An efficient approach to the synthesis of hydrazinyl pseudo-peptides

Article abstract of DOI:10.1002/hlca.201400061

New hydrazinyl pseudo-peptides have been obtained from Ugi four-component reaction (4CR). The 5-hydrazinyl-5-oxopentanoic acids used as starting materials were prepared by the reaction of hydrazides with anhydrides. Mild reaction conditions, high atom eco

Full text of DOI:10.1002/hlca.201400061

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Helvetica Chimica Acta – Vol. 97 (2014)
An Efficient Approach to the Synthesis of Hydrazinyl Pseudo-Peptides
by Vaezeh Fathia), Sorour Ramezanpoura), Saeed Balalaie*a)b), Frank Romingerc),
and Hamid Reza Bijanzadeha)
a) Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416,
Tehran, Iran (fax: þ 98-21-22853650; e-mail: balalaie@kntu.ac.ir)
b) Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
c) Organisch-Chemisches Institut der Universitꢀt Heidelberg, ImNeuenheimer Feld 270, DE-69120
Heidelberg
Dedicated to Prof. Fereydoun Moattar on the occasion of his 75th birthday
New hydrazinyl pseudo-peptides have been obtained from Ugi four-component reaction (4CR). The
5-hydrazinyl-5-oxopentanoic acids used as starting materials were prepared by the reaction of hydrazides
with anhydrides. Mild reaction conditions, high atom economy, bond-forming efficiency, and easy workup
are advantages of this approach. The products have four amide bonds and high potential for H-bonding.
Introduction. – Recently, pseudo-peptides have been attracting increasing attention
because of their extended biological activities; in particular, they have been used in
drug discovery [1 – 5]. Azapeptides are one of these modified peptides, formed through
the replacement of the Ca-atom of one or more amino acid residues with an N-atom
(Fig. 1). They have wide-ranging biological activities [6].
Fig. 1. General partial structure of azapeptides
To modify peptides, suitable starting materials should be selected. The replacement
of one or more a-amino acid(s) by b-amino acid(s) or other functionalized carboxylic
acids is one of the known approaches to synthesize pharmaceutically active peptides
[7]. Using hydrazinyl carboxylic acids and a-aminoacyl benzotriazoles by means of
microwave irradiation was reported by Katritzky and co-workers for the synthesis of
hydrazinyl peptides [8]. Some pseudo-peptides containing hydrazide cores have been
found to exhibit HIV protease inhibitor activities [9]. In this content, Klein and Hecht
reported the synthesis of some novel pseudo-peptide scaffolds based on bis(thiourea)
hydrazide motif, which have the ability to inhibit b-sheet aggregation [10].
Insertion of the hydrazinyl group in the structure of peptides leads to the hydrazinyl
peptides. The hydrazinyl moiety in the peptide structure induces enhanced H-bonding,
which affects the peptide backbone folding. In the presence of more C¼O and NH
functional groups, this ability, as well as their biological activities can be improved [11 –
ꢁ 2014 Verlag Helvetica Chimica Acta AG, Zꢂrich

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13]. These modified peptides have been found important applications as receptor
binding compounds, enzyme inhibitors, drugs, pro-drugs, and imaging agents [14].
Because of their biological activities, development of novel approaches for the
synthesis of the pseudo-peptides has been the focus of increasing attention.
The Ugi four-component reaction (Ugi-4CR) is an important method for the
synthesis of pseudo-peptides [15]. The single-reactant-replacement (SRR) approach,
which affords products with more functional groups, can be used for the synthesis of
highly functionalized products.
The number of amide bonds and also the presence of lipophilic moieties in the
structure of pseudo-peptides can affect their biological activities. With this in mind, our
effort was directed to the preparation of novel pseudo-peptides via Ugi-4CR by using
suitable carboxylic acid moieties.
In continuation of our work to design novel reactions based on hydrazides [16], we
report herein the synthesis of novel hydrazinyl pseudo-peptides using 5-hydrazinyl-5-
oxopentanoic acids (Scheme).
Scheme. Synthesis of Hydrazinyl Pseudo-Peptides through Ugi-4CR
Results and Discussion. – According to our synthetic plan, the carboxylic acids 3
[17] were initially synthesized through reaction of benzohydrazide and 4-methylben-
zenesulfonyl hydrazide with glutaric anhydride. Previously, we used this approach for
the synthesis of some fentanyl derivatives through reaction of amines with glutaric or
succinic anhydride [18]. The reaction was carried out by mixing glutaric anhydride and
benzohydrazide (or 4-methylbenzenesulfonyl hydrazide) in the presence of MeOH as
solvent. After 30 min of stirring at room temperature, the desired product, 3a or 3b,
were isolated in 96 and 94% yield, respectively.
