CC BY ND NC 4.0 · SynOpen 2017; 01(01): 0121-0124
DOI: 10.1055/s-0036-1588574
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New Facile Synthesis of Adamantyl Isothiocyanates

Vladimir Burmistrov, Dmitry Pitushkin, Gennady Butov*
  • Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (Branch) Volgograd State Technical University, 404121 Volzhsky, Engels st., 42a, Russia   Email: butov@volpi.ru
This work was supported by the Russian Fund for Basic Research (grant number 16-33-00172) and by the Ministry of Education and Science of the Russian Federation (base part of state assignment for 2017–2019; project no. 4.7491.2017/BCh).
Further Information

Publication History

Received: 20 July 2017

Accepted after revision: 29 August 2017

Publication Date:
15 September 2017 (online)

 

Abstract

A series of adamantyl isothiocyanates containing different substituents in the nodal positions of adamantane or spacers between the adamantane and isothiocyanate group have been synthesised by using the reaction of the corresponding adamantyl amines with phenyl isothiocyanate.


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Adamantyl isothiocyanates are promising precursors for the synthesis of various biologically active compounds. Thioureas formed from adamantyl isothiocyanates are promising as soluble epoxide hydrolase (sEH, E.C. 3.3.2.10) inhibitors,[1] and as urokinase-type plasminogen activator (uPA, 3.4.21.73) inhibitors.[2] Moreover, thioureas can be readily transformed[3] into ureas, which find wide applications in medicinal chemistry.[4]

Traditional methods for the preparation of 1-adamantyl isothiocyanate require corrosive or toxic reagents, including the reactions of 1-aminoadamantane with CS2 and NaOH,[5] 1-aminoadamantane with thiophosgene and CaCO3,[6] chloroadamantane with trimethylsilyl isothiocyanate and titanium(IV) chloride,[7] along with bromoadamantane with KSCN.[8] Modern methods involve the use of catalysts.[9] However, there is still no simple and effective method for the preparation of 1-adamantyl isothiocyanate and its analogues.

Previously, we reported the synthesis of a library of adamantyl ureas from the reaction of either 1-adamantyl isocyanate or its homologues with various amines or 1-aminoadamantane or its homologues with isocyanates and diisocyanates.[10] These reactions were carried out in the absence of base (Et3N, DIPEA). The reaction of 1-amino-3,5-dimethyladamantane 1 with phenyl isothiocyanate under similar conditions led to the formation of an unexpected mixture of products.[11] Along with the expected thiourea 2, formation of isothiocyanate 3 also took place (Scheme [1]).

Zoom Image
Scheme 1 Reaction in which the functional group metathesis was ­discovered. Reagents and conditions: (a) Ph-NCS (ratio 1:1 with 1), DMF, r.t., overnight, 12% (3).

Initially, the yield of 3 in this first reaction was 12%. We speculated that the course of the reaction is driven by the basicity of the medium and by the structure of the reactants, and we decided to study this reaction with 1-adamantylamine 4 and defined conditions that reduced the thiourea yield. The reaction course was not affected by temperature; stirring in toluene at r.t. overnight gave a small amount of adamantyl isothiocyanate 5 but no 1-(adamantan-1-yl)-3-phenyl thiourea 6 was detected. In nonpolar hexanes, the formation of adamantyl isothiocyanate was not observed. In fact, thiourea 6 precipitated in quantitative yield seconds after addition of the reactants and before heating was initiated. The highest yield for adamantyl isothiocyanate 5 (47%) was achieved at reflux for 3 h in p-xylene (Scheme [2]). Furthermore, quantities of diphenyl thiourea and diadamantyl thiourea were detected in the reaction mixture.

Zoom Image
Scheme 2 Reagents and conditions: (a) Ph-NCS (ratio 1:1 with 4), p-xylene, reflux, 3 h, 47%.
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Scheme 3 Reagents and conditions: (a) Ph-NCS (ratio 1:1 with 6), p-xylene, reflux, 3 h, 95%; (b) Ph-NCS (ratio 1:2 with 4), p-xylene, reflux, 3 h, 95%.

