Ugi reaction of thiouridocarboxylic acids: A synthesis of thiourea-peptoids

Article abstract of DOI:10.1080/10426507.2015.1085048

Benzoylthioureidocarboxylic acids, prepared from benzoyl chlorides, potassium thiocyanate, and α-aminoacids, are used as acid components in the Ugi reaction to produce thiourea-peptoids in moderate to good yields.

Full text of DOI:10.1080/10426507.2015.1085048

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Ugi reaction of thiouridocarboxylic acids: A
synthesis of thiourea-peptoids
Elnaz Ghasemi, Ashraf S. Shahvelayati & Issa Yavari
To cite this article: Elnaz Ghasemi, Ashraf S. Shahvelayati & Issa Yavari (2016): Ugi reaction of
thiouridocarboxylic acids: A synthesis of thiourea-peptoids, Phosphorus, Sulfur, and Silicon
and the Related Elements, DOI: 10.1080/10426507.2015.1085048
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1085048
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Date: 31 March 2016, At: 06:25

PHOSPHORUS, SULFUR, AND SILICON
, VOL. , NO. , –

http://dx.doi.org/./..
Ugi reaction of thiouridocarboxylic acids: A synthesis of thiourea-peptoids
a
b
a
Elnaz Ghasemi , Ashraf S. Shahvelayati , and Issa Yavari
a
b
Department of Chemistry, Islamic Azad University, Science and Research Branch, Ponak, Tehran, Iran; Department of Chemistry, Islamic Azad
University, Shahr-e Ray Branch, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received  June 
Accepted  August 
Benzoylthioureidocarboxylic acids, prepared from benzoyl chlorides, potassium thiocyanate, and α-
aminoacids, are used as acid components in the Ugi reaction to produce thiourea-peptoids in moderate
to good yields.
KEYWORDS
Ugi reaction; peptoid;
peptide mimics;
thioureidocarboxylic acid;
isocyanide; α-amino acid
GRAPHICAL ABSTRACT
Introduction
drug discovery process. Consequently, peptoid libraries have
found application for discovering hits against a wide diversity
of pharmaceutical targets, among which different examples of
Multicomponent reactions (MCRs) are not only an excellent
tool for the creation of chemical diversity, they also represent
a powerful methodology for the synthesis of small peptides and
13–16
antibacterials are found.
As part of our continuing interest
in MCRs,1
7–21
research efforts addressed towards the synthesis
1
their simple analogues. One of the most important MCRs is the
and identification of thiourea-containing peptoids are reported.
The synthesis of thiourea-peptoids can be attractive, since the
thiourea residue is fairly rigid, and may play an important role
in protein secondary structure, and its folding.
Ugi four-component reaction (U-4CR),2 which is of consider-
able interest owing to its exceptional synthetic efficiency and is
widely used in modern combinatorial chemistry. In the U-4CR,
an amine, an aldehyde (or ketone), a carboxylic acid and an iso-
cyanide react simultaneously to afford peptide-like structures in
high diversity. Small peptides are an important group of com-
pounds in medicinal chemistry. Among them, compounds with
–5
Results and discussion
various activities are found.2
–7
The U-4CR between amines 1, ketones 2, isocyanides 3,
and benzoylthiouridocarboxylic acids 4 proceeded slowly in
methanol at room temperature to afford the thioamidodipep-
tides 5a–o with 62–80% yields (Table 1). The carboxylic acid 4
was prepared through a cascade reaction of benzoyl chlorides,
potassium thiocyanate, and α-amino acids in acetonitrile.22
The structure of the compounds 5a–o was characterized by
Unnatural α-amino acids are important substances for
different areas of chemistry,8
–10
and they have a wide biological
activity and hence medicinal applications. The replacement of
natural amino acids in peptides with nonproteinogenic deriva-
tives has become an important task in synthetic organic chem-
istry because their incorporation into biologically relevant pep-
1
13
7
–10
IR, H NMR, and C NMR spectroscopic data. The IR and
tides may influence their properties.
1
H NMR spectra of 5a–o exhibited three characteristic peaks
Peptoids are a developing class of peptide-like compounds
for the NH moieties. The proton decoupled 13C NMR spectra
of 5a–o show four distinct resonances for C = O and C = S
groups. The methylene protons of the ArCH2N groups in 5b–
c, 5f–m, and 5o–r are diastereotopic and exhibit characteristic
AB-spin systems with significant ꢀν values. For example, the
originally invented for drug discovery in the early 1990s.1
1,12
Because of their physicochemical features, ease of adaptation to
combinatorial chemistry approaches, and their stabilities, they
become an important class of peptidomimetics comprised of
N-alkylglycine units that have been successfully developed for
CONTACT Issa Yavari
yavarisa@modares.ac.ir
Department of Chemistry, Islamic Azad University, Science and Research Branch, Ponak, TehranIran.
©
 Taylor & Francis Group, LLC

