An efficient and stereoselective approach to 14-membered hexaaza macrocycles using novel semicarbazone-based amidoalkylation reagents

Article abstract of DOI:10.1016/j.tetlet.2016.11.041

An efficient synthesis of hydrazones of 4-(3-oxobutyl)semicarbazides and 4-(3-oxobutyl)semicarbazones using novel semicarbazone-based amidoalkylation reagents, 1-arylidene-4-[(aryl)(tosyl)methyl]semicarbazides, has been developed. The synthesis involved reaction of the latter with the Na-enolate of acetylacetone, followed by a base-promoted retro-Claisen reaction and treatment of the obtained 4-(3-oxobutyl)semicarbazones with hydrazine or methylhydrazine. The prepared hydrazones were converted stereoselectively into 14-membered cyclic bis-semicarbazones under acidic conditions. Especially high selectivity (trans/cis ? 97:3) was observed upon the macrocyclization of 4-(3-oxobutyl)semicarbazone hydrazones. A plausible reaction pathway and the stereochemistry of this cyclization were discussed.

Full text of DOI:10.1016/j.tetlet.2016.11.041

Tetrahedron Letters 57 (2016) 5784–5787
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient and stereoselective approach to 14-membered hexaaza
macrocycles using novel semicarbazone-based amidoalkylation reagents
⇑
Anastasia A. Fesenko, Alexander N. Yankov, Anatoly D. Shutalev
Department of Organic Chemistry, Moscow Technological University, 86 Vernadsky Ave., 119571 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of hydrazones of 4-(3-oxobutyl)semicarbazides and 4-(3-oxobutyl)semicarbazones
using novel semicarbazone-based amidoalkylation reagents, 1-arylidene-4-[(aryl)(tosyl)methyl]semicar-
bazides, has been developed. The synthesis involved reaction of the latter with the Na-enolate of
acetylacetone, followed by a base-promoted retro-Claisen reaction and treatment of the obtained 4-(3-
oxobutyl)semicarbazones with hydrazine or methylhydrazine. The prepared hydrazones were converted
stereoselectively into 14-membered cyclic bis-semicarbazones under acidic conditions. Especially high
selectivity (trans/cis P 97:3) was observed upon the macrocyclization of 4-(3-oxobutyl)semicarbazone
hydrazones. A plausible reaction pathway and the stereochemistry of this cyclization were discussed.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 2 September 2016
Revised 1 November 2016
Accepted 8 November 2016
Available online 9 November 2016
Keywords:
Semicarbazones
Semicarbazides
Hydrazones
Amidoalkylation
retro-Claisen reaction
Azamacrocycles
Polyaza macrocycles are of considerable importance in various
fields of chemistry, biochemistry, medicine, and material science.
The unique features of these heterocycles arise from their ability
to bind to different inorganic and organic cations, anions, and neu-
macrocycles 1 is able to chelate various metal cations through
the N1, N4, N8, and N11 atoms. Indeed, the neutral complex of
1
14
dianion of 1 (R = Ph, R = H) with Ni(II) was obtained, demon-
strating that hexaaza macrocycles 1 can serve as novel tetraden-
tate ligands for metal ions. However, progress in this area was
hampered by the low availability of macrocycle precursors 2 which
1
,2
tral molecules. Polyaza macrocycles and their metal complexes
3
4
possess a wide range of biological activities including anticancer,
5
6
anti-HIV, antibacterial and antifungal properties. The metal com-
plexes also have applications as contrast agents for magnetic reso-
were prepared in four steps from ethyl carbamate involving a-ami-
doalkylation of sodium acetylacetonates with ethyl N-(tosyl-
methyl)carbamates. The Achilles’ heel of the synthesis was the
low isolated yields (29–42%) for substitution of the ethoxy group
in b-carbamato ketones 3 on the hydrazino fragment due to the
nance imaging, radiopharmaceuticals, sensors,9 NMR shift
7
8
1
0
9c,10b
2d,11
reagents, luminescent materials,
and catalysis.
