Solvent-free synthesis of heterocyclic thioureas using microwave technology

Article abstract of DOI:10.1002/jccs.200100013

A new and rapid solvent-free synthesis of heterocyclic thioureas in a microwave oven has been reported for the first time. Nine heterocyclic thioureas that possess biological activity have been synthesized. The reaction time is short (2-4.5 min) and gives

Full text of DOI:10.1002/jccs.200100013

JournaloftheChineseChemicalSociety, 2001, 48, 73-75
73
Sol vent-free Syn the sis of Heterocyclic Thioureas Using
MicrowaveTechnology
Jian-Ping Li (
Yu-Lu Wang* (
), Qian-Fu Luo (
),
李建平
王玉爐
羅千福
) and Hong Wang (
)
王紅
CollegeofChemistry&EnvironmentalScience,HenanNormalUniversity,
Xinxiang, 453002, China
KeyLaboratoryofEnvironmentalScience&EngineeringofHenanEducationCommission,
Xinxiang, 453002, China
A new and rapid sol vent-free syn the sis of heterocyclic thioureas in a mi cro wave oven has been reported
forthefirsttime.Nineheterocyclicthioureasthatpossessbiologicalactivityhavebeensynthesized.Thereac-
tion time is short (2-4.5 min) and gives ex cel lent yields (82.9-95.5%).
INTRODUCTION
In re cent years, the use of mi cro wave tech nol ogy in or-
vol a tile and poi son ous sol vents and need a long re ac tion
time.
In order to overcome the disadvantages discussed
above, avoid the use of a sol vent and syn the size these valu-
ablecompoundsrapidlyandwithahighefficiently, weinves-
ti gated a new way—sol vent-free syn the sis us ing a mi cro-
wave oven.
ganicsynthesishasreceivedconsiderableattention,1-4 the
reasonisthatthistechnologycanincreasethepurityofthere-
sult ing prod ucts, en hance the chem i cal yield and shorten the
reactiontime.5-7 But most of them use sol vents,8-9 but with the
high vapour pres sure of sol vents, it some times lead ing to ex-
plosions.
Scheme
More over, as we know, sol vent-free or ganic syn the sis
has great ap plied value and ex pan sive pros pects. It has many
advantagessuchashighefficiencyandselectivity,easysepa-
rationandpurificationandenvironmentalacceptability.10 All
these mer its are in ac cord with the green pro duc tion’s re-
quests of en ergy-saving and high ef fi ciency. It is one of the
few clean-productions that can be used by chem ists. To day, it
has been widely used in a va ri ety of or ganic re ac tions.11-15
How ever, the solid-state syn the sis of heterocyclic thioureas
has not been re ported so far.
Microwave
Solid state
X
N C S+ H2N Ar
1
S
Ar
X
NH
C NH
2
a) X=Cl, Ar= 2-Pyridyl
b) X=Cl, Ar =2-Benzothiazolyl
d) X=Br, Ar = 2-Pyridyl
c) X=Cl, Ar = 4-Antipyrinyl
e) X=Br,Ar=2-Benzothiazolyl
g) X=EtO, Ar = 2-Pyridyl
i) X=EtO, Ar= 4-Antipyrinyl
f) X=Br, Ar = 4-Antipyrinyl
h) X=EtO, Ar=2-Benzothiazolyl
RESULTSANDDISCUSSION
Heterocyclic thioureas com pounds are known to ex-
hibitantiviral,16 antituberculous,17 fungicidal,18 and her bi-
cidal activities.19 Meanwhile, some N-heterocyclic com-
pounds (such as antipyrine) have been found to ex hibit wide
physiologicalactivity,20 too. Therefore, particularlyintense
interesthasbeendirectedtowardthesynthesisofthem. Gen-
erally, the prep a ra tion of these com pounds has been car ried
out in so lu tion. All the ex ist ing meth ods have their mer its.
But they also have draw backs such as us ing large amounts of
In this pa per, a new sol vent-free ad di tion re ac tion of
isothiocyanates and heterocyclic pri mary amine was stud ied.