2
E. GHASEMI ET AL.
Table . Formation of thiourea-peptoids 5a–o.
Entry
Ar
R
R
R
R
Product
Yield (%)

Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Pr
Ph
Bn
Bn
Et
Et
Bn
Bn
Me
Me
Me
Me
Me
Et
Me
Me
Me
(CH)
(CH)
(CH)
Me
Me
Et/Me
cHex
cHex
cHex
cHex
cHex
cHex
cHex
cHex
5a
5b
5c
5d
5e
5f
5g
5h
5i





















i
Me
i
Pr
Me
Me
Me
Me
-O NC H

 


p-Tol
Ph
-MeOC H CH



t
Bn
Bu
Bu
Bu
Bu
Bu
Bu
i
t












Ph
Ph
Ph
Ph
Ph
Ph
Pr
Bn
Et
Bn
Bn
Et
5j
t
Me
H
5k
t
5l
i
t
Pr
5m
5n
5o
t
Me
H
t
Bn
Bu
1
H NMR spectrum of 5b in CDCl3 showed two doublets (δ = recorded as KBr pellets with a Shimadzu IR-460 spectrometer.
1
13
5
.65, 11.06 ppm), and a singlet (δ = 8.92 ppm) for NH groups.
H and C NMR spectra were recorded with a Bruker DRX-300
The methyl protons exhibited a doublet (δ = 1.36 ppm) and two Avance instrument using CDCl3 as the deuterated solvent con-
singlets (δ = 1.50 and 1.53 ppm). The methylene protons of 5b taining TMS as internal standard, at 300 and 75 MHz, respec-
2
exhibited an ABq (δ = 4.94 ppm, ꢀν = 127 Hz, J 18.2 Hz). The tively; δ in ppm, J in Hz. Elemental analyses (C, H, N) were
1
13
H-decoupled C NMR spectrum of 5b showed 24 signals in obtained with a Heraeus CHN-O-Rapid analyzer.
agreement with the proposed structure. Partial assignments of
aromatic and cyclohexyl resonances are given in the Experimen-
tal section. The methylene protons of the Et-N and ArCH2-N
General procedure for the preparation of compounds 5a–o
groups in 5b–5o are also diastereotopic and exhibit two distinct The isocyanide 4 (1 mmol) was added to a solution of amine 2
multiple peaks. Similarly, the methyl groups of the oxo moieties (1.1 mmol), ketone 3 (1 mmol), and acid 1 (1 mmol) in MeOH
in 5e, 5g–i, 5m, and 5n are diastereotopic and exhibit two dis- (10 mL) at room temperature, and the solution was stirred for
tinct signals in their NMR spectra.
12 h. The solvent was removed under reduced pressure, and the
These reactions follow the classical U-4CR mechanism, residue was dissolved in EtOAc (8 mL), washed with aqueous
described in the literature.2
,3
NaHCO3 (5 mL) and brine (5 mL), dried (Na2SO4), and the sol-
In summary, we have found that a variety of ketones partici- vent was removed under reduced pressure. The crude product
pate in stepwise one-pot Ugi MCRs to give thiourea-peptoids in was purified by crystallization from EtOH.
good yields. These products possess a number of different func- N-(1-(Phenyl(1-(cyclohexylamino)-2-methyl-1-
tional groups that can be utilized in various reactions. The intro- oxopropan-2-yl)amino)-1-oxopropan-2-ylcarbamothioyl)
duction of a thiourea group in the peptoids 5 may increase the benzamide (5a)
biological and antimicrobial properties of these compounds.
Pale yellow powder; m.p.: 160–163°C; yield: 0.33 g (67%); IR:
ν = 3450, 3310, 3223, 1682, 1592, 1502, 1404, 1228, 1148; EI-MS:
+
m/z = 494 (M , 2), 259 (12), 235 (51), 169 (46), 105 (100), 83
1
(
26), 77 (43), 43 (45); H NMR: 1.15–1.99 (10 H, m, 5 CH2), 1.36
Experimental
3
(
3 H, d, J 6.9 Hz, Me), 1.38 (6 H, s, 2 Me), 3.73–3.82 (1 H, m,
3
3
CH), 4.58 (1 H, quintet, J 6.9 Hz, CH), 6.03 (1 H, d, J 7.9 Hz,
Chemicals and apparatus
NH), 7.33–7.84 (10 H, m, CH-Ar), 8.90 (1 H, s, NH), 10.95 (1
3
13
Chemicals were obtained from Merck and were used without H, d, J 6.9 Hz, NH); C NMR (CDCl3): 17.8 (Me), 25.4 (Me),
further purification. Benzoylthioureidocarboxylic acids have 25.5 (Me), 25.6 (CH2), 26.0 (CH2), 26.1 (CH2), 33.3 (2 CH2),
been synthesized from reaction of benzoyl chlorides, KSCN 49.2 (CH), 54.0 (CH), 63.9 (C), 119.3 (2 CH), 120.3 (C), 127.8
and amino acids.2 Melting points (m.p.) were obtained on (2 CH), 129.5 (2 CH), 130.6 (2 CH), 131.0 (C), 132.2 (CH), 133.8
2
−1
an Electrothermal-9100 apparatus. IR Spectra (ν/cm ) were (C), 166.8 (C = O), 171.4 (C = O), 173.8 (C = O), 179.4 (C =

