Facile and convenient synthesis of N ′1, N ′3-dialkyl- N ′1, N ′3-bis(arylcarbonothioyl)malonohydrazides via propylphosphonic anhydride coupling

Article abstract of DOI:10.1055/s-0034-1378664

A facile and convenient synthetic method for the anticancer agent elesclomol and its analogues, N′¹,N′³-dialkyl-N′¹,N′³-bis(arylcarbonothioyl)malonohydrazides, by the direct coupling of N-alkyl-N-(substituted)be

Full text of DOI:10.1055/s-0034-1378664

3394▌
PAPER
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Facile and Convenient Synthesis of N′ ,N′ -Dialkyl-N′ ,N′ -bis(arylcarbono-
thioyl)malonohydrazides via Propylphosphonic Anhydride Coupling
N′1,N′3-Dialkyl-N′1,N′3-bis(arylcarbonothioyl)malonohydrazides
Zhiqiang Xia, Jun Jiang, Lijun Sun, Noriaki Tatsuta, Keizo Koya, Junyi Zhang, Gary Bohnert, Shoujun Chen*
Synta Pharmaceuticals Corp., 45 Hartwell Ave., Lexington, MA 02421, USA
Fax +1(781)2748228; E-mail: schen@syntapharma.com
Received: 26.06.2014; Accepted after revision: 01.08.2014
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai of the Shanghai Institute of Organic Chemistry (CAS) on the occasion of
their 90th birthdays
inseparable byproducts and to achieve satisfactory yields.
Abstract: A facile and convenient synthetic method for the antican-
Herein, we wish to report a very facile and convenient
synthetic procedure for this type of anticancer agent by
using propylphosphonic anhydride (T3P®) as a coupling
cer agent elesclomol and its analogues, N′1,N′3-dialkyl-N′1,N′3-
bis(arylcarbonothioyl)malonohydrazides, by the direct coupling of
N-alkyl-N-(substituted)benzothiohydrazides and substituted malo-
nic acids using propylphosphonic anhydride (T3P®) under very reagent. Since its first introduction by Wissmann and
Kleiner in 1980, T3P® has become a more and more ver-
mild conditions has been developed.
satile reagent for the formation of C–N and C–O bonds,
and other synthetic applications, due to its low toxicity
and potential to minimize epimerization and facilitate
product purification.8 Besides peptide C–N bond forma-
tion, T3P® has also been widely used for the syntheses of
various types of heterocyclic compounds, such as cyclic
phosphinic acids,9 pyrazolones,10 tetrahydro-β-carbo-
lines,11 Weinreb amides,12 imidazo[1,2-a]pyridines,13 4-
thiazolidinones,14 thienopyrimidines,15 coumarins,16 and
benzothiazoles,17 as well as for the Fischer indolization of
arylhydrazines.18 However, to the best of our knowledge,
there is no precedence reporting the use of T3P® for the
synthesis of malonic thiohydrazides via the direct cou-
pling of malonic acid with a thiohydrazide. As demon-
strated in Table 1, by employing this benign coupling
reagent, a variety of elesclomol derivatives can be synthe-
sized in moderate to high yields under very mild condi-
tions by simply mixing a thiohydrazide 1, a substituted
malonic acid 2, and T3P® with a base 3 in N,N-dimethyl-
formamide at room temperature.
