Microwave and Ultrasound Irradiation-Assisted Synthesis of Novel Disaccharide-Derived Arylsulfonyl Thiosemicarbazides

Article abstract of DOI:10.1080/00397910600588249

The synthesis of 1-arylsulfonyl-4-(1'-N-hepta-O-acetyl-β-lactosyl)thiosemicarbazides by reaction of hepta-O-acetyl-α-D-lactosyl isothiocyanate with substituted phenylsulfonyl hydrazines has been shown to occur in less than 1 min under microwave activation

Full text of DOI:10.1080/00397910600588249

Synthetic Communicationsw, 36: 1471–1477, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600588249
Microwave and Ultrasound
Irradiation-Assisted Synthesis of Novel
Disaccharide-Derived Arylsulfonyl
Thiosemicarbazides
Yu Xin Li, Wei Guang Zhao, Zheng-Ming Li,
Su Hua Wang, and Wei Li Dong
State Key Laboratory of Elemento-Organic Chemistry,
Nankai University, Tianjin, China
Abstract: The synthesis of 1-arylsulfonyl-4-(10-N-hepta-O-acetyl-b-lactosyl)
thiosemicarbazides by reaction of hepta-O-acetyl-a-D-lactosyl isothiocyanate with
substituted phenylsulfonyl hydrazines has been shown to occur in less than 1 min
under microwave activation and 8 min under ultrasound irradiation at room tempera-
ture. It is noteworthy that when ultrasound and microwaves (MW) were utilized, a
cleaner reaction accompanied with higher yields was observed.
Keywords: Lactose, maltose, microwave, thiosemicarbazide, ultrasound irradiation
INTRODUCTION
Some thiosemicarbazides ave been reported as fungicidal,[1] herbicidal,[2] and
pesticidal[3] agents. Recently, it has been well documented that thiosemicarba-
[4]
zides are a novel class of nonpeptide antagonists for the bradykinin B2
which has a therapeutic effect in the symptomatic treatment of chronic pain
and various inflammatory disorders. In addition, thiosemicarbazide is an
useful intermediate in the synthesis of important heterocyclic molecules
such as thiazol-4-one[5] and thiadiazol-2-one.[6] Its derivatives also exhibit
herbicidal anti-inflammatory, and analgesis activities.
Received in Japan December 21, 2005
Address correspondence to Zheng-Ming Li, State Key Laboratory of Elemento-
Organic Chemistry, Nankai University, Tianjin, 300071, China. Fax: þ86-22-
23505948; E-mail: nkzml@nk.sina.net
1471

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Y. X. Li et al.
Over the past two decades the biological properties of carbohydrates have
been reported. They have played key function in cell recognition, cell growth,
cell differentiation, and signal transduction.[7] On the other hand, carbo-
hydrates also compose important structural subunits in some natural pesticides
such as spinosads.[8] A survey of the literature revealed that carbohydrates
linked to phenylsulfonyl hydrazines have seldom been reported. As part of
our program aimed at developing a new class of agrochemicals, we
designed and synthesized the title compounds and studied their bioactivity.
Previously we had synthesized novel 1-arylsulfonyl-4-(10-N-20,30,40,
60-tetra-O-acety1-b-D-glucopyranosyl)thiosemicarbazides via condensation
of 2,3,4,60-tetra-O-actetyl-b-glucopyranosyl isothiocyanote with swastituted
phenylsulfonyl hydrazines by the conventional method.[9] In the synthesis
of 1-arylsulfonyl-4-(10-N-hepta-O-acetyl-b-lactosyl)thiosemicarbazides, we
found that a longer reaction time (at least 24 h at rt or 30 min under reflux)
was needed with the conventional method. At the same time, the by-product
accompained by lower yields was observed under reflux.
It is well documented that ultrasound irradiation and microwave acti-
vation have been widely used in chemical synthesis. The microwave-irradiation
technique has been used to assist in nuclephilic reation,[10] aromatic substi-
tutions,[11] cycloaddition reactions,[12] and so on.[13] Under certain circum-
stances, ultrasonic irradiation can replace the heating procedure.[14] Our
target compounds were synthesized by applying microwave activation, ultra-
sound irradiation, or both. The synthesis of novel 1-arylsulfonyl-4-(10-N-
hepta-O-acetyl-b-lactosyl)thiosemicarbazides 3a–e and 1-arylsulfonyl-4-
(10-hepta-O-acetyl-b-maltosyl)thiosemicarbazides 3f–j are described as in
Scheme 1.
RESULTS AND DISCUSSION
Hepta-O-acetyl-b-D-lactosyl isothiocyanate 2a and hepta-O-acetyl-a-D-
maltosyl isothiocyanate 2b were prepared according to the literature.[15] The
reaction between 2a, b and substituted phenylsulfonyl hydrazines under
the conventional method was investigated. Under conventional conditions,
the reaction between 2a with phenylsulfonyl hydrazines did not proceed
within 20 h at room temperature and 30 min under reflux. For example, if
Scheme 1. Reagents and conditions: (i) Pb(NCS)2, toluene, reflux; (ii) p-R3-Ph-SO2
NHNH2, acetonitrile, ultrasonic, rt.