PHOSPHORUS, SULFUR, AND SILICON
3
S). Anal. Calcd. for C27H34N4O3S (494.65): C, 65.56; H, 6.93; N, N-(1-((1-(Cyclohexylamino)-2-methyl-1-oxopropan-2-yl)
1
1.33%. Found: C, 66.01; H, 6.98; N, 11.37%.
(ethyl)amino)-3-methyl-1-oxobutan-2-ylcarbamothioyl)
benzamide (5e)
N-(1-(Benzyl(1-(cyclohexylamino)-2-methyl-1-
oxopropan-2-yl)amino)-1-oxopropan-2-ylcarbamothioyl)
benzamide (5b)
Cream powder; m.p: 146–148°C; yield: 0.31 g (65%); IR: ν
= 3402, 3299, 3218, 1721, 1686, 1501, 1376, 1210, 1180; EI-MS:
+
Pale yellow powder; m.p.: 180–182°C; yield: 0.38 g (75%); IR: m/z = 474 (M , 3), 263 (53), 211 (8), 169 (43), 105 (100), 83
1
ν = 3417, 3331, 3236, 1731, 1656, 1507, 1361, 1204, 1138; EI-MS: (28), 77 (34), 43 (54), 29 (17). H NMR: δ 0.91–1.93 (10 H, m, 5
+
3
3
m/z = 508 (M , 1), 273 (10), 235 (44), 169 (41), 105 (100), 91 CH2), 1.11 (3 H, d, J 3.9 Hz, Me), 1.13 (3 H, d, J 3.9 Hz, Me),
1
3
(
75), 83 (34), 77 (37), 43 (49). H NMR: δ 0.91–1.90 (10 H, m, 1.46 (3 H, t, J 7.1 Hz, Me), 1.53 (3 H, s, Me), 1.54 (3 H, s, Me),
3
5
CH2), 1.36 (3 H, d, J 6.7 Hz, Me), 1.50 (3 H, s, Me), 1.53 (3 2.25–2.31 (1 H, m, CH), 3.55–3.77 (2 H, m, CH2), 3.78–3.86 (1
2
3
3
3
H, s, Me), 3.71–3.80 (1 H, m, CH), 4.94 (2 H, ABq, J 18.2 Hz, H, m, CH), 5.23 (1 H, dd, J 8.0, J 5.4 Hz, CH), 5.63 (1 H, d, J
ꢀ
3
3
3
3
ν 127.0, CH2), 5.12 (1 H, quintet, J 6.7 Hz, CH), 5.65 (1 H, d, 6.3 Hz, NH), 7.53 (2 H, t, J 7.5 Hz, 2 CH), 7.64 (1 H, t, J 7.5 Hz,
3
J 8.0 Hz, NH), 7.30–7.84 (10 H, m, CH-Ar), 8.92 (1 H, s, NH), CH), 7.64 (2 H, d, J 7.5 Hz, 2 CH), 8.98 (1 H, s, NH), 11.10 (1 H,
1.06 (1 H, d, J 6.7 Hz, NH). C NMR: δ 18.4 (Me), 24.3 (CH2), d, J 5.4 Hz, NH). C NMR: δ 17.7 (Me), 17.9 (Me), 20.6 (Me),
5.3 (Me), 25.4 (Me), 26.0 (CH2), 26.1 (CH2), 33.3 (CH2), 33.4 24.9 (CH2), 25.3 (Me), 25.4 (Me), 26.1 (2 CH2), 32.1 (CH), 33.1
3
13
3
13
1
2
(
CH2), 48.3 (CH), 48.9 (CH2), 53.4 (CH), 63.7 (C), 126.9 (2 CH), (CH2), 33.3 (CH2), 39.6 (CH2), 48.8 (CH), 62.0 (CH), 63.3 (C),
1
27.8 (2 CH), 129.3 (2 CH), 129.5 (2 CH), 131.1 (C),132.2 (CH), 127.8 (2 CH), 129.5 (2 CH), 132.1 (CH), 133.9 (C), 166.8 (C =
1
33.9 (CH), 138.8 (C), 166.8 (C = O), 173.0 (C = O), 173.9 (C O), 170.8 (C = O), 173.9 (C = O), 180.4 (C = S). Anal. Calcd
=
O), 179.2 (C = S). Anal. Calcd for C28H36N4O3S (508.68): C, for C25H38N4O3S (474.66): C, 63.26; H, 8.07; N, 11.80%. Found:
6
6.11; H, 7.13; N, 11.01%. Found: C, 66.43; H, 7.15; N, 11.05%. C, 63.48; H, 8.15; N, 11.86%.
N-(1-(Benzyl(1-(cyclohexylamino)-2-methyl-1-oxopro-
pan-2-yl)amino)-3-methyl-1-oxobutan-2-yl-carbamothioyl)
benzamide (5c)
N-(1-(Benzyl(3-(cyclohexylcarbamoyl)pentan-3-yl)
amino)-1-oxopropan-2-ylcarbamothioyl)benzamide (5f)
Cream powder; m.p.: 170–172°C; yield: 0.33 g (62%); IR: ν
Cream powder; m.p.: 172–174°C; yield: 0.39 g (73%); IR: ν = 3413, 3318, 3209, 1736, 1653, 1549, 1381, 1226, 1119; EI-MS:
+
=
3426, 3290, 3208, 1732, 1666, 1511, 1421, 1202, 1160; EI-MS: m/z = 536 (M , 0.8), 301 (13), 235 (47), 197 (41), 105 (100), 91
+
1
m/z = 536 (M , 2), 273 (9), 263 (39), 169 (43), 105 (100), 91 (77), (68), 83 (29), 77 (33), 29 (17). H NMR: δ 0.79–1.99 (10 H, m, 5
1
3
3
3
8
3 (31), 77 (36), 43 (59). H NMR: δ 0.80 (3 H, d, J 6.8 Hz, Me), CH2), 0.87 (3 H, t, J 7.5 Hz, Me), 0.92 (3 H, t, J 7.5 Hz, Me), 1.62
3
3
1
.02 (3 H, d, J 6.8 Hz, Me), 0.90–1.91 (10 H, m, 5 CH2), 1.48 (3 H, d, J 7.0 Hz, Me), 2.04–2.15 (2 H, m, CH2), 2.33–2.39 (2
2
(
3 H, s, Me), 1.54 (3 H, s, Me), 2.00–2.11 (1 H, m, CH), 3.70– H, m, CH2), 3.77–3.84 (1 H, m, CH), 4.96 (2 H, ABq, J 18.2 Hz,
2
3
3
5