Key words: propylphosphonic anhydride, elesclomol, analogues,
synthesis, anticancer agents
Discovered by serendipity screening and medicinal
chemistry optimization,1 elesclomol [STA-4783, N′1,N′3-
dimethyl-N′1,N′3-bis(phenylcarbonothioyl)malonohydra-
zide] is an anticancer drug that has received both fast track
and orphan drug status from the U.S. FDA and has been
evaluated in various stages of clinical trials together with
Taxol® in humans for the treatment of metastatic melano-
ma or other refractory solid tumors.2–5 Potent anticancer
activities against a broad range of cancer cell lines includ-
ing multidrug resistant (MDR) cell lines have also been
demonstrated for elesclomol and its derivatives, N′1,N′3-di-
alkyl-N′1,N′3-bis(arylcarbonothioyl)malonohydrazides.2,3,6a
Previously, we first reported the synthesis of elesclomol
and its derivatives via the cyclization of malonyl hydra-
zide in perchloric acid followed by thionation with sodi-
um sulfide then acidic hydrolysis or, alternatively, by the
N,N′-dicyclohexylcarbodiimide-mediated coupling of
malonic acid with α-thioacylhydrazides.6 In order to avoid
the use of explosive perchloric acid and the well-known
drawbacks associated with N,N′-dicyclohexylcarbodiim-
ide coupling, recently we also developed a method using
malonyl chloride for the synthesis of elesclomol and its
copper(II) complex that was plausible for the current good
manufacturing practice.7 However, the limited scope and
the fact that malonyl chloride has to be freshly distilled in
order to obtain a satisfactory yield of elesclomol are the
undesirable aspects of this approach and limit its general
application for the synthesis of elesclomol derivatives. In
addition to that, this procedure also requires very low tem-
perature (–20 °C or below) in order to avoid formation of
For the selection of base 3, besides Hünig’s base (N,N-di-
isopropylethylamine, DIPEA), some inorganic bases such
as sodium carbonate and potassium carbonate were also
screened but lower yields resulted. Comparable yields
were achieved when triethylamine was used as the base
(Table 1, entries 2, 11, 14, and 15). When coupling with
malonic acid (2a), N-methyl-substituted phenylhydrazide
1a afforded the highest yield (81%; Table 1, entry 1). Ste-
rically more hindered thiohydrazides such as the ethyl 1b,
n-propyl 1d, and n-butyl 1e derivatives resulted in lower
yields (Table 1, entries 4–6; 59%, 53%, and 51% yield, re-
spectively). Besides malonic acid, methyl-, ethyl-, isopro-
pyl-, and n-butylmalonic acid can also couple with
thiohydrazides in a similar manner to provide the products
in comparable yields (Table 1, entries 2, 3, and 13–18).
Electron-rich arylhydrazides (Table 1, entries 8, 12, and
17) usually afforded better yields than the electron-defi-
cient counterparts (Table 1, entries 9, 10, and 18). In addi-
tion to arylhydrazides (R = Ar) as listed in Table 1, the
SYNTHESIS 2014, 46, 3394–3398
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DOI: 10.1055/s-0034-1378664; Art ID: ss-2014-m0393-op
© Georg Thieme Verlag Stuttgart · New York

PAPER
N′1,N′3-Dialkyl-N′1,N′3-bis(arylcarbonothioyl)malonohydrazides
3395
synthetic method can also be applied to the corresponding heptane or tetrahydrofuran–hexane. No silica gel column
alkylhydrazides (R = alkyl). However, as we have report- chromatography was needed. The proton NMR spectrum
ed previously,6a unlike the arylhydrazide counterparts, the of compound 4a (elesclomol) is complicated by the ex-
corresponding products from alkylhydrazides are chemi- istance of tautomers, due to the presence of different
cally labile which limits the potential therapeutic applica- forms of the compound that create hindered rotation
tion of such derivatives.
around one of the nitrogen-containing bonds and result in
slight inequivalence of the corresponding protons. These
additional peaks were first thought to be due to impurities,
but other purity tests (LC-MS, HPLC, and elemental anal-
yses) did not indicate the presence of any impurity present
at such a high level. Therefore, a variable temperature 1H
Thus, elesclomol (4a) can be readily synthesized in high
yield by simply mixing two equivalents of N-methylben-
zothiohydrazide19 (1a) and one equivalent of malonic acid
(2a) with T3P® and N,N-diisopropylethylamine in N,N-di-
methylformamide at room temperature (Table 1, entry 1).
