Synthesis of symmetrical N,N'-disubstituted thioureas and heterocyclic thiones from amines and CS2 over a ZnO/Al2O3 composite as heterogeneous and reusable catalyst

Full text of DOI:10.1021/jo981629b

J . Org. Chem. 1999, 64, 1029-1032
1029
Syn th esis of Sym m etr ica l
N,N′-Disu bstitu ted Th iou r ea s a n d
Heter ocyclic Th ion es fr om Am in es a n d CS
heterogeneous catalysts: the commercial acid montmo-
rillonite KSF calcined at 200 °C for 10 h and the basic
ZnO/Al O composite [Zn-Al HT(500)] prepared in our
2 3
laboratory from the corresponding hydrotalcite-like hy-
droxycarbonate (Zn-Al HT) and calcined at 500 °C for 15
h (see Experimental Section).
5
2
over a Zn O/Al
2 3
O Com p osite a s
Heter ogen eou s a n d Reu sa ble Ca ta lyst
†
‡
†
The catalytic performance of these materials was
evaluated in comparison with the uncatalyzed process.
A mixture of aniline (0.01 mol, 0.9 g, 0.9 mL), carbon
disulfide (0.05 mol, 3.8 g, 3.0 mL), and the heterogeneous
catalyst (1.0 g) was reacted in a small autoclave equipped
with a stirrer, at 100 °C for 5 h. Figure 1 shows the
results in terms of the yield of N,N′-diphenylthiourea 3a
through each of the reactions described above as a
function of time. Both catalysts enhance the reactivity
of the system with respect to the uncatalyzed process.
In particular, after 2 h, product 3a was produced in 83%
yield by using the basic catalyst Zn-Al HT(500), in 43%
yield with the acid clay KSF, and in only in 17% yield by
carrying out the reaction without any catalyst. It should
also be noted that both catalysts become rapidly inhibited
during the reaction and that the more active deactivates
faster. It is reasonable to assume that the reason for the
superiority of the Zn-Al HT(500) for achieving catalytic
activity is related to the presence of basic oxy and
Marco Ballabeni, Roberto Ballini, Franca Bigi,
†
‡
Raimondo Maggi, Mauro Parrini,
Giovanni Predieri, and Giovanni Sartori*
§
,†
Dipartimento di Chimica Organica e Industriale
dell’Universit a` , Viale delle Scienze, I-43100 Parma, Italy,
Dipartimento di Scienze Chimiche dell’Universit a` , Via S.
Agostino 1, I-62032 Camerino (MC), Italy, and Dipartimento
di Chimica Generale ed Inorganica, Chimica Analitica,
Chimica Fisica dell’Universit a` , Viale delle Scienze,
I-43100 Parma, Italy
Received August 11, 1998
In tr od u ction
The reaction of carbon disulfide with amines has been
widely studied in the past few decades. In particular it
has been reported that primary amines react with carbon
disulfide in pyridine or ethanol giving symmetrical
thioureas. The process is catalyzed by different reagents
such as sulfur and dimethylchloroformiminium chloride;
moreover addition of hydrogen peroxide, iodine, or so-
dium hydroxide to remove hydrogen sulfide formed in the
reaction greatly increases the rate of thiourea formation.1
Since the possibility of performing fundamental chemi-
cal reactions in the presence of heterogeneous catalysts
under solventless conditions to minimize waste produc-
2
hydroxy groups which can favor the abstraction of H S.
On the contrary, the acid clay KSF can enhance the
electrophilicity of carbon disulfide, but at the same time
it can reduce the nucleophilicity of the amine by acid-
base interaction.6
Moreover, in comparison experiments with calcined
7
zinc and aluminum oxides, product 3a was obtained in
2
tion is the subject of active investigation in our group,
4
5% yield and 30% yield, respectively, thus proving a
we reinvestigated the above-described thiourea synthesis
by using clay-derived materials as heterogeneous cata-
lysts.
remarkable synergistic effect of both oxides in the mixed
material.
Different primary amines were reacted with CS in the
2
presence of the catalyst Zn-Al HT(500) at 100 °C for 2 h.