.72 (1 H, m, CH), 4.93 (2 H, ABq, J 18.0 Hz, ꢀν 109.1, CH2), ꢀν 157.5, CH2), 5.01–5.06 (1 H, m, CH), 5.61 (1 H, d, J 7.6 Hz,
3
.14–5.18 (1 H, m, CH), 5.62 (1 H, d, J 7.8 Hz, NH), 7.30–7.87 NH), 7.29–7.87 (10 H, m, CH-Ar), 8.93 (1 H, s, NH), 10.97 (1 H,
3
3
13
(
10 H, m, CH-Ar), 8.96 (1 H, s, NH), 11.09 (1 H, d, J 7.9 Hz, d, J 7.9 Hz, NH). C NMR: δ 8.7 (Me), 9.0 (Me), 17.5 (Me), 18.0
13
NH). C NMR: δ 17.4 (Me), 20.4 (Me), 24.2 (CH2), 25.3 (Me), (CH2), 18.5 (CH2), 25.4 (CH2), 26.1 (2 CH2), 33.4 (CH2), 33.6
5.4 (Me), 25.6 (CH2), 26.1 (CH2), 31.8 (CH), 33.1 (CH2), 33.3 (CH2), 49.0 (CH2), 53.6 (CH), 55.4 (CH), 69.6 (C), 127.9(2 CH),
2
(
1
CH2), 48.3 (CH), 49.0 (CH2), 62.0 (CH), 63.7 (C), 127.3 (2 CH), 128.1 (2 CH), 129.1 (2 CH), 129.4 (2 CH), 131.9 (CH), 132.2 (C),
27.8 (2 CH), 129.2 (2 CH), 129.5 (2 CH), 133.7 (CH), 133.9 (C), 133.8 (CH), 134.0 (C), 167.0 (C = O), 170.9 (C = O), 172.7 (C
1
39.1 (CH), 144.0 (C), 166.8 (C = O), 172.1 (C = O), 174.0 (C = O), 180.1 (C = S). Anal. Calcd for C30H40N4O3S (536.73): C,
=
O), 180.4 (C = S). Anal. Calcd for C30H40N4O3S (536.73): C, 67.13; H, 7.51; N, 10.44%. Found: C, 67.50; H, 7.56; N, 10.49%.
67.13; H, 7.51; N, 10.44%. Found: C, 67.49; H, 7.55; N, 10.49%. N-(1-(Benzyl(1-(cyclohexylamino)-2-methyl-1-oxopro-
N-(1-((1-(Cyclohexylamino)-2-methyl-1-oxopropan-
-yl)(ethyl)amino)-1-oxopropan-2-ylcarbamothioyl)
benzamide (5d)
pan-2-yl)amino)-1-oxopropan-2-ylcarbamothioyl)-4-
nitrobenzamide (5g).
2
Cream powder; m.p.: 171–175°C; yield: 0.35 g (64%); IR: ν
Cream powder; m.p.: 152–153°C; yield: 0.31 g (70%); IR: ν = 3420, 3342, 3243, 1732, 1676, 1562, 1349, 1210, 1153; EI-MS:
+
=
3414, 3321, 3249, 1679, 1588, 1511, 1452, 1242, 1093; EI-MS: m/z = 553 (M , 1.5), 280 (52), 273 (10), 169 (43), 150 (100), 122
+
1
m/z = 446 (M , 2), 235 (47), 211 (12), 169 (39), 105 (100), 83 (24), 91 (73), 83 (31). H NMR: δ 0.89–1.95 (10 H, m, 5 CH2),
1
3
(
1
42), 77 (32), 29 (27). H NMR: δ 0.91–1.91 (10 H, m, 5 CH2), 1.37 (3 H, d, J 6.7 Hz, Me), 1.49 (3 H, s, Me), 1.51 (3 H, s, Me),
3
3
2
.10 (3 H, t, J 10.5 Hz, Me), 1.53 (3 H, d, J 9.6 Hz, Me), 1.56 (6 3.69–3.79 (1 H, m, CH), 4.87 (2 H, ABq, J 18.2 Hz, ꢀν 95.5,
3
3
H, s, 2 Me), 3.46–3.55 (1 H, m, CH2), 3.72–3.76 (1 H, m, CH2), CH2), 5.12 (1 H, quintet, J 6.7 Hz, CH), 5.61 (1 H, d, J 8.0 Hz,
3
3
3
.75–3.83 (1 H, m, CH), 5.24–5.27 (1 H, m, CH), 5.63 (1 H, d, NH), 7.29 (1 H, t, J 7.4 Hz, CH), 7.40 (2 H, t, J 7.4 Hz, 2 CH),
3
3
3
3
3
J 7.7 Hz, NH), 7.52 (2 H, t, J 7.3 Hz, 2 CH), 7.63 (1 H, t, J 7.51 (2 H, d, J 7.4 Hz, 2 CH), 8.04 (2 H, t, J 8.7 Hz, 2 CH), 8.35
3
3
7
1
2
(
1
.3 Hz, 2 CH), 7.84 (2 H, d, J 7.3 Hz, 2 CH), 8.98 (1 H, s, NH), (2 H, d, J 8.7 Hz, 2 CH), 9.28 (1 H, br s, NH), 10.96 (1 H, d,
13
3
13
1.13 (1 H, br s, NH). C NMR (CDCl3): δ 17.5 (Me), 19.0 (Me),
J 6.7 Hz, NH). C NMR: δ 18.3 (Me), 24.2 (CH2), 25.3 (Me),
4.9 (CH2), 25.2 (Me), 25.3 (Me), 26.1 (2 CH2), 33.2 (CH2), 33.3 26.0 (Me), 29.7 (CH2), 31.3 (CH2), 33.3 (CH2), 33.4 (CH2), 48.2
CH2), 39.2 (CH2), 47.4 (CH), 61.7 (CH), 62.9 (C), 128.0 (2 CH), (CH), 48.9 (CH2), 53.5 (CH), 63.7 (C), 124.6 (2 CH), 126.9 (2
29.2 (2 CH), 132.7 (CH), 133.4 (C), 167.9 (C = O), 172.8 (C = CH), 128.0 (2 CH), 129.3 (2 CH), 129.4 (CH), 137.8 (C), 138.5
O), 174.0 (C = O), 179.2 (C = S). Anal. Calcd for C23H34N4O3S (C), 151.0 (C), 165.0 (C = O), 172.8 (C = O), 173.8 (C = O),
446.61): C, 61.85; H, 7.67; N, 12.55%. Found: C, 61.57; H, 7.63; 178.7 (C = S). Anal. Calcd for C28H35N4O3S (553.67): C, 60.74;
N, 12.63%. H, 6.37; N, 12.65%. Found: C, 60.86; H, 6.41; N, 12.71%.
(