The desired product was readily precipitated out of the
solution by pouring the reaction mixture into acidified
ice–water and the pure product, N′1,N′3-dimethyl-N′1,N′3-
bis(phenylcarbonothioyl)malonohydrazide (4a), was ob-
tained conveniently by recrystallization from acetone–
1
NMR experiment was conducted. Consequently, the H
NMR spectrum of elesclomol (40 mg/mL in DMSO-d6) at
100 °C or higher shows the coalescence of the minor and
major peaks for such corresponding protons present in the
molecule.
Table 1 Synthesis of Elesclomol and Analogues via T3P® Couplinga
R4
R3
R2
R3 R4
O
O
T3P®, base (3)
R1
N
R2
R1
R2
R1
HO
OH
+
NH2
NH HN
N
N
DMF, r.t., 5–15 h
46–83%
S
O
O
S
S
1
2
4
Entry
Substrates
R
R1
R2
R3
Product
Yieldb (%)
1
2
1a, 2a
1b, 2b
1c, 2c
1b, 2a
1d, 2a
1e, 2a
1f, 2a
1g, 2a
1h, 2a
1i, 2a
1j, 2a
1k, 2a
1a, 2b
1a, 2d
1a, 2e
1a, 2f
1l, 2b
1i, 2b
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
81
75c
60
59
53
51
69
78
60
58
46c
75
82
74c
68c
51
83
51
Me
Me
H
3
Ph
4
Et
5
n-Pr
H
6
n-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
7
4-N3C6H4
4-MeOC6H4
4-ClC6H4
4-NCC6H4
3-Me2NC6H4
2,5-(MeO)2C6H3
Ph
H
4g
4h
4i
8
H
9
H
10
11
12
13
14
15
16
17
18
H
4j
H
4k
4l
H
Me
Et
i-Pr
4m
4n
4o
4p
4q
4r
Ph
Ph
Ph
n-Bu
Me
2,3-(MeO)2C6H3
4-NCC6H4
Me
a DIPEA was used as the base, unless otherwise indicated.
b Isolated yield.
c Et3N was used as the base.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3394–3398

3396
Z. Xia et al.
PAPER
2,2-Dimethyl-N′1,N′3-diphenyl-N′1,N′3-bis(phenylcarbono-
In conclusion, a facile and very convenient synthetic
method was developed for the novel anticancer agent eles-
clomol and its derivatives by employing T3P® as a cou-
pling reagent. Moderate to high yields were obtained for a
wide range of substituted malonic acids and thiohydra-
zides. The facile and environment-friendly reaction con-
ditions and easy isolation of products makes the synthesis
of a wide range of elesclomol analogues feasible for fur-
ther biological evaluation and other mechanistic studies.
thioyl)malonohydrazide (4c)
Yellow solid; yield: 3.31 g (60%); mp 218–220 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 0.4–1.8 (m, 6 H), 6.8–7.6 (m,
20 H), 11.1–11.3 (m, 2 H).
LC-MS: m/z = 552.1 [M]+; tR = 4.6 min.
Anal. Calcd for C31H28N4O2S2: C, 67.36; H, 5.11; N, 10.14. Found:
C, 67.01; H, 5.36; N, 10.05.
N′1,N′3-Diethyl-N′1,N′3-bis(phenylcarbonothioyl)malonohydra-
zide (4d)
Yellow solid; yield: 2.52 g (59%); mp 183–185 °C (dec).
Melting points were obtained with a Mel-Temp II apparatus (Labo-
ratory Devices, Inc., Holliston, MA, USA) or a TA Instruments
Q100 DSC (with heating ramp 10.0 °C/min, nitrogen purge), and
are uncorrected. 1H NMR data were obtained with a Bruker instru-
ment at 400 MHz using TMS as an internal standard; 13C NMR data
were recorded at 100 MHz. FTIR analysis was performed on a Per-
kin Elmer Spectrum 1000 FTIR spectrometer (Norwalk, CT, USA).