Although a large variety of polyaza macrocycles have been
synthesized, the design of new members, particularly tetradentate
1
3b
2 4
harsh reaction conditions (N H , reflux, 20–24 h).
1
4-membered hexaazacycles, is a topic of great interest. Among
We hypothesized that hydrazones 2 could be readily prepared
from N1-protected semicarbazides following the same strategy.
Additionally, treatment of 4-(3-oxobutyl)semicarbazides with
hydrazine could give access not only to N1-unprotected semicar-
bazide hydrazones 2, but N1-protected analogues which could also
serve as macrocycle precursors.
them, 14-membered 1,2,4,8,9,11-hexaaza macrocycles remain
1
2
underexploited. Recently, we reported a general approach to novel
4-membered cyclic bis-semicarbazones 1 based on the acid-
catalyzed cyclization of 4-(3-oxobutyl)semicarbazide hydrazones
1
1
3
2
(Scheme 1).
In contrast to the 14-membered 1,2,4,8,9,11-hexaaza macrocy-
Herein, we describe a convenient multi-gram synthesis of
hydrazones of 4-(3-oxobutyl)-substituted semicarbazides and
semicarbazones from 1-arylidenesemicarbazides, and the acid-
catalyzed stereoselective cyclization of these hydrazones to give
14-membered cyclic bis-semicarbazones 1. The preparation of
cles previously described in the literature,12 compounds 1 are con-
formationally more flexible because they possess only two double
1
3a
bonds in the heterocyclic ring. Powder X-ray diffraction analysis
and DFT calculations showed that the internal cavity of
novel
a-amidoalkylation reagents, 1-arylidene-4-(tosylmethyl)
semicarbazides, is also reported.
1
3b,15
⇑
Corresponding author.
E-mail addresses: anatshu@gmail.com, shutalev@orc.ru (A.D. Shutalev).
Based on previous experience,
the amidoalkylation
reagents 4a–d were obtained by the three-component
http://dx.doi.org/10.1016/j.tetlet.2016.11.041
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

A.A. Fesenko et al. / Tetrahedron Letters 57 (2016) 5784–5787
5785
Scheme 1. Synthesis of hexaaza macrocycles 1.13
Scheme 3. Synthesis of macrocyclic precursors 10a–c and 11a–e.
Scheme 2. Synthesis of semicarbazone-based amidoalkylation reagents 4a–d.
condensation of (E)-1-arylidenesemicarbazides 5a–d with the
corresponding aromatic aldehydes 6a–d and p-toluenesulfinic
acid (7) (Scheme 2). Under optimized reaction conditions (EtOH,
rt, 3–8 days, 30–50 mol% excess of 6 and 7), (E)-semicarbazones
1
4
a–d were isolated in 96–99% yield with >95% purity ( H NMR)
after filtration of the precipitate formed upon reaction completion.
It should be noted that the prepared semicarbazones 4a–d rep-
16
resent novel amidoalkylation reagents and can be widely used in
1
7
organic synthesis.
Nucleophilic substitution of the tosyl-group in sulfones 4a–d
proceeded smoothly under the action of the Na-enolate of acety-
lacetone in MeCN to give the corresponding (E)-semicarbazones
Scheme 4. Syntheses of 14-membered hexaaza macrocycles 12a–d.
8
8
a–d in 97–98% yields (Scheme 3). Treatment of compounds
a–d with KOH (5 equiv.) in aqueous EtOH at room temperature
Recently, we reported the TsOH-catalyzed transformation of
hydrazones 10a–c into hexaaza macrocycles 12a–c (Scheme 4).13
The reaction proceeded smoothly in EtOH or MeCN at room tem-
perature or at reflux to give compounds 12a–c in 85–93% yields
as mixtures of trans- and cis-isomers whose ratio was dependent
on the reaction conditions. Thus, the effective synthesis of the
key precursors 10a–c on a multi-gram scale as described herein,
provides an improved access to macrocycles 12a–c.
for 3–6 h afforded (E)-4-(3-oxobutyl)semicarbazones 9a–d in
9
5–97% yields.
