2 in Et), 15.7 (CH3), 15.3 (CH3). Anal. Calcd
for C19H23N3O: C, 73.76; H, 7.49; N, 13.58. Found: C, 73.45; H, 7.66;
N, 13.46.
4.3.7. 4-Isobutyl-1-(4-methylbenzylidene)semicarbazide (5g)
Compound 5g (0.341 g, 95%) was prepared from sulfone 7e
(0.598 g, 1.54 mmol) and NaBH4 (0.117 g, 3.09 mmol) in EtOH
(5.5 mL) (rt, 1.5 h) as described for compound 5a. Mp 170e172 ꢀC
(EtOH); IR (Nujol) nmax 3357 (s), 3168 (s), 3094 (s) (NH), 3057 (w),
3025 (w) (CHarom), 1674 (vs) (amide-I), 1612 (m) (C]N), 1550 (s),
1518 (m) (amide-II), 817 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz,
4.3.11. (E)-1-(4-Ethylbenzylidene)-4-propylsemicarbazide (5k)
Compound 5k (0.351 g, 91%) was prepared from sulfone 7g
(0.643 g,1.66 mmol) and NaBH4 (0.126 g, 3.33 mmol) in EtOH (6 mL)
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
15
(rt, 1.5 h) as described for compound 5a. Mp 120.5e122 ꢀC (EtOH);
Found: C, 68.01; H, 8.32; N, 17.03.
IR (Nujol) nmax 3390 (s), 3368 (m), 3181 (br s), 3090 (br s) (NH),
3055 (w), 3034 (w) (CHarom), 1672 (vs) (amide-I), 1611 (m) (C]N),
4.3.15. (E)-4-Butyl-1-(4-isopropylbenzylidene)semicarbazide (5o)
1553 (s), 1512 (m) (amide-II), 833 (m) (CHarom) cmꢁ1
;
1H NMR
Compound 5o (0.352 g, 81%) was prepared from sulfone 7j
(0.687 g,1.65 mmol) and NaBH4 (0.125 g, 3.30 mmol) in EtOH (6 mL)
(rt, 1.5 h) as described for compound 5a. Mp 96e96.5 ꢀC (EtOH); IR
(Nujol) nmax 3410 (s), 3209 (br s), 3167 (br m), 3109 (br s) (NH), 3022
(w) (CHarom), 1675 (vs) (amide-I), 1608 (m) (C]N), 1539 (s), 1515
(300.13 MHz, DMSO‑d6)
d 10.19 (s, 1H, NHeN), 7.81 (s, 1H, CH]N),
7.60e7.65 (m, 2H, ArH), 7.20e7.25 (m, 2H, ArH), 6.93 (br t,
3J ¼ 6.0 Hz, 1H, NH), 3.06e3.15 (m, 2H, NCH2), 2.61 (q, 3J ¼ 7.6 Hz,
2H, CH2 in Et), 1.42e1.56 (m, 2H, CH2 in Pr), 1.18 (t, 3J ¼ 7.6 Hz, 3H,
CH3 in Et), 0.86 (t, 3J ¼ 7.4 Hz, 3H, CH3 in Pr); 13C NMR (75.48 MHz,
(m) (amide-II), 825 (m) (CHarom) cmꢁ1
DMSO‑d6)
;
1H NMR (300.13 MHz,
d 10.19 (s, 1H, NHeN), 7.80 (s, 1H, CH]N), 7.60e7.65 (m,
DMSO‑d6)
d
155.6 (C]O), 144.8 (C), 139.2 (CH]N), 132.3 (C), 127.9
(2CH), 126.5 (2CH), 40.7 (NCH2), 28.0 (CH2 in Et), 23.2 (CH2 in Pr),
15.3 (CH3 in Et),11.2 (CH3 in Pr). Anal. Calcd for C13H19N3O: C, 66.92;
H, 8.21; N, 18.01. Found: C, 66.98; H, 8.39; N, 18.18.
2H, ArH), 7.23e7.28 (m, 2H, ArH), 6.89 (br t, 3J ¼ 6.0 Hz, 1H, NH),
3.10e3.19 (m, 2H, NCH2), 2.90 (septet, 3J ¼ 6.9 Hz, 1H, CH in i-Pr),
1.41e1.52 (m, 2H, CH2 in Bu), 1.23e1.37 (m, 2H, CH2 in Bu), 1.20 (d,
3J ¼ 6.9 Hz, 6H, CH3 in i-Pr), 0.90 (t, 3J ¼ 7.3 Hz, 3H, CH3 in Bu); 13C
4.3.12. (E)-1-(4-Ethylbenzylidene)-4-butylsemicarbazide (5l)
Compound 5l (0.351 g, 88%) was prepared from sulfone 7h
(0.644 g,1.60 mmol) and NaBH4 (0.131 g, 3.46 mmol) in EtOH (6 mL)
(rt, 1.5 h) as described for compound 5a. Mp 108e109.5 ꢀC (EtOH);
IR (Nujol) nmax 3394 (s), 3176 (s), 3087 (br s) (NH), 1672 (vs) (amide-
NMR (75.48 MHz, DMSO‑d6) d 155.5 (C]O), 149.4 (C), 139.2 (CH]
N), 132.4 (C), 126.5 (2CH), 126.4 (2CH), 38.6 (NCH2), 33.2 (CH in i-
Pr), 32.1 (CH2 in Bu), 23.6 (CH3 in i-Pr), 19.5 (CH2 in Bu), 13.7 (CH3 in
Bu). Anal. Calcd for C15H23N3O: C, 68.93; H, 8.87; N, 16.08. Found: C,
69.16; H, 8.98; N, 16.22.
I), 1607 (m) (C]N), 1554 (s), 1515 (m) (amide-II), 830 (m) (CHarom
)
cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d
10.19 (s, 1H, NHeN), 7.81
4.3.16. (E)-1-(4-tert-Butylbenzylidene)-4-[(4-tert-butylphenyl)
methyl]semicarbazide (5p)
(s, 1H, CH]N), 7.59e7.65 (m, 2H, ArH), 7.20e7.25 (m, 2H, ArH), 6.91
(br t, 3J ¼ 6.0 Hz, 1H, NH), 3.10e3.19 (m, 2H, NCH2), 2.61 (q,
3J ¼ 7.6 Hz, 2H, CH2 in Et), 1.41e1.52 (m, 2H, CH2 in Bu), 1.23e1.37
(m, 2H, CH2 in Bu), 1.18 (t, 3J ¼ 7.6 Hz, 3H, CH3 in Et), 0.90 (t,
Compound 5p (0.355 g, 88%) was prepared from sulfone (E)-4f
(0.576 g, 1.11 mmol) and NaBH4 (0.047 g, 1.24 mmol) in EtOH (4 mL)
(rt, 1.5 h) as described for compound 5a. Mp 200e200.5 ꢀC (EtOH);
IR (Nujol) nmax 3425 (s), 3186 (br s), 3087 (br s), 3060 (br m) (NH),
1687 (vs) (amide-I), 1606 (m) (C]N), 1538 (s), 1517 (m) (amide-II),
3J ¼ 7.3 Hz, 3H, CH3 in Bu); 13C NMR (75.48 MHz, DMSO‑d6)
d 155.5
(C]O), 144.8 (C), 139.2 (CH]N), 132.3 (C), 127.9 (2CH), 126.5 (2CH),
38.7 (NCH2), 32.1 (CH2 in Bu), 28.0 (CH2 in Et), 19.5 (CH2 in Bu), 15.3
(CH3 in Et), 13.7 (CH3 in Bu). Anal. Calcd for C14H21N3O: C, 67.99; H,
8.56; N, 16.99. Found: C, 68.10; H, 8.79; N, 17.18.
829 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 10.33 (s,
1H, NHeN), 7.84 (s, 1H, CH]N), 7.62e7.67 (m, 2H, ArH), 7.46 (br t,
3J ¼ 6.3 Hz,1H, NH), 7.37e7.42 (m, 2H, ArH), 7.30e7.35 (m, 2H, ArH),
7.21e7.26 (m, 2H, ArH), 4.32 (d, 3J ¼ 6.3 Hz, 2H, CH2), 1.28 (s, 9H,
3CH3 in t-Bu), 1.26 (s, 9H, 3CH3 in t-Bu); 13C NMR (75.48 MHz,
4.3.13. (E)-1-(4-Isopropylbenzylidene)-4-[(4-isopropylphenyl)
methyl]semicarbazide (5m)
DMSO‑d6)
d 155.7 (C]O), 151.7 (C), 148.8 (C), 139.4 (CH]N), 137.7
Compound 5m (0.221 g, 60%) was prepared from sulfone (E)-4e
(0.533 g, 1.08 mmol) and NaBH4 (0.045 g, 1.19 mmol) in EtOH (4 mL)
(rt, 1.5 h) as described for compound 5a. Mp 146.5e147.5 ꢀC (EtOH);
IR (Nujol) nmax 3423 (s), 3188 (br s), 3093 (br s) (NH), 1682 (vs)
(C), 132.0 (C), 126.8 (2CH), 126.3 (2CH), 125.2 (2CH), 124.8 (2CH),
42.1 (NCH2), 34.4 (C in t-Bu), 34.0 (C in t-Bu), 31.1 (CH3 in t-Bu), 30.9
(CH3 in t-Bu). Anal. Calcd for C23H31N3O: C, 75.58; H, 8.55; N, 11.50.
Found: C, 75.45; H, 8.59; N, 11.54.
(amide-I), 1610 (m) (C]N), 1578 (w) (
n CCarom), 1551 (s), 1514 (s)
(amide-II), 829 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
4.3.17. (E)-1-(4-tert-Butylbenzylidene)-4-propylsemicarbazide (5r)
Compound 5r (0.435 g, 99%) was prepared from sulfone 7k
(0.697 g,1.68 mmol) and NaBH4 (0.127 g, 3.36 mmol) in EtOH (6 mL)
(rt, 1.5 h) as described for compound 5a except washing of crude
product with petroleum ether. Mp 90e92 ꢀC (EtOHeH2O, 1:1 v/v);
IR (Nujol) nmax 3360 (br s), 3210 (br s), 3111 (br s) (NH), 3025 (w)
(CHarom), 1670 (vs) (amide-I), 1609 (m) (C]N), 1538 (s), 1513 (m)
(amide-II), 836 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d
10.32 (s, 1H, NHeN), 7.84 (s, 1H, CH]N), 7.62e7.67 (m, 2H, ArH),
7.48 (br t, 3J ¼ 6.3 Hz,1H, NH), 7.20e7.27 (m, 4H, ArH), 7.15e7.20 (m,
2H, ArH), 4.32 (d, 3J ¼ 6.3 Hz, 2H, CH2), 2.78e2.96 (m, 2H, CH in two
i-Pr), 1.20 (d, 3J ¼ 6.9 Hz, 6H, 2CH3 in i-Pr), 1.18 (d, 3J ¼ 6.9 Hz, 6H,
2CH3 in i-Pr); 13C NMR (75.48 MHz, DMSO‑d6)
d 155.7 (C]O), 149.5
(C), 146.6 (C), 139.5 (CH]N), 138.1 (C), 132.4 (C), 127.1 (2CH), 126.6
(2CH), 126.4 (2CH), 126.0 (2CH), 42.2 (NCH2), 33.2 (CH in i-Pr), 33.0
(CH in i-Pr), 23.9 (CH3 in i-Pr), 23.6 (CH3 in i-Pr). Anal. Calcd for
d
10.21 (s, 1H, NHeN), 7.81 (s, 1H, CH]N), 7.60e7.65 (m, 2H, ArH),
C
21H27N3O: C, 74.74; H, 8.06; N, 12.45. Found: C, 74.86; H, 7.89; N,
7.37e7.42 (m, 2H, ArH), 6.90 (br t, 3J ¼ 6.0 Hz, 1H, NH), 3.06e3.15
(m, 2H, NCH2), 1.43e1.56 (m, 2H, CH2 in Pr),1.28 (s, 9H, CH3 in t-Bu),
0.86 (t, 3J ¼ 7.4 Hz, 3H, CH3 in Pr); 13C NMR (75.48 MHz, DMSO‑d6)
12.56.