Initially, the proposed mechanism for the described reaction was based on the mechanism of urea formation described by Satchell and co-workers.[12] Formation of urea goes through the three molecular transition state formed by amine, isocyanate and base. In some cases, another molecule of amine could act as a base. However, trimolecular mechanisms are usually only suitable when one of the reactants is added in excess. A metathesis reaction was earlier investigated between phenyl isothiocyanates and sterically hindered aromatic amines by Habib and Rieker.[13] The authors stated that the reaction proceeds through the formation of the thiourea, followed by its thermal decomposition (190 °C). Thus, we proposed that thiourea 6 could be an intermediate in this reaction. To confirm this assumption, 1-(adamantan-1-yl)-3-phenyl thiourea 6 was synthesised according to a known method[14] and then heated at reflux in toluene for 8 hours, but no traces of the corresponding adamantyl isothiocyanate 5 were detected. Most likely, 110 °C is not high enough to result in thermal decomposition of the thiourea. This was also the situation after 6 was treated under the same conditions in the presence of 1 equivalent of 1-adamantylamine 4. However, heating thiourea 6 at reflux in toluene with 1 equivalent of phenyl isothiocyanate led to the formation of adamantyl isothiocyanate 5 with 95% yield (Scheme [3, b ]). Another product of this reaction was diphenyl thiourea. Furthermore, this means that phenyl isothiocyanate can furnish adamantyl isothiocyanates from nonsymmetric thioureas (Scheme [4]). This new mechanism requires the thiourea formed in the first step to be soluble in a selected solvent in order to react with phenyl isothiocyanate; in hexanes, the formation of adamantyl isothiocyanate 5 was not observed because thiourea 6 precipitated from the solution. Thiourea is reported to have isothiourea tautomers.[15] Moreover, the yield of adamantyl isothiocyanate cannot exceed 50% when the reagents are added in a 1:1 ratio. The proposed mechanism also explains the difference in yields between various conditions. In basic medium (DMF), most of the phenyl isothiocyanate was ­rapidly consumed in the formation of thiourea 2, and only 12% of it managed to react with thiourea to give isothio­cyanate 3. In contrast, in nonbasic p-xylene, the formation of thiourea 2 was slowed and excess phenyl isothiocyanate could convert it into isothiocyanate 3 with 47% yield.

The next step was to determine the scope of this reaction. Firstly, aminoadamantanes containing two and three methyl substituents at the nodal positions, 1-amino-3,5-­dimethyladamantane and 1-amino-3,5,7-trimethyladamantane, respectively, were reacted with 2 equivalents of phenyl isothiocyanate to give the corresponding isothiocyanates 3 and 7 with 80% and 75% yield (Table [1]). Next, the influence of the distance between amino and adamantane groups was studied. For this purpose, aminoadamantanes with aliphatic spacers between the amino group and adamantane, 1-(aminomethyl)adamantane,1-(2-aminoethyl)adamantane and 1-(1-aminoethyl)adamantane were used. 2-Aminoadamantane used in the preparation of isothiocyanate 11 behaved like 1-aminoadamantane.[17]

Table 1 Functional Group Metathesis Reaction between Adamantyl Amines and Phenyl Isothiocyanate

Entry

R′

R′′

R′′′

Z

Yield (%)

1

CH3

CH3

H

no spacer

 3, 80

2

H

H

H

no spacer

5, 95

3

CH3

CH3

CH3

no spacer

 7, 75

4

H

H

H

CH2

 8, 75

5

H

H

H

CH2CH2

 9, 78

6

H

H

H

CH(CH3)

10, 86

7

11, 92

a Reagents and conditions: Ph-NCS (ratio 1:2 with adamantane starting material), p-xylene, reflux, 3 h.