Synthetic results are shown in Table 1. Thioureas 3 were
easily recovered by dissolving the final reaction mixture
in methanol, removing the catalyst by filtration, and
adding water until the precipitation was complete.
Clay minerals are materials composed of layers of
metal or non-metal oxides and hydroxides stacked on top
of each other. The ubiquitous cationic clays contain
negatively charged sheets neutralized by interlayer
+
+
2+
3
cations (Na , K , Ca , etc.). The far less common anionic
clays, which were particularly used in this study as
catalyst precursors, are rare in nature but relatively
simple and inexpensive to prepare in the laboratory. They
consist of positively charged metal oxide or hydroxide
(
4) (a) Reichle, W. T. J . Catal. 1985, 94, 547. (b) Reichle, W. T.
Chemtech 1986, 58. (c) Cavani, F.; Trifir o` , F.; Vaccari, A. Catal. Today
991, 11, 173. (d) Trifir o` , F.; Vaccari, A. Hydrotalcite-like Anionic Clays
1
4
layers with anions located interstitially.
(Layered Double Hydroxides). In Comprehensive Supramolecular
Chemistry; Alberti, G., Bein, T., Eds.; Pergamon Press: Oxford, 1996;
Vol. 7, pp 251-291.
(5) KSF (Fluka) is an acid-activated naturally occurring clay mainly
consisting of montmorillonite with the following chemical composition
Resu lts a n d Discu ssion
The reaction of aniline 1a with carbon disulfide 2 to
produce N,N′-diphenylthiourea 3a was studied over two
(average values) SiO
2
(54.0%), Al
2
O
2
3
(17.0%), Fe
O (1.5%) [information kindly fur-
2 3
O (5.2%), CaO (1.5%),
MgO (2.5%), Na O (0.4%), and K
2
nished by S u¨ d Chemie AG] and showing the following physicochemical
parameters: surface acidity 0.85 mequiv of H /g [determined in our
laboratory by temperature-programmed desorption of ammonia gas
+
†
Dipartimento di Chimica Organica e Industriale dell’Universit a` .
Dipartimento di Scienze Chimiche dell’Universit a` .
Dipartimento di Chimica Generale ed Inorganica, Chimica Anal-
‡
(NH -TPD): Berteau, P.; Delmon, B. Catal. Today 1989, 5, 121],
3
§
2
surface area 15 ( 10 m /g [determined in our laboratory by B.E.T.
method: Brunauer, S.; Hemmett, P. H.; Teller, E. J . Am. Chem. Soc.
1938, 60, 309]. The catalyst was calcined at 200 °C for 10 h to remove
the mobile surfacial and interstitial water avoiding the collapse of the
laminar structure [Alberti, G.; Costantino, U. Layered Solids and their
Intercalation Chemistry. In Comprehensive Supramolecular Chemistry;
Alberti, G., Bein, T., Eds.; Pergamon: Oxford, 1996; Vol. 7, pp 1-23].
(6) Casal, B.; Ruiz-Hitzki, E.; Serratosa, J . M.; Fripiat, J . J . J . Chem.
Soc., Faraday Trans. 1984, 80, 2225. Budjak, J .; Slosiarikova, H.; Cicel,
B. J . Inclusion Phenom. 1992, 13, 321.
itica, Chimica Fisica dell’Universit a` .
(
1) Dunn, A. D.; Rudorf, W. D. Carbon Disulphide in Organic
Chemistry; Ellis Horwood Lim.: Chichester, 1997; pp 226-315. Ozaki,
S. Chem. Rev. 1972, 72, 457. Yamazaki, N.; Tomioka, T.; Higashi, F.
Synthesis 1975, 384.
(2) Arienti, A.; Bigi, F.; Maggi, R.; Marzi, E.; Moggi, P.; Rastelli,
M.; Sartori, G.; Tarantola, F. Tetrahedron 1997, 53, 3795. Bigi, F.;
Carloni, S.; Maggi, R.; Muchetti, C.; Sartori, G. J . Org. Chem. 1997,
6
2, 7024. Bigi, F.; Maggi, R.; Sartori, G.; Zambonin, E. J . Chem. Soc.,
Chem. Commun. 1998, 513.
3) Corn e´ lis, A.; Laszlo, P. Synlett 1994, 155. Balogh, M.; Laszlo, P.