Disaccharide-Derived Arylsulfonyl Thiosemicarbazides
1473
the synthesis of 3a and 3h was carried out at room temperature, 24 h was
needed; if refluxed, 30 min was needed. Obviously, temperature is one
decisive factor for this reaction. However, although the reaction can
proceed within 30 min under conventional heating conditions, lower yields
were obtained because 2a or 2b was decomposed. In general, the common
method for the synthesis of 1-arylsulfonyl thiosemicarbazide compounds
involves the reaction of isothiocyanate with hydrazine in ethonal,[16] but
this reaction did not proceed well because the addition product N-(hepta-O-
acetyl-b-D-maltosyl) thiocarbamic acid O-ethyl ester was obtained as the
major compound. If acetonitrile is used as the solvent, target compound
could be obtained with reasonable yields (70–80%).
The same reaction under ultrasound required only 5–8 min to complete
with excellent yields (Table 1). Ultrasonic irradiation was carried out with
KQ-218 ultrasonic cleaner 20 kHz/50 W. It is reported that when an ultrasonic
wave passes through a liquid medium, a large number of microbubbles form,
grow, and collapse in a very short time (a few microseconds), an effect that is
called the cavitation effect.[14] Sonochemical theory calculations suggested
that ultrasonic cavitation could generate local temperatures as high as
5000 K and local pressures as 500 atm, with heating and cooling rates
greater than 108 K/s, a very rigorous environment.[7] Compared with the
conventional method, a shorter time, lower temperature, cleaner reaction
accompained with higher yields were observed (from 70–80% to 92–99%
compared with conventional method at rt). Therefore, the bound breakdown
was avoided by using ultrasound irradiation at rt. After the ultrasonication,
the solvent was evporated in vaccum. The crude product was purified by a
silicon-gel column eluted with ethyl acetate/petroleum ether (1:2).
Generally, the reaction proceeded quickly with excellent yield as shown in
Table 2. The excellent yield of 3a–j is shown in Tables 1 and 2.
The reaction under microwave (MW) heating conditions was also
investigated to demonstrate the specific microwave effect. As we all know,
microwave-assisted reactions have several advantages over conventional
heating by not only significantly reducing the reaction time but also
improving the reaction yield dramatically and, in the process, greatly
Table 1. Effect of different reaction conditions
Reaction time
Yield (%)
MW
Compound
Reflux
MW
Ultrasound
Reflux
Ultrasound
3a
3b
3d
3f
30 min
30 min
20 min
30 min
30 min
1 min
1 min
30 s
8 min
8 min
6 min
8 min
5 min
71.8
73.6
80.2
74.0
76.5
100
96.8
97.2
98.2
94.3
99.0
96.9
96.2
95.5
98.3
1 min
30 s
3h