HPLC analyses were performed on a Hewlett-Packard Series 1100
reversed-phase liquid chromatograph equipped with a UV detector
(254 nm) and an Agilent Eclipse XDB-C18 (150 mm × 4.6 mm) 5-
μm column. LC-MS data were acquired on a Finnigan LCQ LC-MS
system (equipped with an Agilent Series 1100 HPLC). Microanaly-
ses were conducted by Atlantic Microlab, Inc., Norcross, GA, USA.
All reagents and solvents were commercially available with the
highest possible purity supplied and were used without further pu-
rification, unless otherwise stated. N-Alkyl-substituted benzothio-
hydrazides 1 were prepared according to literature procedures.6,19
1H NMR (400 MHz, DMSO-d6): δ = 1.0–1.4 (m, 6 H), 2.9–4.3 (m,
6 H), 7.1–7.5 (m, 10 H), 10.8–11.1 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 10.6, 48.7, 99.5, 125.7, 127.3,
128.8, 142.0, 163.0, 202.0.
LC-MS: m/z = 428 [M]+; tR = 4.15 min.
Anal. Calcd for C21H24N4O2S2: C, 58.85; H, 5.64; N, 13.07. Found:
C, 58.47; H, 5.39; N, 12.89.
N′1,N′3-Bis(phenylcarbonothioyl)-N′1,N′3-dipropylmalonohy-
drazide (4e)
Yellow solid; yield: 2.42 g (53%); mp 141–143 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 0.7–1.0 (m, 6 H), 1.5–1.8 (m,
4 H), 2.8–4.2 (m, 6 H), 7.2–7.5 (m, 10 H), 10.8–11.2 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 11.09, 18.65, 54.79, 125.62,
125.70, 127.79, 128.65, 142.07, 162.91, 202.67.
LC-MS: m/z = 456 [M]+; tR = 4.37 min.
N′1,N′3-Dimethyl-N′1,N′3-bis(phenylcarbonothioyl)malonohy-
drazide (Elesclomol, 4a); Typical Procedure
Anal. Calcd for C23H28N4O2S2: C, 60.50; H, 6.18; N, 12.27. Found:
C, 60.21; H, 6.38; N, 12.05.
To a stirred solution of malonic acid (2a; 1.04 g, 10 mmol) and N-
methyl-N-thiobenzoylhydrazine19 (1a; 3.32 g, 20 mmol) in DMF
(25 mL) and DIPEA (10 mL) was added T3P® (50% solution in
DMF, 12 mL, 20 mmol) slowly at r.t. The resultant red solution was
stirred at r.t. for 12 h (monitored by LC-MS). With stirring, the re-
action mixture was then poured into ice–H2O (350 mL) containing
6 N HCl (20 mL). The resultant yellow solid was collected by filtra-
tion and dried in vacuo to provide 4a as a yellow powder; yield: 3.25
g (81%). An analytically pure sample was obtained by recrystalliza-
tion (acetone–heptane); mp 190–192 °C (Lit.6a 191–193 °C).
N′1,N′3-Dibutyl-N′1,N′3-bis(phenylcarbonothioyl)malonohy-
drazide (4f)
Yellow solid; yield: 2.47 g (51%); mp 146–148 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 0.6–1.0 (m, 6 H), 1.1–1.8 (m,
8 H), 2.8–4.3 (m, 6 H), 7.2–7.5 (m, 10 H), 10.9–11.2 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 13.6, 19.1, 23.8, 25.0, 52.8,
125.5, 127.2, 128.6, 141.9, 162.8, 202.6.
LC-MS: m/z = 484 [M]+; tR = 4.57 min.
HPLC: tR = 13.73 min (98.7% purity).
Anal. Calcd for C25H32N4O2S2: C, 61.95; H, 6.65; N, 11.56. Found:
C, 61.54; H, 6.93; N, 11.38.