Organic Chemistry Using Clays; Springer-Verlag: New York, 1993.
(7) Calcined zinc and aluminium oxides were prepared from the
corresponding nitrates following the same methodology utilized in the
preparation of Zn-Al HT(500) (see ref 4a).
(
1
0.1021/jo981629b CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/09/1999

1
030 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
Ta ble 2. Rea ction of Am in es Bea r in g a n Ad d ition a l
Nu cleop h ilic Gr ou p w ith CS2 over th e Ca ta lyst Zn Al
HT(500)
F igu r e 1.
Ta ble 1. Rea ction of P r im a r y Am in es w ith Ca r bon
Disu lfid e over th e Ca ta lyst Zn -Al HT(500)
3
yield
favoring the abstraction of the NH proton. Supporting
evidence for the isothiocyanate intermediacy is suggested
by isolation of (()-1-phenylethyl isothiocyanate in 22%
yield in the reaction of (()-1-phenylethylamine and
carbon disulfide at 25 °C for 1 h in the presence of Zn-Al
HT(500). Evidently, secondary amines cannot produce the
active intermediate 5 and are thus recovered unchanged.
However, when amine 1 contains an additional nucleo-
philic group, a fast intramolecular attack converts inter-
mediate 4 into different heterocyclic thiones in high yield
irrespective of the nature of the amino group (see, for
example, Table 2, entry a).
entry
R
[selectivity] (%)
a
b
c
d
e
f
g
h
i
C6H5
83 [98]
87 [100]
69 [99]
4-CH3C6H4
4-ClC6H4
2-pyridyl
C6H5CH2
(R)-C6H5(CH3)CH
C6H11
57 [92]
98 [100]
100 [100]
91 [97]
95 [98]
97 [98]
C5H11
C8H17
j
(CH3)3C
100 [100]
Sch em e 1
Thus, oxazolidine-2-thiones 710 and 8,11 1-mercapto-
benzothiazole 9,12 and imidazolidine-2-thione 10 were
synthesized in high yield and in short reaction time,
avoiding use of strong homogeneous acids and bases.
We next studied the reusability of the catalyst in the
model reaction with aniline. Thus, methanol was added
to the final reaction mixture, and the catalyst was
recovered by filtration and further washed with hot
methanol to completely remove organic compounds and
traces of sulfur which can act as inhibitors.14 After being
dried under vacuum at 120 °C for 2 h, the catalyst was
reused. Five cycles were thus repeated without apparent
loss of the catalytic activity, with compound 3a being
obtained in 82%, 78%, 75%, 80%, and 78% yield.
13
The yields of products 3 are affected by the nature of
the amine utilized. In fact, as expected for a typical
nucleophilic addition, aliphatic amines show higher
reactivity than the aromatic ones (compare, for example,
Table 1, entries a-d with e-j). Moreover, complete
retention of optical activity is observed in the reaction
with a chiral amine (Table 1, entry f).
The procedure is efficiently applicable to primary
amines, but not to the secondary ones which are quan-
titatively recovered unchanged. This fact strongly sug-
Finally, X-ray diffraction (XRD) analysis of the catalyst
was performed to check its stability and to recognize
possible transformations during the reaction. The XRD
analysis, carried out on the Zn-Al HT(500) fresh catalyst,
15a
clearly shows the XRD pattern of ZnO (zincite) as the
unique crystalline phase, suggesting that this material
gests that the dithiocarbamic acid 4 initially formed by
8
nucleophilic attack of the amine to CS
2
can be converted
(9) See, for example: Gilsdorf, R. T.; Nord, F. F. J . Org. Chem. 1950,
into the more electrophilic isothiocyanate 5 (Scheme 1).
One equivalent of H S is released in this step.Thiourea
is thus produced by a rapid addition of a second
15, 807. Robbins, J . D.; Neal, J . R. Synth. Commun. 1986, 16, 891.
Walter, W.; Bode, K.-D. Angew. Chem., Int. Ed. Engl. 1967, 6, 281.
2
(
10) Moreno-Manas, M.; Padros, I. J . Heterocycl. Chem. 1993, 30,
235.