The reaction of the pentanoic acid 3a, 4-bromobenzaldehyde, 4-chloroaniline, and
tert-butyl isocyanide in MeOH was selected as a model Ugi-4CR. The desired product
5a was formed in 63% yield. The reaction has four-points of diversity. The scope of the
reaction with regard to a substitution pattern in different primary amines, aromatic
aldehydes, isocyanides and also two hydrazinyl-pentanoic acids was investigated. The
results are compiled in the Table.
The structures of compounds 5a – 5l were deduced from their spectroscopic data
and high-resolution mass spectra (HR-ESI-MS). The characteristic peaks in the range
1
of 5.92 – 6.22 ppm in the H-NMR spectra of the products arose from the H-atoms of
the Ar1ꢀCHꢀN moities. For instance, the 1H-NMR spectrum of 5d displayed a singlet
at 6.03 ppm, and the NH H-atoms resonated at 7.44 ppm. The 13C-NMR spectrum
revealed four distinct peaks at 165.3, 168.9, 171.1, and 171.3 ppm for the C¼O groups.

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Table. Synthesis of Novel Hydrazinyl Pseudo-Peptides 5a – 5l through Ugi-4CR of Aromatic Aldehydes 1,
Aromatic Primary Amines 2, 5-Hydrazinyl-5-oxopentanoic Acids 3a or 3b, and Isocyanides 4a)
Product
Ar1
Ar2
R3
R4
Yield [%]b)
5a
5b
5c
5d
5e
5f
5g
5h
5i
4-BrꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-BrꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-ClꢀC6H4
4-BrꢀC6H4
Bz
Ts
Ts
Bz
Ts
Bz
Bz
Ts
Bz
Bz
Ts
Ts
tBu
63
65
66
62
65
58
65
68
60
62
65
63
4-BrꢀC6H4
tBu
5-Brꢀ(furan-2-yl)
4-ClꢀC6H4
tBu
tBu
4-ClꢀC6H4
tBu
4-Me2NꢀC6H4
4-FꢀC6H4
tBu
tBu
4-FꢀC6H4
tBu
4-FꢀC6H4
Cyclohexyl
5j
5k
5l
2-(Prop-2-ynyloxy)ꢀC6H4
2-(Prop-2-ynyloxy)ꢀC6H4
Thiophen-2-yl
tBu
tBu
tBu
a) For the structures of the products, see the Scheme. b) Yields of isolated products.
The structure of 5j was confirmed by single-crystal X-ray diffraction (Fig. 2). Both
H-bond formation and pꢀp stacking play essential roles in the molecular association.
In the solid state, both H-atoms of the hydrazinyl moiety are involved in
intermolecular H-bridges. Whereas N(10)ꢀH of two neighboring molecules mutally
form bridges to the keto O(1)-atoms of the other molecule, building pairs of molecules,
N(9)ꢀH moieties build H-bridges to crystal H2O molecules. Both H-atoms of the
crystal H2O molecules again undergo bridging to the keto atoms O(4) and O(10) of
different surrounding molecule pairs. The crystal H2O molecules thus play a key role in
interconnection of the pseudo-peptides (Fig. 3).
Fig. 2. ORTEP Presentation of the structure of compound 5j

Helvetica Chimica Acta – Vol. 97 (2014)
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Fig. 3. Intramolecular and intermeolecular H-bonding in hydrazinyl pseudo-peptide 5j
In all cases, the products have four amide bonds. In the case of 5j and 5k, an
additional alkyne bond provides opportunity for further cyclization. The presence of
four amide bonds in the structure increases the activity and also rigidity of the products.
The molecular aggregation is usually mediated through low-energy interactions.
The main forces involved in construction and controlling the size and shape of these
supramolecular structures are the electrostatic interactions, Van der Waals bonds, H-
bonds, and p-stacking forces.
As shown in Fig. 4, spherical structures (300 nm in diameter) are produced in the
three-component solvent mixture (1,1,1,3,3,3-hexafluoroisopropanol/MeOH/H2O
1:4 :5), confirming highly ordered self-aggregation of compound 5c. The presence of
aromatic moieties and H-bonds could be responsible for the stabilization and formation
of the spherical structures of molecules.