4.3.14. (E)-1-(4-Isopropylbenzylidene)-4-propylsemicarbazide (5n)
Compound 5n (0.383 g, 92%) was prepared from sulfone 7i
(0.678 g,1.69 mmol) and NaBH4 (0.128 g, 3.38 mmol) in EtOH (6 mL)
(rt, 1.5 h) as described for compound 5a. Mp 131.5e132 ꢀC (EtOH);
IR (Nujol) nmax 3407 (s), 3211 (br s), 3167 (br m), 3109 (br s) (NH),
1676 (vs) (amide-I), 1609 (m) (C]N), 1543 (s), 1515 (m) (amide-II),
d 155.5 (C]O), 151.6 (C), 139.1 (CH]N), 132.0 (C), 126.3 (2CH), 125.2
(2CH), 40.7 (NCH2), 34.4 (C in t-Bu), 30.9 (CH3 in t-Bu), 23.2 (CH2 in
Pr), 11.2 (CH3 in Pr). Anal. Calcd for C15H23N3O: C, 68.93; H, 8.87; N,
16.08. Found: C, 68.90; H, 8.73; N, 16.07.
4.3.18. (E)-4-Butyl-1-(4-tert-butylbenzylidene)semicarbazide (5s)
Compound 5s (0.434 g, 100%) was prepared from sulfone 7k
(0.678 g, 1.58 mmol) and NaBH4 (0.120 g, 3.17 mmol) in EtOH
(5.5 mL) (rt, 1.5 h) as described for compound 5a except washing of
crude product with petroleum ether. Mp 105.5e107.5 ꢀC
(EtOHeH2O,1:1 v/v); IR (Nujol) nmax 3417 (s), 3185 (br s), 3094 (br s)
(NH), 1677 (vs) (amide-I), 1607 (m) (C]N), 1545 (s), 1515 (m)
(amide-II), 834 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
824 (m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 10.20 (s,
1H, NHeN), 7.81 (s, 1H, CH]N), 7.60e7.65 (m, 2H, ArH), 7.23e7.28
(m, 2H, ArH), 6.92 (br t, 3J ¼ 6.0 Hz, 1H, NH), 3.06e3.15 (m, 2H,
NCH2), 2.90 (septet, 3J ¼ 6.9 Hz, 1H, CH in i-Pr), 1.43e1.55 (m, 2H,
CH2 in Pr), 1.20 (d, 3J ¼ 6.9 Hz, 6H, CH3 in i-Pr), 0.86 (t, 3J ¼ 7.4 Hz,
3H, CH3 in Pr); 13C NMR (75.48 MHz, DMSO‑d6)
d 155.5 (C]O),
149.4 (C), 139.2 (CH]N), 132.4 (C), 126.5 (2CH), 126.4 (2CH), 40.7
(NCH2), 33.2 (CH in i-Pr), 23.6 (CH3 in i-Pr), 23.2 (CH2 in Pr), 11.2
(CH3 in Pr). Anal. Calcd for C14H21N3O: C, 67.99; H, 8.56; N, 16.99.
d
: 10.20 (1H, s, NHeN), 7.81 (1H, s, CH]N), 7.60e7.65 (2H, m, ArH),
7.37e7.42 (2H, m, ArH), 6.88 (1H, br t, 3J ¼ 6.0 Hz, NH), 3.10e3.19
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

16
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
(2H, m, NCH2), 1.41e1.52 (2H, m, CH2 in Bu), 1.23e1.37 (2H, m, CH2
in Bu), 1.28 (9H, s, CH3 in t-Bu), 0.90 (3H, t, 3J ¼ 7.3 Hz, CH3 in Bu);
3151 (m), 3122 (br s) (NH), 1696 (vs), 1663 (m) (amide-I), 1576 (s),
1545 (s), 1520 (s), 1507 (m), 1494 (s) (C]N, amide-II, NO2, CCarom),
13C NMR (75.48 MHz, DMSO‑d6)
d
: 155.51 (C]O), 151.62 (C), 139.08
1311 (vs) (NO2) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
; d 10.87 (s,
(CH]N), 132.02 (C), 126.26 (2CH), 125.22 (2CH), 38.64 (NCH2),
34.38 (C in t-Bu), 32.11 (CH2 in Bu), 30.93 (CH3 in t-Bu), 19.49 (CH2
in Bu), 13.68 (CH3 in Bu). Anal. Calcd for C16H25N3O: C, 69.78; H,
9.15; N, 15.26. Found: C, 69.47; H, 8.92; N, 15.33.
1H, NHeN), 7.80 (d, 3J ¼ 4.0 Hz, 1H, H-4 in furan moiety), 7.78 (s, 1H,
CH]N), 7.22 (d, 3J ¼ 4.0 Hz, 1H, H-3 in furan moiety), 6.98 (br t,
3J ¼ 6.0 Hz, 1H, NH), 3.10e3.18 (m, 2H, NCH2), 1.39e1.51 (m, 2H,
CH2), 1.21e1.35 (m, 2H, CH2), 0.89 (t, 3J ¼ 7.3 Hz, 3H, CH3); 13C NMR
(75.48 MHz, DMSO‑d6)
d 154.7 (C]O), 153.1 (C), 151.3 (C), 127.3
4.3.19. (E)-4-[(5-Nitro-2-furyl)methyl]-1-[(5-nitro-2-furyl)
methylene]semicarbazide (5t)
(CH]N), 115.3 (CH), 112.4 (CH), 38.8 (NCH2), 32.0 (CH2), 19.5 (CH2),
13.8 (CH3). Anal. Calcd for C10H14N4O4: C, 47.24; H, 5.55; N, 22.04.
Found: C, 47.23; H, 5.59; N, 21.84.
To a mixture of NaBH4 (0.086 g, 2.27 mmol) and sulfone (E)-4g
(0.727 g, 1.52 mmol) was added EtOH (7.6 mL), the resulting
mixture was stirred in an ice bath for 10 min and then at room
temperature for 1 h 20 min. The obtained suspension was cooled
(0 ꢀC), the precipitate was filtered, washed with cold EtOH, ice-cold
H2O, diethyl ether, and dried to give compound 5t (0.438 g, 89%) as
a yellow solid. Mp 222.5 ꢀC (decomp, MeCN); IR (Nujol) nmax 3419
(s), 3142 (br m), 3127 (br s), 3080 (br s), 3045 (br s) (NH), 1689 (s)
(amide-I), 1605 (m), 1590 (m), 1554 (s), 1531 (s), 1497 (s) (C]N,
4.3.22. (E)-4-Isobutyl-1-[(5-nitro-2-furyl)methylene]semicarbazide
(5w)
Compound 5w (0.326 g, 85%) was prepared from sulfone 7o
(0.618 g, 1.51 mmol) and NaBH4 (0.086 g, 2.27 mmol) in EtOH
(5.3 mL) (rt, 1.5 h) as described for compound 5u. The analytically
pure sample as a yellow solid was obtained from crude 5w by
column chromatography on silica gel 60 eluting with MeOH/CHCl3
(from 1:200 to 1:100) followed by crystallization from EtOH. Mp
185e186 ꢀC (decomp, EtOH) (lit [27]. mp 178 ꢀC); IR (Nujol) nmax
3393 (s), 3151 (br m), 3116 (br m), 3082 (br m), 3035 (br m) (NH),
1687 (s) (amide-I), 1605 (m), 1582 (s), 1559 (s), 1523 (s), 1505
amide-II, NO2, CCarom), 1357 (s), 1345 (s) (NO2) cmꢁ1
;
1H NMR
11.12 (s, 1H, NHeN), 7.83 (s, 1H, CH]N),
(300.13 MHz, DMSO‑d6)
d
7.80 (d, 3J ¼ 4.0 Hz, 1H, H-4 in furylmethylene moiety), 7.75 (br t,
3J ¼ 6.0 Hz, 1H, NH), 7.65 (d, 3J ¼ 3.8 Hz, 1H, H-4 in furylmethyl
moiety), 7.23 (d, 3J ¼ 4.0 Hz, 1H, H-3 in furylmethylene moiety),
6.68 (d, 3J ¼ 3.8 Hz, 1H, H-3 in furylmethyl moiety), 4.45 (d,
(s) (C]N, amide-II, NO2, CCarom), 1325 (s) (NO2) cmꢁ1
;
1H NMR
(300.13 MHz, DMSO‑d6) 10.87 (s, 1H, NHeN), 7.80 (s, 1H, CH]N),
d
3J ¼ 6.0 Hz, 2H, NCH2); 13C NMR (75.48 MHz, DMSO‑d6)
d 158.1 (C]
7.79 (d, 3J ¼ 4.0 Hz, 1H, H-4 in furan moiety, one of the signals
overlaps with the CH]N proton signal), 7.23 (d, 3J ¼ 4.0 Hz, 1H, H-3
in furan moiety), 6.96 (br t, 3J ¼ 6.1 Hz, 1H, NH), 2.97 (dd, 3J ¼ 7.1,
3J ¼ 6.1 Hz, 2H, NCH2), 1.77 (triplet of septet, 3J ¼ 7.1, 3J ¼ 6.7 Hz, 1H,
CH in i-Bu), 0.85 (d, 3J ¼ 6.7 Hz, 6H, CH3); 13C NMR (75.48 MHz,
O), 154.7 (C), 152.6 (C), 151.3 (C), 150.8 br (C), 128.4 (CH]N), 115.0
(CH), 114.2 (CH), 112.9 (CH), 110.9 (CH), 36.5 (CH2). Anal. Calcd for
C
11H9N5O7: C, 40.88; H, 2.81; N, 21.67. Found: C, 41.12; H, 2.62; N,
21.62.
DMSO‑d6)
d 154.8 (C]O), 153.0 (C), 151.3 (C), 127.4 (CH]N), 115.3
4.3.20. (E)-1-[(5-Nitro-2-furyl)methylene]-4-propylsemicarbazide
(5u)
(CH), 112.5 (CH), 46.5 (NCH2), 28.6 (CH in i-Bu), 20.0 (two CH3 in i-
Bu). Anal. Calcd for C10H14N4O4: C, 47.24; H, 5.55; N, 22.04. Found:
C, 47.34; H, 5.62; N, 22.13.
To a mixture of NaBH4 (0.089 g, 2.35 mmol) and sulfone 7m
(0.621 g, 1.57 mmol) was added EtOH (5.5 mL), and the resulting
mixture was stirred at room temperature for 1.5 h. The solvent was
removed under vacuum, the residue was triturated with saturated
aqueous NaHCO3 until crystallization was complete. The obtained
suspension was cooled (0 ꢀC), the precipitate was filtered, washed
with ice-cold H2O, diethyl ether, and dried to give 5u (0.322 g, 85%).
The analytically pure sample as a yellow solid was obtained from
crude 5u by column chromatography on silica gel 60 eluting with
MeOH/CHCl3 (1:100) followed by crystallization from EtOH. Mp
174.5e175 ꢀC (EtOH) (lit [27]. mp 170e171 ꢀC); IR (Nujol) nmax 3405
(s), 3157 (m), 3132 (br s) (NH), 1697 (s), 1658 (m) (amide-I), 1577 (s),
1547 (s), 1519 (s), 1507 (m), 1496 (s) (C]N, amide-II, NO2, CCarom),
4.4. Reaction of 4-(tosylmethyl)semicarbazones with O-, S-, N-, P-,
and C-nucleophiles. Synthesis of semicarbazones 8a-c, 9a-d, 10a-c,
11a-d, 12a-f, and 13a-c
4.4.1. (E)-4-[(Methoxy)(4-methylphenyl)methyl]-1-
(4-methylbenzylidene)semicarbazide (8a)
To a solution of Na (0.081 g, 3.53 mmol) in anhydrous MeOH
(25 mL) was added sulfone (E)-4b (1.414 g, 3.25 mmol), and the
obtained mixture was stirred at room temperature for 3 h. The
resulting suspension was cooled in an ice bath, AcOH (0.020 mL,
0.35 mmol) was added, and the solvent was removed under vac-
uum. The residue was triturated with saturated aqueous NaHCO3,
the resulting suspension was cooled (0 ꢀC), the precipitate was
filtered, washed with ice-cold H2O, petroleum ether, and dried to
give semicarbazone 8a (0.990 g, 98%). Mp 159e160.5 ꢀC (decomp,
MeCN); IR (Nujol) nmax 3348 (s), 3197 (br s), 3093 (br s) (NH), 3028
(w) (CHarom), 1672 (vs) (amide-I), 1615 (m) (C]N), 1581 (w)
(CCarom), 1524 (sh), 1510 (s) (amide-II), 1075 (s) (CeO), 809 (m)
1313 (vs) (NO2) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
; d 10.87 (s,
1H, NHeN), 7.793 (d, 3J ¼ 4.0 Hz, 1H, H-4 in furan moiety, one of the
signals overlaps with the CH]N proton signal), 7.787 (s, 1H, CH]
N), 7.22 (d, 3J ¼ 4.0 Hz, 1H, H-3 in furan moiety), 6.99 (br t,
3J ¼ 6.0 Hz, 1H, NH), 3.06e3.14 (m, 2H, NCH2), 1.41e1.54 (m, 2H,
CH2), 0.85 (t, 3J ¼ 7.4 Hz, 3H, CH3); 13C NMR (75.48 MHz, DMSO‑d6)
d
154.7 (C]O), 153.0 (C), 151.3 (C), 127.3 (CH]N), 115.3 (CH), 112.5
(CH), 40.9 (NCH2), 23.1 (CH2), 11.3 (CH3). Anal. Calcd for C9H12N4O4:
C, 45.00; H, 5.04; N, 23.32. Found: C, 45.11; H, 5.10; N, 23.36.
(CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
; d 10.58 (s, 1H,
NHeN), 7.87 (s, 1H, CH]N), 7.58e7.63 (m, 2H, ArH), 7.33e7.38 (m,
2H, ArH), 7.34 (d, 3J ¼ 9.9 Hz, 1H, NH, signals partly overlap with
signals of aromatic protons), 7.15e7.21 (m, 4H, ArH), 5.99 (d,
3J ¼ 9.9 Hz, 1H, CHeN), 3.34 (s, 3H, OCH3), 2.302 (s, 3H, CH3 in
CH3C6H4), 2.299 (s, 3H, CH3 in CH3C6H4); 13C NMR (75.48 MHz,
4.3.21. (E)-4-Butyl-1-[(5-nitro-2-furyl)methylene]semicarbazide
(5v)
Compound 5v (0.225 g, 84%) was prepared from sulfone 7n
(0.428 g, 1.05 mmol) and NaBH4 (0.060 g, 1.59 mmol) in EtOH
(3.7 mL) (rt, 1.5 h) as described for compound 5u. The analytically
pure sample as a yellow solid was obtained from crude 5v by col-
umn chromatography on silica gel 60 eluting with MeOH/CHCl3
(from 0:100 to 1:100) followed by crystallization from EtOH. Mp
182e182.5 ꢀC (EtOH) (lit [27]. mp 179 ꢀC); IR (Nujol) nmax 3409 (s),
DMSO‑d6)
d 155.2 (C]O), 140.8 (CH]N), 139.0 (C), 137.4 (C), 137.1
(C), 131.7 (C), 129.2 (2CH), 128.8 (2CH), 126.8 (2CH), 126.1 (2CH),
81.9 (CHeN), 54.8 (OCH3), 21.0 (CH3 in CH3C6H4), 20.7 (CH3 in
CH3C6H4). Anal. Calcd for C18H21N3O2: C, 69.43; H, 6.80; N, 13.50.
Found: C, 69.32; H, 7.05; N, 13.33.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
17
4.4.2. (E)-1-(4-Methoxybenzylidene)-4-
[(methoxy)(4-methoxyphenyl)methyl]semicarbazide (8b)
129.00 (2CH), 128.95 (2CH), 127.3 (CH), 126.9 (2CH), 126.8 (2CH),
59.4 (CHeN), 21.0 (CH3), 20.7 (CH3). Anal. Calcd for C23H23N3OS: C,
70.92; H, 5.95; N, 10.79. Found: C, 70.85; H, 6.01; N, 10.71.
Semicarbazone 8b (2.051 g, 97%) was obtained from sulfone (E)-
4c (2.866 g, 6.13 mmol) and Na (0.155 g, 6.73 mmol) in anhydrous
MeOH (25 mL) (rt, 3 h), then AcOH (0.034 mL, 0.59 mmol) as
described for compound 8a. Mp 133e134 ꢀC (decomp, MeCN); IR
(Nujol) nmax 3336 (s), 3195 (br s), 3165 (m), 3092 (br s) (NH), 3042
(w), 3007 (w) (CHarom), 1668 (vs) (amide-I), 1608 (s) (C]N), 1588
(w), 1571 (w) (CCarom), 1530 (s), 1511 (vs) (amide-II), 1250 (vs), 1069
4.4.5. (E)-1-(4-Methoxybenzylidene)-4-
[(4-methoxyphenyl)(phenylthio)methyl]semicarbazide (9b)
Semicarbazone 9b (1.647 g, 96%) was obtained from sulfone (E)-
4c (1.905 g, 4.07 mmol), NaH (0.107 g, 4.46 mmol) and PhSH
(0.507 g, 4.60 mmol) in dry THF (20 mL) (rt, 3 h) as described for
compound 9a. Mp 170e170.5 ꢀC (decomp, MeCN); IR (Nujol) nmax
3393 (s), 3195 (br s), 3102 (br s) (NH), 3034 (w) (CHarom), 1683 (vs)
(amide-I), 1609 (s) (C]N), 1583 (w), 1575 (w) (CCarom), 1523 (sh),
1509 (s) (amide-II), 1252 (vs), 1034 (s) (CeO), 836 (m), 742 (m), 690
(s), 1031 (s) (CeO), 835 (m), 826 (s) (CHarom) cmꢁ1 1H NMR
;
(300.13 MHz, DMSO‑d6)
d 10.50 (s, 1H, NHeN), 7.85 (s, 1H, CH]N),
7.64e7.69 (m, 2H, ArH), 7.36e7.42 (m, 2H, ArH), 7.30 (d, 3J ¼ 9.9 Hz,
1H, NH), 6.90e6.96 (m, 4H, ArH), 5.97 (d, 3J ¼ 9.9 Hz, 1H, CHeN),
3.77 (s, 3H, CH3 in CH3OC6H4), 3.75 (s, 3H, CH3 in CH3OC6H4), 3.33
(m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 10.41 (s, 1H,
(s, 3H, OCH3). 13C NMR (75.48 MHz, DMSO‑d6)
d 160.2 (C), 158.9 (C),
NHeN), 7.79 (s, 1H, CH]N), 7.68e7.74 (m, 2H, ArH), 7.64 (d,
3J ¼ 10.0 Hz, 1H, NH), 7.41e7.53 (m, 4H, ArH), 7.21e7.34 (m, 3H,
ArH), 6.90e7.00 (m, 4H, ArH), 6.53 (d, 3J ¼ 10.0 Hz, 1H, CHeN), 3.79
(s, 3H, OCH3), 3.75 (s, 3H, OCH3); 13C NMR (75.48 MHz, DMSO‑d6)
155.2 (C]O), 140.6 (CH]N), 132.4 (C), 128.4 (2CH), 127.4 (2CH),
127.0 (C), 114.1 (2CH), 113.6 (2CH), 81.7 (CHeN), 55.2 (CH3 in
CH3OC6H4), 55.1 (CH3 in CH3OC6H4), 54.7 (OCH3). Anal. Calcd for
C
18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C, 62.71; H, 6.40; N,
d
160.2 (C), 158.8 (C), 154.1 (C]O), 140.6 (CH]N), 134.1 (C), 132.0
12.18.
(C), 131.3 (2CH), 128.9 (2CH), 128.3 (2CH), 128.0 (2CH), 127.2 (CH),
127.0 (C), 114.0 (2CH), 113.7 (2CH), 59.2 (CHeN), 55.2 (OCH3), 55.1
(OCH3). Anal. Calcd for C23H23N3O3S: C, 65.54; H, 5.50; N, 9.97.
Found: C, 65.65; H, 5.76; N, 9.99.
4.4.3. (E)-1-(4-Methylbenzylidene)-4-(1-methoxybut-1-yl)
semicarbazide (8c)
Semicarbazone 8c (0.817 g, 96%) was obtained from sulfone 7d
(1.259 g, 3.25 mmol) and Na (0.082 g, 3.56 mmol) in anhydrous
MeOH (25 mL) (rt, 3 h), then AcOH (0.020 mL, 0.35 mmol) as
described for compound 8a. Mp 141e142 ꢀC (MeCN); IR (Nujol) nmax
3401 (s), 3354 (m), 3199 (br s), 3095 (br s) (NH), 3054 (w), 3026 (w)
(CHarom), 1680 (vs) (amide-I), 1612 (m) (C]N), 1541 (s), 1523 (s),
1516 (s) (amide-II), 1079 (s) (CeO), 807 (m) (CHarom) cmꢁ1; 1H NMR
4.4.6. (E)-1-(4-Methylbenzylidene)-4-[1-(phenylthio)but-1-yl]
semicarbazide (9c)
Semicarbazone 9c (1.364 g, 89%) was obtained from sulfone 7d
(1.736 g, 4.48 mmol), NaH (0.118 g, 4.92 mmol) and PhSH (0.566 g,
5.14 mmol) in dry THF (20 mL) (rt, 3 h) as described for compound
9a. Mp 120.5e122 ꢀC (decomp, MeCN); IR (Nujol) nmax 3387 (s),
3197 (br s), 3083 (br s) (NH), 3023 (w) (CHarom), 1675 (vs) (amide-I),
1611 (m) (C]N), 1583 (w), 1573 (w) (CCarom), 1528 (s), 1511 (s)
(300.13 MHz, DMSO‑d6)
d 10.43 (s, 1H, NHeN), 7.84 (s, 1H, CH]N),
7.63e7.68 (m, 2H, ArH), 7.18e7.23 (m, 2H, ArH), 7.08 (d, 3J ¼ 9.9 Hz,
1H, NH), 4.97 (dt, 3J ¼ 9.9, 3J ¼ 6.6 Hz, 1H, CHeN), 3.21 (s, 3H, OCH3),
2.32 (s, 3H, CH3 in CH3C6H4), 1.56e1.78 (m, 2H, CH2 in Pr), 1.25e1.39
(m, 2H, CH2 in Pr), 0.88 (t, 3J ¼ 7.3 Hz, 3H, CH3 in Pr); 13C NMR
(amide-II), 1479 (w) (CCarom), 809 (m), 744 (s), 688 (m) (CHarom
)
cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d
10.43 (s, 1H, NHeN), 7.80
(s, 1H, CH]N), 7.60e7.66 (m, 2H, ArH), 7.42e7.48 (m, 2H, ArH),
7.18e7.33 (m, 6H, ArH and NH), 5.38 (ddd, 3J ¼ 10.1, 3J ¼ 8.9,
3J ¼ 5.8 Hz, 1H, CHeN), 2.32 (s, 3H, CH3 in CH3C6H4), 1.71e1.98 (m,
2H, CH2 in Pr), 1.31e1.49 (m, 2H, CH2 in Pr), 0.87 (t, 3J ¼ 7.4 Hz, 3H,
(75.48 MHz, DMSO‑d6)
d 155.5 (C]O), 140.3 (CH]N), 138.9 (C),
131.8 (C), 129.2 (2CH), 126.8 (2CH), 81.1 (CHeN), 54.3 (OCH3), 36.5
(CH2), 21.0 (CH3 in CH3C6H4), 18.2 (CH2), 13.6 (CH3 in Pr). Anal. Calcd
for C14H21N3O2: C, 63.86; H, 8.04; N, 15.96. Found: C, 63.86; H, 8.11;
N, 15.96.
CH3 in Pr); 13C NMR (75.48 MHz, DMSO‑d6)
d 154.5 (C]O), 140.4
(CH]N), 138.9 (C), 134.2 (C), 131.8 (C), 131.5 (2CH), 129.2 (2CH),
128.9 (2CH), 126.9 (CH), 126.8 (2CH), 57.6 (CHeN), 37.7 (CH2), 21.0
(CH3 in CH3C6H4), 19.4 (CH2), 13.3 (CH3 in Pr). Anal. Calcd for
4.4.4. (E)-1-(4-Methylbenzylidene)-4-
[(4-methylphenyl)(phenylthio)methyl]semicarbazide (9a)
C19H23N3OS: C, 66.83; H, 6.79; N, 12.31. Found: C, 66.88; H, 6.99; N,
To a cooled in an ice bath, stirred suspension of NaH (0.099 g,
4.13 mmol) in dry THF (6 mL) was added a solution of thiophenol
(0.477 g, 4.33 mmol) in dry THF (7 mL) over 2 min. The resulting
suspension was stirred at room temperature for 30 min, then sul-
fone (E)-4b (1.635 g, 3.75 mmol) and dry THF (7 mL) were added.
The obtained mixture was stirred at room temperature for 3 h, and
the solvent was removed under vacuum. The oily residue was
triturated with petroleum ether (5 mL) and saturated aqueous
NaHCO3 (5 mL) until crystallization was completed. The suspension
was cooled (0 ꢀC), the precipitate was filtered, washed with ice-cold
H2O, petroleum ether, and dried to give semicarbazone 9a (1.447 g,
99%). Mp 185.5e186 ꢀC (decomp, MeCN); IR (Nujol) nmax 3399 (s),
3198 (br m), 3180 (br m), 3106 (br s) (NH), 3055 (w), 3019 (w)
(CHarom), 1685 (vs) (amide-I), 1616 (m) (C]N), 1580 (w) (CCarom),
12.36.
4.4.7. (E)-1-(4-Methylbenzylidene)-4-(phenylthiomethyl)
semicarbazide (9d)
Semicarbazone 9d (1.493 g, 83%) was obtained from sulfone 7f
(2.065 g, 5.98 mmol), NaH (0.158 g, 6.58 mmol) and PhSH (0.736 g,
6.68 mmol) in dry THF (21 mL) (rt, 3 h) as described for compound
9a followed by column chromatography on silica gel 60 (25.13 g)
eluting with CHCl3. Mp 152.5e153 ꢀC (EtOH); IR (Nujol) nmax 3375
(s), 3196 (br m), 3178 (br m), 3092 (br s) (NH), 3050 (w), 3021 (w)
(CHarom), 1681 (vs) (amide-I), 1614 (m) (C]N), 1583 (w), 1577 (w)
(CCarom), 1532 (s), 1519 (m) (amide-II), 1482 (w) (CCarom), 815 (m),
742 (s), 693 (m) (CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
;
1522 (s), 1510 (s) (amide-II), 815 (m), 751 (s), 688 (m) (CHarom
)
d
10.49 (s, 1H, NHeN), 7.82 (s, 1H, CH]N), 7.70 (t, 3J ¼ 6.6 Hz, 1H,
cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d
10.49 (s, 1H, NHeN), 7.81
NH), 7.56e7.62 (m, 2H, ArH), 7.45e7.50 (m, 2H, ArH), 7.28e7.36 (m,
2H, ArH), 7.17e7.25 (m, 3H, ArH), 4.78 (d, 3J ¼ 6.6 Hz, 1H, CH2), 2.32
(s, 1H, CH]N), 7.68 (d, 3J ¼ 10.0 Hz, 1H, NH, signals partly overlap
with signals of aromatic protons), 7.63e7.68 (m, 2H, ArH),
7.42e7.49 (m, 4H, ArH), 7.16e7.34 (m, 7H, ArH), 6.54 (d, 3J ¼ 10.0 Hz,
1H, CHeN), 2.33 (s, 3H, CH3), 2.29 (s, 3H, CH3); 13C NMR
(s, 3H, CH3); 13C NMR (75.48 MHz, DMSO‑d6)
d 154.9 (C]O), 140.3
(CH]N), 138.9 (C), 135.6 (C), 131.8 (C), 129.4 (2CH), 129.1 (2CH),
128.9 (2CH), 126.6 (2CH), 126.1 (CH), 44.3(CH2), 20.9 (CH3). Anal.
