Synthesis of some new carbohydrate-containing thiouriedonaphtho-quinones

Article abstract of DOI:10.1007/s11164-013-1401-z

Abstract New alkyl, aryl, and glycosylthiouriedo derivatives of 2,3-diamino-1,4-naphthoquinone were synthesized via the reaction of isothiocyanates with 2,3-diamino-1,4-naphthoquinone. The new compounds were fully characterized through their physicochemical properties.

Full text of DOI:10.1007/s11164-013-1401-z

Res Chem Intermed
DOI 10.1007/s11164-013-1401-z
Synthesis of some new carbohydrate-containing
thiouriedonaphtho-quinones
•
Bader A. Salameh Raed A. Al-Qawasmeh
•
•
Kumait Al-Jabari Wolfgang Voelter
Received: 30 June 2013 / Accepted: 12 September 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract New alkyl, aryl, and glycosylthiouriedo derivatives of 2,3-diamino-1,4-
naphthoquinone were synthesized via the reaction of isothiocyanates with 2,3-dia-
mino-1,4-naphthoquinone. The new compounds were fully characterized through
their physicochemical properties.
Keywords Thiourea ꢀ Quinones ꢀ Glycosylthioureido derivatives ꢀ
2,3-diaminonaphthoquinones
Introduction
Flora with naphthoquinone constituents are widely used in folk medicine in Asia
and South America to treat malignant and parasitic diseases. Many naturally
occurring compounds with a naphthoquinone nucleus are well known for their
biological activities, such as alkanin [1], shikonin [1], lawsone [2], lapachol [3],
plumbagone [2], juglone [2] or streptonigrin (1) [4], which is a potent antitumor
agent. Many synthetic 1,4-napththoquinone-containing compounds exhibit
significant pharmacological properties including antitumor, wound-healing,
B. A. Salameh (&) ꢀ K. Al-Jabari
Chemistry Department, The Hashemite University, P.O. Box 150459, Zarqa 13115, Jordan
e-mail: bader04@gmail.com; bader@hu.edu.jo
R. A. Al-Qawasmeh
Department of Chemistry, The University of Jordan, Amman 11942, Jordan
W. Voelter
¨
Interfakultares Institutfur Biochemie, Eberhard-Karls-Universitat Tubingen, Hoppe-Seyler-Str. 4,
72076 Tu¨bingen, Germany
¨
¨
¨
123

B. A. Salameh et al.
anti-inflammatory, antiparasitic, antibacterial, antifungal, antiviral, insecticidal,
antipyretic, or cytotoxic [5, 6]. In fact, some clinically important anticancer drugs,
such as daunorubicin or mitomycin C (2), contain the quinone moiety as a relevant
part of their structures. These biological activities have justified the large number of
studies found in the literature aimed at the synthesis and evaluation of either natural
quinones or their analogs as potential pharmacological agents [7–9].
Among naphthoquinone derivatives, aminonaphthoquinones are considered as
lead structures for the development of antifungal and antimalarial drugs. Simple
2-amino-3-chloro-1,4-naphthoquinone (3) shows good potency as an antimalarial
agent, and its potency is greater than chloroquine (4) which has been used to treat
malaria for many decades [2]. Also, 2,3-diamino-1,4-naphthoquinone (5) has
promising antibacterial activity [2]. Several derivatives of aminonaphthoquinone
have been reported in the literature including various amide [10], heterocycle [11–
13], and alkyl derivatives (see Fig. 1).
As no uriedo or thiouriedo derivatives of naphthoquinone have so far appeared
in the literature, we report in this paper selected derivatives of this class of
compounds. The thiourea linkage is well known for its stability [14], ease of
synthesis, and tendency to undergo various transformations including cycloaddi-
tion reactions. Thiourea was reported to be transformed into various heterocycles
such as thiohydantoins [15], imidazolidines [16], isoxazoles [17], and imidazoles,
or to be part of linkages [18]. Sugar derivatives of thioureas have been extensively
studied and still constitute a field with a promising future due to the biological
activities of some derivatives and their ability to be converted into different types
of nucleosides [15].
OCH3
H3CO
O
HO
OCONH2
OCH3
O
O
NH2
Cl
H2N
CH3
H2N
H3C
O
O
H2N
N
CO2H
N
NH
O
H3CO
N
3
2
1
O
NH2
NH2
N
HN
O
Cl
N
4
5
Fig. 1 Structures of streptonigrin (1), mitomycin
chloroquine (4), and 2,3-diaminonaphthoquinone (5)
C (2), 2-amino-3-chloronaphthoquinone (3),
123