Fig. 4. SEM Micrographs of compound 5c

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Helvetica Chimica Acta – Vol. 97 (2014)
Conclusions. – In conclusion, we have developed an efficient procedure for the
preparation of some novel hydrazinyl pseudo-peptides. Both high yields and bond-
forming efficiencies, in addition to tolerance of various groups toward the reaction
conditions, are important advantages of this protocol. This method may have
interesting implications on the construction of structurally diverse molecules, which
contain four amide bonds and find applications in combinatorial chemistry, diversity-
oriented synthesis, and drug discovery.
Saeed Balalaie gratefully acknowledges the Alexander von Humboldt Foundation for a research
fellowship.
Experimental Part
General. M.p.: Electrothermal 9100 apparatus; uncorrected. IR Spectra: ABB FT-IR FTLA 2000
spectrometer; as KBr disks. 1H- and 13C-NMR spectra: Bruker DRX-300 Avance spectrometer at 300 and
75 MHz, resp.; in (D6)DMSO; chemical shifts, d, in ppm; and coupling constants (J) in Hz; HR-MS:
Mass-ESI-POS (Apex Qe-FT-ICR instrument) spectrometer; in m/z (relative intensity). Scanning
electron microscopy: Hitachi 4160.
General Procedures for the Synthesis of Acids 3a and 3b [17]. The pentanoic acids 3a and 3b were
prepared as described in [17]. A mixture of benzohydrazide (or 4-methylbenzenesulfonohydrazide
(20 mmol)) and glutaric anhydride (22 mmol) in CHCl3 (100 ml) was stirred at r.t. overnight. The
progress of the reaction was monitored by TLC (hexane/AcOEt 1: 3). Then, the solvent was evaporated,
and the resulting crude product was recrystallized from AcOEt/hexane to give pure products 3a and 3b.
5-(2-Benzoylhydrazinyl)-5-oxopentanoic Acid (3a) [17]. Yield: 240 mg (96%). White solid. M.p.
1
170 – 1728. Rf (33% AcOEt/hexane) 0.45. IR (KBr): 3259, 3034, 2964, 1711, 1613. H-NMR: 1.66 – 1.81
(m, CH2); 2.22 (t, J ¼ 7.5, CH2); 2.29 (t, 7.5, CH2); 7.45 – 7.58 (m, 3 arom. H); 7.85 (d, J ¼ 7.5, 2 arom. H);
9.86 (s, NH); 10.28 (s, NH); 12.08 (br. s, COOH). 13C-NMR: 20.5; 32.4; 32.8; 127.4; 128.5; 131.8; 132.5;
165.5; 171.2; 174.2. HR-ESI-MS: 523.1799 ([2M þ Na]þ, C24H28N4NaO8þ ; calc. 523.1805).
5-{2-[(4-Methylphenyl)sulfonyl]hydrazinyl}-5-oxopentanoic Acid (3b) [17]. Yield: 282 mg (94%).
White solid. M.p. 142 – 1448. Rf (33% AcOEt/hexane) 0.35. IR (KBr): 3388, 3343, 3065, 2947, 1695.
1H-NMR: 1.62 – 1.72 (m, CH2); 2.06 – 2.12 (m, 2 CH2); 2.40 (s, Me); 7.33 (d, J ¼ 8.0, 2 arom. H); 7.76 (d,
J ¼ 8.0, 2 arom. H). 13C-NMR: 21.5; 21.7; 33.4; 33.6; 129.6; 130.5; 136.3; 145.6; 173.2; 176.6. HR-ESI-MS:
623.1452 ([2M þ Na]þ, C24H32N4NaO10S2þ ; calc. 623.1458).
General Procedure for the Synthesis of the Hydraziyl Pseudo-Peptides 5a – 5l. Aldehyde 1 (1 mmol)
and amine 2 (1 mmol) were dissolved in MeOH (5 ml), and the mixture was stirred at r.t. for 30 min.
Pentanoic acid 3a or 3b (1 mmol) was, then, added, and stirring was continued for 15 min, followed by
addition of isocyanide 4 (1 mmol). The mixture was stirred for 24 h. The progress of the reaction was
monitored by TLC. Then, the solvent was evaporated, the resulting mixture was washed with sat.