(11) Chanon, M.; Chanon, F.; Metzger, J . J . Chem. Soc., Chem.
Commun. 1974, 425.
3
1
9
molecule of amine 1 to 5. We assume that the basic
catalyst can enhance the isothiocyanate production by
(12) Sebrell, L. B.; Boord, C. E. J . Am. Chem. Soc. 1923, 45, 2390.
(
13) Allen, C. F. H.; Edens, C. O.; VanAllan, J . Organic Syntheses;
(8) We did not isolate from our reaction mixtures any dithiocar-
Wiley: New York, 1955; Collect. Vol. 3, p 394.
bamate-amine salts which were previously obtained by carrying out
the reaction in acetone or ethanol solution and in the presence of an
excess of amine: Foye, W. O.; Speranza, J . P. Eur. J . Med. Chem. 1977,
(14) A dramatic drop in the yield of 3a (∼40% yield) was effectively
observed by carrying out the model reaction in the presence of sulfur
(200 mg).
(15) Powder Diffraction File cards (a) No. 5-0664 and (b) No. 5-0566,
J CPDS, International Center for Diffraction Data, Swarthmore, PA.
9
, 177. Bazavova, I. M.; Dubenko, R. G.; Shevchenko, L. I.; Pel′Kis, P.
S. Ukr. Khim. Zh. 1980, 46, 286 (Chem. Abstr. 1980, 93, 71237p).

Notes
J . Org. Chem., Vol. 64, No. 3, 1999 1031
is a composite system consisting of crystalline grains of
zinc oxide in amorphous alumina. After the catalyst runs,
two XRD patterns are observed, i.e., that of zincite
powder pattern of this material corresponds to that of a mixture
of ZnO and Zn-Al HT. This material was calcined at 500 °C for
2
1
[
5 h, giving a catalyst with a surface area of 124 ( 6 m /g
determined in our laboratory by B.E.T. method: see ref 5] and
superimposed by a set of large peaks due to ZnS
with the following chemical composition (average values): Zn
5b
(
sfalerite),1 probably produced by the reaction of H
2
S
(33.70%), Al (7.63%).
with the catalyst. Despite this, the permanence of
adequate amounts of zinc oxide allows a high level of
catalytic activity at least for five cycles as stated before.
One could suppose from these results that after the first
Syn th esis of N,N′-Disu bstitu ted Th iou r ea s 3. Gen er a l
P r oced u r e. The selected amine (0.01 mol), Zn-Al HT(500) (1.0
g), and CS (3 mL) were heated at 100 °C in a small autoclave
2
under vigorous stirring. After 2 h the reaction mixture was
cooled to room temperature and the excess of carbon disulfide
removed under reduced pressure. Hot methanol (50 mL) was
added, and the catalyst was removed by filtration and washed
with hot methanol (50 mL). After cooling to room temperature,
the N,N′-disubstituted thiourea was precipitated by adding
distilled water (250 mL). The product was isolated by Buchner
filtration and recrystallized from methanol.
run the new catalyst could be a mixture of ZnS and Al
or ZnS alone. However, when commercial zinc sulfide
X-ray peak widths (2ϑ) ca. 0.2°] was used as heteroge-
neous promoter, no catalytic effect was observed (3a yield
6%; compound 3a was obtained in 17% yield without
catalyst). On the other hand, an additional experiment
with a 4:1 molar ratio mixture of ZnS:basic Al gave
product 3a in 35% yield. A quite similar result (42% yield)
was achieved with basic Al alone. From these data
2 3
O
[
1
N,N′-Dip h en ylth iou r ea (3a ): yield 0.95 g (83%), white solid;
2
O
3
mp 152-3 °C (lit.17 mp 152 °C).
N,N′-Bis[4-m eth ylph en yl]th iou r ea (3b): yield 1.12 g (87%),
2
O
3
17
white solid; mp 173-5 °C (lit. mp 174-5 °C).
we do not exclude the possibility that ZnS could behave
as cocatalyst; however, this effect would operate to a
significant extent only in the case of the composite
system, where ZnS nanocrystallites [X-ray peak widths
N,N′-Bis[4-ch lor op h en yl]th iou r ea (3c): yield 1.03 g (69%),
white solid; mp 166-7 °C (lit.17 mp 167 °C).