We also examined whether a similar reaction took place when the isothiocyanate was replaced by an isocyanate. Replacement of phenyl isothiocyanate with phenyl isocyanate led to the formation of the corresponding urea in quantitative yield. Thiourea was the only product formed when the adamantyl amine was replaced with an aliphatic amine (ethyl, i-propyl, tert-butyl, hexadecyl or octadecyl amine). This probably happens due to the higher basicity and thus rapid interaction with phenyl isothiocyanate of aliphatic amines and impossibility of thermal decomposition of thioureas under the reported conditions. Consequently, when aliphatic diamines (1,2-ethanediamine, 1,3-propanediamine, 1,4-butanediamine and 1,6-hexanediamine) were reacted with phenyl isothiocyanate under the same conditions,[16] trace amounts of imidazolidine-2-thione, tetrahydropyrimidine-2(1H)-thione and 1,3-diazepane-2-thione, respectively, were obtained. These are the cyclisation products of 2-isothiocyanatoethan-1-amine, 3-isothiocyanatopropan-1-amine and 4-isothiocyanatobutan-1-amine. In the case of 1,6-hexanediamine, the corresponding thione was not detected.

Zoom Image
Scheme 4 Proposed mechanism of the functional group metathesis reaction

In conclusion, a promising new method for the synthesis of isothiocyanates bearing the adamantane moiety was developed. The described method gives high yields under mild conditions without requiring additional catalysts.


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Acknowledgment

The authors thank Dr. Sung Hee Hwang for support in discussions of the results.