NaHCO3 (10 ml), and the crude was extracted with AcOEt (2 ꢁ 10 ml), and the org. phase was separated
i
and dried (Na2SO4). The solvent was evaporated, and the residue was washed with Pr2O to give pure
products 5a – 5l (yields 58 – 68%). In the case of 5j, a single crystal was obtained by recrystallizing from
EtOH.
5-(2-Benzoylhydrazinyl)-N-[1-(4-bromophenyl)-2-(tert-butylamino)-2-oxoethyl]-N-(4-chlorophen-
yl)-5-oxopentanamide (5a). Yield: 395 mg (63%). White solid. M.p. 189 – 1918. Rf (33% AcOEt/hexane)
1
t
0.31. IR (KBr): 3316, 3150, 2970, 1692. H-NMR: 1.22 (s, Bu); 1.65 – 1.82 (m, CH2); 1.97 – 2.10 (m, 2
CH2); 6.02 (s, CHN); 6.90 (d, J ¼ 7.2, 4 arom. H); 7.25 – 7.36 (m, 3 arom. H, NH); 7.47 – 7.56 (m, 4 arom.
H); 7.80 – 7.86 (m, 3 arom. H); 9.77 (s, NH); 10.24 (s, 1 NH). 13C-NMR: 22.8; 28.4; 32.4; 33.7; 50.4; 62.9;
120.9; 127.4; 128.4; 130.9; 131.8; 132.1; 132.5; 132.8; 135.2; 138.6; 165.4; 168.8; 171.3; 171.4. HR-ESI-MS:
627.1377 ([M þ H]þ, C30H3379Br35ClN4Oþ4 ; calc. 627.1368), 649.1192 ([M þ Na]þ, C30H3279Br35ClN4NaOþ4 ;
calc. 649.1193), 665.0931 ([M þ K]þ, C30H3279Br35ClN4KO4þ ; calc. 665.0933).

Helvetica Chimica Acta – Vol. 97 (2014)
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N-[1-(4-Bromophenyl)-2-(tert-butylamino)-2-oxoethyl]-N-(4-chlorophenyl)-5-{2-[(4-methylphen-
yl)sulfonyl]hydrazinyl}-5-oxopentanamide (5b). Yield: 440 mg (65%). White solid. M.p. 206 – 2088. Rf
1
t
(33% AcOEt/hexane) 0.31. IR (KBr): 3371, 3288, 2970, 1670. H-NMR: 1.22 (s, Bu); 1.47 – 1.51 (m,
CH2); 1.73 – 1.85 (m, 2 CH2); 2.36 (s, Me); 5.98 (s, CHN); 6.96 (d, J ¼ 8.1, 2 arom. H); 7.25 – 7.36 (m, 7
arom. H, NH); 7.60 (d, J ¼ 8.1, 2 arom. H); 7.78 (br. s, 2 arom. H); 9.67 (s, NH); 9.82 (s, 1 NH). 13C-NMR:
21.0; 22.8; 28.4; 32.1; 33.4; 50.4; 62.8; 120.9; 127.6; 128.5; 129.2; 130.8; 132.1; 132.8; 135.1; 136.1; 138.6;
143.1; 168.8; 170.5; 171.2. HR-ESI-MS: 677.1202 ([M þ H]þ, C30H3579Br35ClN4O5Sþ; calc. 677.1195),
699.1017 ([M þ Na]þ, C30H3479Br35ClN4NaO5Sþ; calc. 699.1020), 715.0756 ([M þ K]þ,
C30H3479Br35ClKN4O5Sþ; calc. 715.0759).