Synthesis of some new carbohydrate-containing thiouriedonaphtho-quinones
Experimental
General
Thin-layer chromatography (TLC) was performed using Merck-GF254 silica gel
plates with a 0.25-mm silica layer. TLC plates were developed in a variety of solvent
systems as indicated. Solvent system ratios refer to volume per volume ratios.
Detection of compounds was accomplished by their florescence under ultraviolet light
(254 nm). Melting points were determined on a SMP2 Stuart apparatus. Infrared
spectra (IR) were obtained as potassium bromide (KBr) disks on a Nicolet-MAGNA-
IR-560 apparatus, and only characteristic peaks are indicated as wave numbers
(cm-1). 1H and 13C NMR spectra were recorded on a Bruker DBX-300 spectrometer
with DMSO-d6 as solvent and TMS as standard. The peak multiplicities of the signals
are abbreviated as follows: s, singlet; d, doublet; and m, multiplet. The coupling
constants (J) were calculated and reported to the nearest 0.10 Hz. High-resolution
mass spectral data (HRMS) were recorded on a FT-MS Bruker APEX IV mass
spectrometer operated in the electron spray-ionization (ESI) mode.
Reactions of diamine 2 with isothiocyanates; typical procedure
An amount of 1 mmol of isothiocyanate [24] was added to a solution of 2,3-
diamino-1,4-naphthoquinone (5, 206 mg, 1.1 mmol) in dichloromethane (10 ml).
The mixture was stirred for 24 h at room temperature. The solvent was removed by
evaporation under vacuum and the residue purified by column chromatography
(hexane:ethyl acetate 2:1) to afford the thiourea products 6a–h.
2-(N0-Phenylthiouriedo)-3-amino-1,4-naphthoquinone (6a)
Yield: 216 mg, 67 %; m.p. (206–208 °C). IR (KBr): m = 2,919, 1,572, 1,608, 1,741,
3,339 cm-1. 1H NMR (DMSO-d6): d 9.20 (s, 1H), 8.73 (s, 2H), 6.97–7.97 (m, 9H),
6.84 (s, 1H). 13C NMR (DMSO-d6): 182.1, 178.7, 153.3, 142.0, 140.2, 135.1, 133.1,
132.4, 130.7, 129.2, 126.1, 126.1, 122.3, 118.6, 114.8. HRESIMS m/z: calcd. for
C17H13N3O2SNa [M ? H]? (346.06262), found (346.06207).
2-(N0-Methylthiouriedo)-3-amino-1,4-naphthoquinone (6b)
Yield: 208 mg, 80 %; m.p. (216–218 °C). IR (KBr): m = 3,395, 2,925, 1,608,
1,557 cm-1. 1H NMR (DMSO-d6): d 8.37 (s, 1H), 7.97 (t, J = 6.3 Hz, 2H), 7.83 (t, J =
7.2 Hz, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.60 (s, 1H), 6.92 (s, 2H), 2.85 (s, 3H). 13C NMR
(DMSO-d6): 182.2, 178.2, 146.8, 135.2, 133.1, 132.7, 130.8, 126.1, 126.0, 112.8, 31.9.
HRESIMS m/z: calcd. for C12H12N3O2S [M ? H]? (262.06502), found (262.06447).
2-(N0-p-Chlorophenylthiouriedo)-3-amino-1,4-naphthoquinone (6c)
Yield: 318 mg, 82 %; m.p. (213–215 °C). IR (KBr): m = 3,339, 2,919, 1,644,
1,557 cm-1. 1H NMR (DMSO-d6): d 9.63 (s, 1H), 8.77 (s, 2H), 7.35–8.00 (m, 8H),
123