Calcd for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04. Found: C, 64.12; H,
5.96; N, 14.18.
(75.48 MHz, DMSO‑d6)
d 154.1 (C]O), 140.9 (CH]N), 139.0 (C),
137.15 (C), 137.09 (C), 134.1 (C), 131.7 (C), 131.2 (2CH), 129.2 (2CH),
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

18
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
4.4.8. (E)-1-(4-Methylbenzylidene)-4-
[(4-methylphenyl)(pyrrolidino)methyl]semicarbazide (10a)
NHeN), 7.904 (s, 1H, CH]N), 7.897 (d, 3J ¼ 10.5 Hz, 1H,
NH),7.48e7.54 (m, 2H, ArH), 7.17e7.26 (m, 6H, ArH), 6.98 (d,
3J ¼ 10.5 Hz, 1H, CHeN), 2.64e2.83 (m, 4H, CH2CH2), 2.32 (s, 3H,
To a solution of pyrrolidine (0.176 g, 2.47 mmol) in MeCN (5 mL)
was added sulfone (E)-4b (0.488 g, 1.12 mmol) and MeCN (7 mL),
and the obtained suspension was stirred at room temperature for
1.5 h. Then the solvent was removed under vacuum, the residue
was triturated with H2O, and the resulting suspension was cooled
(0 ꢀC). The precipitate was filtered, washed with ice-cold H2O, pe-
troleum ether, and dried to give semicarbazone 10a (0.373 g, 95%).
The crude product was obtained in analytically pure form (Note:
crystallization from boiling MeCN led to partial decomposition of
10a). Mp 141e141.5 ꢀC (decomp); IR (Nujol) nmax 3401 (m), 3194 (br
m), 3087 (br s) (NH), 3023 (w) (CHarom), 1674 (vs) (amide-I), 1613
(m) (C]N), 1578 (w) (CCarom), 1523 (sh), 1511 (s) (amide-II), 811 (m)
CH3), 2.29 (s, 3H, CH3); 13C NMR (75.48 MHz, DMSO‑d6)
d 177.6 (O]
CeNeC]O), 154.0 (NHeC]O), 141.3 (CH]N), 139.4 (C), 137.5 (C),
134.9 (C), 131.4 (C), 129.5 (2CH), 129.2 (2CH), 126.4 (2CH), 125.5
(2CH), 57.8 (CHeN), 28.1 (CH2CH2), 21.0 (CH3), 20.6 (CH3). HRMS
(ESI-TOF) m/z calcd for C21H22N4NaO3 (M þ Na)þ 401.1590, found
401.1584.
4.4.11. (E)-1-(4-Methoxybenzylidene)-4-
[(4-methoxyphenyl)(succinimido)methyl)]semicarbazide (11b)
Compound 11b (0.840 g, with ca. 86% purity according to 1H
NMR spectroscopic data) was obtained from sulfone (E)-4c (1.030 g,
2.20 mmol), NaH (0.079 g, 3.29 mmol) and succinimide (0.341 g,
3.44 mmol) in dry THF (20 mL) (rt, 3.5 h) as described for 11c. The
crude product was purified using column chromatography on silica
gel (25.41 g) eluting with CHCl3/MeOH (100:1). The main fraction
was concentrated under vacuum, the obtained foam was triturated
with H2O and petroleum ether until crystallization was complete,
the precipitate was filtered, and dried to give 11b (0.675 g, 75%) in
analytically pure form (Note: crystallization from AcOEt/petroleum
ether mixture led to a partial decomposition of this compound). Mp
104e110 ꢀC (decomp); IR (Nujol) nmax 3401 (br s), 3204 (br s), 3103
(br s), 3074 (br s) (NH), 1774 (m), 1708 (br vs), 1684 (sh) (amide-I),
1607 (s) (C]N), 1586 (w), 1574 (w) (CCarom), 1505 (br vs) (amide-II),
(CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
; d 10.39 (s, 1H,
NHeN), 7.86 (s, 1H, CH]N), 7.56e7.61 (m, 2H, ArH), 7.33e7.39 (m,
2H, ArH), 7.13e7.24 (m, 4H, ArH), 7.00 (d, 3J ¼ 9.7 Hz, 1H, NH), 5.51
(d, 3J ¼ 9.7 Hz, 1H, CHeN), 2.40e2.62 (m, 4H, two NCH2, signals
partly overlap with signals of the residual proton in the solvent),
2.32 (s, 3H, CH3), 2.29 (s, 3H, CH3), 1.61e1.75 (m, 4H, CH2CH2); 13C
NMR (75.48 MHz, DMSO‑d6)
d 154.8 (C]O), 140.4 (CH]N), 138.9
(C), 138.7 (C), 136.5 (C), 131.7 (C), 129.2 (2CH), 128.8 (2CH), 126.7
(2CH), 126.5 (2CH), 69.8 (CHeN), 49.0 (two NCH2), 23.1 (CH2CH2),
20.9 (CH3), 20.6 (CH3). Anal. Calcd for C21H26N4O: C, 71.97; H, 7.48;
N, 15.99. Found: C, 71.73; H, 7.56; N, 15.89.
4.4.9. (E)-1-(4-Methoxybenzylidene)-4-
1251 (vs), 1030 (s) (CeO), 832 (s) (CHarom) cmꢁ1 1H NMR
;
[(4-methoxyphenyl)(pyrrolidino)methyl]semicarbazide (10b)
Semicarbazone 10b (0.402 g, 92%) was obtained from sulfone
(E)-4c (0.536 g, 1.15 mmol) and pyrrolidine (0.177 g, 2.49 mmol) in
MeCN (10 mL) (rt, 1.5 h) as described for compound 10a. The crude
product was obtained in analytically pure form (Note: crystalliza-
tion from boiling MeCN led to partial decomposition of 10b). Mp
129.5e130 ꢀC (decomp); IR (Nujol) nmax 3406 (m), 3194 (br m), 3090
(br s) (NH), 3039 (w) (CHarom), 1677 (vs) (amide-I), 1610 (s) (C]N),
1577 (w) (CCarom), 1527 (m), 1510 (vs) (amide-II), 1247 (vs), 1038 (s)
(300.13 MHz, DMSO‑d6)
d
10.70 (s, 1H, NHeN), 7.90 (d, 3J ¼ 10.6 Hz,
1H, NH), 7.89 (s, 1H, CH]N), 7.54e7.60 (m, 2H, ArH), 7.23e7.29 (m,
2H, ArH), 6.92e7.03 (m, 5H, CHeN and ArH), 3.79 (s, 3H, OCH3),
3.75 (s, 3H, OCH3), 2.63e2.82 (m, 4H, CH2CH2); 13C NMR
(75.48 MHz, DMSO‑d6) d 177.4 (O]CeNeC]O), 160.4 (C), 159.0 (C),
154.0 (NHeC]O), 141.0 (CH]N), 129.9 (C), 127.9 (2CH), 126.9
(2CH), 126.7 (C), 114.3 (2CH), 114.0 (2CH), 57.8 (CHeN), 55.2 (OCH3),
55.1 (OCH3), 28.0 (CH2CH2). HRMS (ESI-TOF) m/z calcd for
C
21H22N4NaO3 (M þ Na)þ 433.1488, found 433.1482.
(CeO), 833 (m) (CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
;
d
10.35 (s, 1H, NHeN), 7.83 (s, 1H, CH]N), 7.62e7.68 (m, 2H, ArH),
4.4.12. (E)-1-(4-Methylbenzylidene)-4-[1-(succinimido)but-1-yl]
semicarbazide (11c)
7.36e7.42 (m, 2H, ArH), 7.02 (d, 3J ¼ 9.7 Hz, 1H, NH), 6.88e6.98 (m,
4H, ArH), 5.47 (d, 3J ¼ 9.7 Hz, 1H, CHeN), 3.78 (s, 3H, OCH3), 3.74 (s,
3H, OCH3), 2.37e2.61 (m, 4H, two NCH2, signals partly overlap with
signals of the residual proton in the solvent), 1.62e1.75 (m, 4H,
The suspension of NaH (0.108 g, 4.50 mmol) and succinimide
(0.459 g, 4.63 mmol) in dry THF (10 mL) was stirred at room tem-
perature for 10 min, then sulfone 7d (1.169 g, 3.02 mmol) and dry
THF (10 mL) were added. The reaction mixture was stirred at room
temperature for 3.5 h. Weak gas evolution was observed for about
2 h from the beginning of the reaction. The solvent was removed
under vacuum. The residue was triturated with H2O upon cooling
(0 ꢀC) until crystallization was complete. The resulting suspension
was cooled (0 ꢀC), the precipitate was filtered, washed with ice-cold
H2O, petroleum ether, and dried. The obtained crude product
(0.928 g, with ca. 92% purity according to 1H NMR spectroscopic
data) was purified using column chromatography on silica gel
(25.04 g) eluting with CHCl3/MeOH (from 100:0.25 to 100:0.75).
The main fraction was concentrated under vacuum, the obtained
foam was triturated with H2O and petroleum ether until crystalli-
zation was complete, the precipitate was filtered, and dried to give
compound 11c (0.744 g, 75%). Mp 84e86 ꢀC (AcOEt - petroleum
ether, 1:2 v/v); IR (Nujol) nmax 3420 (br m), 3202 (br m), 3097 (br m)
(NH), 1774 (m), 1707 (br vs), 1684 (sh) (amide-I), 1613 (m) (C]N),
CH2CH2); 13C NMR (75.48 MHz, DMSO‑d6)
d 160.2 (C), 158.5 (C),
154.9 (C]O), 140.2 (CH]N), 133.8 (C), 128.1 (2CH), 127.9 (2CH),
127.1 (C), 114.1 (2CH), 113.6 (2CH), 69.7 (CHeN), 55.2 (OCH3), 55.0
(OCH3), 49.1 (two NCH2), 23.1 (CH2CH2). Anal. Calcd for
C
21H26N4O3: C, 65.95; H, 6.85; N, 14.65. Found: C, 65.61; H, 6.70; N,
14.47.
4.4.10. (E)-1-(4-Methylbenzylidene)-4-
[(4-methylphenyl)(succinimido)methyl)]semicarbazide (11a)
Compound 11a (0.918 g, with ca. 92% purity according to 1H
NMR spectroscopic data) was obtained from sulfone (E)-4b (1.135 g,
2.61 mmol), NaH (0.094 g, 3.92 mmol) and succinimide (0.404 g,
4.08 mmol) in dry THF (20 mL) (rt, 3.5 h) as described for 11c. The
crude product was purified using column chromatography on silica
gel (25.06 g) eluting with CHCl3/MeOH (from 100:0.5 to 100:0.75).
The main fraction was concentrated under vacuum, the obtained
foam was triturated with H2O and petroleum ether until crystalli-
zation was complete, the precipitate was filtered, and dried to give
11a (0.824 g, 84%). Mp 176e177.5 ꢀC (AcOEt - petroleum ether, 3:4
v/v); IR (Nujol) nmax 3408 (m), 3197 (br m), 3093 (br s) (NH), 3031
(w) (CHarom), 1771 (m), 1737 (s), 1708 (vs), 1683 (s) (amide-I), 1614
(m) (C]N), 1583 (w) (CCarom), 1533 (s), 1513 (s) (amide-II), 808 (m)
1523 (sh), 1514 (s) (amide-II), 816 (m) (CHarom) cmꢁ1
;
1H NMR
10.50 (s, 1H, NHeN), 7.86 (s, 1H, CH]N),
(300.13 MHz, DMSO‑d6)
d
7.49e7.55 (m, 2H, ArH), 7.36 (d, 3J ¼ 10.2 Hz, 1H, NH), 7.21e7.27 (m,
2H, ArH), 5.86 (dt, 3J ¼ 10.2, 3J ¼ 7.6 Hz, 1H, CHeN), 2.60e2.68 (m,
4H, CH2CH2), 2.33 (s, 3H, CH3 in 4-CH3C6H4), 1.75e1.94 (m, 2H, CH2
in Pr), 1.19e1.37 (m, 2H, CH2 in Pr), 0.90 (t, 3J ¼ 7.3 Hz, 3H, CH3 in
(CHarom) cmꢁ1
;
1H NMR (300.13 MHz, DMSO‑d6)
d
10.84 (s, 1H,
Pr); 13C NMR (75.48 MHz, DMSO‑d6)
d 177.2 (O]CeNeC]O), 153.8
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
19
(NHeC]O), 140.8 (CH]N), 139.1 (C), 131.4 (C), 129.2 (2CH), 126.2
(2CH), 56.6 (CHeN), 34.8 (CH2 in Pr), 27.8 (CH2CH2), 20.8 (CH3 in
4-CH3C6H4), 18.1 (CH2 in Pr), 13.1 (CH3 in Pr). Anal. Calcd for
(amide-II), 1494 (w) (CCarom), 1258 (s) (P]O), 1051 (s), 1022 (vs)
(CeO), 756 (s), 704 (s), 688 (s) (CHarom) cmꢁ1; 1H NMR (300.13 MHz,
DMSO‑d6) d 10.76 (s, 1H, NHeN), 7.93 (s, 1H, CH]N), 7.67e7.73 (m,
3
C
17H22N4O3: C, 61.80; H, 6.71; N, 16.96. Found: C, 61.73; H, 7.04; N,
2H, ArH), 7.27e7.49 (m, 8H, ArH), 7.21 (dd, 3J ¼ 9.8, JP,H ¼ 5.2 Hz,
1H, NH), 5.34 (dd, 2JP,H ¼ 22.1, 3J ¼ 9.8 Hz, 1H, CHeN), 3.74e4.14 (m,
4H, two OCH2), 1.21 (t, 3J ¼ 7.0 Hz, 3H, CH3), 1.09 (t, 3J ¼ 7.0 Hz, 3H,
16.90.