Table 2. Physical data of title compounds and elemental analysis
Elemental analysis, % (calcd., %)
Yield
(%)
Compound
R1
R2
R3
mp (8C)
C
H
N
3a
3b
3c
3d
3e
3f
OAc
OAc
OAc
OAc
OAc
H
H
H
96.8
97.2
91.5
98.2
99.1
94.3
92.7
98.4
98.6
93.4
218–221
212–215
214–216
213–215
213–215
180–183
187–188
186–190
191–193
171–173
46.40 (46.64)
47.04 (47.27)
45.44 (45.67)
44.72 (44.82)
42.40 (42.68)
46.50 (46.64)
46.52 (47.27)
44.69 (44.82)
42.90 (42.68)
45.50 (45.67)
4.97 (5.10)
5.19 (5.25)
4.72 (4.88)
4.79 (4.74)
4.54 (4.56)
5.10 (5.10)
4.94 (5.25)
4.77 (4.74)
4.53 (4.56)
4.95 (4.88)
5.07 (4.94)
4.74 (4.86)
5.07 (4.84)
5.04 (4.75)
4.68 (4.52)
4.99 (4.94)
5.08 (4.86)
4.83 (4.75)
4.45 (4.52)
4.96 (4.84)
H
CH3
F
H
H
Cl
Br
H
H
OAc
OAc
OAc
OAc
OAc
3g
3h
3i
H
CH3
Cl
Br
F
H
H
3j
H

Disaccharide-Derived Arylsulfonyl Thiosemicarbazides
1475
suppressing the side reactions. This increase in reaction rate is due in large part
to the vast amount of microwave energy being absorbed by the system a mpared
with the required energy necessary to attain the requisite activation energy.[18]
The same reaction under MW heating conditions for only 30–60s afforded
excellent product yield. The yield of synthesis of 3a–h increased from 70–
80% to 95–100% respectively, compared with refluxing under conventional
conditions The effects of different reaction conditions are shown in Table 1.
In conclusion, we have described a straightforward and high-yielding
method for the synthesis of 3a–h from their corresponding 2a–b under
mild conditions using microwave irradiation or ultrasonic irradiation. It is
noteworthy that when microwave and ultrasound were utilized, a cleaner
reaction accompanied with higher yields was observed. The application of
microwave activation and ultrasonic irradiation to this reaction has been
shown significantly enhance the rate.
EXPERIMENTAL
Melting points were conducted on a Yanaco MP-500 micro melting-point
apparatus 1H NMR and 13C NMR spectra were recorded in CDCl3 as
solvent on Bruker AC-400 instrument using TMS as an internal standard.
Elemental analysis was performed on a Yanaco CHN Corder MF-3
automatic elemental analyzer. Mass spectra were recorded with VG
ZAB-HS, 8kV, 1mA using the Fast Atom Bombardment (FAB) method Ultra-
sonic irradiation was carried out with Ultrasonic Cleaning 20 kHz/50 W.
Microwave activation was carried out with LWMC-201.
General Procedure of 1-phenylsulfonyl-4-(10-N-hepta-O-acetyl-b-
lactosyl)Thiosemicarbazide 3a
2a (0.68 g, 10 mmol) and benzenesulfonyl hydrazide (0.18 g, 10 mmol) were
dissolved in 10 mL of acetonitrile. The reaction mixture was heated for
1 min under MW heating conditions. After the microwave heating, the
solvent was evaporated in vacuum. The crude product obtained was purified
by silicon-gel column eluted with ethyl acetate/petroleum ether (1:2) and
1
3a (0.82 g, 96.8%) was obtained. Mp 218–2218C. H NMR (CDC13): d
1.95, 1.99, 2.04, 2.05, 2.07, 2.08, 215 (s, 21H, CH3), 3.68–5.53 (m, 14H,
lactosyl ring), 7.04 (bs, IH, NH), 7.55–7.90 (m, 7H, Ar-H, 2 ꢀ NH). MS
(FAB): 850.0 (849.83 calcd. for C33H43N3O19S2, M).
3b. Yield: 97.2% Mp 212–2158C. 1H NMR (CDCl3): d 1.96, 2.00, 2.04, 2.06,
2.07, 2.09, 2.15 (s, 21H, CH3), 2.44 (s, 3H, CH3), 3.69–5.54 (m, 14H, lactosyl
ring), 6.90 (bs, 1H, NH), 7.35–7.37 (m, 2H, Ar-H), 7.45 (bs, 1H, NH), 7.75–
7.77 (m, 2H, Ar-H), 7.92 (bs, 1H, NH).

