Novel self-condensation of ammonium dithiocarbamates leading to symmetrical substituted thioureas

Article abstract of DOI:10.1080/10426507.2016.1223075

For the first time, the formation of symmetrical substituted thiourea analogues generated by the selfcondensation of trialkylammoniumdithiocarbamates is reported. The reactions occurred under mild conditions. The method allows the use of amines possessing a weak nucleophilic feature in good yields. The highlight of the study is a novel self-condensation mechanism based on dithiocarbamates as a basic compound in organic chemistry.

Full text of DOI:10.1080/10426507.2016.1223075

ACCEPTED MANUSCRIPT
Novel Self-Condensation of Ammonium Dithiocarbamates Leading to Symmetrical
Substituted Thioureas
Şevket Hakan Üngören*, Fatih Sırça
Department of Chemistry, Faculty of Arts and Sciences, Bozok University, 66200 Yozgat, Turkey
*Corresponding author: Tel.: +90 354 242 1021; fax: +90 354 242 1022. Email:
shakan.ungoren@bozok.edu.tr
Abstract
For the first time, the formation of symmetrical substituted thiourea analogues generated by
the self-condensation of trialkylammonium dithiocarbamates is reported. The reactions
occurred under mild conditions. The method allows the use of amines possessing a weak
nucleophilic feature in good yields. The highlight of the study is a novel self-condensation
mechanism based on dithiocarbamates as a basic compound in organic chemistry.
1
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Keywords
Self-Condensation, N,N'-disubstituted thiourea, ammonium dithiocarbamate, competing
reactions.
2
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Introduction
In organic synthesis, ammonium alkyl/aryl-dithiocarbamates have been widely used as an
ambient nucleophile. These building blocks are capable of condensation with alkyl and acyl
halides,[1−6] ketones,[7] esters,[8] aryldiazonium chlorides.[9] Besides, the dithiocarbamate
derivatives could react to alkenes[10] and alkynes[8] functionalized with carbonyl group under
mild conditions via Michael Addition. In addition, they are very useful starting materials for the
synthesis of isothiocyanates by means of desulfurizing agents.[11,12]
The synthesis of thiourea from dithiocarbamate derivatives has caught the attention of
chemists over several decades.[13] The published classical methods involve the preparations of
thioureas from amine and isothiocyanate derivatives as key-intermediate in presence of KOH,
Lac-sulfur, MCM-41-TBD, Scheme 1.[14] Recently published green and improved methods
reveals that amines react with dithiocarbamic acids and their ammonium salts by sun light,[15]
microwave,[16] ultra sound[17] and thermal effects[18] to afford various substituted thioureas.
With this paper we provide information about the thiourea synthesis via novel self-
condensation mechanism of trialkylammonium dithiocarbamates.
Results and discussion
According to the published procedure,[5] triethylamonnium phenylditihiocarbamate (1a) was
prepared from the reaction of aniline, carbon disulfide and triethylamine without any solvent at
0-5 ˚C, and purified by washing with diethyl ether. Then, a suspension of 10 mmol 1a in ethyl
3
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
acetate (EtOAc) was refluxed for 15 min. At the end of the reaction time, the crude products
were filtered from the cooled reaction medium, in 66% yield. 1H and 13C NMR data and melting
point of the product clearly revealed the structure of N,N'-diphenylthiourea (2a).[5]
In order to propose a general reaction equation as shown Table 1, additional thiourea
compounds (2b-i) were prepared at different patterns from various alkyl and aryl
dithiocarbamates (1b-i),[5, 19] in moderate and good yields (55-85%).
In these reactions, notably, the transformation of ADCs to the corresponding thioureas via this
method depends on the solubility of trialkylammonium dithiocarbamates in the warmed
solvent. For instance, compound 1h was insoluble in hot EtOAc, DMF and 1,4-dioxane. So, the
self-condensation of 1h in these solvents failed to synthesize the corresponding thiourea.
However, when 1h was warmed in DMSO to 100˚C for 15 min, the reaction product 2h was
isolated from the reaction mixture successfully, in 49%. yield Therefore some reactions were
performed in DMSO and DMF as polar and inert solvents, as shown in Table 1.