B. A. Salameh et al.
7.15 (s, 1H). 13C NMR (DMSO-d6): 182.3, 180.9, 178.0, 146.5, 139.2, 135.3, 133.1,
132.8, 130.8, 128.8, 128.5, 126.1. HRESIMS m/z: calcd. for C17H11Cl1N3O2S [M–
H]? (356.02605), found (356.02660).
2-(N0-Benzylthiouriedo)-3-amino-1,4-naphthoquinone (6d)
Yield: 202 mg, 60 %; m.p. (200–202 °C). IR (KBr): m = 3,288, 2,925, 1,608,
1
1,578 cm-1. H NMR (DMSO-d6): 8.53 (s, 1H), 8.17 (s, 1H), 7.27–7.98 (m, 9H),
7.01 (s, 1H), 4.72 (d, J = 6.0 Hz, 2H). 13C NMR (DMSO-d6): 182.3, 178.3, 147.1,
139.8, 135.2, 134.5, 133.2, 132.7, 130.9, 128.5, 127.5, 127.0, 126.5, 126.1, 126.0,
48.0. HRESIMS m/z: calcd. for C18H15N3O2S1Na [M ? Na]? (360.0783), found
(360.0777).
2-(N0-2,3,4,6 Tetra-O-acetyl-b-D-glucopyranosylthiouriedo)-3-amino-1,
4-naphthoquinone (6e)
Yield: 410 mg, 71 %; m.p. (163–165 °C). [a]2D5 = ? 84° (c 0.14, CH2Cl2). IR
1
(KBr): m = 3,308, 2,925, 1,613, 1,536, 1,747 cm-1. H NMR (DMSO-d6): d 8.84
(s, 1H), 8.15 (s, 1H), 7.94 (d, J = 7.4 Hz,1H), 7.88 (d, J = 7.3 Hz,1H), 7.78 (t,
J = 7.3 Hz, 1H), 7.69 (t, J = 7.3 Hz, 1H), 6.95 (s, 2H), 5.86 (t, J = 9.3, 1H), 5.24
(t, J = 9.2 Hz, 1H), 4.84 (d, J = 9.1 Hz, 2H), 4.15 (m, 1H), 3.93 (m, 2H),
1.86–2.01 (s, 12H). 13C NMR (DMSO-d6): d 183.2, 182.2, 177.7, 170.5, 170.0,
169.8, 169.6, 135.2, 133.2, 132.7, 130.8, 126.2, 126.0, 82.9, 73.6, 72.6, 70.8, 68.0,
62.1, 21.1, 20.90, 20.8. HRESIMS m/z: calcd. for C25H27N3O11SNa [M ? Na]?
(600.1264), found (600.1319).
2-(N0-2,3,4,6 Tetra-O-acetyl-b-D-galactopyranosylthiouriedo)-3-amino-1,
4-naphthoquinone (6f)
Yield: 311 mg, 54 %; m.p. (155–157 °C). [a]2D5 = ? 440° (c 0.05, CH2Cl2). IR
(KBr): m = 3,323, 2,919, 1,752, 1,623, 1,537 cm-1. 1H NMR (DMSO-d6): d 8.80 (s,
1H), 8.30 (s, 1H), 7.97 (d, J = 6.2 Hz, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.81 (t,
J = 7.0 Hz, 1H), 7.74 (t, J = 7.1 Hz, 1H), 6.92 (s, 2H), 5.84 (m, 1H), 5.26–5.02
(m, 3H), 4.25 (m, 1H), 4.00 (m, 2H), 1.87,, 1.89, 2.11 (each s, each 3H, 4 CH3). 13
C
NMR (DMSO-d6): d 183.3, 182.2, 170.4, 170.1, 169.8, 135.2, 133.1, 132.7, 130.8,
126.2, 126.0, 92.1, 71.5, 68.7, 68.5, 68.0, 61.7, 21.3. HRESIMS m/z: calcd. for [M-
H]- (576.1288), found (576.1294).
2-(N0-2,3,4-Tri-O-acetyl-a-L-arabinopyranosylthiouriedo)-3-amino-1,4-
naphthoquinone (6g)
Yield: 303 mg, 60 %; m.p. (132–134 °C). [a]2D5 = ? 252° (c 0.11, CH2Cl2). IR
1
(KBr): m = 3,323, 2,919, 1,752, 1,623, 1,537 cm-1. H NMR (CDCl3-d): 8.18 (s,
1H), 8.06 (d, J = 6 Hz, 2H), 7.74 (t, J = 6.0 Hz, 1H), 7.65 (t, J = 6.0 Hz, 1H),
7.34 (s, 1H), 6.05 (s, 2H), 5.53 (d, J = 9.0 Hz, 1H), 5.27 (m, 2H), 4.04 (d,
J = 12.0 Hz, 2H), 3.79 (d, J = 12.0 Hz, 1H), 1.92–2.15 (s, 9H). 13C NMR (CDCl3-
123