FTIR (KBr): 3205 (N–H stretching), 1688 (C=O stretching), 1297
(C–N stretching), 1247 (C=S stretching) cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.6–3.0 (m, 2 H), 3.2–3.6 (m,
6 H), 7.2–7.5 (m, 10 H), 11.0–11.2 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 40.1, 43.1, 125.9, 127.4,
128.9, 141.7, 163.2, 202.5.
N′1,N′3-Bis[(4-azidophenyl)carbonothioyl]-N′1,N′3-dimethyl-
malonohydrazide (4g)
Yellow solid; yield: 3.33 g (69%); mp 173–175 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 2.6–3.7 (m, 8 H), 7.0–7.6 (m,
LC-MS: m/z = 400 [M]+; tR = 3.97 min.
8 H), 11.0–11.3 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 39.2, 43.1, 118.1, 128.0,
138.3, 140.1, 163.2, 202.5.
LC-MS: m/z = 482 [M]+; tR = 4.25 min.
Compounds 4b–4r were prepared from the corresponding malonic
acids and thiohydrazides in a similar manner as described for 4a.
N′1,N′3-Diethyl-2-methyl-N′1,N′3-bis(phenylcarbono-
thioyl)malonohydrazide (4b)
Yellow solid; yield: 3.32 g (75%); mp 208–210 °C (dec).
Anal. Calcd for C19H18N10O2S2: C, 47.29; H, 3.76; N, 29.03. Found:
C, 46.90; H, 3.97; N, 28.83.
1H NMR (400 MHz, DMSO-d6): δ = 0.3 (d, J = 8.0 Hz, 3 H), 1.0–
1.4 (m, 6 H), 2.5 (m, 1 H), 3.6–4.5 (m, 4 H), 7.1–7.5 (m, 10 H), 10.9
(br, 2 H).
N′1,N′3-Bis[(4-methoxyphenyl)carbonothioyl]-N′1,N′3-dimeth-
ylmalonohydrazide (4h)
Yellow solid; yield: 3.59 g (78%); mp 176–178 °C (dec).
13C NMR (100 MHz, DMSO-d6): δ = 10.5, 40.5, 48.6, 125.5, 127.2,
128.6, 142.1, 166.2, 195.0.
1H NMR (400 MHz, DMSO-d6): δ = 3.0–3.8 (m, 14 H), 6.7–7.4 (m,
8 H), 10.9–11.2 (m, 2 H).
LC-MS: m/z = 443.2 [M + 1]+; tR = 4.23 min.
13C NMR (100 MHz, DMSO-d6): δ = 39.2, 41.5, 53.4, 110.4, 126.3,
131.7, 157.8, 161.2, 200.2.
LC-MS: m/z = 460 [M]+; tR = 4.02 min.
Anal. Calcd for C22H26N4O2S2: C, 59.70; H, 5.92; N, 12.66. Found:
C, 59.33; H, 6.15; N, 12.43.
Synthesis 2014, 46, 3394–3398
© Georg Thieme Verlag Stuttgart · New York

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N′1,N′3-Dialkyl-N′1,N′3-bis(arylcarbonothioyl)malonohydrazides
3397
Anal. Calcd for C21H24N4O4S2: C, 54.76; H, 5.25; N, 12.16. Found:
C, 54.70; H, 5.33; N, 11.77.
2-Ethyl-N′1,N′3-dimethyl-N′1,N′3-bis(phenylcarbono-
thioyl)malonohydrazide (4n)
Yellow solid; yield: 3.17 g (74%); mp 190–192 °C (dec).
N′1,N′3-Bis[(4-chlorophenyl)carbonothioyl]-N′1,N′3-dimethyl-
malonohydrazide (4i)
Yellow solid; yield: 2.81 g (60%); mp 194–196 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 2.6–3.6 (m, 8 H), 7.2–7.4 (m,
1H NMR (400 MHz, DMSO-d6): δ = 0.1–1.8 (m, 5 H), 2.9–3.6 (m,
7 H), 7.2–7.4 (m, 10 H), 10.96 (s, 2 H).
LC-MS: m/z = 428 [M]+; tR = 4.15 min.