4.4.13. (E)-1-(4-Methylbenzylidene)-4-[(succinimido)methyl]
semicarbazide (11d)
CH3); 13C NMR (75.48 MHz, DMSO‑d6)
d
154.4 (d, J ¼ 9.6 Hz, C]O),
141.1 (CH]N), 136.3 (C), 134.2 (C), 129.6 (CH), 128.8 (2CH), 128.3 (d,
J ¼ 2.2 Hz, 2CH), 127.8 (d, J ¼ 5.6 Hz, 2CH), 127.7 (d, J z 3.0 Hz, CH,
one signal overlaps with one of the signals of 2CH), 126.5 (2CH),
62.6 (d, J ¼ 6.9 Hz, OCH2), 62.5 (d, J ¼ 6.8 Hz, OCH2), 50.1 (d,
J ¼ 152.7 Hz, CHeN), 16.2 (d, J ¼ 5.4 Hz, CH3), 16.1 (d, J ¼ 5.4 Hz,
CH3). Anal. Calcd for C19H24N3O4P: C, 58.61; H, 6.21; N, 10.79.
Found: C, 58.79; H, 6.27; N, 10.79.
Method A: Compound 11d (0.831 g, with ca. 93% purity according
to 1H NMR spectroscopic data) was obtained from sulfone 7f
(1.069 g, 3.09 mmol), NaH (0.112 g, 4.67 mmol) and succinimide
(0.480 g, 4.84 mmol) in dry THF (20 mL) (rt, 3.5 h) as described for
11c.
Method B: Compound 11d (0.932 g, with ca. 87% purity according
to 1H NMR spectroscopic data) was obtained from sulfone 7f
(1.239 g, 3.59 mmol), NaH (0.130 g, 5.42 mmol) and succinimide
(0.544 g, 5.49 mmol) in dry MeCN (20 mL) (rt, 3.5 h) as described for
11c. The crude product was purified using column chromatography
on silica gel (23.69 g) eluting with CHCl3/MeOH (from 100:0.5 to
100:1). The main fraction was concentrated under vacuum, the
obtained foam was triturated with H2O and petroleum ether until
crystallization was complete, the precipitate was filtered, and dried
to give 11d (0.581 g, 56%). Mp 210.5e211 ꢀC (MeCN); IR (Nujol) nmax
3384 (s), 3205 (m), 3183 (br m), 3089 (br s) (NH), 3016 (w) (CHarom),
1790 (m), 1705 (br vs), 1677 (s) (amide-I), 1609 (m) (C]N), 1541(s),
4.4.16. (E)-4-[(Dimethoxyphosphoryl)(4-methylphenyl)methyl]-1-
(4-methylbenzylidene)semicarbazide (12c)
The mixture of sulfone (E)-4b (1.091 g, 2.50 mmol) and P(OMe)3
(0.927 g, 7.47 mmol) in MeCN (20 mL) was refluxed under stirring
for 1 h. After 5 min from the beginning of the reaction the solution
formed. The solvent was removed under vacuum, the residue was
triturated with H2O (4 mL) and petroleum ether (5 mL) until crys-
tallization was complete. The obtained suspension was cooled
(0 ꢀC). The precipitate was filtered, washed with ice-cold H2O, pe-
troleum ether, and dried to give phosphonate 12c (0.952 g, 98%).
Mp 196.5e197 ꢀC (MeCN); IR (Nujol) nmax 3399 (s), 3198 (br m),
3178 (br m), 3091 (br s) (NH), 3051 (w), 3025 (w) (CHarom),1684 (vs)
(amide-I), 1616 (m) (C]N), 1580 (w) (CCarom), 1529 (s), 1514 (s)
1519 (s) (amide-II), 806 (m) (CHarom) cmꢁ1 1H NMR (300.13 MHz,
;
DMSO‑d6) d 10.52 (s, 1H, NHeN), 7.82 (s, 1H, CH]N), 7.54e7.59 (m,
2H, ArH), 7.31 (t, 3J ¼ 6.2 Hz, 1H, NH), 7.19e7.24 (m, 2H, ArH), 4.87
(d, 3J ¼ 6.2 Hz, 2H, NCH2), 2.62 (s, 4H, CH2CH2), 2.32 (s, 3H, CH3); 13
C
(amide-II), 1264 (s) (P]O), 1040 (vs) (CeO), 814 (m) (CHarom) cmꢁ1
;
NMR (75.48 MHz, DMSO‑d6)
d
177.2 (O]CeNeC]O), 154.5
1H NMR (300.13 MHz, DMSO‑d6)
d
10.65 (s, 1H, NHeN), 7.89 (s, 1H,
(NHeC]O), 140.5 (CH]N), 139.1 (C), 131.7 (C), 129.3 (2CH), 126.6
(2CH), 43.5 (CH2N), 28.0 (CH2CH2), 21.0 (CH3). Anal. Calcd for
CH]N), 7.56e7.62 (m, 2H, ArH), 7.32e7.38 (m, 2H, ArH), 7.22e7.28
(m, 2H, ArH), 7.16e7.22 (m, 2H, ArH), 7.17 (dd, 3J ¼ 10.0,
3JP,H ¼ 4.5 Hz,1H, NH, signals partly overlap with signals of aromatic
C
14H16N4O3: C, 58.33; H, 5.59; N, 19.43. Found: C, 58.44; H, 5.79; N,
2
19.58.
protons), 5.37 (dd, JP,H ¼ 21.8, 3J ¼ 10.0 Hz, 1H, CHeN), 3.68 (d,
3JP,H ¼ 10.6 Hz, 3H, OCH3), 3.51 (d, 3JP,H ¼ 10.6 Hz, 3H, OCH3), 2.33 (s,
7
4.4.14. (E)-1-Benzylidene-4-[(dimethoxyphosphoryl)(phenyl)
methyl]semicarbazide (12a)
3H, CH3 in 4-CH3C6H4), 2.29 (d, JP,H ¼ 1.6 Hz, 3H, CH3 in
4-CH3C6H4); 13C NMR (75.48 MHz, DMSO‑d6)
d
154.4 (d, J ¼ 9.2 Hz,
Phosphonate 12a (1.068 g, 98%) was obtained from sulfone (E)-
4a (1.234 g, 3.03 mmol) and P(OMe)3 (1.125 g, 9.07 mmol) in MeCN
(15 mL) (reflux,1 h) as described for compound 12c. Mp 134e135 ꢀC
(AcOEt - petroleum ether, 1:1 v/v); IR (Nujol) nmax 3412 (m), 3394
(s), 3202 (br s), 3100 (br s) (NH), 3028 (w) (CHarom), 1686 (vs)
(amide-I), 1611 (m) (C]N), 1599 (m), 1585 (w) (CCarom), 1529 (vs)
(amide-II), 1493 (m) (CCarom), 1259 (s) (P]O), 1187 (PeO), 1059 (s),
C]O), 141.3 (CH]N), 139.3 (C), 137.1 (d, J ¼ 2.9 Hz, C), 133.1 (C),
131.5 (C), 129.4 (2CH), 129.0 (d, J ¼ 2.0 Hz, 2CH), 127.7 (d, J ¼ 5.7 Hz,
2CH), 126.6 (2CH), 53.4 (d, J ¼ 7.0 Hz, OCH3), 53.3 (d, J ¼ 6.8 Hz,
OCH3), 49.1 (d, J ¼ 153.8 Hz, CHeN), 21.0 (CH3 in 4-CH3C6H4), 20.7
(d, J ¼ 0.8 Hz, CH3 in 4-CH3C6H4). Anal. Calcd for C19H24N3O4P: C,
58.61; H, 6.21; N, 10.79. Found: C, 58.52; H, 6.25; N, 10.66.
1028 (vs) (CeO), 760 (s), 703 (s), 688 (s) (CHarom) cmꢁ1
;
1H NMR
4.4.17. (E)-4-[(Diethoxyphosphoryl)(4-methylphenyl)methyl]-1-
(4-methylbenzylidene)semicarbazide (12d)
(300.13 MHz, DMSO‑d6)
d 10.74 (s, 1H, NHeN), 7.93 (s, 1H, CH]N),
7.68e7.74 (m, 2H, ArH), 7.28e7.51 (m, 8H, ArH), 7.27 (dd, 3J ¼ 9.9,
Phosphonate 12d (1.138 g, 96%) was obtained from sulfone (E)-
4b (1.236 g, 2.84 mmol) and P(OEt)3 (1.408 g, 8.47 mmol) in MeCN
(15 mL) (reflux, 1 h) as described for compound 12c. Mp
119e120.5 ꢀC (AcOEt - petroleum ether, 1:2 v/v); IR (Nujol) nmax
3395 (br m), 3194 (br m), 3094 (br s) (NH), 3026 (w) (CHarom), 1685
(vs) (amide-I), 1615 (m) (C]N), 1579 (w) (CCarom), 1528 (s), 1513 (s)
3JP,H ¼ 4.5 Hz, 1H, NH), 5.43 (dd, 2JP,H ¼ 22.1, 3J ¼ 9.9 Hz, 1H, CHeN),
3
3
3.69 (d, JP,H ¼ 10.6 Hz, 3H, OCH3), 3.52 (d, JP,H ¼ 10.6 Hz, 3H,
OCH3); 13C NMR (75.48 MHz, DMSO‑d6)
d
154.4 (d, J ¼ 9.3 Hz, C]O),
141.3 (CH]N), 136.1 (C), 134.2 (C), 129.6 (CH), 128.8 (2CH), 128.4 (d,
J ¼ 2.0 Hz, 2CH), 127.823 (d, J ¼ 5.7 Hz, 2CH), 127.817 (d, J z 2.5 Hz,
CH, one signal overlaps with one of the signals of 2CH), 126.6 (2CH),
53.4 (d, J ¼ 7.0 Hz, OCH3), 53.3 (d, J ¼ 6.8 Hz, OCH3), 49.5 (d,
J ¼ 152.7 Hz, CHeN). Anal. Calcd for C17H20N3O4P: C, 56.51; H, 5.58;
N, 11.63. Found: C, 56.45; H, 5.61; N, 11.55.
(amide-II), 1254 (s) (P]O), 1033 (vs) (CeO), 813 (m) (CHarom) cmꢁ1
1H NMR (300.13 MHz, DMSO‑d6)
10.67 (s, 1H, NHeN), 7.89 (s, 1H,
;
d
CH]N), 7.55e7.60 (m, 2H, ArH), 7.29e7.35 (m, 2H, ArH), 7.22e7.28
(m, 2H, ArH), 7.15e7.21 (m, 2H, ArH), 7.12 (dd, 3J ¼ 9.9, 3JP,H ¼ 5.1 Hz,
1H, NH), 5.27 (dd, 2JP,H ¼ 21.9, 3J ¼ 9.9 Hz, 1H, CHeN), 3.74e4.13 (m,
4H, two OCH2), 2.33 (s, 3H, CH3 in 4-CH3C6H4), 2.29 (d,
7JP,H ¼ 1.6 Hz, 3H, CH3 in 4-CH3C6H4), 1.21 (t, 3J ¼ 7.0 Hz, 3H, CH3 in
OEt), 1.10 (t, 3J ¼ 7.0 Hz, 3H, CH3 in OEt); 13C NMR (75.48 MHz,
4.4.15. (E)-1-Benzylidene-4-[(diethoxyphosphoryl)(phenyl)methyl]
semicarbazide (12b)
Phosphonate 12b (0.857 g, 88%) was obtained from sulfone (E)-
4a (1.024 g, 2.52 mmol) and P(OEt)3 (1.235 g, 7.43 mmol) in MeCN
(12 mL) (reflux, 1 h) as described for compound 12c. Mp 89e91.5 ꢀC
(AcOEt - petroleum ether, 3:4 v/v); IR (Nujol) nmax 3416 (m), 3382
(br m), 3197 (br s), 3100 (br s) (NH), 3027 (w) (CHarom), 1684 (vs)
(amide-I), 1611 (m) (C]N), 1599 (m), 1584 (w) (CCarom), 1528 (vs)
DMSO‑d6)
d
154.4 (d, J ¼ 9.5 Hz, C]O), 141.2 (CH]N), 139.3 (C),
136.9 (d, J ¼ 2.9 Hz, C), 133.3 (C), 131.5 (C), 129.4 (2CH), 128.9 (d,
J ¼ 2.1 Hz, 2CH), 127.7 (d, J ¼ 5.6 Hz, 2CH), 126.5 (2CH), 62.50 (d,
J ¼ 7.0 Hz, OCH2), 62.47 (d, J ¼ 6.9 Hz, OCH2), 49.7 (d, J ¼ 152.9 Hz,
CHeN), 21.0 (CH3 in 4-CH3C6H4), 20.7 (d, J ¼ 1.0 Hz, CH3 in
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

20
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
4-CH3C6H4), 16.2 (d, J ¼ 5.5 Hz, CH3 in OEt), 16.1 (d, J ¼ 5.5 Hz, CH3 in
OEt). Anal. Calcd for C21H28N3O4P: C, 60.42; H, 6.76; N,10.07. Found:
C, 60.38; H, 6.64; N, 10.03.