Supporting Information

  • References and Notes

  • 1 Butov GM. Burmistrov VV. Danilov DV. Pitushkin DA. Morisseau C. Hammock BD. Russ. Chem. Bull. 2015; 64: 1569
  • 2 Venkatraj M. Messagie J. Joossens J. Lambeir AM. Haemers A. Van der Veken P. Augustyns K. Bioorg. Med. Chem. 2012; 20: 1557
  • 3 Lakouraj MM. Ghodrati K. Monatsh. Chem. 2008; 139: 549
    • 4a Kodani SD. Hammock BD. Drug Metab. Dispos. 2015; 43: 788
    • 4b Lee KS. S. Liu J.-Y. Wagner KM. Pakhomova S. Dong H. Morisseau C. Fu SH. Yang J. Wang P. Ulu A. Mate CA. Nguyen LV. Hwang SH. Edin ML. Mara AA. Wulff H. Newcomer ME. Zeldin DC. Hammock BD. J. Med. Chem. 2015; 57: 7016
  • 5 Takeda K. Tsuboyama K. Takeura M. Chem. Pharm. Bull. 1989; 37: 2334
  • 6 Nam KD. Han M. Yoon J. Kim E. Cho S. Hahn H. Bull. Korean Chem. Soc. 2013; 34: 271
  • 7 Sasaki T. Nakanishi A. Ohno M. J. Org. Chem. 1981; 46: 5445
  • 8 Stetter J. Wulff D. Chem. Ber. 1962; 95: 2302
  • 9 Scattolin T. Klein A. Schoenebeck F. Org. Lett. 2017; 19: 1831
    • 10a Burmistrov V. Morisseau C. Lee KS. S. Shihadih DS. Harris TR. Butov GM. Hammock BD. Bioorg. Med. Chem. Lett. 2014; 24: 2193
    • 10b Burmistrov V. Morisseau C. Danilov D. Harris TR. Dalinger I. Vatsadze I. Shkineva T. Butov GM. Hammock BD. Bioorg. Med. Chem. Lett. 2015; 25: 5514
    • 10c Butov GM. Burmistrov VV. Danilov DV. Pitushkin DA. Morisseau C. Hammock BD. Russ. Chem. Bull. 2015; 64: 1569
  • 11 Burmistrov VV. Butov GM. Pitushkin DA. Russ. J. Org. Chem. 2015; 51: 1795
  • 12 Satchell DP. N. Satchell RS. Chem. Soc. Rev. 1975; 2: 231
  • 13 Habib NS. Rieker A. Synthesis 1984; 825
  • 14 Turkevich NM. Agaev KA. Steblyuk PN. Sementsiv GN. Khim.-Farm. Zh. 1982; 16: 1068
  • 15 Sbei N. Haouas B. Chebbi M. Smida YB. Arfaoui Y. Boujlel K. Benkhoud ML. J. Sulfur Chem. 2017; 38: 152
  • 16 Burmistrov VV. Pitushkin DA. Dyachenko VS. Sdvijkov DV. Kirilov SS. Rasskazova EV. Butov GM. Izvestia VSTU 2016; 4: 68
  • 17 General Experimental Procedure: To a solution of amine (5–10 mmol) in p-xylene (10–20 mL) was added phenyl isothiocyanate (2 equiv) at room temperature. After heating to reflux for 3 h, the reaction mixture was cooled to r.t. and conc HCl (1–2 mL) was added. After stirring for 1 h, the precipitate was filtered off, the filtrate was concentrated in vacuo and the residue was purified either by crystallization from EtOH (for solid compounds 5, 7, 8, 11) or by column chromatography (for liquid compounds 3, 9, 10).Analytical Data for Compound 3: Yield: 80%; yellow oil; MS (EI): m/z (%) = 221 (5%) [M]+, 163 (100%) [Ad]+; 1H NMR (500 MHz, CDCl3): δ = 2.17 (s, 1 H), 1.81 (s, 2 H), 1.62 (dd, J = 13.0, 12.0 Hz, 4 H), 1.32 (dd, J = 16.0, 12.5 Hz, 4 H), 1.15 (s, 2 H), 0.87 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ = 129.92 (s, 1 C, NCS), 59.75 (s, 1 C, C-NCS), 49.88 (s, 1 C, Ad), 49.61 (s, 2 C, Ad), 42.26 (s, 1 C, Ad), 41.89 (s, 2 C, Ad), 32.58 (s, 1 C, Ad), 29.90 (s, 2 C, Ad), 29.62 (s, 2 C, 2CH3). Elemental analysis calcd for C13H19NS: C, 70.54; H, 8.65; N, 6.33; S, 14.48; found: C, 70.59; H, 8.67; N, 6.29; S, 14.44.Analytical Data for Compound 9: Yield: 78%; yellow oil; MS (EI): m/z (%) = 221 (15) [M]+, 135 (100) [Ad]+. 1H NMR (500 MHz, CDCl3): δ = 3.51 (t, J = 7.5 Hz, 2 H, CH2-NCS), 1.96 (s, 3 H), 1.67 (dd, J = 32.0, 12.0 Hz, 4 H), 1.54–1.49 (m, 10 H). 13C NMR (125 MHz, CDCl3): δ = 128.99 (s, 1 C, NCS), 43.89 (s, 1 C, CH2-NCS), 41.88 (s, 3 C, Ad), 40.19 (s, 1 C, Ad-CH2), 36.79 (s, 3 C, Ad), 28.38 (s, 3 C, Ad), 27.54 (s, 1 C, quaternary C in Ad). Elemental analysis calcd for C13H19NS: C, 70.54; H, 8.65; N, 6.33; S, 14.48; found: C, 70.50; H, 8.66; N, 6.33; S, 14.45.Analytical Data for Compound 10: Yield: 86%; brown oil; MS (EI): m/z (%) = 221 (12) [M]+, 163 (8) [Ad-CH(CH3]+, 135 (100) [Ad]+. 1H NMR (500 MHz, CDCl3): δ = 3.35 (q, J = 6.5 Hz, 1 H, CH), 2.03 (s, 3 H), 1.74–1.46 (m, 12 H), 1.27 (d, J = 6.5 Hz, 3 H, CH3). 13C NMR (125 MHz, CDCl3): δ = 128.50 (s, NCS), 63.68 (s, 1 C, CH), 38.22 (s, 3 C, Ad), 36.90 (s, quaternary C in Ad), 36.72 (s, 3 C, Ad), 28.17 (s, 3 C, Ad), 15.13 (s, 1 C, CH3). Elemental analysis calcd for C13H19NS: C, 70.54; H, 8.65; N, 6.33; S, 14.48; found: C, 70.51; H, 8.66; N, 6.32; S 14.45