4
E. GHASEMI ET AL.
N-(1-((1-(Cyclohexylamino)-2-methyl-1-oxopropan-2-yl)(4-
White powder; m.p.: 188–190°C; yield: 0.41 g (80%); IR: ν
methoxybenzyl)am-ino)-1-oxopropan-2-yl-carbamothioyl)- = 3441, 3309, 3198, 1669, 1581, 1509, 1443, 1208, 1112; EI-MS:
+
4
-methylbenzamide (5h).
m/z = 508 (M , 1.3), 273 (11), 235 (47), 169 (31), 105 (100), 91
1
Pale yellow powder; m.p.: 160–163°C; yield: 0.40 g (72%); IR: (74), 77 (32), 58 (26). H NMR: δ 1.55–2.60 (8 H, m, 4 CH2), 1.34
3
2
ν = 3411, 3352, 3235, 1668, 1580, 1512, 1455, 1248, 1168; EI-MS: (9 H, s, CMe3), 1.36 (3 H, d, J 6.6 Hz, Me), 4.91 (2 H, ABq, J
+
m/z = 552 (M , 1.3), 303 (21), 249 (48), 169 (40), 121 (78), 119 18.1 Hz, ꢀν 135.0, CH2), 5.05–5.10 (1 H, m, CH), 6.50 (1 H, br s,
1
(
100), 91 (23), 83 (36), 43 (24). H NMR: δ 1.01–1.97 (10 H, m, NH), 7.31–7.85 (10 H, m, CH-Ar), 8.93 (1 H, s, NH), 11.10 (1 H,
3
3
13
5
CH2), 1.36 (3 H, d, J 6.8 Hz, Me), 1.48 (3 H, s, Me), 1.52 (3 d, J 6.6 Hz, NH). C NMR: δ 18.4 (Me), 23.9 (CH2), 24.0 (CH2),
H, s, Me), 2.44 (3 H, s, Me), 3.69–3.76 (1 H, m, CH), 3.80 (3 H, 29.0 (CMe3), 36.5 (CH2), 36.6 (CH2), 50.9 (C), 51.3 (CH2), 53.7
2
s, OMe), 4.85 (2 H, ABq, J 18.0 Hz, ꢀν 113.0, CH2), 5.16 (1 H, (CH), 75.1 (C), 126.5 (2 CH), 127.8 (2 CH), 127.9 (CH), 129.4
3
3
quintet, J 6.8 Hz, CH), 5.64 (1 H, d, J 8.0 Hz, NH), 6.93 (2 H, (2 CH), 129.5 (2 CH), 132.2 (C),133.9 (CH), 138.7 (C), 166.8 (C
3
3
d, J 8.6 Hz, 2 CH), 7.31 (2 H, d, J 8.1 Hz, 2 CH), 7.43 (2 H, = O), 172.9 (C = O), 174.7 (C = O), 179.2 (C = S). Anal. Calcd
3
3
d, J 8.6 Hz, 2 CH), 7.73 (2 H, d, J 8.1 Hz, 2 CH), 8.93 (1 H, s, for C28H36N4O3S (508.68): C, 66.11; H, 7.13; N, 11.01%. Found:
3
13
NH), 11.10 (1 H, d, J 6.8 Hz, NH). C NMR: δ 18.4 (Me), 22.0 C, 66.53; H, 7.16; N, 11.09%.
Me), 24.4 (CH2), 25.3 (Me), 25,4 (Me), 26.1 (CH2), 31.3 (CH2), N-(1-(Benzyl(1-(tert-butylcarbamoyl)cyclohexyl)amino)-1-
(
3
3.2 (CH2), 33.4 (CH2), 47.7 (CH), 48.9 (CH2), 53.4 (CH), 55.7 oxopropan-2-ylcarbamothioyl)benzamide (5l)
(
OMe), 63.6 (C), 114.7 (2 CH), 127.9 (2 CH), 128.1 (2 CH), 129.3
Pale yellow powder; m.p: 177–179°C; yield: 0.41 g (78%); IR:
(
C), 130.2 (2 CH), 130.7 (C), 144.9 (C), 159.3 (C), 166.6 (C = ν = 3395, 3303, 3225, 1658, 1586, 1519, 1450, 1132; EI-MS: m/z
+
O), 172.9 (C = O), 174.9 (C = O), 179.3 (C = S). Anal. Calcd = 522 (M , 1.8), 287 (9), 235 (45), 183 (28), 105 (100), 91 (71),
1