8 H), 11.0–11.3 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 39.3, 42.7, 127.4, 127.6,
Anal. Calcd for C21H24N4O2S2: C, 58.85; H, 5.64; N, 13.07. Found:
C, 58.81; H, 5.53; N, 13.02.
133.4, 140.3, 163.1, 200.7.
LC-MS: m/z = 469.1 [M + 1]+; tR = 4.29 min.
2-Isopropyl-N′1,N′3-dimethyl-N′1,N′3-bis(phenylcarbono-
thioyl)malonohydrazide (4o)
Yellow solid; yield: 3.01 g (68%); mp 208–210 °C (dec).
Anal. Calcd for C19H18Cl2N4O2S2: C, 48.62; H, 3.87; Cl, 15.11; N,
11.94. Found: C, 48.23; H, 3.99; Cl, 15.03; N, 11.65.
1H NMR (400 MHz, DMSO-d6): δ = 0.1–1.7 (m, 7 H), 2.3–3.6 (m,
7 H), 7.2–7.4 (m, 10 H), 10.96 (s, 2 H).
LC-MS: m/z = 442 [M]+; tR = 4.22 min.
N′1,N′3-Bis[(4-cyanophenyl)carbonothioyl]-N′1,N′3-dimethyl-
malonohydrazide (4j)
Yellow solid; yield: 2.61 g (58%); mp 146–148 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 2.6–4.0 (m, 8 H), 7.4–7.9 (m,
Anal. Calcd for C22H26N4O2S2: C, 59.70; H, 5.92; N, 12.66. Found:
C, 59.57; H, 5.72; N, 12.57.
8 H), 11.1 (br, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 42.6, 111.1, 118.1, 126.2,
131.7, 145.7, 163.1, 200.1.
LC-MS: m/z = 450 [M]+; tR = 4.02 min.
2-Butyl-N′1,N′3-dimethyl-N′1,N′3-bis(phenylcarbono-
thioyl)malonohydrazide (4p)
Yellow solid; yield: 2.33 g (51%); mp 181–183 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 0.3–1.6 (m, 9 H), 3.2–3.6 (m,
7 H), 7.2–7.3 (m, 10 H), 10.96 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 11.9, 22.6, 26.4, 31.8, 40.9,
45.9, 124.3, 125.4, 127.1, 140.4, 164.1, 202.3.
Anal. Calcd for C21H18N6O2S2: C, 55.98; H, 4.03; N, 18.65. Found:
C, 55.59; H, 4.15; N, 18.37.
N′1,N′3-Bis{[3-(dimethylamino)phenyl]carbonothioyl}-N′1,N′3-
dimethylmalonohydrazide (4k)
LC-MS: m/z = 456.1 [M]+; tR = 4.33 min.
Isolated by silica gel chromatography eluting gradiently with a mix-
ture of CH2Cl2–MeOH.
Anal. Calcd for C23H28N4O2S2: C, 60.50; H, 6.18; N, 12.27. Found:
C, 60.13; H, 6.39; N, 12.02.
Red solid; yield: 2.24 g (46%); mp 119–121 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 2.6–3.0 (m, 12 H), 3.2–3.7 (m,
8 H), 6.5–6.7 (m, 6 H), 7.1–7.2 (m, 2 H), 10.9–11.1 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 39.7, 43.1, 109.4, 112.9,
113.9, 128.0, 142.4, 149.0, 163.4, 203.6.
LC-MS: m/z = 486.1 [M]+; tR = 3.65 min.
N′1,N′3-Bis[(2,3-dimethoxyphenyl)carbonothioyl]-N′1,N′3,2-
trimethylmalonohydrazide (4q)
Dark yellow solid; yield: 4.44 g (83%); mp 178–180 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 0.3–1.7 (m, 3 H), 2.5–2.6 (m,
1 H), 3.0–3.8 (m, 18 H), 6.5–7.1 (m, 6 H), 10.3–11.1 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 12.9, 55.4, 59.8, 112.4, 117.7,
123.2, 136.7, 141.9, 151.7. 167.1, 199.1.