1476
Y. X. Li et al.
3c. Yield: 91.5% Mp 214–2168C. 1H NMR (CDCl3): d 1.96, 1.99, 2.04, 2.06,
2.07, 2.09, 2.16 (s, 21H, CH3), 3.67–5.50 (m, 14H, lactosyl ring), 7.14 (bs,
1H, NH), 7.23–7.27 (m, 3H, Ar-H, NH), 7.78 (bs, 1H, NH), 7.90–7.92 (bs,
2H, NH).
3d. Yield: 98.2%. Mp 213–2148C. 1H NMR (CDCl3): d 1.96, 1.98, 2.03, 2.04,
2.07, 2.08, 2.16 (s, 21H, CH3), 3.66–5.49 (m, 14H, lactosyl ring), 7.24 (bs, lH,
NH),7.53–7.55 (m, 2H, Ar-H), 7.82–7.84 (m, 2H, Ar-H), 7.90 (bs, 2H, NH).
3e. Yield: 99.1%. Mp 213–2158C. 1H NMR (CDCl3): d 1.96, 1.99, 2.04, 2.04,
2.07, 2.08, 2.16 (s, 21H, CH3), 3.67–5.47 (m, 14H, lactosyl ring), 7.15 (bs, lH,
NH), 7.70–7.76 (m, 4H, Ar-H), 7.84 (bs, 1H, NH), 7.90 (bs, 1H, NH).
1
3f. Yield: 94.3% Mp 180–1838C. H NMR (CDCl3); d 1.99, 2.00, 2.02, 2.06,
2.10, 2.11 (6s, 21H, CH3), 3.79–5.61 (m, 14H, maltosyl ring), 7.09 (bs, 1H,
NH), 7.56–7.67 (m, 5H, 2 ꢀ Ar-H, NHNH), 7.87–7.89 (m, 3H, 3 ꢀ Ar-H).
3g. Yield: 92.7% Mp 187–1888C. 1H NMR (CDCl3): d 2.00, 2.01, 2.02, 2.03,
2.07, 2.10, 2.12 (7s, 21H, CH3), 2.45 (s, 3H, CH3), 3.77–5.54 (m, 14H, CH2),
7.50–7.83 (m, 6h, 4 ꢀ Ar-H, NHNH).
1
1
3h. Yield: 98.4%. Mp 186–1908C H NMR (CDCl3) H NMR (CDCl3):
d 1.98, 2.01, 2.02, 2.04, 2.06, 308, 2.10 (7s, 21H, CH3), 3.77–5.54
(m, 14H, CH2), 7.50–7.83 (m, 6H, 4 ꢀ Ar-H, NHNH).
3i. Yield: 98.6%. Mp 191–1938C. 1H NMR (CDCl3): d 1.98, 1.99, 2.01, 2.02,
2.05, 2.09, 2.10 (7s, 21H, CH3), 3.72–5.54 (m, 14H, CH2), 7.56–7.74 (m,4H,
4X Ar-H), 7.87 (bs, 1H, NH), 8.07 (bs, 1H, NH), 8.12 (bs, lH, NH).
3j. Yield: 93.4%. Mp 171–1738C. 1H NMR (CDCl3): d 1.92, 1.98, 1.99, 2.02,
2.09, 2.11 (s, 21H, CH3), 3.77–5.57 (m, 14H, maltosyl ring), 7.15 (bs, 1H, NH),
7.22–7.25 (m, 2H, Ar-H, NH), 7.34 (bs, 1H, NH). 7.84 (bs, 1H, NH), 7.89–7.92
(m, 2H, Ar-H). 13C NMR (CDCl3): d 20.81, 21.02, 21.17 (7 ꢀ CH3), 60.61,
61.25 (2 ꢀ CH2), 62.50, 68.20, 68.72, 69.49, 70.30, 70.77, 72.72, 74.47,
75.11, 82.20, 95.75 (sugar ring), 116.97, 117.21, 131.67, 131.76, 165.08,
167.63 (6 ꢀ Ar-H), 169.67, 169.93, 169.94, 170.07, 170.79, 171.10, 171.67
(7 ꢀ C55O), 184.10 (C55S). Anal. calcd. for C33H42FN3O19S2: C, 45.67; H,
4.88; N, 4.84. Found: C, 45.50; H, 4.95; N, 4.96.
ACKNOWLEDGMENTS
The project was supported by National Natural Science Foundation of
China (NNSFC) (No. 20432010) and Tianjin Natural Science Foundation
(No. 033803411).