N,N′-Bis[2-p yr id yl]th iou r ea (3d ): yield 0.66 g (57%), white
solid; mp 152-3 °C (lit.18 mp 152-4 °C).
N,N′-Diben zylth iou r ea (3e): yield 1.26 g (98%), white solid;
(2ϑ) ca. 2°] are dispersed in the amorphous alumina.
mp 145-7 °C (lit.19 mp 146-8 °C).
(
R,R)-N,N′-Bis[r-m eth ylben zyl]th iou r ea (3f): yield 1.42
20
Con clu sion s
g (100%), pale gray solid; mp 200-1 °C (lit. mp 202-3 °C);
2
5
20
25
[
R]
D
) -104.2 [c ) 1.3; CHCl
]).
3
] (lit. [R]
D
) -105.4 [c ) 1.3;
2 3
In conclusion we have shown that the ZnO/Al O
CHCl
3
composite [Zn-Al HT(500)], easily prepared in the labora-
tory, can afford an efficient and reusable catalyst in the
synthesis of symmetric N,N′-disubstituted thioureas from
primary amines and carbon disulfide. This procedure can
also be applicable to the synthesis of different heterocyclic
thiones by using amines bearing additional nucleophilic
groups.
N,N′-Dicycloh exylth iou r ea (3g): yield 1.09 g (91%), white
solid; mp 179-80 °C (lit. mp 180-2 °C).
N,N′-Dip en tylth iou r ea (3h ): yield 1.03 g (95%), white solid;
21
1
mp 56-8 °C; H NMR (300 MHz, CDCl
3
) δ 0.8-1.0 (6 H, m),
1
.2-1.5 (8 H, m), 1.5-1.7 (4 H, m), 3.4 (4 H, br s), 5.8 (2 H, br
-
1
+
s); IR (KBr) 3220, 1560 cm ; MS m/z (M ) 216 (3), 183 (4), 127
6), 43 (100). Anal. Calcd for C11 S: C, 61.1; H, 11.2; N,
3.0. Found: C, 61.3; H, 11.1; N, 12.9).
(
1
24 2
H N
The use of this heterogeneous catalyst makes product
isolation easier, gives a clean reaction, and is of course
advantageous in an economical and environmental sense.
A possible drawback of the present methodology is
N,N′-Dioctylth iou r ea (3i): yield 1.46 g (97%), white solid;
mp 55-6 °C (lit.22 mp 53-55 °C).
N,N′-Di-ter t-bu tylth iou r ea (3j): yield 0.94 g (100%), white
solid; mp 129-31 °C (lit.23 mp 131-2 °C).
(
()-1-P h en yleth yl isoth iocya n a te (5): yield 0.36 g (22%),
24
2
represented by the production of H S. However, removal
pale yellow oil; bp 131-134 °C/20 mmHg (lit. bp 133-134 °C/
0 mmHg).
of this hazardous compound from reaction mixtures
2
represents a general and previously solved problem.16
Syn th esis of Heter ocyclic Th ion es 7, 8, 9, a n d 10.
Gen er a l P r oced u r e. The selected amine (0.01 mol), Zn-Al HT-
(500) (1.0 g), and CS (3 mL) were heated at 100 °C in a small
Exp er im en ta l Section
2
autoclave under vigorous stirring. After 2 h the reaction mixture
was cooled to room temperature and the excess of carbon
disulfide removed under reduced pressure. The crude was
chromatographed on silica gel column with hexane-ethyl
acetate mixtures (20-30%) to give the products.
Gen er a l. Melting points are uncorrected. 1H NMR spectra
were recorded at 300 MHz. Mass spectra were obtained in EI
mode at 70 eV. Microanalyses were carried out by the Diparti-
mento di Chimica Generale ed Inorganica, Chimica Analitica,
Chimica Fisica dell′Universit a` di Parma, Italy. TLC analyses
were performed on Merck 60 PF254 silica gel plates using
mixtures of hexane-ethyl acetate (25-35%). XRD spectra were
obtained on a Philips PW 1050 instrument using the Cu-KR
radiation. All the reagents were of commercial quality from
freshly opened containers.