for C30H40N4O3S (552.73): C, 65.19; H, 7.29; N, 10.14%. Found: 77 (34), 58 (22). H NMR: δ 1.19–2.48 (10 H, m, 5 CH2), 1.35
3
2
C, 65.06; H, 7.27; N, 10.21%.
(9 H, s, CMe3), 1.42 (3 H, d, J 6.7 Hz, Me), 4.84 (2 H, ABq, J
3
N-(1-(Benzyl(1-(tert-butylamino)-2-methyl-1-oxopro-
pan-2-yl)amino)-1-oxopropan-2-yl-carbamothioyl)
benzamide (5i)
18.1 Hz, ꢀν 80.1, CH2), 5.22 (1 H, quintet, J 6.7 Hz, CH), 6.23
3
(1 H, s, NH), 7.27–7.40 (5 H, m, CH-Ar), 7.52 (2 H, t, J 8.1 Hz,
3
3
2 CH), 7.63 (1 H, t, J 8.1 Hz, CH), 7.85 (2 H, d, J 8.1 Hz, 2 CH),
3
13
Pale yellow powder; m.p.: 184–85°C; yield: 0.37 g (77%); IR: ν 8.94 (1 H, s, NH), 11.18 (1 H, d, J 6.7 Hz, NH). C NMR: δ 18.6
=
3423, 3295, 3210, 1679, 1569, 1515, 1350, 1220, 1080; EI-MS: (Me), 23.2 (CH2), 23.4 (CH2), 25.8 (CH2), 29.0 (CMe3), 33.1
+
m/z = 482 (M , 1.8), 247 (15), 235 (42), 143 (38), 105 (100), 91 (CH2), 33.7 (CH2), 48.3 (C), 51.4 (CH2), 54.2 (CH), 67.9 (C),
1
(
66), 77 (38), 58 (26). H NMR: δ 1.36 (9 H, s, CMe3), 1.40 (3 126.8 (2 CH), 127.8 (2 CH), 127.9 (CH), 129.3 (2 CH), 129.5 (2
3
H, d, J 6.8 Hz, Me), 1.46 (3 H, s, Me), 1.49 (3 H, s, Me), 4.88 CH), 132.2 (C),133.9 (CH), 138.7 (C), 166.7 (C = O), 172.1 (C =
2
3
(
2 H, ABq, J 17.9 Hz, ꢀν 101.8, CH2), 5.16 (1 H, quintet, J O), 174.1 (C = O), 179.0 (C = S). Anal. Calcd for C29H38N4O3S
3
6
.8 Hz, CH), 5.58 (1 H, s, NH), 7.31 (1 H, t, J 7.2 Hz, CH), 7.41 (522.70): C, 66.64; H, 7.33; N, 10.72%. Found: C, 66.85; H, 7.39;
3
3
(
2 H, t, J 7.2 Hz, 2 CH), 7.49 (2 H, d, J 7.2 Hz, 2 CH), 7.52 (2 N, 10.80%.
3
3
H, t, J 7.5 Hz, 2 CH), 7.63 (1 H, t, J 7.5 Hz, CH), 7.84 (2 H, N-(1-(Benzyl(1-(tert-butylamino)-2-methyl-1-oxopro-
3
3
t, J 7.5 Hz, 2 CH), 8.94 (1 H, s, NH), 11.11 (1 H, d, J 6.8 Hz, pan-2-yl)amino)-3-methyl-1-oxobutan-2-ylcarbamothioyl)
13
NH). C NMR: δ 18.4 (Me), 24.3 (Me), 25.3 (Me), 28.9 (CMe3), benzamide (5m)
4
8.3 (CH2), 51.4 (C), 53.4 (CH), 64.1 (C), 126.9 (2 CH), 127.8 (2
White powder; m.p.: 179–181°C; yield: 0.42 g (82%); IR: ν
CH), 127.9 (CH), 129.3 (2 CH), 129.5 (2 CH), 132.2 (C), 133.9 = 3440, 3302, 3261, 1683, 1592, 1560, 1369, 1205, 1170; EI-MS:
+
(
1
CH), 138.7 (C), 166.7 (C = O), 172.9 (C = O), 173.9 (C = O), m/z = 510 (M , 0.9), 263 (38), 235 (40), 143 (47), 105 (100),
1
3
79.2 (C = S). Anal. Calcd for C26H34N4O3S (482.64): C, 64.70; 91 (53), 77 (28), 58 (32), 43 (49). H NMR: δ 0.84 (3 H, d, J
3
H, 7.10; N, 11.61%. Found: C, 64.85; H, 7.14; N, 11.68%.