3J ¼ 8.2 Hz, 1H, CHeC]O), 3.91e4.17 (m, 4H, two OCH2), 1.09 (t,
3J ¼ 7.1 Hz, 3H, CH3 in OEt), 1.00 (t, 3J ¼ 7.1 Hz, 3H, CH3 in OEt); 13C
NMR (75.48 MHz, DMSO‑d6) d 167.5 (C]O in COOEt), 166.7 (C]O in
COOEt), 154.7 (NeC]O), 140.4 (C), 140.0 (CH]N), 134.5 (C), 129.3
(CH), 128.7 (2CH), 128.3 (2CH), 127.4 (CH), 127.0 (2CH), 126.5 (2CH),
61.12 (OCH2), 61.11 (OCH2), 56.4 (O]CeCHeC]O), 52.2 (CHeN),
13.8 (CH3 in OEt), 13.7 (CH3 in OEt). Anal. Calcd for C22H25N3O5: C,
64.22; H, 6.12; N, 10.21. Found: C, 64.22; H, 6.30; N, 10.08.
4.4.18. (E)-1-(4-Methoxybenzylidene)-4-
[(4-methoxyphenyl)(dimethoxyphosphoryl)methyl]semicarbazide
(12e)
Phosphonate 12e (0.938 g, 95%) was obtained from sulfone (E)-
4c (1.097 g, 2.35 mmol) and P(OMe)3 (0.873 g, 7.04 mmol) in MeCN
(15 mL) (reflux, 1 h) as described for compound 12c. Mp
164.5e166 ꢀC (MeCN); IR (Nujol) nmax 3411 (m), 3189 (br m), 3095
(br m), 3073 (br m) (NH), 3033 (w) (CHarom), 1680 (vs) (amide-I),
1609 (m) (C]N), 1583 (m), 1574 (w) (CCarom), 1535 (s), 1512 (s)
(amide-II), 1264 (s) (P]O), 1250 (s), 1054 (s), 1034 (s), 1016 (s)
4.4.21. (E)-4-{[2,2-Di(ethoxycarbonyl)-1-(4-methylphenyl)]ethyl}-
1-(4-methylbenzylidene)semicarbazide (13b)
To a cooled in an ice-bath, stirred suspension of NaH (0.285 g,
11.88 mmol) in dry MeCN (10 mL) was added a solution of diethyl
malonate (1.900 g, 11.86 mmol) in MeCN (26 mL), and the obtained
mixture was stirred for 10 min. To the resulting suspension were
added sulfone (E)-4b (4.317 g, 9.91 mmol) and MeCN (1 mL), the
reaction mixture was stirred at room temperature for 8 h, and the
solvent was removed under vacuum. To the obtained residue was
added saturated aqueous NaHCO3 (10 mL), the mixture was tritu-
rated until suspension was formed, and left overnight at room
temperature. The resulting suspension was cooled (0ꢀС), the pre-
cipitate was filtered, washed with ice-cold H2O, petroleum ether,
and dried to give 13b (4.099 g, 94%). Mp 148e149 ꢀC (AcOEt - pe-
troleum ether); IR (Nujol) nmax 3400 (s), 3175 (br m), 3099 (br s)
(NH), 3049 (w) (CHarom), 1740 (s), 1727 (s) (C]O in COOEt), 1689
(vs) (amide-I), 1613 (m) (CCarom), 1529 (s), 1515 (s) (amide-II), 808
(CeO), 831 (m) (CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
;
d
10.57 (s, 1H, NHeN), 7.86 (s, 1H, CH]N), 7.61e7.67 (m, 2H, ArH),
7.35e7.42 (m, 2H, ArH), 7.13 (dd, 3J ¼ 10.0, JP,H ¼ 4.2 Hz, 1H, NH),
6.97e7.03 (m, 2H, ArH), 6.91e6.97 (m, 2H, ArH), 5.35 (dd,
2JP,H ¼ 21.5, 3J ¼ 10.0 Hz, 1H, CHeN), 3.79 (s, 3H, OCH3 in
4-CH3OC6H4), 3.75 (s, 3H, OCH3 in 4-CH3OC6H4), 3.68 (d,
3
3JP,H ¼ 10.6 Hz, 3H, PeOCH3), 3.51 (d, JP,H ¼ 10.5 Hz, 3H, PeOCH3);
3
13C NMR (75.48 MHz, DMSO‑d6)
d
160.4 (C), 158.9 (d, J ¼ 2.6 Hz, C),
154.4 (d, J ¼ 9.4 Hz, C]O), 141.1 (CH]N), 129.1 (d, J ¼ 5.8 Hz, 2CH),
128.2 (2CH), 128.0 (C), 126.8 (C), 114.3 (2CH), 113.9 (d, J ¼ 1.8 Hz,
2CH), 55.3 (OCH3 in 4-CH3OC6H4), 55.1 (OCH3 in 4-CH3OC6H4), 53.3
(d, J ¼ 7.0 Hz, PeOCH3), 53.2 (d, J ¼ 6.9 Hz, PeOCH3), 48.7 (d,
J ¼ 154.8 Hz, CHeN). Anal. Calcd for C19H24N3O6P: C, 54.16; H, 5.74;
N, 9.97. Found: C, 54.09; H, 5.80; N, 9.94.
(m) (CHarom) cmꢁ1; 1H NMR (300.13 MHz, DMSO‑d6)
d 10.40 (s, 1H,
NHeN), 7.83 (s, 1H, CH]N), 7.56e7.62 (m, 2H, ArH), 7.56 (d,
3J ¼ 9.6 Hz, 1H, NH, one signal overlaps with signals of aromatic
protons), 7.21e7.32 (m, 4H, ArH), 7.10e7.15 (m, 2H, ArH), 5.48 (dd,
3J ¼ 9.6, 3J ¼ 8.0 Hz, 1H, CHeN), 4.37 (d, 3J ¼ 8.0 Hz, 1H, CHeC]O),
3.95e4.18 (m, 4H, two OCH2), 2.33 (s, 3H, CH3 in 4-CH3C6H4), 2.26
(s, 3H, CH3 in 4-CH3C6H4), 1.11 (t, 3J ¼ 7.1 Hz, 3H, CH3 in OEt), 1.03 (t,
4.4.19. (E)-1-(4-Methylbenzylidene)-4-[1-(dimethoxyphosphoryl)
but-1-yl]semicarbazide (12f)
Phosphonate 12f (0.435 g, 94%) was obtained from sulfone 7d
(0.523 g, 1.35 mmol) and P(OMe)3 (0.832 g, 6.71 mmol) in MeCN
(8 mL) (reflux, 6 h) as described for compound 12c. Mp
132.5e134 ꢀC (AcOEt - petroleum ether, 1:1 v/v); IR (Nujol) nmax
3300 (br s), 3185 (br s), 3082 (br s) (NH), 3027 (w) (CHarom), 1662
(vs) (amide-I), 1613 (m) (C]N), 1604 (m) (CCarom), 1537 (vs), 1517
(s) (amide-II), 1256 (s) (P]O), 1049 (s), 1029 (s) (CeO), 814 (s)
3J ¼ 7.1 Hz, 3H, CH3 in OEt); 13C NMR (75.48 MHz, DMSO‑d6)
d 167.4
(C]O in COOEt), 166.7 (C]O in COOEt), 154.6 (NeC]O), 140.0
(CH]N), 138.9 (C), 137.4 (C), 136.4 (C), 131.8 (C), 129.2 (2CH), 128.7
(2CH), 126.7 (2CH), 126.4 (2CH), 60.98 (OCH2), 60.95 (OCH2), 56.4
(O]CeCHeC]O), 51.8 (CHeN), 20.9 (CH3 in 4-CH3C6H4), 20.5 (CH3
in 4-CH3C6H4), 13.7 (CH3 in OEt), 13.6 (CH3 in OEt). Anal. Calcd for
(CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
; d 10.40 (s, 1H,
NHeN), 7.87 (s, 1H, CH]N), 7.56e7.62 (m, 2H, ArH), 7.19e7.25 (m,
C24H29N3O5: C, 65.59; H, 6.65; N, 9.56. Found: C, 65.58; H, 6.64; N,
9.37.
2
2H, ArH), 6.62 (d, 3J ¼ 9.9 Hz, 1H, NH), 4.24 (dddd, JP,H ¼ 16.3,
3J ¼ 9.9, 3J ¼ 9.9, 3J ¼ 4.9 Hz, 1H, CHeN), 3.679 (d, 3JP,H ¼ 10.5 Hz, 3H,
3
OCH3), 3.676 (d, JP,H ¼ 10.4 Hz, 3H, OCH3), 2.34 (s, 3H, CH3 in
4.4.22. (E)-4-{[2,2-Di(ethoxycarbonyl)-1-(4-methoxylphenyl)]
ethyl}-1-(4-methoxylbenzylidene)semicarbazide (13с)
4-CH3C6H4), 1.60e1.83 (m, 2H, CH2), 1.21e1.53 (m, 2H, CH2), 0.89 (t,
3J ¼ 7.3 Hz, 3H, CH3 in Pr); 13C NMR (75.48 MHz, DMSO‑d6)
d
154.8
Compound 13c (1.212 g, 88%) was prepared from sulfone (E)-4c
(1.363 g, 2.92 mmol), diethyl malonate (0.557 g, 3.48 mmol) and
NaH (0.084 g, 3.50 mmol) in dry MeCN (10 mL) (rt, 8 h) as described
for 13b. Mp 134e134.5 ꢀC (AcOEt - petroleum ether, 4:3 v/v); IR
(Nujol) nmax 3395 (s), 3178 (br s), 3084 (br s) (NH), 1752 (s), 1735
(s) (C]O in COOEt), 1680 (vs) (amide-I), 1610 (s), 1574 (w) (CCarom),
1534 (s) (amide-II), 1512 (s) (CCarom), 1256 (s), 1036 (s) (CeO), 831
(d, J ¼ 4.9 Hz, C]O), 140.6 (CH]N), 138.8 (C), 131.6 (C), 129.1 (2CH),
126.5 (2CH), 52.7 (d, J ¼ 7.0 Hz, OCH3), 52.4 (d, J ¼ 6.7 Hz, OCH3),
44.6 (d, J ¼ 155.3 Hz, CHeN), 31.0 (d, J ¼ 3.3 Hz, CH2), 20.8 (CH3 in
4-CH3C6H4), 18.5 (d, J ¼ 13.2 Hz, CH2), 13.2 (d, J ¼ 0.9 Hz, CH3 in Pr).
Anal. Calcd for C15H24N3O4P: C, 52.78; H, 7.09; N, 12.31. Found: C,
52.73; H, 6.88; N, 12.15.