By this new method, nine heterocyclic thioureas have been
syn the sized in ex cel lent yields (82.9-95.5%). This method
needs only a short re ac tion time (2-4.5 min). The struc tures of
theproductswereconfirmedbyElementalanalysisIRand1H
NMRspectroscopy.Thereferencesintheliteraturesofthese
com pounds were given.21

74 J. Chin. Chem. Soc., Vol. 48, No. 1, 2001
Li et al.
EXPERIMENTALSECTION
N-(4-bromophenyl)-N -(2-pyridyl) thiourea (2d)
Whiteneedle;Yield87.2 ; mp 207.5-208.5 C; IR
max
Melting points were de ter mined with a Kofler mi cro
(KBr): 3215, 3170 (m, N-H), 3082 (w, ArH), 1599, 1535 (m,
1
melt ing point ap pa ra tus and were un cor rected. IR spec tra
Ar), 1264 (m, C=S), 1187 (m, C-N), 826, 776, 720 cm ; 1H
1
were re corded on a SP3-300 spectrophotometer in KBr. H
NMR : 6.67-8.26 (m, 8H, ArH), 9.20 (s, 1H, NH), 13.75 (s,
1H, NH); Anal. Calcd. for C 12H10BrN3S: C, 46.75; H, 3.25; N,
13.64. Found: C, 46.45; H, 3.02; N, 13.79.
NMR spec tra were mea sured on a Bruker DPX-400M spec-
trom e ter us ing TMS as in ter nal stan dard and CDCl3 as sol-
vent.ElementalanalyseswereperformedonaPE-2400CHN
elemental analyser. Mass spectra were recorded on a
KRATOS-AEI-MS50 (U.K.).
N-(4-bromophenyl)-N -(2-benzothiazolyl) thiourea (2e)
White nee dle; Yield 84.0 ; mp221-223 C; IR
max
(KBr): 3175 (m, N-H), 3035 (w, ArH), 1600, 1590 (m, Ar),
1
1
General Procedure for the PreparationofN-Aryl-N -
heterocyclyl Thiourea (2a-2i)
1260 (m, C=S), 1188 (m, C-N), 837, 756 cm ; H NMR :
7.18-7.77 (m, 8H, ArH), 9.30 (s, 1H, NH), 12.05 (s, 1H, NH);
Anal. Calcd. for C14H10BrN3S2: C, 46.15; H, 2.75; N, 11.54.
Found: C, 46.50; H, 2.72; N, 11.33.
Aryl isothiocyanate (1 mmol) and heterocyclic pri mary
amine (1 mmol) were mixed thor oughly in an ag ate mor tar.
Then the mix ture was put into a house hold mi cro wave oven
(the power out put is 750W). The ad jus tor of the mi cro wave
oven was set to the proper tem per a ture (about 50 C). The re-
actantswereirradiatedforaperiodof2-4.5min.Thereaction
was traced with thin-layer chro ma tog ra phy. Af ter the re ac-
tion was com pleted, the crude prod ucts were recrystallized
with eth a nol and dried un der vac uum to yield the pure prod-
ucts.
N-(4-bromophenyl)-N -(4-antipyrinyl) thiourea (2f)