Heating compounds 9a–c in EtOH at reflux for 8.5–10 h in the
presence of N
H
2 4
2
ÁH O (30 equiv.) afforded hydrazones of semicar-
bazides 10a–c (78–93%) as mixtures of (E)- and (Z)-isomers in
ratios of 92:8, 94:4, and 95:5, respectively. Under all conditions
tested, MeO-derivative 9d failed to give the desired hydrazone
with sufficient purity. Thus, compounds 10a–c, the key precursors
of 14-membered hexaaza macrocycles, were prepared in four steps
from semicarbazones 5a–c in 71–83% overall yield on a multi-gram
scale, while the overall yields of these compounds obtained in four
steps from ethyl carbamate were only 22–32% (see Scheme 1).
ÁH
Treatment of semicarbazones 9a–d with N O (30 equiv.)
in EtOH at room temperature for 5 h gave mixtures of (E)- and
Having successfully prepared the hydrazones of semicar-
bazones 11a–e, we took on the challenge to transform them into
the corresponding macrocycles 12a–d. Under optimal conditions
for the cyclization of hydrazone 10a (TsOH 1.07 equiv., EtOH,
1
3b
13b
reflux, 2 h),
compound 11a predominantly afforded
1
H
2 4
2
semicarbazone 5a, and no macrocycle was detected ( H NMR).
The reaction of 11a with 0.09 equivalents of TsOH (EtOH, reflux,
2 h) resulted in the formation of a complex mixture containing
(Z)-hydrazones of (E)-semicarbazones 11a–d in high yield
(94–98%), with significant predominance of the (E)-isomer
(91–98%). Analogously, a 92:8 mixture of (E)- and (Z)-methylhy-
1
12a (24% H NMR estimated yield of 12a, trans/cis = 57:43).
We found that the macrocyclization of 11a proceeded well in
aprotic solvents (Table 1). In MeCN at reflux, under the action of
TsOH (0.10 equiv.), a 89:11 mixture of trans- and cis-12a was
cleanly formed from semicarbazone 11a in 72% yield (Entry 1).
Increasing the concentration of 11a led to an increase in the
cyclization stereoselectivity (Entry 2 vs Entry 1). Decreasing the
concentration of 11a resulted in a higher yield of 12a and lower
reaction stereoselectivity (Entry 7 vs Entry 1). Use of an increased
amount of TsOH improved both the selectivity and yield of the
cyclization (Entry 2 vs Entry 6). When the reaction of 11a with
TsOH was performed in THF, the yield of 12a increased while the
drazones of (E)-semicarbazone 11e was obtained in 91% yield from
the reaction of compound 9a with methylhydrazine. The configu-
rations of the major and minor isomers of compounds 11a,c were
unambiguously determined using 1H, H NOESY experiments in
1
DMSO-d
observed between the CH
the (E)-configuration of the C@N double bond. Since the H and
6
. For the major isomer of 11a,c, a diagnostic NOE was
3
and C@NNH protons, thus indicating
2
1
1
3
C NMR spectra of the major isomers of 11a,c and 11b,d,e were
similar, we concluded that the major isomers of 11b,d,e also had
the (E)-configuration.

5
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A.A. Fesenko et al. / Tetrahedron Letters 57 (2016) 5784–5787
Table 1
Acid-catalyzed cyclization of semicarbazones 11a–d to give 14-membered hexaaza macrocycles 12a–d.a
Entry
Starting compound
R
Conc. (mol/L)
Solvent
Acid (equiv.)