N-[1-(5-Bromofuran-2-yl)-2-(tert-butylamino)-2-oxoethyl]-N-(4-bromophenyl)-5-{2-[(4-methylphen-
yl)sulfonyl]hydrazinyl}-5-oxopentanamide (5c). Yield: 470 mg (66%). Yellow solid. M.p. 1188. Rf (33%
AcOEt/hexane) 0.33. IR (KBr): 3295, 3250, 3083, 2970, 1671. 1H-NMR 1.23 (s, tBu); 1.45 – 1.50 (m, CH2);
1.73 – 1.86 (m, 2 CH2); 2.36 (s, Me); 5.98 (s, CHN); 6.06 (br. s, 1 H (furanyl)); 6.29 (d, J ¼ 1.8, 2 H
(furanyl)); 7.30 (d, J ¼ 7.8, 2 arom. H); 7.36 ꢀ 7.46 (m, 4 arom. H); 7.60 (d, J ¼ 7.8, 2 arom. H); 7.88 (s,
NH); 9.84 (br. s, 2 NH). 13C-NMR: 20.5; 21.0; 28.3; 32.0; 33.1; 50.5; 57.8; 112.4; 113.8; 121.1; 121.3; 127.6;
129.2; 131.5; 136.1; 138.9; 143.1; 151.1; 166.0; 170.4; 171.0. HR-ESI-MS: 711.0491 ([M þ H]þ,
C28H3279Br2N4O6Sþ; calc. 711.0482), 733.0312 ([M þ Na]þ, C28H3279Br2N4NaO6Sþ; calc. 733.0307),
749.0048 ([M þ K]þ, C28H3279Br2KN4O6Sþ; calc. 749.0046).
5-(2-Benzoylhydrazinyl)-N-[2-(tert-butylamino)-1-(4-chlorophenyl)-2-oxoethyl]-N-(4-chlorophen-
yl)-5-oxopentanamide (5d). Yield: 361 mg (62%). White solid. M.p. 185 – 1878. Rf (33% AcOEt/hexane)
1
t
0.32. IR (KBr): 3305, 3064, 2970, 1661. H-NMR: 1.22 (s, Bu); 1.72 – 1.74 (m, CH2); 1.92 – 2.09 (m, 2
CH2); 6.03 (s, CHN); 7.04 (d, J ¼ 8.1, 2 arom. H); 7.21 (d, J ¼ 8.1, 4 arom. H); 7.44 (br. s, NH); 7.48 (d, J ¼
6.6, 2 arom. H); 10.03 (br. s, 2 NH). 13C-NMR: 22.8; 28.4; 32.4; 33.7; 50.4; 62.8; 127.4; 127.9; 128.4; 131.8;
132.1; 132.2; 132.6; 132.8; 134.7; 138.6; 165.3; 168.9; 171.1; 171.3. HR-ESI-MS: 583.1883 ([M þ H]þ,
C30H33Cl2N4O4þ ; calc. 583.1873), 605.1697 ([M þ Na]þ, C30H3235Cl2N4NaOþ4 ; calc. 605.1698), 621.1437
([M þ K]þ, C30H3235Cl2N4KOþ4 ; calc. 621.14382.
N-[2-(tert-Butylamino)-1-(4-chlorophenyl)-2-oxoethyl]-N-(4-chlorophenyl)-5-{2-[(4-methylphen-
yl)sulfonyl]hydrazinyl}-5-oxopentanamide (5e). Yield: 411 mg (65%). White solid. M.p. 202 – 2058. Rf
1
t
(33% AcOEt/hexane) 0.33. IR (KBr): 3288, 3194, 2971, 1666. H-NMR: 1.22 (s, Bu); 1.47 – 1.52 (m,
CH2); 1.78 – 1.97 (m, 2 CH2); 2.36 (s, Me); 6.00 (s, CHN); 7.02 (d, J ¼ 8.1, 2 arom. H); 7.20 (d, J ¼ 8.1, 4
arom. H); 7.31 (d, J ¼ 7.8, 4 arom. H); 7.60 (d, J ¼ 7.8, 2 arom. H); 7.78 (s, NH); 9.90 (br. s, 2 NH).
13C-NMR: 20.6; 21.1; 22.8; 28.4; 32.1; 33.4; 50.3; 62.8; 127.6; 127.9; 128.5; 129.2; 131.8; 132.1; 132.8; 134.7;
136.1; 138.6; 143.1; 168.9; 170.5; 171.2. HR-ESI-MS: 633.1710 ([M þ H]þ, C30H3535Cl2N4O5Sþ; calc.
633.1700).
5-(2-Benzoylhydrazinyl)-N-{2-(tert-butylamino)-1-[4-(dimethylamino)phenyl]-2-oxoethyl}-N-(4-
chlorophenyl)-5-oxopentanamide (5f). Yield: 343 mg (58%). White solid. M.p. 137 – 1398. Rf (33%
EtOAc/hexane) 0.32. IR (KBr): 3303, 2968, 1686. 1H-NMR: 1.22 (s, tBu); 1.71 – 1.73 (m, CH2); 1.97 – 2.09
(m, 2 CH2); 2.77 (s, Me2N); 5.92 (s, CHN); 6.43 (d, J ¼ 8.4, 2 arom. H); 6.81 (d, J ¼ 8.4, 2 arom. H); 7.21
(br. s, NH); 7.44 – 7.55 (m, 7 arom. H); 7.84 (d, J ¼ 7.5, 2 arom. H); 9.75 (s, NH); 10.22 (s, 1 NH).