White nee dle; Yield 93.9 ; mp 210-212 C; IR
max
(KBr): 3261, 3111 (m, N-H), 3066 (w, ArH), 2930 (w, CH3),
1635 (m, C=O), 1617, 1576 (m, Ar), 1294 (m, C=S), 829,
1
1
761, 721 cm ; H NMR : 2.32 (s, 3H, CH3), 3.17 (s, 3H,
CH3), 7.41-7.69 (m, 8H, ArH), 8.61 (s, 1H, NH), 10.23 (s, 1H,
NH); Anal. Calcd. for C18H17BrN4OS: C, 51.80; H, 4.08; N,
13.43. Found: C, 51.61; H, 4.33; N, 13.15.
N-(4-chlorophenyl)-N -(2-pyridyl) thiourea (2a)
White tab u lar; Yield 88.5 ; mp 198-200 C; IR
N-(4-ethoxyphenyl)-N -(2-pyridyl) thiourea (2g)
max
(KBr): 3217, 3170 (m, N-H), 3080 (w, ArH), 1600, 1540 (m,
White nee dle; Yield 88.2%; mp 200-202 C; IR
max
1
Ar), 1260 (m, C=S), 1186 (m, C-N), 825, 776, 725 cm ; 1H
(KBr): 3219, 3169 (m, N-H), 3084 (w, ArH), 2980, 2935 (w,
Et), 1596, 1536 (m, Ar), 1244 (m, C=S), 1188 (m, C-N), 820,
NMR : 6.69-8.26 (m, 8H, ArH), 9.38 (s, 1H, NH), 13.74 (s,
1H, NH); Anal. Calcd. for C 12H10ClN3S: C, 54.65; H, 3.80; N,
15.94. Found: C, 54.51; H, 3.55; N, 15.96.
1
776, 746 cm-1; H NMR : 1.44 (t, 3H, CH3), 4.07 (q, 2H,
CH2), 6.65-8.27 (m, 8H, ArH), 9.46 (s, 1H, NH), 13.48 (s, 1H,
NH); MS (m/z): 273 (M+) 179, 137, 108, 94 (B), 78; Anal.
Calcd. for C14H15N3OS: C, 61.54; H, 5.49; N, 15.38. Found:
C, 61.14; H, 5.76; N, 15.21.
N-(4-chlorophenyl)-N -(2-benzothiazolyl) thiourea (2b)
White stick; Yield 83.7 ; mp 219.5-221.5 C; IR
max
(KBr): 3174 (m, N-H), 3030 (w, ArH), 1605, 1590 (m, Ar),
1
1
1262 (m, C=S), 1189 (m, C-N), 836, 757 cm ; H NMR :
7.28-7.75 (m, 8H, ArH), 9.15 (s, 1H, NH), 12.98 (s, 1H, NH);
Anal. Calcd. for C14H10ClN3S2: C, 52.58; H, 3.13; N, 13.15.
Found: C, 52.39; H, 3.25; N, 13.10.
N-(4-ethoxyphenyl)-N -(2-benzothiazolyl) thiourea (2h)
White stick; Yield 82.9%; mp 212-214 C; IR
max
(KBr): 3174 (m, N-H), 3025 (w, ArH), 2983, 2920 (w, Et),
1594, 1573 (m, C=O), 1242 (m, C=S), 1188 (m, C-N), 839,
1
756 cm-1; H NMR : 1.44 (t, 3H, CH3), 4.08 (q, 2H, CH2),
N-(4-chlorophenyl)-N -(4-antipyrinyl) thiourea (2c)
6.91-7.79 (m, 8H, ArH), 9.31 (s, 1H, NH), 12.55 (s, 1H, NH);
Anal. Calcd. for C16H15N3OS2:C, 58.36; H, 4.56; N, 12.77.
Found: C, 58.22; H, 4.57; N, 12.42.
White nee dle; Yield 95.5 ; mp 210-212 C; IR
max
(KBr): 3262, 3110 (m, N-H), 3066 (w, ArH), 2929 (w, CH3),
1636 (m, C=O), 1617, 1574 (m, Ar), 1293 (m, C=S), 833,
1
1
726, 721 cm ; H NMR : 2.30 (s, 3H, CH3), 3.17 (s, 3H,
CH3), 7.17-7.59 (m, 9H, ArH), 8.88-8.07 (s, 1H, NH), 10.10
(s, 1H, NH); Anal. Calcd. for C18H17ClN4OS: C, 57.99; H,
4.56; N, 15.03. Found: C, 57.72; H, 4.39; N, 14.89.
N-(4-ethoxyphenyl)-N -(4-antipyrinyl) thiourea (2i)
White nee dle; Yield 91.1%; mp 206-208 C; IR
max
(KBr): 3262, 3111 (m, N-H), 3065 (w, ArH), 2929 (w CH3),
1637 (m, C=O), 1618, 1574 (m, C=O), 1293 (m, C=S), 830,

Solvent-freeSynthesisofHeterocyclicThioureas
J. Chin. Chem. Soc., Vol. 48, No. 1, 2001 75
1
761, 720 cm-1; H NMR : 1.37 (t, 3H, CH3), 2.31 (s, 3H,
10. Goff, D. A.; Zuckermann, R. N. J. Org. Chem. 1995, 60,
5744.