Time (h)
Product
trans/cis ratiob
Yieldc (%)
1
2
3
4
5
6
7
8
9
11a
11a
11a
11a
11a
11a
11a
11b
11b
11b
11b
11b
11b
11c
11c
11c
11c
11d
11d
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC
4-MeC
4-MeC
4-MeC
4-MeC
4-MeC
4-t-BuC
4-t-BuC
4-t-BuC
4-t-BuC
0.123
0.217
0.218
0.157
0.195
0.243
0.039
0.125
0.243
0.243
0.207
0.223
0.216
0.119
0.118
0.116
0.119
0.204
0.210
MeCN
MeCN
MeCN
MeCN
THF
TsOHÁH
2
O (0.10)
O (0.10)
2
1
2
9
4
2
2
2
2
1
2
6
4
1
4
4
8
2
4
12a
12a
12a
12a
12a
12a
12a
12b
12b
12b
12b
12b
12b
12c
12c
12c
12c
12d
12d
89:11
93:7
95:5
20:80
93:7
97:3
54:46
26:74
64:36
46:54
63:37
96:4
72
70
77
TsOHÁH
2
CF
3
COOH (0.10)
d
AcOH (50)
14
TsOHÁH
TsOHÁH
TsOHÁH
TsOHÁH
TsOHÁH
TsOHÁH
2
2
2
2
2
2
O (0.10)
O (0.20)
O (0.10)
O (0.10)
O (0.10)
O (0.10)
78
75
87
68
79
79
80
80
78
75
70
68
92
58
60
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
6
6
6
6
6
6
H
H
H
H
H
H
4
4
4
4
4
10
11
12
13
14
15
16
17
18
19
3
CF COOH (0.11)
TsOHÁH
TsOHÁH
TsOHÁH
TsOHÁH
TsOHÁH
TsOHÁH
TsOHÁH
TsOHÁH
2
2
2
2
2
2
2
2
O (0.10)
O (0.20)
O (0.09)
O (0.10)
O (0.20)
O (0.20)
O (0.20)
O (0.10)
4
98:2
6
6
6
6
H
4
4
4
4
49:51
59:41
78:22
100:0
97:3
H
H
H
4-MeOC
4-MeOC
6
H
4
6
H
4
99:1
a
b
c
Reaction conditions: MeCN or THF, reflux, 1–9 h.
According to 1H NMR spectroscopy of the crude product.
Isolated yield.
d
NMR estimated yield.
stereoselectivity remained unchanged compared with those con-
ducted in MeCN (Entry 2 vs Entry 5).
resulting in a gradual increase in the trans-selectivity of the
process.
The stereoselective transformation of 11a into 12a was also
promoted by the strong acid TFA (Entry 3). However, only a small
amount of 12a (14% H NMR estimated yield, trans/cis = 20:80),
along with numerous side-products, was obtained in the presence
of the relatively weak acetic acid (50 equiv., MeCN, reflux, 9 h)
Acid-catalyzed macrocyclization of N-methylhydrazone 11e
could proceed via two possible pathways involving nucleophilic
participation of the N1-atom to give macrocycle 12a or the NHMe
nitrogen atom to give the 2,9-dimethyl derivative of 12a. At reflux
for 2.5 h or at room temperature for 96 h in MeCN in the presence
of TsOH (0.10 equiv.), compound 11e afforded macrocycle 12a
1
(
Entry 4).
Previously, we reported that the macrocyclization of semicar-
bazide 10a in the presence of TsOH proceeded to completion in
1
along with various side and intermediate products ( H NMR).
Prolonging the reaction time at reflux to 9 h led to predominant
13b
1
4
h in EtOH at room temperature.
In contrast, the TsOH-
formation of 12a (trans:cis = 58:42). No H NMR signals corre-
catalyzed conversion of 11a into 12a at room temperature was
slow. The crude product obtained after treatment of 11a with
sponding to the 2,9-dimethyl derivative of 12a were observed.