The 1H spectrum of 2g showed the two NH2 group protons at δ 7.31 ppm and two NHAr protons
at 10.29 ppm. The 13C atoms of 2g were resonated by giving five signals at 180.1 ppm (C = S),
and 142.8, 139.8, 126.7, 123.3 ppm (C = C). The HRMS spectrum reveals the exact chemical
composition of 2g by showing M + H signal at 387.02499.
Taking account of the nucleophilic and electrophilic characteristics of ADCs, we may suggest a
three reaction pathway;
4
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Firstly, the reactions have a self-condensation mechanism as shown Scheme 2a. In this
mechanism, mercaptobis(alkyl/arylamino)methanethiolate might be occurred as a key-
intermediate which offered for condensation mechanism of sodium dithiocarbamate salts with
amines by Maddani et al.[20]
Another scenario could be outlined in Scheme 2b, perhaps, any amount of ADC in reaction
mixture might lead to the corresponding isothiocyanate as key intermediate by elimination of 1
equivalent H2S from the structure. Then, the isothiocyanate derivative reacts with the
remaining ADC derivative, and yields the N,N'-disubstituted thiourea derivative.
A third possibility is that ammonium dithiocarbamate slowly decomposes back into an amine
and CS2 by thermal effect in the reaction media. This amine might react with the rest of the
dithiocarbamate in the reaction mixture to form the thiourea derivative, Scheme 2c.
To reach a reliable mechanism, we investigated the intramolecular condensation of
aryldithiocarbamate salts substituted with carboxylic acid group at 2-position (3a, b) in DMF at
100 ˚C for 15 min. When the molecular structures of the isolated products (4a, b) were
illuminated by spectroscopic techniques, it was seen that there was no occurrence of
isothiocyanate derivatives which would yield benzoxazine-4-ones, Scheme 3. Instead, the
reactions have been started via intramolecular attack of S-atom to C = O group of carboxylic
acid moiety and gave benzothiazin-4-one derivatives, in good yield (53-61%). Ccompound 4a
have been reported from same reaction earlier,[21] and its NMR data are identical with our
5
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
spectral data. Thus, it was seen that isothiocyanate does not occur as key intermediate in
remarkable yields under these working reaction conditions and Scheme 2b is improbable.
In another respect, is Scheme 2c a possible way for the formations of the corresponding
thiourea derivatives? For this question, we investigated the crude reaction products of 1f in the
presence of p-toluidine.
2 mmol of 1f and 1 mmol p-toluidine were refluxed in dioxane for 15-20 min., Scheme 4. After
evaporation of the dioxane, the crude product of competing reactions was washed with cold
1
petroleum ether and analyzed by a H NMR experiment. We have not observed evidence for
the corresponding condensation product 5. On the other hand, compound 2f and p-toluidine
were clearly detected from the spectrum of the crude product, and TLC. Amines are less
reactive than ADCs for condensation to ADCs as shown Scheme 4, and the reaction pathway in
Scheme 2c has is not dominant under the reaction conditions. Thus, probable self-condensation
mechanism of ADCs has been confirmed by interpretation of the experiments including Scheme
3 and Scheme 4.
In summary, we have described an interesting and novel sample of self-condensation in organic
chemistry. The present method for the synthesis of symmetrical substituted thioureas is
different from the numerous published ones which include the condensation of amines with
thiourea,[22] thiophosgene,[23] O-alkyl arylthiocarbamates,[24] dithiocarbamic acid or its
derivatives.[14−18] This improved method corresponds to the usage of the amines bearing
6
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
electron withdrawing groups for synthesis of thioureas in good yield. Nine symmetrical N,N'-
disubstituted thioureas were prepared via this method and three of them (2g-i) are new.