6.8 Hz, Me), 1.04 (3 H, d, J 6.8 Hz, Me), 1.35 (9 H, s, CMe3),
N-(1-(Benzyl(1-(tert-butylcarbamoyl)cyclopentyl)amino)-3- 1.44 (3 H, s, Me), 1.49 (3 H, s, Me), 2.10–2.15 (1 H, m, CH), 4.89
2
3
methyl-1-oxobutan-2-ylcarbamothioyl)benzamide (5j)
(2 H, ABq, J 17.9 Hz, ꢀν 82.0, CH2), 5.19 (1 H, dd, J 8.0 Hz,
3
Pale yellow powder; m.p.: 180–185°C; yield: 0.35 g (65%); IR:
J 4.0 Hz, CH), 5.57 (1 H, s, NH), 7.31–7.87 (10 H, m, CH-Ar),
3
13
ν = 3431, 3292, 3206, 1729, 1681, 1520, 1413, 1209, 1087; EI-MS: 8.99 (1 H, s, NH), 11.12 (1 H, d, J 4.0 Hz, NH). C NMR: δ 17.2
+
1
m/z = 536 (M , 1.2), 263 (41), 235 (45), 169 (33), 105 (100), 91 (Me), 20.4 (Me), 23.9 (Me), 25.6 (Me), 28.9 (CMe3), 31.3 (CH),
3
(
72), 58 (23). H NMR: δ 0.79 (3 H, d, J 6.8 Hz, Me), 1.02 (3 H, 48.3 (C), 51.3 (CH2), 62.0 (CH), 64.0 (C), 127.3 (2 CH), 127.9 (2
3
d, J 6.8 Hz, Me), 1.33 (9 H, s, CMe3), 1.68–2.10 (8 H, m, 4 CH2), CH), 129.2 (2 CH), 129.5 (2 CH), 130.8 (CH), 132.2 (C), 133.9
2
2
.55–2.59 (1 H, m, CH), 4.94 (2 H, ABq, J 18.0 Hz, ꢀν 135.5, (CH), 139.0 (C), 166.9 (C = O), 172.1 (C = O), 174.1 (C = O),
3
3
CH2), 5.07 (1 H, dd, J 8.1 Hz, J 4.6 Hz, CH), 6.39 (1 H, s, NH), 180.5 (C = S). Anal. Calcd for C28H38N4O3S (510.69): C, 65.85;
7
.32–7.87 (10 H, m, CH-Ar), 8.96 (1 H, s, NH), 11.12 (1 H, d, H, 7.50; N, 10.97%. Found: C, 65.98; H, 7.53; N, 11.06%.
3
J 4.6 Hz, NH). 13C NMR: δ 17.3 (Me), 20.4 (Me), 24.0 (CH2), N-(1-((1-(tert-Butylamino)-2-methyl-1-oxopropan-
2
5
4.3 (CH2), 28.9 (CMe3), 29.9 (CH), 36.3 (CH2), 37.0 (CH2), 2-yl)(ethyl)amino)-1-oxopropan-2-ylcarbamothioyl)
0.7 (C), 51.3 (CH2), 62.2 (CH), 75.0 (C), 127.0 (2 CH), 127.8 (2 benzamide (5n)
CH), 128.0 (CH), 129.3 (2 CH), 129.5 (2 CH), 132.1 (C), 133.9
White powder; m.p.: 132–135°C; yield: 0.28 g (68%); IR: ν
(
1
CH), 138.9 (C), 166.9 (C = O), 173.1 (C = O), 173.7 (C = O), = 3415, 3311, 3215, 1680, 1593, 1510, 1421, 1231, 1087; EI-MS:
+
80.5 (C = S). Anal. Calcd for C30H40N4O3S (536.73): C, 67.13; m/z = 420 (M , 2.2), 235 (69), 185 (21), 143 (52), 105 (100), 77
1
H, 7.51; N, 10.44%. Found: C, 67.52; H, 7.56; N, 10.51%.
(35), 58 (26), 29 (17). H NMR: δ 1.32 (9 H, s, CMe3), 1.41 (3
3
N-(1-(Benzyl(1-(tert-butylcarbamoyl)cyclopentyl)amino)-1- H, d, J 7.0 Hz, Me), 1.49 (3 H, s, Me), 1.54 (3 H, s, Me), 1.56 (3
3
oxopropan-2-ylcarbamothioyl)benzamide (5k)
H, d, J 6.8 Hz, Me), 3.48–3.52 (1 H, m, CH2), 3.71–3.75 (1 H,