The presence of the hydrazone fragment in the starting semi-
carbazones 11 was proved to be essential for macrocycle forma-
tion. Indeed, treatment of 9a with TsOH (0.10 equiv.) in EtOH
(2 h) or MeCN (4 h) at reflux resulted in partial decomposition of
the starting material to give semicarbazone 5a, benzylideneace-
tone, and unidentified by-products without formation of macrocy-
cle 12a ( H NMR spectroscopy). The starting material was
completely recovered after heating 9a at reflux in EtOH for 3 h in
the presence of AcOH (4.06 equiv.).
TsOH (0.10 equiv.) in MeCN (rt, 24 h) contained starting material
1
(
3 mol%), macrocycle 12a (42%
H NMR estimated yield,
trans/cis = 67:33) and various unidentified compounds.
Thus, under the optimal conditions (Entry 6), macrocycle 12a
was obtained in 75% yield as a 97:3 mixture of trans- and cis-iso-
mers. Analogously, reaction conditions were optimized for the
transformation of 11b–d into the corresponding macrocycles
1
1
2b–d (Table 1). These compounds were prepared in good yields
(
60–92%) and with excellent trans-selectivity (up to 100%). It is
Thus, the experimental data show that the macrocyclization of
11a–e proceeds via nucleophilic attack of the N1 nitrogen atom of
one molecule on the electrophilic carbon of the hydrazone moiety
of the second molecule after its activation by the catalyst. How-
noteworthy, that under the optimal conditions, the stereoselectiv-
ity for formation of macrocycles 12 from the hydrazones of semi-
carbazones 11 was significantly higher than that from the
hydrazones of semicarbazides 10.1
3b
2
ever, the nucleophilicity of the N1 atom with sp -hybridization is
Table 1 shows that the trans-stereoselectivity of the macrocy-
clization of compounds 11a–d increases with an increase in
starting material concentration, reaction time, and catalyst load-
ing. Therefore, we propose that the reaction of 11a–d, initially
proceeds rapidly with low diastereoselectivity to give mixtures
of cis- and trans-12a–d which is then followed by a slow irre-
versible transformation of the cis-isomers into the trans-isomers
via ring opening by a retro-aza-Michael reaction. Calculations
performed at the DFT B3LYP/6-311++G(d,p) level of theory using
the PCM solvation model showed that trans-12a was less stable
not sufficient for the cyclization. We propose that under the exam-
ined reaction conditions, a more nucleophilic sp -hybridized nitro-
gen is generated by the addition of a nucleophile to the C@N
3
double bond, for example, the water from TsOHÁH
2
O. A plausible
O-catalyzed macrocyclization of hydra-
pathway for the TsOHÁH
2
zones 11a–e is shown in Scheme 5.
This pathway involves hydrolytic cleavage of the semicar-
bazone moiety followed by reaction of the free NH -group of the
2
obtained semicarbazide with the protonated hydrazone fragment
of second molecule to give acyclic intermediate A which cyclizes
into the product 12 following the same steps.
than cis-12a in both MeCN and EtOH solutions (
DG = 1.67 and
2
.08 kcal/mol, respectively; 298 K, 1 atm). The predominant for-
In conclusion, a stereoselective five-step synthesis of novel
14-membered bis-semicarbazones based on the acid-catalyzed
cyclization of hydrazones of 4-(3-oxobutyl)semicarbazides or
4-(3-oxobutyl)semicarbazones has been developed. Hydrazones
mation of trans-12a–d from 11a–d can be explained by their sig-
nificantly lower solubility compared with that of the cis-isomers;
therefore, trans-12a–d precipitates from the reaction media

A.A. Fesenko et al. / Tetrahedron Letters 57 (2016) 5784–5787
5787
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Scheme 5. Plausible pathway for the macrocyclization of semicarbazones 11a–e.
1
(
2
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41. These data include detailed experimental procedures, analyt-
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13
ical data, copies of IR, H and C NMR spectra of all the synthesized
compounds, computational data as well as MOL files and InChiKeys
of the most important compounds described in this article.
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6. Generally, amidoalkylation reagents are constructed by using various amides,
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1
(
(
of
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Ligand
1
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