Anal. Calcd for C23H30N6O2S2: C, 56.76; H, 6.21; N, 17.27. Found:
C, 56.65; H, 6.18; N, 16.92.
LC-MS: m/z = 534.7 [M]+; tR = 4.18 min.
Anal. Calcd for C24H30N4O6S2: C, 53.92; H, 5.66; N, 10.48. Found:
C, 53.57; H, 5.94; N, 10.28.
N′1,N′3-Bis[(2,5-dimethoxyphenyl)carbonothioyl]-N′1,N′3-di-
methylmalonohydrazide (4l)
Dark yellow solid; yield: 3.90 g (75%); mp 166–168 °C (dec).
N′1,N′3-Bis[(4-cyanophenyl)carbonothioyl]-N′1,N′3,2-trimethyl-
malonohydrazide (4r)
Dark yellow solid; yield: 2.37 g (51%).
1H NMR (400 MHz, DMSO-d6): δ = 0.4–0.95 (m, 3 H), 2.6–2.8 (m,
1 H), 3.2–3.6 (m, 6 H), 7.3–7.9 (m, 8 H), 11.0 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 12.9, 42.4, 110.8, 118.4,
126.2, 131.5, 145.7, 166.4, 200.1.
LC-MS: m/z = 464.1 [M]+; tR = 4.07 min.
1H NMR (400 MHz, DMSO-d6): δ = 2.4–3.8 (m, 20 H), 6.8–8.0 (m,
6 H), 10.7–11.1 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 41.9, 55.1, 56.0, 96.6, 111.8,
113.1, 114.5, 115.2, 130.8, 131.7, 143.3, 146.9, 152.2, 153.1, 163.3,
199.3.
LC-MS: m/z = 520.1 [M]+; tR = 4.05 min.
Anal. Calcd for C23H28N4O6S2: C, 53.06; H, 5.42; N, 10.76. Found:
C, 53.45; H, 5.14; N, 10.37.
Anal. Calcd for C22H20N6O2S2·0.45H2O: C, 55.90; H, 4.46; N,
17.78. Found: C, 56.12; H, 4.42; N, 17.82.
N′1,N′3,2-Trimethyl-N′1,N′3-bis(phenylcarbonothioyl)malono-
hydrazide (4m)
Yellow solid; yield: 3.40 g (82%); mp 213–214 °C (dec).
1H NMR (400 MHz, DMSO-d6): δ = 0.4 (d, J = 8.0 Hz, 3 H), 2.6–
Acknowledgment
The authors thank Drs Mitsunori Ono, Jun-Yong Choi, Dinesh
Chimmanamada, Weiwen Ying, Teresa Przewloka, Chi-Wan Lee,
Steve Bloom, Andrew Sonderfan, Suresh Babu, Wendy Rieder, and
Nick Triano for helpful discussion and valuable suggestions. We
would also like to thank Jingyang Wang from Pharm-Eco (a Johnson
Matthey Co.) for measuring the NMR spectrum of elesclomol
(STA-4783) at variable temperatures.
2.7 (m, 1 H), 3.1–4.7 (m, 6 H), 7.2–7.5 (m, 10 H), 10.9–11.0 (m, 2
H).
13C NMR (100 MHz, DMSO-d6): δ = 12.9, 42.6, 125.5, 127.2,
128.6, 141.6, 166.4, 202.8.
LC-MS: m/z = 414.1 [M]+; tR = 4.07 min.
Anal. Calcd for C20H22N4O2S2: C, 57.95; H, 5.35; N, 13.52. Found:
C, 58.02; H, 5.25; N, 13.46.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3394–3398

3398
Z. Xia et al.
PAPER
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Synthesis 2014, 46, 3394–3398
© Georg Thieme Verlag Stuttgart · New York