13C-NMR: 20.7; 28.5; 32.5; 33.7; 50.1; 59.7; 63.2; 111.4; 122.4; 127.4; 128.2; 128.4; 130.7; 131.7; 132.5;
132.9; 139.1; 149.4; 165.4; 169.9; 170.3; 171.3. HR-ESI-MS: 592.2697 ([M þ H]þ, C32H3935ClN5O4þ ; calc.
592.2685), 614.2508 ([M þ Na]þ, C32H3835ClN5NaOþ4 ; calc. 614.2510), 630.2249 ([M þ K]þ,
C32H3835ClKN5Oþ4 ; calc. 630.2249).
5-(2-Benzoylhydrazinyl)-N-[2-(tert-butylamino)-1-(4-fluorophenyl)-2-oxoethyl]-N-(4-chlorophen-
yl)-5-oxopentanamide (5g). Yield: 368 mg (65%). White solid. M.p. 170 – 1728. Rf (33% AcOEt/hexane)
0.31. IR (KBr): 3316, 3085, 2971, 1658. 1H-NMR 1.23 (s, tBu); 1.72 – 1.75 (m, CH2); 1.95 – 2.10 (m, 2 CH2);
6.04 (s, CHN); 6.93 – 6.99 (m, 4 arom. H); 7.04 – 7.08 (m, 2 arom. H); 7.23 (br. s, NH); 7.44 – 7.56 (m, 4
arom. H); 7.67 – 7.77 (m, 1 arom. H); 7.84 (d, J ¼ 7.5, 2 arom. H); 9.76 (s, NH); 10.24 (s, NH). 13C-NMR:
22.8; 28.4; 32.4; 33.7; 50.3; 62.7; 101.3; 114.6; 114.9; 127.4; 128.4; 131.7; 132.0; 132.1; 132.5; 132.9; 138.7;
159.7; 165.4; 169.2; 171.3. HR-ESI-MS: 567.2172 ([M þ H]þ, C30H3335ClFN4O4þ ; calc. 567.2169), 589.1991
([M þ Na]þ, C30H3235ClFN4NaOþ4 ; calc. 589.1994).
N-[2-(tert-Butylamino)-1-(4-fluorophenyl)-2-oxoethyl]-N-(4-chlorophenyl)-5-{2-[(4-methylphenyl)-
sulfonyl]hydrazinyl}-5-oxopentanamide (5h). Yield: 419 mg (68%). White solid. M.p. 170 – 1728.

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1
t
Rf (33% AcOEt/hexane) 0.31. IR (KBr): 3291, 3195, 3081, 2972, 1661. H-NMR 1.21 (s, Bu); 1.48 –
1.50 (m, CH2); 1.77 – 1.84 (m, 2 CH2); 2.35 (s, Me); 5.98 (s, CHN); 6.92 – 7.02 (m, 4 arom. H); 7.20 –
7.39 (m, 5 arom. H, NH); 7.59 (d, J ¼ 7.5, 2 arom. H); 7.75 (br. s, 2 arom. H); 9.85 (br. s, 2 NH).
13C-NMR: 20.6; 21.0; 28.3; 32.0; 33.4; 50.3; 62.7; 114.6; 114.9; 127.6; 128.4; 129.2; 132.0; 132.8; 135.9;
138.6; 143.2; 169.1; 170.6; 171.1. HR-ESI-MS: 617.2013 ([M þ H]þ, C30H3535ClFN4O5Sþ; calc. 617.1995),
639.1820 ([M þ Na]þ, C30H3435ClFN4NaO5Sþ; calc. 639.1820), 655.1562 ([M þ K]þ, C30H3435ClFKN4O5Sþ;
calc. 655.1560).