Experimental Section
Mp was measured on an Electro thermal 9100 apparatus and are uncorrected. Elemental
1
analyses for C, H and N were carried out using a LECO-932 CHNS-O Elemental Analyzer. H and
13C NMR spectra were recorded on Bruker Advance 400 spectrometer using CDCl3 or DMSO−d6
solvents. The IR spectra were recorded with ATR method using a Shimadzu 8400 and Perkin
Elmer Spectrum Two Model FT-IR spectrometer. HR-MS analyses were carried out with Agilent
Technologies 6224 TOF LC/MS. The compounds 1a-f[5] and 1g19 were prepared according to
published procedures. The Supplemental Materials contains characterization data and sample
spectra for products 2a-I (Figures S 1 -- S 21)
Triethylammonium 4-carbamoylphenylcarbamodithioate (1h)
To a suspension of CS2 (4 mmol 0.304) and 4-aminobenzamide (3 mmol, 0.408 g) in methanol (3
mL) was added triethylamine (3 mmol, 0.303 g) and the mixture was stirred at 30-40 ˚C for 20
min. During the reaction, the mixture was become a clear yellow solution, and then the product
precipitated. The white precipitated solid was filtered and washed with diethyl ether.
White solid; yield: 230 mg (73%); mp 175--178°C.
Triethylammonium pyrimidin-2-ylcarbamodithioate (1i)
To solution of CS2 (12 mmol 0.912 g) and 2-aminopyrimidine (10 mmol, 0.951 g) in DMSO (3 mL)
was added triethylamine (10 mmol, 1.012 g) and the mixture was stirred at 30-40 ˚C for 1 h. The
7
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
solution contains the corresponding ammonium dithiocarbamate salt (1i) and this compound
was used without additional purification.
General procedures for the preparation of symmetrical substituted thiourea analogs (2a-h)
A suspension of 10 mmol ADC (1a-h) in solvent (5 mL) given in Table 1 was warmed at the
temperature which was showed in Table 1 for 15-20 min. After cooling the mixture to 5 ˚C, the
precipitated product was filtered. In the event that there was no precipitate when cooling the
solvent (in general for DMF or DMSO), the product was precipitated by adding 3-4 mL water.
The crude products were recrystallized from corresponding solvent in Table 1.
4,4'-Thiocarbonylbis(azanediyl)dibenzenesulfonamide (2g)
White solid; yield: 1216 mg (63%); mp 230--231°C. IR (ATR): 3340, 3242, 3192, 3106 (NH), 3011
1
cm1 (CH, Ar). H NMR (400 MHz, DMSO-d6):  = 10.29 (s, 21H, NH), 7.787.67 (m, 8H, Ar‒H),
7.31 (s, 22H, NH2). 13C NMR (DMSO-d6, 100 MHz):  = 180.1 (C = S), 142.8, 139.8, 126.7, 123.3
(C = C, Ar). HRMS (ESI): m/z [M + H]+ calcd for C13H15N4O4S3: 387.02455; found: 387.02499. Anal.
Calcd for C13H14N4O4S3: C, 40.40; H, 3.65; N, 14.50; S, 24.89. Found: C, 40.54; H, 3.59; N, 14.26;
S, 25.01.
4,4'-Thiocarbonylbis(azanediyl)dibenzamide (2h)
White solid; yield: 769 mg (49%); mp 283--284°C. IR (ATR): 3411 (NH), 3254, 3198 (NH2), 1652
1
cm1 (C = O). H NMR (400 MHz, DMSO-d6):  = 10.16 (s, 21H, NH), 7.31 (s, 22H, NH2),
7.937.56 (m, 8H, Ar‒H). 13C NMR (DMSO-d6, 100 MHz):  = 179.7 (C = S), 167.8 (C = O), 142.5,
8
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
130.2, 128.4, 122.6 (C = C, Ar). Anal. Calcd for C15H14N4O2S: C, 57.31; H, 4.49; N, 17.82; S, 10.20.
Found: C, 57.34; H, 4.44; N, 17.73; S, 10.45.
N,N'-Dipyrimidin-2-ylthiourea (2i)
The solution of 1i in 3 mL DMSO was warmed at 100 ˚C for 15 min. After the mixture was
cooled to room temperature, 2-3 mL H2O was added. Precipitated yellow solid was filtered and
then recrystallized from DMF-H2O (1:1).