(
4S,5R)-3,4-Dim eth yl-5-p h en yloxa zolid in e-2-th ion e (7):
10
yield 2.03 g (98%), white solid; mp 49-50 °C (lit. mp 48-9 °C);
25
10
25
[
R]
MeOH]).
,4-Dim eth yloxa zolid in e-2-th ion e (8): yield 1.21 g (92%),
D
) -214 [c ) 1.3; MeOH] (lit. [R]
D
) -216 [c ) 1.3;
3
1
1
white solid; mp 121-2 °C (lit. mp 123 °C).
-Mer ca p toben zoth ia zole (9): yield 1.54 g (92%), white
4
a
Syn th esis of Zn -Al HT(500). NaOH (1.75 mol, 70.0 g), Na
2
-
1
CO (0.47 mol, 50.0 g), and distilled water (500 mL) were
3
1
2
solid; mp 176-7 °C (lit. mp 177 °C).
introduced in a 2-L flask equipped with a mechanical stirrer, a
dropping funnel, and a thermometer. Then a solution of Zn-
(
9
NO
3
)
2
‚6H
2
O (0.50 mol, 148.7 g) and Al(NO
3
)
3
‚9H
2
O (0.25 mol,
(17) Chattopadhyaya, J . B.; Rama Rao, A. V. Synthesis 1974, 289.
(
18) Sudha, L. V.; Sathyanarayana, D. N. J . Chem. Soc., Perkin
Trans. 2 1986, 1647.
19) Boas, U.; J akobsen, M. H. J . Chem. Soc., Chem. Commun. 1995,
995.
20) Chinchilla, R.; Najera, C.; Sanchez-Agullo, P. Tetrahedron:
3.8 g) in distilled water (300 mL) was added dropwise at room
temperature during 5 h under vigorous stirring. Following the
addition which results in a heavy slurry, the flask content was
heated at 65 ( 5 °C for about 18 h with continuous vigorous
stirring. The slurry was then cooled to room temperature,
filtered, and washed until the sodium content in the resulting
solid was below 0.1% (dry basis). The solid was then dried under
vacuum at 125 °C for 18 h, giving a white powder. The X-ray
(
1
(
Asymmetry 1994, 5, 1393.
(21) Wragg, R. T. Tetrahedron Lett. 1970, 3931.
(22) Foye, W. O.; LaSala, E. F.; Georgiadis, M.; Meyer, W. L. J .
Pharm. Sci. 1965, 54, 557.
(23) Sakai, S.; Fujinami, T.; Aizawa, T. Bull. Chem. Soc. J pn. 1977,
5
0, 425.
(16) Kirk-Othmer. Encyclopedia of Chemical Technology, 3rd ed.;
(24) Luskin, L. S.; Gantert, G. E.; Craig, W. E. J . Am. Chem. Soc.
1
983; Vol. 22, pp 267-297. Startsev, A. N. Catal. Rev. 1995, 37, 353.
1956, 78, 4965.

1
032 J . Org. Chem., Vol. 64, No. 3, 1999
Notes
Im id a zolid in e-2-th ion e (10): yield 1.02 g (100%), white
solid; mp 195-6 °C (lit. mp 195-7 °C).
delle Ricerche (CNR), Italy and the Universities of
Parma and Camerino (MC) (National Project “Stereo-
selezione in Sintesi Organica. Metodologie ed Appli-
cazioni”). The facilities of the Centro Interdipartimen-
tale Misure (CIM) [NMR and mass instruments] and
of the Centro di Studio per la Strutturistica Diffratto-
metrica del CNR [XRD] were used. Thanks are due to
Mr Pier Antonio Bonaldi for technical collaboration.
2
5
Ack n ow led gm en t. The authors are grateful to Prof.
Angelo Vaccari (Dipartimento di Chimica Industriale e
dei Materiali, Universit a` di Bologna, Italy) for helpful
discussions. The authors acknowledge the support of the
Ministero dell’Universit a` e della Ricerca Scientifica e
Tecnologica (MURST), Italy, the Consiglio Nazionale
(25) Field, L.; Kim, H. K. J . Org. Chem. 1966, 31, 597.
J O981629B