5-(2-Benzoylhydrazinyl)-N-(4-chlorophenyl)-N-[2-(cyclohexylamino)-1-(4-fluorophenyl)-2-oxoeth-
yl]-5-oxopentanamide (5i). Yield: 355 mg (60%). White solid. M.p. 220 – 2228. Rf (33% AcOEt/hexane)
1
0.33. IR (KBr): 3261, 3070, 2932, 1655. H-NMR: 1.00 – 1.90 (m, 5 CH2 of cyclohexyl, CH2); 1.97 – 2.10
(m, 2 CH2); 3.56 – 3.59 (m, CHN); 6.05 (s, CHN); 6.94 – 7.08 (m, 6 arom. H); 7.23 (br. s, NH); 7.45 – 7.58
(m, 4 arom. H); 7.80 (d, J ¼ 7.5, 2 arom. H); 8.02 (d, J ¼ 7.5, 1 arom. H); 9.76 (br. s, NH); 10.23 (br. s, NH).
13C-NMR: 20.7; 24.4; 24.6; 25.2; 32.1; 32.2; 32.4; 33.6; 47.9; 62.5; 114.6; 114.9; 127.4; 128.4; 131.7; 132.1;
132.2; 132.6; 132.8; 138.6; 159.8; 163.0; 165.4; 168.6; 170.3. HR-ESI-MS: 593.2333 ([M þ H]þ,
C32H3435ClFN4Oþ4 ; calc. 593.2325), 615.2151 ([M þ Na]þ, C32H3435ClFN4NaOþ4 ; calc. 615.2150),
631.1892 ([M þ K]þ, C32H3435ClFKN4Oþ4 ; calc. 631.1890).
5-(2-Benzoylhydrazinyl)-N-{2-(tert-butylamino)-2-oxo-1-[2-(prop-2-yn-1-yloxy)phenyl]ethyl}-N-
(4-chlorophenyl)-5-oxopentanamide (5j). Yield: 373 mg (62%). White solid. M.p. 130 – 1338. Rf (33%
t
AcOEt/hexane) 0.32. IR (KBr): 3288, 3201, 3091, 2969, 1656. 1H-NMR: 1.25 (s, Bu); 1.73 – 1.75 (m,
CH2); 1.93 – 2.10 (m, 2 CH2); 3.68 (s, ꢂ CH); 4.83 (s, OCH2); 6.19 (s, NH); 6.67 (t, J ¼ 7.2, 1 arom. H);
6.81 (d, J ¼ 7.2, 1 arom. H); 6.90 (d, J ¼ 7.8, 1 arom. H); 7.10 (t, J ¼ 7.8, 1 arom. H); 7.15 (br. s, NH); 7.45 –
7.55 (m, 5 arom. H); 7.84 (m, 4 arom. H); 9.90 (br. s, 2 NH). 13C-NMR: 22.8; 28.5; 32.5; 33.7; 50.3; 55.4;
58.6; 78.5; 79.2; 111.4; 120.3; 124.1; 127.4; 128.2; 128.4; 129.1; 129.8; 131.8; 132.5; 138.8; 155.1; 165.4;
169.5; 170.9; 171.3. HR-ESI-MS: 603.2381 ([M þ H]þ, C33H3635ClN4O5þ ; calc. 603.2369), 625.2198 ([M þ
Na]þ, C33H3535ClN4NaOþ5 ; calc. 625.2194).
X-Ray Crystal-Structure Determination. Colorless crystals (plate); dimensions, 0.24ꢁ 0.06ꢁ 0.01 mm;
¯
crystal system, triclinic, space group, P1, Z ¼ 2, a ¼ 9.859(4) ꢃ, b ¼ 10.204(4) ꢃ, c ¼ 18.089(7) ꢃ, a ¼
73.884(8)8, b ¼ 83.878(9)8, g ¼ 71.071(9)8, V ¼ 1653.5(11) ꢃ3, 1 ¼ 1.248 g/cm3, T ¼ 200(2) K, qmax
¼
19.598, radiation, MoKa, l ¼ 0.71073 ꢃ; 0.58 w-scans with CCD area detector, covering the asymmetric
unit in reciprocal space with a mean redundancy of 2.13 and a completeness of 99.9% to a resolution of
1.06 ꢃ; 6193 reflections measured; 2904 unique (R(int) ¼ 0.0878); 1456 observed (I > 2s(I)), intensities
were corrected for Lorentz and polarization effects, an empirical absorption correction was applied using
SADABS [19a] based on the Laue symmetry of the reciprocal space, m ¼ 0.16 mmꢀ1, Tmin ¼ 0.96, Tmax
¼
1.00; structure solved by direct methods and refined against F2 with a full-matrix least-squares algorithm
using the SHELXTL (Version 2008/4) software package[19b], 403 parameters refined, H-atoms were
treated using appropriate riding models, except those at the crystal water O(11), which were refined
restrained, goodness-of-fit, 1.05 for observed reflections, final residual values, R1(F) ¼ 0.076, wR(F2) ¼
0.149 for observed reflections; residual electron density, ꢀ0.27 to 0.32 eꢃꢀ3. CCDC-950020 contains the
supplementary crystallographic data for this article. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data request/cif.