Synthesis of some new carbohydrate-containing thiouriedonaphtho-quinones
d): 182.0, 181.1, 179.1, 171.7, 170.1, 169.6, 134.9, 132.7, 132.3, 130.4, 126.6,
126.6, 84.0, 70.4, 68.4, 68.2, 66.0, 20.8, 20.7, 20.5. HRESIMS m/z: calcd. for
C22H23N3O9SNa [M ? Na]? (528.1053), found (528.1047).
2-(N0-Hepta-O-acetyl-b-lactosylthiouriedo)-3-amino-1,4-naphthoquinone (6h)
Yield: 545 mg, 63 %; m.p. (108–110 °C). [a]2D5 = -267° (c 0.06, CH2Cl2). IR (KBr):
m = 3,334, 2,925, 1,747, 1,618, 1,536 cm-1. 1H NMR (DMSO-d6): 8.80 (s, 1H), 8.15
(s, 1H), 7.94 (d, J = 7.5, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.80 (t, J = 7.2 Hz, 1H), 7.70
(t, J = 7.3 Hz, 1H), 6.90 (s, 2H), 5.76 (s, 1H), 5.18 (m, 1H), 5.09 (d, J = 9.5 Hz, 2H),
4.80 –4.71 (m, 3H), 4.02 (m, 2H), 3.97 (m, 3H), 3.75 (m, 2H), 1.86, 1.88, 1.93, 2.00,
2.06 (each s, 7 CH3). 13C NMR (DMSO-d6): 183, 182.2, 170.8, 170.4, 170.4, 170.0,
169.9, 169.6, 135.2, 133.1, 132.8, 130.8, 126.2, 126.1, 100.0, 76.3, 73.8, 70.8, 70.1,
69.3, 67.6, 62.8, 61.4, 21.2, 21.1, 21.0, 20.9, 20.8. HRESIMS m/z: calcd. for
C37H43N3O19SNa [M ? Na]? (888.2110), found (888.2002).
Results and discussion
Our strategy to prepare naphthoquinone-containing compounds starts with the
reaction of 2-amino-3-chloro-1,4-naphthoquinone (3) [19] with two different
isothiocyanates (Scheme 1). Under standard conditions [15], the target thiourea
could not be isolated. Our attempt to prepare the desired compound was
unsuccessful, even after using various solvents (DMSO, DMF, pyridine, acetoni-
trile) and temperatures (up to 80 °C), or the addition of a strong base, such as
sodium hydride.
The low nucleophilicity of amine 3 could be attributed to the amide-like
character of its nitrogen [20], due to the crowded presence of neighboring electron-
withdrawing groups, in addition to electronic factors arising from the aromatic
nature of the amine. As the nucleophilicity of the amine can be increased by
introducing a neighboring amino group, thereby enlarging the electron density over
the quinone ring, the naphthoquinone derivative 5 was prepared via reaction of 2,3-
dichloro-1,4-naphthoquinone with potassium phthalamide followed by treatment
with hydrazine as reported in the literature [21] (Scheme 2).
The available reactive diamine reacted smoothly with phenyl isothiocyanate in
dichloromethane at room temperature affording the phenylthiourea 6a in good yield.
O
O
H
N
NH2
Cl
NHR
+
R
NCS
S
Cl
O
O
3
R= Me, Ph
Scheme 1 Reaction of 2-amino-3-chloro-1,4-naphthoquinone with methyl and phenyl isothiocyanates
123