Disaccharide-Derived Arylsulfonyl Thiosemicarbazides
REFERENCES
1477
1. Van Der Lans, R. G. J. M. Proceedings of the Fourth British Insecticide and
Fungicide Conference, Brighton, England, 1967, 2, 562–569.
2. Achgill, R. K.; Call, L. W. Preparation of 4-methyl-3-thiosemicarbazide as
herbicide intermediate. EP 339964, 1989.
3. Heuer, L.; Kugler, M.; Paulus, W.; Lorentzen, J. P.; Dehne, H. W.; Erdelen, C. EP
571857, 1993.
4. Dziadulewicz, E. K.; Ritchie, T. J.; Hallett, A.; Snell, C. R.; Ko, S. Y. 1-(2-Nitro-
phenyl)thiosemicarbazides: A novel class of potent, orally active non-peptide
antagonist of the bradykinin B2 receptor. J. Med. Chem. 2000, 43, 769–771.
5. Schenone, S.; Bruno, O.; Ranise, A.; Bondavalli, F.; Filippelli, W.; Falcone, G.
3-Arylsulphonyl-5-arylamino-1,3,4-thiadiazol-2(3H)ones as anti-inflammatory
and analgesic agents. Bioorg. Med. Chem. 2001, 9, 2149–2153.
6. Suzuki, M.; Morita, K. Synthesis and herbicidal activity of 4-thiazolone deriva-
tives and their effect on plant secretory pathway. J. Pest. Sci. 2003, 28 (1), 37–43.
7. Wells, L.; Vosseller, K.; Hart, G. W. Glycosylation of nucleocytoplasmic proteins:
Signal transduction and O-GlcNAc. Science 2001, 291 (23), 2376–2378.
8. Thompson, G. D.; Dutton, R.; Sparks, T. C. Spinosad—a case study: An example
from a natural products discovery programme. Pest. Manag. Sci. 2000, 56,
696–702.
9. Li, Y. X.; Li, Z. M.; Zhao, W. G.; Wang, S. H.; Dong, W. L. Synthesis of novel
l-arylsulfonyl-4-(10-N-20,30,40,6-tetra-O-acetyl-b-D-glucopyranosyl)thiosemicarba-
zides. Chin. Chem. Lett. 2006, 2, 152–155.
10. Hamilton, S. K.; Wilkinson, D. E.; Hamilton, G. S.; Wu, Y. Q. Microwave assisted
synthesis of N,N0-diaryl cyanoguanidines. Org. Lett. 2005, 7 (12), 2429–2431.
11. Laurent, R.; Laporteire, A.; Dubac, J.; Berlan, J. Microwave-assisted Lewis acid
catalysis: Application to the synthesis of alkyl- or arylhalogermanes. Organo-
metallics 1994, 2493–2495.
12. Alan, R. K.; Sandeep, K. S. Synthesis of C-carbamoyl-1,2,3-triazoles by
microwave-induced 1,3-dipolar cycloaddition of organic azides to acetylenic
amides. J. Org. Chem. 2002, 67, 9077–9079.
13. Lin, M. J.; Sun, C. M. Microwave-assisted traceless synthesis of thiohydantoin.
Tetrahedron. Lett. 2003, 44, 8739–8742.
14. Rathke, M. W.; Weipert, P. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, K., Eds.; Pergamon: New York, 1991; Vol. 2, p. 277.
15. Lemieux, R. U. Methods in Carbohydrate Chemistry II; Academic Press:
New York, 1963; Vol. 2, pp. 221–222.
16. Yu, J. X.; Yi, Y. X. Stereoselective synthesis of 1-[10-aroyl thiosemicarbazide-40-
YL]-N-b-D-glycopyranosides. Chin. J. Syn. Chem. 2000, 8 (2), 137–141.
17. Suslick, K. S. Sonochemistry. Science 1990, 247, 1439–1445.
18. Hayes, B. L. Microwave Synthesis, Chemistry at the Speed of Light; CEM Publish-
ing: Matthews, NC, 2002; Chap. 1, p. 16.