N-{2-(tert-Butylamino)-2-oxo-1-[2-(prop-2-yn-1-yloxy)phenyl]ethyl}-N-(4-chlorophenyl)-5-{2-[(4-
methylphenyl)sulfonyl]hydrazinyl}-5-oxopentanamide (5k). Yield: 424 mg (65%). White solid. M.p.
176 – 1788. Rf (33% AcOEt/hexane) 0.31. IR (KBr): 3320, 3249, 3068, 2968, 1684, 1649. 1H-NMR: 1.24 (s,
tBu); 1.47 – 1.52 (m, CH2); 1.73 – 1.91 (m, 2 CH2); 2.36 (s, Me); 3.64 (s, ꢂCH); 4.81 (s, OCH2); 6.15 (s,
CHN); 6.66 (t, J ¼ 7.5, 1 arom. H); 6.80 (d, J ¼ 6.6, 1 arom. H); 6.88 (d, J ¼ 8.0, 1 arom. H); 7.10 (t, J ¼ 7.8,
1 arom. H); 7.30 – 7.39 (m, 4 arom. H); 7.60 (d, J ¼ 7.8, 4 arom. H); 7.80 (s, NH); 9.64 (s, NH). 9.85 (s, NH).
13C-NMR: 21.1; 22.8; 28.5; 32.1; 33.5; 50.3; 55.4; 58.5; 78.5; 79.1; 111.4; 120.3; 124.0; 127.6; 128.1; 129.2;
129.8; 131.8; 136.0; 138.8; 143.1; 155.1; 169.4; 170.5; 170.8. HR-ESI-MS: 653.2213 ([M þ H]þ,
C33H3835ClN4O6Sþ; calc. 653.2195), 675.2026 ([M þ Na]þ, C33H3735ClN4NaO6Sþ; calc. 675.2020).
N-(4-Bromophenyl)-N-[2-(tert-butylamino)-2-oxo-1-(thiophen-2-yl)ethyl]-5-{2-[(4-methylphenyl)-
sulfonyl]hydrazinyl}-5-oxopentanamide (5l). Yield: 409 mg (63%). Yellow solid. M.p. 83 – 858. Rf (33%
1
t
AcOEt/hexane) 0.33. IR (KBr): 3335, 3239, 2970, 1682. H-NMR: 1.22 (s, Bu); 1.39 – 1.50 (m, CH2);
1.72 – 1.97 (m, 2 CH2); 2.36 (s, Me); 6.22 (s, CHN); 6.78 (d, J ¼ 3.5, 2 H of thienyl); 6.89 – 7.38 (m, 7 arom.

Helvetica Chimica Acta – Vol. 97 (2014)
1637
H, 1 H of thienyl); 7.60 (d, J ¼ 7.8, 1 arom. H); 7.80 (s, NH); 9.70 (br. s, NH); 9.85 (br. s, 1 NH). 13C-NMR:
21.1; 22.8; 28.3; 32.0; 33.4; 50.4; 58.5; 120.9; 123.3; 126.3; 127.5; 127.6; 129.1; 129.2; 131.3; 132.1; 133.1;
136.0; 137.4; 138.8; 143.1; 168.4; 170.5; 170.9. HR-ESI-MS: 649.1161 ([M þ H]þ, C28H3379BrN4O5S2þ ; calc.
649.1149), 671.0973 ([M þ Na]þ, C28H3379BrN4NaO5Sþ2 ; calc. 671.0973), 687.0713 ([M þ K]þ,
C28H3379BrKN4O5Sþ2 ; calc. 687.0713).
Scanning Electron Microscopy. The self-aggregation of compound 5c was studied by dissolving 2 mg
of the sample in 1 ml of the solvent system 1,1,1,3,3,3-hexafluoroisopropanol/MeOH/mili Q H2O 1:4 :5.
The scanning electron micrographs (SEM; Hitachi 4160, Japan) of the assembled constructions were
obtained after 4 h.
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Received February 23, 2014