B. A. Salameh et al.
O
O
O
O
O
NPhth
NPhth
NH2
Cl
Cl
(ii)
(i)
NH2
O
5
R NCS
O
H
N
NHR
6a R=C6H5
6b R=CH3
6c R=4-Cl-C6H4
6d R=Benzyl
S
NH2
O
6a-d
Scheme 2 Reagents and conditions: (i) potassium phthalamide, CH3CN, reflux 5 h; (ii) NH2NH2ꢀH2O
The result of this synthesis shows that only one amino group of the diamine reacts
with the isothiocyanate, as no traces of bis-thiourea were observed, even when using
excess isothiocyanate up to five equivalents.
All three applied isothiocyanate derivatives (methyl, p-chlorophenyl, and benzyl)
produced monothiourea products only. The structures of the new compounds were
confirmed by their 1H NMR 13C NMR, IR, and mass spectra. Signals at
d & 180 ppm identified the C=S functional groups in the 13C NMR spectra, and
NH groups were characterized by IR-bands around 3,300 cm-1. Exchangeable NH
1
protons appear around 7–9 ppm downfield in the H NMR spectra [22, 23].
Our major goal in this work was to incorporate carbohydrate moieties into
naphthoquinones via an urido linkage, and, as examples, four different sugar
isothiocyanate derivatives (7a–d) were synthesized (Scheme 3) [24]: b-D-gluco-
pyranosyl (7a), a-L-arabinopyranosyl (7b), b-D-galactopyranosyl (7c), and b-
lactosyl isothiocyanates (7d) were reacted with the diamine 5, under standard
conditions as given in Scheme 2 to produce the new compounds 6e–h (Scheme 3).
The products were isolated in good to excellent yields as shown in Table 1.
All new sugar-containing naphthoquinones were characterized via their spectro-
scopic properties. The IR spectra of sugar thioureas 6e–h show bands around 1,750
and 2,920 cm-1 corresponding to C=O of acetates and to stretching C–H bonds of
1
the sugar moieties, respectively. The H NMR spectra show signals in agreement
with the proposed structures for the thioureas. Three exchangeable NH signals
appear in the range of 6.05–8.73 ppm. Sugar proton signals resonate in the range of
3.79–5.84 ppm. The b-linkage of the sugar moiety (a in the case of 6g was deduced
via the coupling constant of the anomeric protons which were in all cases around
9 Hz [24]), clearly indicating a 1,2-trans configuration. The 4C1 conformation of the
pyranoid ring was established from the vicinal coupling constants between the
protons in the sugar pyranoid ring (J = 7–10 Hz). The 13C NMR spectra show
peaks around 183 ppm arising from the C=S group. The carbonyls of the quinone
123

Synthesis of some new carbohydrate-containing thiouriedonaphtho-quinones
R1
O
NCS
OAc
R1
O
Br
R1
O
OAc
OAc
(i)
(ii)
R3
R2
R3
R2
R3
R2
OAc
OAc
OAc
OAc
7a-d
6e, 7a: R1=CH2OAc, R2=OAc,R3=H.
6f, 7b: R1=CH2OAc, R2=H,R3=OAc.
6g, 7c: R1=H, R2=H,R3=OAc.
(iii)
6h, 7d: R1=CH2OAc, R2=2,3,4,6-tetra-O-acetyl-β-
D
-galactopyranosyl,R3=H.
AcO
O
H
N
H
OAc
R2
N
O
S
NH2
R3
R1
O
6e-h
Scheme 3 (i) 33 % HBr in AcOH (glacial), (ii) KSCN, melt 190 °C, 5 min, (iii) 2,3-
diaminonaphthoquinone, DCM, r.t.
Table 1 Preparation of thiouriedodiaminonaphthoquinone 6a-h
O
H
H
N
N
R
S
NH2
O
R
Time (h)
24
% Yield
67
m.p.
6a
206–208
6b
6c
H3C–
24
24
80
82
216–218
213–215
CI
123

B. A. Salameh et al.
Table 1 continued
R
Time (h)
24
% Yield
60
m.p.
6d
200–202
6e
24
71
163–165
AcOH2C
O
AcO
OAc
OAc
OAc
O
6f
24
24
24
54
60
63
155–157
132–134
108–110
AcOH2C
AcO
OAc
6g
O
AcO
OAc
OAc
6h
AcOH2C
O
OAc
AcOH2C
AcO
O
O
OAc
OAc
OAc
123