(s) (CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
; d 10.31 (s, 1H,
4.4.20. (E)-1-Benzylidene-4-[2,2-di(ethoxycarbonyl)-1-phenyl]
ethyl}semicarbazide (13a)
NHeN), 7.81 (s, 1H, CH]N), 7.62e7.67 (m, 2H, ArH), 7.52 (d,
3J ¼ 9.6 Hz,1H, NH), 7.30e7.35 (m, 2H, ArH), 6.96e7.01 (m, 2H, ArH),
6.85e6.91 (m, 2H, ArH), 5.46 (dd, 3J ¼ 9.6, 3J ¼ 8.2 Hz, 1H, CHeN),
4.35 (d, 3J ¼ 8.2 Hz, 1H, CHeC]O), 3.96e4.18 (m, 4H, two OCH2),
3.80 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 1.11 (t, 3J ¼ 7.1 Hz, 3H, CH3 in
OEt), 1.03 (t, 3J ¼ 7.1 Hz, 3H, CH3 in OEt); 13C NMR (75.48 MHz,
Compound 13a (9.110 g, 91%) was prepared from sulfone (E)-4a
(9.900 g, 24.29 mmol), diethyl malonate (4.900 g, 30.59 mmol) and
NaH (0.728 g, 30.34 mmol) in dry MeCN (100 mL) (rt, 8 h) as
described for 13b. Mp 141.5e142 ꢀC (AcOEt - petroleum ether, 6:5 v/
v); IR (KBr) nmax 3395 (s), 3201 (br s), 3086 (br s) (NH), 3028 (w)
(CHarom), 1752 (s), 1731 (s) (C]O in COOEt), 1677 (vs) (amide-I),
1609 (m), 1585 (m), 1574 (w) (CCarom), 1528 (s) (amide-II), 754 (s),
DMSO‑d6) d 167.4 (C]O in COOEt), 166.7 (C]O in COOEt), 160.2 (C),
158.4 (C), 154.6 (NeC]O), 139.8 (CH]N), 132.4 (C), 128.0 (2CH),
127.9 (2CH), 127.1 (C), 114.1 (2CH), 113.5 (2CH), 60.94 (OCH2), 60.93
(OCH2), 56.6 (O]CeCHeC]O), 55.2 (OCH3), 55.0 (OCH3), 51.6
(CHeN), 13.7 (CH3 in OEt), 13.6 (CH3 in OEt). Anal. Calcd for
700 (s), 691 (s) (CHarom) cmꢁ1 1H NMR (300.13 MHz, DMSO‑d6)
;
d
10.55 (s, 1H, NHeN), 7.86 (s, 1H, CH]N), 7.69e7.74 (m, 2H, ArH),
7.65 (d, 3J ¼ 9.6 Hz, 1H, NH), 7.29e7.47 (m, 7H, ArH), 7.21e7.28 (m,
C24H29N3O7: C, 61.14; H, 6.20; N, 8.91. Found: C, 60.98; H, 6.27; N,
1H, ArH), 5.52 (dd, 3J ¼ 9.6, 3J ¼ 8.2 Hz, 1H, CHeN), 4.43 (d,
8.69.
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
(c) Y.S. Lee, M. Alam, R.S. Keri, Chem. Asian J. 8 (2013) 2906e2919;
21
Acknowledgments
(d) M.M. Heravi, S. Asadi, B.M. Lashkariani, Mol. Divers. 17 (2013) 389e407;
(e) R. Matsubara, S. Kobayashi, Acc. Chem. Res. 41 (2008) 292e301;
(f) J. Royer, M. Bonin, L. Micouin, Chem. Rev. 104 (2004) 2311e2352;
(g) B. Yin, Y. Zhanga, L.-W. Xu, Synthesis (2010) 3583e3595.
[8] (a) A.A. Fesenko, M.S. Grigoriev, A.D. Shutalev, J. Org. Chem. 82 (2017)
8085e8110;
This research was financially supported by the Russian Foun-
dation for Basic Research (Grant No. 19-316-70006).
(b) A.H. Antropow, K. Xu, R.J. Buchsbaum, M. Movassaghi, J. Org. Chem. 82
(2017) 7720e7731;
(c) V.J. Lillo, J.M. Saa, Chem. Eur J. 22 (2016) 17182e17186;
Appendix. Supplementary data
ꢀ
Supplementary data associated with this article can be found in
the online version, at https://doi.org/10.1016/j.tet.2019.130527.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
(d) P.A. Solovyev, A.A. Fesenko, A.D. Shutalev, J. Fluorine Chem. 182 (2016)
28e33;
(e) A.A. Fesenko, A.D. Shutalev, J. Org. Chem. 78 (2013) 1190e1207;
(f) F.A. Meece, C. Jayasinghe, G. Histand, D.H. Burns, J. Org. Chem. 74 (2009)
3156e3159.
[9] (a) Yu A. Martinovich, S.M. Ramsh, F. Hamoud, V.S. Fundamenskii, V.V. Gurzhii,
V.I. Zakharov, E.S. Khrabrova, Russ. J. Org. Chem. 54 (2018) 878e885;
(b) R.R. Khairullina, A.R. Geniyatova, T.V. Tyumkina, D.S. Karamzina,
A.G. Ibragimov, U.M. Dzhemilev, Tetrahedron 73 (2017) 7079e7084;
(c) A.A. Fesenko, D.A. Cheshkov, A.D. Shutalev, Mendeleev Commun. 18 (2008)
51e53;
References
[1] For selected reviews on a-amidoalkylation, see: (a) H.E. Zaugg, W.B. Martin,
Org. React. 14 (1965) 52e269;
(d) A.D. Shutalev, Chem. Heterocycl. Compd. 33 (1998) 1469e1470;
(e) A.D. Shutalev, Chem. Heterocycl. Compd. 29 (1993) 1192e1199.
[10] (a) A.D. Shutalev, A.A. Fesenko, Tetrahedron 67 (2011) 6883e6888;
(b) P.A. Solovyev, A.D. Shutalev, Chem. Heterocycl. Compd. 45 (2009)
809e814;
(c) M. Takimoto, T. Ebisuno, R. Shiba, Bull. Chem. Soc. Jpn. 56 (1983)
3319e3322.
[11] (a) L.A. Trafimova, M.O. Zimin, A.D. Shutalev, J. Chem. Res. 41 (2017) 149e156;
(b) D. Kroeger, F. Brockmeyer, C. Kahrs, Org. Biomol. Chem. 13 (2015)
7223e7229;
(b) H.E. Zaugg, Synthesis (1970) 49e73;
(c) H.E. Zaugg, Synthesis (1984) 85e110;
(d) H.E. Zaugg, Synthesis (1984) 181e212;
(e) W.N. Speckamp, M.J. Moolenaar, Tetrahedron 56 (2000) 3817e3856;
(f) B.E. Maryanoff, H.-C. Zhang, J.H. Cohen, I.J. Turchi, C.A. Maryanoff, Chem.
Rev. 104 (2004) 1431e1628;
ꢀ
ꢀ
(g) R. Mazurkiewicz, A. Pazdzierniok-Holewa, J. Adamek, K. Zielinska, Adv.
Heterocycl. Chem. 111 (2014) 43e94;
(h) P. Wu, T.E. Nielsen, Chem. Rev. 117 (2017) 7811e7856;
(i) E. Marcantoni, A. Palmieria, M. Petrini, Org. Chem. Front. 6 (2019), https://
doi.org/10.1039/c9qo00196d;
(c) T. Stalling, W. Saak, J. Martens, Eur. J. Org. Chem. (2013) 8022e8032;
(d) A.R. Katritzky, S. Singh, P.P. Mohapatra, N. Clemens, K. Kirichenko, ARKI-
VOC (ix) (2005) 63e79;
(e) J.A.M. Hamersma, P.M.M. Nossin, W.N. Speckamp, Tetrahedron 41 (1985)
1999e2005.
(j) M. Petrini, Chem. Rev. 105 (2005) 3949e3977.
ꢀ
ꢀ
ꢀ
ꢀ
[2] (a) S. Alujas-Burgos, C. Oliveras-Gonzalez, A. Alvarez-Larena, P. Bayon,
M. Figueredo, J. Org. Chem. 83 (2018) 5052e5057;
(b) K. Srinivas, N. Singh, D. Das, D. Koley, Org. Lett. 19 (2017) 274e277;
(c) M. Chrzanowska, A. Grajewska, M.D. Rozwadowska, Chem. Rev. 116 (2016)
12369e12465;
(d) B.K. Anderson, T. Livinghouse, J. Org. Chem. 80 (2015) 9847e9855;
(e) A. Plas, F. Marchand, A. Eschalier, Y. Troin, P. Chalard, Eur. J. Org. Chem.
(2012) 6070e6079;
(f) S. Peixoto, T.M. Nguyen, D. Crich, B. Delpech, C. Marazano, Org. Lett. 12
(2010) 4760e4763;
(g) G. Han, M.G. LaPorte, J.J. Folmer, K.M. Werner, S.M. Weinreb, J. Org. Chem.
65 (2000) 6293e6306.
[12] (a) J.M. Shikora, S.R. Chemler, Org. Lett. 20 (2018) 2133e2137;
(b) T. Boultwood, D.P. Affron, J.A. Bull, Tetrahedron 71 (2015) 4949e4957;
(c) Y. Hayashi, T. Urushima, D. Sakamoto, K. Torii, H. Ishikawa, Chem. Eur. J. 17
(2011) 11715e11718;
~
ꢀ
(d) S. Fustero, A.C. Cunat, S. Flores, C. Baez, J. Oliver, M. Cynamon,
M. Gütschow, M.D. Mertens, O. Delgado, G. Tresadern, A.A. Trabanco, Chem.
Eur. J. 17 (2011) 14772e14784;
(e) S.D. Kuduk, C. Ng Di Marco, S.M. Pitzenberger, N. Tsou, Tetrahedron Lett. 47
(2006) 2377e2381;
(f) C.H. Lee, H. Kohn, J. Org. Chem. 55 (1990) 6098e6104.
[13] (a) S. Qiao, S. Pindi, P.T. Spigener, B. Jiang, G. Li, Tetrahedron Lett. 57 (2016)
619e622;
[3] (a) Y.-S. Lee, J.-W. Jung, S.-H. Kim, J.-K. Jung, S.-M. Paek, N.-J. Kim, D.-J. Chang,
J. Lee, Y.-G. Suh, Org. Lett. 12 (2010) 2040e2043;
(b) J.Y.L. Chung, F.W. Hartner, R.J. Cvetovich, Tetrahedron Lett. 49 (2008)
6095e6100;
(c) R.S. Coleman, F.-X. Felpin, W. Chen, J. Org. Chem. 69 (2004) 7309e7316;
(d) E. Metais, L.E. Overman, M.I. Rodriguez, B.A. Stearns, J. Org. Chem. 62
(1997) 9210e9216;
(b) C. Skarbek, L.L. Lesueur, H. Chapuis, A. Deroussent, C. Pioche-Durieu,
A. Daville, J. Caron, M. Rivard, T. Martens, J.-R. Bertrand, E. Cam, G. Vassal,
P. Couvreur, D. Desmaele, A. Paci, J. Med. Chem. 58 (2015) 705e717;
(c) R. Almansa, J.F. Collados, D. Guijarro, M. Yus, Tetrahedron: Asymmetry 24
(2013) 116e120;
(d) E.M. Vieira, M.L. Snapper, A.H. Hoveyda, J. Am. Chem. Soc. 133 (2011)
3332e3335;
(e) E. Sierecki, G. Errasti, T. Martens, J. Royer, Tetrahedron 66 (2010)
10002e10007.
(e) T. Nishikawa, M. Isobe, T. Goto, Synlett (1991) 99e101;
(f) C.J. Flann, L.E. Overman, J. Am. Chem. Soc. 109 (1987) 6115e6118.
[4] (a) X. Wang, J. Li, R.A. Saporito, N. Toyooka, Tetrahedron 69 (2013)
10311e10315;
(b) I.R. Vlahov, Y. Wang, M. Vetzel, S. Hahn, P.J. Kleindl, J.A. Reddy,
C.P. Leamon, Bioorg. Med. Chem. Lett 21 (2011) 6778e6781;
(c) O. Iwamoto, H. Koshino, D. Hashizume, K. Nagasawa, Angew. Chem. Int. Ed.
46 (2007) 8625e8628;
[14] For some reviews on useful properties of semicarbazide-containing com-
pounds, see: (a) C.B. Scarim, D.H. Jornada, M.G.M. Machado, C.M.R. Ferreira,
J.L. dos Santos, M.C. Chung, Eur. J. Med. Chem. 162 (2019) 378e395;
(b) R. Chingle, C. Proulx, W.D. Lubell, Acc. Chem. Res. 50 (2017) 1541e1556;
(c) S.N. Pandeya, Acta Pharm. 62 (2012) 263e286;
(d) C. Proulx1, D. Sabatino, R. Hopewell, J. Spiegel, Y.G. Ramos, W.D. Lubell,
Future Med. Chem. 3 (2011) 1139e1164;
(e) H. Beraldo, D. Gambino, Mini Rev. Med. Chem. 4 (2004) 31e39;
(f) B.S. Garg, V.K. Jain, Microchem. J. 38 (1988) 144e169.
[15] (a) J.R. Dimmock, S.C. Vashishtha, J.P. Stables, Eur. J. Med. Chem. 35 (2000)
241e248;
(d) T. Hjelmgaard, I. Søtofte, D. Tanner, J. Org. Chem. 70 (2005) 5688e5697.
[5] (a) S.P. Chavan, A.G. Chittiboyina, T. Ravindranathan, S.K. Kamat, U.R. Kalkote,
J. Org. Chem. 70 (2005) 1901e1903;
(b) M.J. Moolenaar, W.N. Speckamp, H. Hiemstra, E. Poetsch, M. Casutt, Angew.
Chem. Int. Ed. 34 (1995) 2391e2393.
[6] (a) S. Pomplun, Y. Wang, A. Kirschner, C. Kozany, A. Bracher, F. Hausch, Angew.
Chem. Int. Ed. 54 (2015) 345e348;
(b) Y.-S. Yao, J.-L. Liu, J. Xi, B. Miu, G.-S. Liu, S. Wang, L. Meng, Z.-J. Yao, Chem.