Yellow solid; yield: 638 mg (55%); mp 332--333°C. IR (ATR): 3158, 3124 (NH), 1619 cm1 (C = N).
1H NMR (400 MHz, DMSO-d6):  = 13.66 (s, 1H, NH), 13.15 (s, 1H, NH), 8.307.30 (m, 6H, Ar‒H).
13C NMR (DMSO-d6, 100 MHz):  = 188.4 (C = S), 170.9, 136.8, 136.5, 130.6, 125.7, 123.1, 116.7
(C = C, Ar). Anal. Calcd for C9H8N6S: C, 56.54; H, 3.47; N, 36.18; S, 13.81. Found: C, 56.63; H,
3.41; N, 36.26; S, 14.03.
General procedures for the preparation of 2-thioxo-1,2-dihydro-4H-3,1-benzothiazin-4-one
analogs (4a-b)
To solutions of anthranilic acid derivatives (10 mmol) and triethylamine (11 mmol) in 2 mL DMF
were added 15 mmol CS2, than stirred for 30 min. Meantime, triethylammonium 2-
carboxyphenylcarbamodithioate derivatives were occurred in the DMF. Then, the solutions
were warmed at 100 ˚C for 15 min. After cooling reaction mixtures to 5 ˚C, the products were
precipitated by adding 2-3 mL water.
9
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
6-Hydroxy-2-thioxo-1H-benzo[d][1,3]thiazin-4(2H)-one (4b)
Orange-red solid; yield: 1280 mg (61%); mp 276--278°C. IR (ATR): 3318 (OH), 3133 (NH), 1629 (C
1
= O), 1330 cm1 (C = S). H NMR (400 MHz, DMSO-d6):  = 13.67 (s, 1H, NH), 10.34 (s, 1H, OH),
7.487.22 (m, 3H, Ar‒H). 13C NMR (DMSO-d6, 100 MHz):  = 185.7 (C = S), 184.2 (C = O), 155.6,
135.6, 125.8, 121.9, 120.4, 119.2 (C = C, Ar). Anal. Calcd for C8H5NO2S2: C, 45.48; H, 2.39; N,
6.63; S, 30.36. Found: C, 45.23; H, 2.32; N, 6.77; S, 30.55.
Acknowledgment
This work was financially supported by Bozok University Research Fund, Project No:
2015FBE/T199.
10
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
References
[1] Sontakke, M. M.; Bhaskar, C. S.; Berad, B. N.; Dhonde, M. G. Lett. Org. Chem. 2015, 12, 115-
121.
[2] Ramesh, V.; Ananda, R. B.; Sharma, P.; Swarna, B.; Thummuri, D.; Srinivas, K.; Naidu, V. G.
M.; Jayathirtha, R. V. Eur. J. Med. Chem. 2014, 83, 569-580.
[3] Wong, R.; Dolman, S. J. J. Org. Chem. 2007, 72, 3969-3971.
[4] Ritter W. Tetrahedron Lett. 1967, 8, 4593-4594.
[5] Fülöp, V.; Kalman, A.; Beckert, R.; Fabian, J. Monatsh. Chem. 1989, 120, 561-569.
*6+ Üngören, Ş. H.; Albayrak, S.; Günay, A.; Yurtseven, L.; Yurttaş, N. Tetrahedron 2015, 71,
4312-4323.
[7] Emami, S.; Hosseinimehr, S. J.; Shahrbandi, K.; Enayati, A. A.; Esmaeeli, Z. Arch. Pharm. 2012,
345, 629-637.
[8] Alizadeh, A.; Rostamnia, S.; Zohreh, N.; Hosseinpour, R. Tetrahedron Lett. 2009, 50, 1533-
1535.
[9] Haque, M. Z.; Ali, M. U.; Ali, M. H. J. Indian. Chem. Soc. 2001, 78, 372-373.
[10] Yadav, L. D. S.; Rai, V. K. Tetrahedron 2006, 62, 8029-8034.
[11] Harisadhan, G.; Ramesh ,Y.; Jayashree, N.; Bhisma, K. P. Eur. J. Org. Chem. 2008, 36, 6189-
6196.