Synthesis of some new carbohydrate-containing thiouriedonaphtho-quinones
moiety resonate in the range of 177.7–182.2 ppm, which is in full agreement with
the reported signals in the literature [25].
The biological evaluation of the new aminonaphthoquinone thioureido deriva-
tives are in progress in our laboratory.
Acknowledgment The authors would like to thank the Hashemite University for financial support.
References
1. V.P. Papageorgiou, A.N. Assimopoulou, E.A. Couladouros, D. Hepworth, K.C. Nicolaou, Angew.
Chem. Int. Ed. 38, 270 (1999)
2. A.A. Aly, E.A. Ishak, M.A. Alsharari, N.S. Al-Muaikel, T.M.I. Bedair, J. Heterocycl. Chem. 49, 9
(2012)
3. H. Hussain, K. Krohn, V.U. Ahmad, G.A. Miana, I.R. Greend, ARKIVOC 2007, 145 (2007)
4. T.J. Donohoe, C.R. Jones, L.C.A. Barbosa, J. Am. Chem. Soc. 133, 16418 (2011)
5. J.M. Miguel del Corral, M.A. Castro, M. Gordaliza, M.L. Martin, A.M. Gamito, C. Cuevas, A.S.
Feliciano, Bioorg. Med. Chem. 14, 2816 (2006)
6. V.K. Tandon, D.B. Yadav, H.K. Maurya, A.K. Chaturvedi, P.K. Shukla, Bioorg. Med. Chem. 14,
6120 (2006)
7. K.C. Nicolaou, D. Hepworth, Angew. Chem. Int. Ed. 37, 839 (1998)
8. C. Donner, M. Gill, L. Tewierik, Molecules 9, 498 (2004)
9. R.H. Thomson, in: Total Synthesis of Natural Products (Wiley, New York, 2007), p. 311
10. S.-C. Kuo, T. Ibuka, L.-J. Huang, J.-C. Lien, S.-R. Yean, S.-C. Huang, D. Lednicer, S. Morris-
Natschke, K.-H. Lee, J. Med. Chem. 39, 1447 (1996)
11. P. Anzenbacher, M.A. Palacios, K. Jursikova, M. Marquez, Org. Lett. 7, 5027 (2005)
12. M. Jamkratoke, V. Ruangpornvisuti, G. Tumcharern, T. Tuntulani, B. Tomapatanaget, J. Org. Chem.
74, 3919 (2009)
13. S. Van Aeken, J. Deblander, J. De Houwer, T. Mosselmans, K. Abbaspour Tehrani, Tetrahedron 67,
512 (2011)
14. J.M. Garcia Fernandez, C.O. Mellet, H. Derek, in: Advances in Carbohydrate Chemistry and Bio-
chemistry (Academic, New York, 2000), p. 35
15. J. Fuentes, B.A.B. Salameh, M. Angeles Pradera, F.J. Fernandez de Cordoba, C. Gasch, Tetrahedron
62, 97 (2006)
16. C. Gasch, M.A. Pradera, B.A.B. Salameh, J.L. Molina, J. Fuentes, Tetrahedron: Asymmetry 11, 435
(2000)
17. O. Lopez, I. Maya, J. Fuentes, J.G. Fernandez-Bolan˜os, Tetrahedron 60, 61 (2004)
18. S. Perveen, N. Fatima, M. Khan, A. Dar, K. Khan, N. Afza, W. Voelter, Med. Chem. Res. 21, 2709
(2012)
19. J.R.E. Hoover, A.R. Day, J. Am. Chem. Soc. 76, 4148 (1954)
20. A.J. Hamdan, S. Al-Jaroudi, Arab. J. Sci. Eng. 28, 51 (2003)
21. E. Winkelmann, Tetrahedron 25, 2427 (1969)
22. W. Kowollik, G. Janairo, W. Voelter, J. Org. Chem. 53, 3943 (1988)
23. E. Breitmaier, W. Voelter, Carbon-13 Nuclear Magnetic Resonance (VCH, Weinheim, 1978)
24. T.K. Lindhorst, C. Kieburg, Synthesis 1995, 1228 (1995)
25. X.L. Wang, X.F. Zheng, R.H. Liu, J. Reiner, J.B. Chang, Tetrahedron 63, 3389 (2007)
123