CH3), 3.16 (s, 3H, CH3), 3.98 (q, 2H, CH2), 6.74-7.40 (m, 9H,
ArH), 8.40 (s, 1H, NH), 9.51 (s, 1H, NH); Anal. Calcd. for
C20H22N4O2S: C, 62.83; H, 5.76; N, 14.66. Found: C, 62.74;
H, 5.47; N, 14.56.
11. Toda, F.; Tanaka, K.; Hamai, K. J. Chem. Soc., Perkin
Trans. I 1990, 3207.
12. Morey, J.; Frontera, A. J. Chem. Ed. 1995, 72, 63.
13. Toda, F.; Shigemasa, T. J. Chem. Soc., Perkin Trans. I
1989, 209.
Received July 28, 2000.
14. Toda, F.; Takumi, H.; Akehi, M. J. Chem. Soc. Chem.
Commun. 1990, 1270.
Key Words
15. Strauss, C. R. Aust. J. Chem. 1999, 52, 83-96.
16. Galabov, A. S.; Galabov, B. S.; Neykova, N. A. J. Med.
Chem. 1980, 23, 1048.
Solvent-free synthesis; Microwave technology;
Heterocyclic thioureas.
17. (a) Doub, L.; Rich ard son, L. M.; Herbst, D. R.; Black, M.
L.; Stevenson, D. L.; Bambas, L. L.; Youmans, G. P.;
Youmans, A. S. J. Am. Chem. Soc. 1958, 80, 2205. (b)
Glas ser, A. C.; Doughty, R. M. J. Pharm. Sci. 1962, 51,
1031.
18. (a) Vasilev, G.; Tomaleva, Z. Arch. Phytopathol.
Pflanzenshuts 1973, 9, 309. (b) Krause, G.; Franke, R.;
Vasilev, G. N. Biochem. Physiol. Pflanz. 1979, 174, 128.
19. Vasilev, G.; Iliev, L.; Vasilev, R. Mekh Deistviya Gerbits
1971, 187 [Chem. Abstr. 1977, 86, 5117d].
REFERENCES
1. Galema, S. A. Chem. Soc. Rev. 1997, 26, 233.
2. Caddick, S. Tetrahedron 1995, 51, 10403-10432.
3. Mingos, D. M. P. Res. Chem. Intermed. 1994, 20, 85-91.
4. Sridar, V. Curr. Sci. 1998, 74, 446-450.
5. Loupy, A.; Petit, A.; Hamelin, J.; Texierboullet, F.;
Jacquault, P.; Mathe, D. Synthesis1998, 1213-1234.
6. Loupy, A. Top. Curr. Chem. 1999, 206, 153-207.
7. Majetich, G.; Hicks, R. Radiat. Phys. Chem. 1995, 45,
567-579.
20. Li, X.-L.; Wang, Y.-M.; Do, D.-M.; Wen, Z.; Xiong,
G.-Q.; Meng, J.-B. Sci ence In China (Se ries B) 1997,
27(3), 202.
8. Mingos, D. M. P.; Baghurst, D. R. Chem. Soc. Rev. 1991,
20, 1-47.
9. Gedye, R. J.; Smith, F.; Westaway, K. C.; Baldisera, L.;
Laberge, L.; Rousell, J. TetrahedronLett.1986, 27, 279.
21. (a) Buu-Hoi, N. G.; Xuong, N. D.; Nam, N. H. J. Chem.
Soc. 1995, 1573-81. (b) Bhargava, P. N.; Devi, K. S. J. In-
dia. Chem. Soc. 1963, 40(10), 868-70. (c) Takahashi, T.;
Kanematsu, K. Yakugaku Zasshi 79. 1959, 172-7.