PHOSPHORUS, SULFUR, AND SILICON
5
3
m, CH2), 5.25 (1 H, quintet, J 6.8 Hz, CH), 5.53 (1 H, s, NH),
2. Ugi, I. Angew. Chem., Int. Ed. 1982. 21, 810-819.
3
3
3. Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
4. Zhu, J. Eur. J. Org. Chem. 2003, 1133-1144.
7
.52 (2 H, t, J 7.4 Hz, 2 CH), 7.63 (1 H, t, J 7.4 Hz, CH), 7.84
3
3
(
2 H, d, J 7.4 Hz, 2 CH), 8.95 (1 H, s, NH), 11.14 (1 H, d, J
.8 Hz, NH). 13C NMR: δ 17.5 (Me), 18.6 (Me), 24.9 (Me), 25.0
Me), 28.9 (CMe3), 39.3 (CH2), 51.2 (C), 53.2 (CH), 63.6 (C),
5
6
. Dömling, A. Chem. Rev. 2006, 106, 17-89.
6
. Kalinski, C.; Lemoine, H.; Schmidt, J.; Burdack, C.; Kolb, J.; Umkehrer,
(
1
M.; Ross, G. Synthesis 2008, 4007-4011.
27.8 (2 CH), 129.5 (2 CH), 132.2 (CH), 133.9 (C), 166.7 (C =
7. Valente, C.; Guedes, R. C.; Moreira, R.; Iley, J.; Gutc, I.; Rosenthal, P. J.
Bioorg. Med. Chem. Lett. 2006, 16, 4115-4129.
O), 171.8 (C = O), 173.9 (C = O), 179.3 (C = S). Anal. Calcd
for C21H32N4O3S (420.57): C, 59.97; H, 7.67; N, 13.32%. Found:
C, 60.23; H, 7.70; N, 13.40%.
8
9
. Hanessian, S.; Ersmark, K.; Wang, X.; Del Valle, J. R.; Blomberg, N.;
Xuec, Y.; Fjellstrom, O. Bioorg. Med. Chem. Lett. 2007, 17, 3480-3485.
. Masip, I.; Pérez-Payá, E.; Messeguer, A. Comb. Chem. High Throughput
Screen. 2005, 8, 235-239.
N-(2-(Benzyl(1-(tert-butylamino)-2-methyl-1-oxobutan-2-
yl)amino)-2-oxoethylcarbamothioyl)benzamide (5o)
Pale yellow powder; m.p.: 192–194°C; yield: 0.35 g (72%); IR:
ν = 3410, 3236, 3063, 1658, 1585, 1512, 1408, 1244, 1163; EI-MS:
10. Zuckermann, R. N.; Kerr, J. M.; Kent, S. B. H.; Moos, W. H. J. Am.
Chem. Soc. 1992, 114, 10646-10647.
1
1. Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner, V. D.; Jew-
ell, D. A.; Sanville, S.; Ng, S.; Wang, L.; Rosenberg, S.; Marlowe, C. K.;
Spellmeyer, D. C.; Tans, R.; Frankel, A. D.; Santi, D. V.; Cohen, F. E.;
Bartlett, P. A. Proc. Nad. Acad. Sci. USA. 1992, 89, 9367-9371.
12. Gorske, B. C.; Nelson, R. C.; Bowden, Z. S.; Kufe, T. A.; Childs, A. M.
J. Org. Chem. 2013, 78, 11172-11183.
13. Mironov, M. A.; Tokareva, M. I.; Ivantsova, M. N.; Mokrushin, V. S.
Russ. J. Org. Chem. 2004, 40, 847-853.
+
m/z = 482 (M , 2.1), 261 (14), 221 (39), 157 (43), 105 (100), 91
1
3
(
78), 77 (34), 57 (53). H NMR: δ 0.89 (3 H, t, J 7.4 Hz, Me),
1
.38 (9 H, s, CMe3), 1.45 (3 H, s, Me), 1.78–1.87 (1 H, m, CH2),
2
3
2
.02–2.09 (1 H, m, CH2), 4.48 (2 H, ABX, JAB 18.5 Hz, JAX =
3
2
JBX 4.4 Hz, ꢀν 5.3, CH2NH), 4.69 (2 H, ABq, J 18.5 Hz, ꢀν
1
5.7, CH2N), 5.64 (1 H, s,NH), 7.28–7.87 (10 H, m, CH-Ar),
.01 (1 H, s, NH), 11.20 (1 H, br s, NH). 13C NMR: δ 9.06 (Me),
0.8 (Me), 29.05 (CMe3), 29.7 (CH2), 48.0 (C), 49.2 (CH2), 51.6
1
4. Kalinski, C.; Umkehrer, M.; Gonnard, S.; Jäger, N.; Ross, G.; Hiller, W.
9
2
Tetrahedron Lett. 2006, 47, 2041-2044.
15. Simila, S. T. M.; Martin, S. F. Tetrahedron Lett. 2008, 49, 4501-4504.
1
6. Yavari, I.; Sanaeishoar, T.; Piltan, M.; Azad, L. Phosphorus Sulfur Silicon
Relat. Elem. 2011, 186, 1612-1619.
(
(
CH2), 67.3 (C), 126.5 (2 CH), 127.9 (2 CH), 128.0 (CH), 129.4
2 CH), 129.6 (2 CH), 132.3 (C),133.8 (CH), 138.3 (C), 166.6 (C
1
7. Zabarjad-Shiraz, N.; Yavari, I.; Biglari, A.; Izadiar, S. A.; Bijanzadeh, H.
R. Phosphorus Sulfur Silicon Relat. Elem. 2009, 184, 3023-3037.
=
O), 168.2 (C = O), 172.9 (C = O), 179.8 (C = S). Anal. Calcd.
for C26H34N4O3S (482.64): C, 64.70; H, 7.10; N, 11.61%. Found:
18. Yavari, I.; Ghanbari, M. M.; Shahvelayati, A. S.; Ghazvini, M. Phospho-
rus Sulfur Silicon Relat. Elem. 2010, 185, 2551-2557.
C, 64.82; H, 7.14; N, 11.67%.
19. Yavari, I.; Ghazanfarpour-Darjani, M. J. Sulfur Chem. 2014, 35, 477-
4
83.
References
20. Tavakoli, Z.; Yavari, I. Phosphorus Sulfur Silicon Relat. Elem. 2015, 185,
4
40-448.
1
. Hulme, C. In: J. Zhu, H. Bienayme (Eds.), Multicomponent Reactions;
Wiley-VCH: Weinheim, 2005.
21. Li, Z.; Zhang, Y.; Wang, Y. Phosphorus Sulfur Silicon Relat. Elem. 2003,
178, 293-302.