[12] Furukawa, I.; Abe, N.; Hashimoto, S. Nippon Kagaku Kaishi 1989, 5, 822-825.
[13] Schroeder, D. C. Chem. Rev., 1955, 55, 181-228.
11
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
[14] (a) Zhang, Z.; Wu, H. H.; Tan, Y. J. RSC Advances 2013, 3, 16940-16944. (b) Ramadas, K.;
Janarthanan, N.; Velmathi, S. Synthetic Commun. 1997, 27, 2255-2260. (c) Ballini, R.; Bosica,
G.; Fiorini, D.; Maggi, R.; Righi, P.; Sartori, G.; Sartorio, R. Tetrahedron Lett. 2002, 43, 8445-
8447.
[15] (a) Priyanka, P.; Kumavat, A. D.; Jangale, D. R.; Patil, K. S.; Dalal, J. S.; Meshram, D. S. D.
Environ. Chem. Lett. 2013, 11, 177-182. (b) Jangale, A. D.; Kumavat P. P.; Wagh, Y. B.; Tayade,
Y. A.; Mahulikar, P. P.; Dalal, D. S. Synthetic Commun. 2015, 45, 236-244.
[16] Brindaban, C. R.; Suvendu, S. D.; Santanu, B. Arkivoc 2003, 9, 14-20.
[17] Azizi, N.; Rahimzadeh-Oskooee, A.; Yadollahy, Z.; Ourimi, A. G. Monatsh. Chem. 2014, 145,
1675-1680.
[18] Azizi N.; Khajeh, A. A.; Ghafuri, H.; Bolourtchian, M. Mol. Divers. 2011, 15, 157-161.
[19] Ram, S.; Çelik, G.; Khloya, P.; Vullo, D.; Supuran, C. T.; Sharma, P. K. Bioorg. Med. Chem.
2014, 22, 1873-1882.
[20] Maddani, M. R.; Prabhu, K. R. J. Org. Chem. 2010, 75, 2327-2332.
[21] (a) Ottersbach, P. A.; Häcker, H. G.; Elsinghorst, P. W.; Schnakenburg, G.; Gütschow, M.
Tetrahedron Lett. 2010, 51, 2727-2729. (b) Li-Rong, L.; Wei, F.; Rong-Bin H.; Lan-Sun, Z. Chin.
J. Struct. Chem. 2008, 27, 1059-1064.
[22] Pasha, M. A.; Madhusudana, R. M. B. Synth. Commun. 2009, 39, 2928-2934.
[23] Sharma, S. Synthesis 1978, 11, 803-820.
[24] Halimehjani, A. Z.; Pourshojaei, Y.; Saidi, M. R. Tetrahedron Lett. 2009, 50, 32-34.
12
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Table 1 Self−condensation of ADCs and the experimental data.
Entry Product R1
Solvent Recryst
Mp(oC)
Yield (%)a Mp [Lit.]
(2a-i)
Temp.
EtOAc
77 ˚C
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
EtOH
66
150−153
150−151[14]
EtOAc
77 ˚C
Xylene
78
182−183
182−183[14]
192−194
195−196[14]
EtOAc
77 ˚C
MeOH
71
EtOAc
77 ˚C
MeOH
79
190−191
188−190[14]
198−199
198−199[15]
EtOAc
77 ˚C
MeOH
85
Dioxane EtOH
146−147
101 ˚C
DMF
80
146−147[14]
230−231
DMF&H2O
63
2g
2h
2i
100˚C
DMSO
100˚C
DMSO
100˚C
DMF
49
283−284
DMF&H2O 332−333
55
aIsolated yields.
13
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 1. Synthesis of thiourea derivatives in the literature.
14
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 2. Probable three mechanisms of ADCs giving to symmetrical substituted thioureas.
15
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 3. Intramolecular condensation of aryldithiocarbamate salts substituted with carboxylic
acid group at 2-position.
16
ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Scheme 4. The competing reactions in one-pot reaction media at 100 ˚C for 15-20 min.
17
ACCEPTED MANUSCRIPT