Eur J. 17 (2011) 10462e10469;
(b) J.R. Dimmock, S.N. Pandeya, J.W. Quail, U. Pugazhenthi, T.M. Allen,
G.Y. Kao, J. Balzarini, E. DeClercq, Eur. J. Med. Chem. 30 (1995) 303e314.
[16] J.D. Warren, D.L. Woodward, R.T. Hargreaves, J. Med. Chem. 20 (1977)
1520e1521.
(c) P. Kuntiyong, S. Akkarasamiyo, N. Piboonsrinakara, C. Hemmara,
P. Songthammawat, Tetrahedron 67 (2011) 8034e8040;
(d) J.C. Lorenz, C.A. Busacca, X.W. Feng, N. Grinberg, N. Haddad, J. Johnson,
S. Kapadia, H. Lee, A. Saha, M. Sarvestani, E.M. Spinelli, R. Varsolona, X. Wei,
X. Zeng, C.H. Senanayake, J. Org. Chem. 75 (2010) 1155e1161;
(e) T.S. McDermott, L. Bhagavatula, T.B. Borchardt, K.M. Engstrom,
J. Gandarilla, B.J. Kotecki, A.W. Kruger, M.J. Rozema, A.Y. Sheikh, S.H. Wagaw,
S.J. Wittenberger, Org. Process Res. Dev. 13 (2009) 1145e1155;
(f) J. Joossens, P. Van der Veken, A.-M. Lambeir, K. Augustyns, A. Haemers,
J. Med. Chem. 47 (2004) 2411e2413;
[17] (a) S. Ren, R. Wang, K. Komatsu, P. Bonaz-Krause, Y. Zyrianov, C.E. McKenna,
C. Csipke, Z.A. Tokes, E.J. Lien, J. Med. Chem. 45 (2002) 410e419;
(b) S.E. Asís, A.M. Bruno, A.R. Martínez, M.V. Sevilla, C.H. Gaozza, A.M. Romano,
J.D. Coussio, G. Ciccia, Il Farmaco 54 (1999) 517e523.
ꢀ
[18] H. Cerecetto, R. Di Maio, M. Gonzalez, M. Risso, G. Sagrera, G. Seoane,
A. Denicola, G. Peluffo, C. Quijano, A.O.M. Stoppani, M. Paulino, C. Olea-Azar,
M.A. Basombrío, Eur. J. Med. Chem. 35 (2000) 343e350.
[19] J.S. Casas, M.S. García-Tasende, J. Sordo, Coord. Chem. Rev. 209 (2000)
197e261.
(g) C. Guo, S. Reich, R. Showalter, E. Villafranca, L. Dong, Tetrahedron Lett. 41
(2000) 5307e5311.
[20] W.P. Jencks, M. Gilchrist, J. Am. Chem. Soc. 90 (1968) 2622e2637.
[21] H.M. Grant, P. McTigue, D.G. Ward, Aust. J. Chem. 36 (1983) 2211e2218.
[22] A.A. Fesenko, A.N. Yankov, A.D. Shutalev, Tetrahedron Lett. 57 (2016)
5784e5787.
[7] For some reviews on enantioselective versions of a-amidoalkylation reaction,
see: (a) M.G. Vinogradov, O.V. Turova, S.G. Zlotin, Russ. Chem. Rev. 86 (2017)
1e17;
(b) E. Marcantoni, M. Petrini, Adv. Synth. Catal. 358 (2016) 3657e3682;
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527

22
A.A. Fesenko et al. / Tetrahedron xxx (xxxx) xxx
[23] A. Kleemann, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical Substances:
Synthesis, Patents, Applications, fourth ed., Georg Thieme, Stuttgart, 2001.
[24] B.S. Furniss, A.J. Hannaford, P.W.G. Smith, A.R. Tatchell, Vogel's Textbook of
Practical Organic Chemistry, fifth ed., Longman Scientific & Technical; John
Wiley & Sons, New York, 1989, p. 1258.
(2015) 387e391;
(c) F.J. Wilson, I.V. Hopper, A.B. Crawford, J. Chem. Soc. Trans. 121 (1922)
866e870;
(d) W. Borsche, C. Merkwitz, Chem. Ber. 37 (1904) 3177e3187.
[35] M.-C. Chung, R.V.C. Güido, T.F. Martinelli, M.F. Gonçalves, M.C. Polli,
K.C.A. Botelho, E.A. Varanda, W. Colli, M.T.M. Miranda, E.I. Ferreira, Bioorg.
Med. Chem. 11 (2003) 4779e4783.
[25] (a) M.A.M. Alho, R. Baggio, N.B. D'Accorso, ARKIVOC (iii) (2013) 129e138;
€
(b) E.R. Garbelini, M. Horner, V.F. Giglio, A.H. Silva, A. Barison, F.S.Z. Nunes,
Anorg. Allg. Chem. 635 (2009) 1236e1241;
(c) R.N. Puthucode, U. Pugazhenthi, J.W. Quail, J.P. Stables, J.R. Dimmock, Eur. J.
Med. Chem. 33 (1998) 595e607;
(d) T.A. Olszak, O.M. Peeters, N.M. Blaton, C.J. De Ranter, Acta Crystallogr. Sect.
C Cryst. Struct. Commun. 50 (1994) 948e950;
(e) J.R. Dimmock, K.K. Sidhu, R.S. Thayer, P. Mack, M.J. Duffy, R.S. Reid,
J.W. Quail, U. Pugazhenthi, A. Ong, J.A. Bikker, D.F. Weaver, J. Med. Chem. 36
(1993) 2243e2252;
[36] 1H NMR spectrum of 10c (300.13 MHz, DMSO‑d6)
d: 10.28 (1H, br s, NHeN),
7.83 (1H, s, CH]N), 6.66 (1H, d, 3J ¼ 9.6 Hz, NH), 4.66 (1H, ddd, 3J ¼ 9.6, 3J1
þ
3J2 ¼ 14.2 Hz, CHeN), 2.47e2.60 (4H, m, two NCH2, signals partly overlap with
signals of the residual proton in the solvent), 1.55e1.70 (6H, m, CH2CH2 and
CH2 in Pr), 1.21e1.39 (2H, m, CH2 in Pr), 0.88 (3H, t, 3J ¼ 7.3 Hz, CH3 in Pr).
Signals of other protons overlap with signals of p-methylbenzaldehyde
semicarbazone.
€
[37] (a) H. Mohrle, G.Z. Keller, Naturforscher 58B (2003) 885e902;
(f) B. Mergardt, K. Weber, G. Adiwidjaja, E. Schaumann, Angew. Chem. Int. Ed.
30 (1991) 1687e1688;
(g) A.E. Koziol, R.C. Palenik, G.J. Palenik, J. Chem. Soc., Chem. Commun. (1988)
226e227.
(b) S. Joshi, A.D. Manikpuri, P. Tiwari, Int. J. Chem. Sci. 7 (2009) 869e877.
[38] (a) V.P. Kukhar, H.R. Hudson (Eds.), Aminophosphonic and Aminophosphinic
Acids: Chemistry and Biological Activity, John Wiley & Sons, New York, 2000;
(b) P. Kafarski, B. Lejczak, Phosphorus, sulfur silicon, Relat. Elem. 63 (1991)
193e215.
[26] (a) A.A. Fesenko, A.A. Trafimova, A.D. Shutalev, Org. Biomol. Chem. 10 (2012)
447e462;
[39] (a) F.R. Atherton, C.H. Hassal, R.W. Lambert, J. Med. Chem. 29 (1986) 29e40;
(b) J.G. Allen, F.R. Atherton, M.J. Hall, C.H. Hassall, S.W. Holmes, R.W. Lambert,
L.J. Nisbet, P.S. Ringrose, Nature 272 (1978) 56e58.
(b) A.D. Shutalev, A.A. Fesenko, Tetrahedron 67 (2011) 6883e6888;
(c) N.N. Kurochkin, A.A. Fesenko, D.A. Cheshkov, M.M. Davudi, A.D. Shutalev,
Tetrahedron Lett. 52 (2011) 88e91;
ꢀ
[40] G. Lavielle, P. Hautefaye, C. Schaeffer, J.A. Boutin, C.A. Cudennec, A. Pierre,
(d) A.D. Shutalev, N.N. Kurochkin, Mendeleev Commun. 15 (2005) 70e72;
(e) A.D. Shutalev, E.A. Kishko, N.V. Sivova, A. Yu Kuznetsov, Molecules 3 (1998)
100e106.
J. Med. Chem. 34 (1991) 1998e2003.
[41] J. Bird, R.C.D. Mello, G.P. Harper, D.J. Hunter, E.H. Karran, R.E. Markwell,
A.J. Miles-Williams, S.S. Rahman, R.W. Ward, J. Med. Chem. 37 (1994)
158e169.
[42] (a) J.A. Kirby, S.G. Warren, The Organic Chemistry of Phosphorus, Elsevier,
Amsterdam, 1967;
(b) R.F. Hudson, Structure and Mechanism in Organophosphorus Chemistry,
Academic Press, New York, 1965.
[43] (a) M. Balouiri, M. Sadiki, S.K. Ibnsouda, J. Pharm. Anal. 6 (2016) 71e79;
(b) I.A. Edwards, A.G. Elliott, A.M. Kavanagh, J. Zuegg, M.A.T. Blaskovich,
M.A. Cooper, ACS Infect. Dis. 2 (2016) 442e450.
[27] K. Kawabe, T. Suzui, M. Iguchi, Yakugaku Zasshi 80 (1960) 65e68. Chem. Abs.
1960, 54, 62648.
[28] S. Nain, A. Sharma, H. Singh, S. Paliwal, J. Biomed. Ther. Sci. 2 (2015) 1e7.
[29] V. Mishra, S.N. Pandeya, C. Pannecouque, M. Witvrouw, E. DeClercq, Arch.
Pharm. 335 (2002) 183e186.
ꢀ
[30] (a) G. Aguirre, M. Boiani, E. Cabrera, H. Cerecetto, R. Di Maio, M. Gonzalez,
A. Denicola, C.M.R. Sant'Anna, E.J. Barreiro, Eur. J. Med. Chem. 41 (2006)
457e466;
ꢀ
(b) G. Aguirre, E. Cabrera, H. Cerecetto, R. Di Maio, M. Gonzalez, G. Seoane,
[44] (a) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that
Grow Aerobically; Approved Standard, ninth ed., vol. 32, Clinical and Labo-
ratory Standards Institute, Wayne, PA, 2012;
A. Duffaut, A. Denicola, M.J. Gil, V. Martínez-Merino, Eur. J. Med. Chem. 39
(2004) 421e431.
[31] Tilles, H. U.S. Patent 3,712,914, 1973; Chem. Abs., 1973, 78, 97352.
[32] (a) H. Cerecetto, R. Di Maio, G. Ibarruri, G. Seoane, A. Denicola, G. Peluffo,
C. Quijano, M. Paulino, Il Farmaco 53 (1998) 89e94;
(b) Reference Method for Broth Dilution Antifungal Susceptibility Testing of
Yeasts; Approved Standard, second ed., vol. 22, Clinical and Laboratory
Standards Institute, Wayne, PA, 2002.
(b) R. Ohme, H. Preuschhof, J. Prakt. Chem. 313 (1971) 626e635.
[33] (a) A. Arshia, A. Khan, K.M. Khan, S.M. Saad, N.I. Siddiqui, S. Javaid, S. Perveen,
M.I. Choudhary, Med. Chem. Res. 25 (2016) 2666e2679;
(b) R. Milcent, G. Barbier, B. Yver, F. Mazouz, J. Het. Chem. 28 (1991)
1511e1516.(c) Pilgram, K. H. G. Patent DE 2,342,688, 1974; Chem. Abs., 1974,
80, 145845.
[45] (a) M.K. McMillian, L. Li, J.B. Parker, L. Patel, Z. Zhong, J.W. Gunnett,
W.J. Powers, M.D. Johnson, Cell Biol. Toxicol. 18 (2002) 157e173;
(b) J. O'Brien, I. Wilson, T. Orton, F. Pognan, Eur. J. Biochem. 267 (2000)
5421e5426.
€
[46] J. Harder, J. Bartels, E. Christophers, J.M. Schroder, J. Biol. Chem. 276 (2001)
5707e5713.
[34] (a) J.-F. Vincent-Rocan, R.A. Ivanovich, C. Clavette, K. Leckett, J. Bejjani,
A.M. Beauchemin, Chem. Sci. 7 (2016) 315e328;
[47] L. Field, R.D. Clark, Org. Synth. 38 (1958) 62e63.
[48] M. Uda, S.J. Kubota, J. Heterocycl. Chem. 15 (1978) 807e812.
ꢀ
(b) N.-D. Doan, J. Zhang, M. Traore, W. Kamdem, W.D. Lubell, J. Pept. Sci. 21
Please cite this article as: A.A. Fesenko et al., A general and convenient synthesis of 4-(tosylmethyl)semicarbazones and their use in
amidoalkylation of hydrogen, heteroatom, and carbon nucleophiles, Tetrahedron, https://doi.org/10.1016/j.tet.2019.130527