  • References and Notes

  • 1 Butov GM. Burmistrov VV. Danilov DV. Pitushkin DA. Morisseau C. Hammock BD. Russ. Chem. Bull. 2015; 64: 1569
  • 2 Venkatraj M. Messagie J. Joossens J. Lambeir AM. Haemers A. Van der Veken P. Augustyns K. Bioorg. Med. Chem. 2012; 20: 1557
  • 3 Lakouraj MM. Ghodrati K. Monatsh. Chem. 2008; 139: 549
    • 4a Kodani SD. Hammock BD. Drug Metab. Dispos. 2015; 43: 788
    • 4b Lee KS. S. Liu J.-Y. Wagner KM. Pakhomova S. Dong H. Morisseau C. Fu SH. Yang J. Wang P. Ulu A. Mate CA. Nguyen LV. Hwang SH. Edin ML. Mara AA. Wulff H. Newcomer ME. Zeldin DC. Hammock BD. J. Med. Chem. 2015; 57: 7016
  • 5 Takeda K. Tsuboyama K. Takeura M. Chem. Pharm. Bull. 1989; 37: 2334
  • 6 Nam KD. Han M. Yoon J. Kim E. Cho S. Hahn H. Bull. Korean Chem. Soc. 2013; 34: 271
  • 7 Sasaki T. Nakanishi A. Ohno M. J. Org. Chem. 1981; 46: 5445
  • 8 Stetter J. Wulff D. Chem. Ber. 1962; 95: 2302
  • 9 Scattolin T. Klein A. Schoenebeck F. Org. Lett. 2017; 19: 1831
    • 10a Burmistrov V. Morisseau C. Lee KS. S. Shihadih DS. Harris TR. Butov GM. Hammock BD. Bioorg. Med. Chem. Lett. 2014; 24: 2193
    • 10b Burmistrov V. Morisseau C. Danilov D. Harris TR. Dalinger I. Vatsadze I. Shkineva T. Butov GM. Hammock BD. Bioorg. Med. Chem. Lett. 2015; 25: 5514
    • 10c Butov GM. Burmistrov VV. Danilov DV. Pitushkin DA. Morisseau C. Hammock BD. Russ. Chem. Bull. 2015; 64: 1569
  • 11 Burmistrov VV. Butov GM. Pitushkin DA. Russ. J. Org. Chem. 2015; 51: 1795
  • 12 Satchell DP. N. Satchell RS. Chem. Soc. Rev. 1975; 2: 231
  • 13 Habib NS. Rieker A. Synthesis 1984; 825
  • 14 Turkevich NM. Agaev KA. Steblyuk PN. Sementsiv GN. Khim.-Farm. Zh. 1982; 16: 1068
  • 15 Sbei N. Haouas B. Chebbi M. Smida YB. Arfaoui Y. Boujlel K. Benkhoud ML. J. Sulfur Chem. 2017; 38: 152
  • 16 Burmistrov VV. Pitushkin DA. Dyachenko VS. Sdvijkov DV. Kirilov SS. Rasskazova EV. Butov GM. Izvestia VSTU 2016; 4: 68
  • 17 General Experimental Procedure: To a solution of amine (5–10 mmol) in p-xylene (10–20 mL) was added phenyl isothiocyanate (2 equiv) at room temperature. After heating to reflux for 3 h, the reaction mixture was cooled to r.t. and conc HCl (1–2 mL) was added. After stirring for 1 h, the precipitate was filtered off, the filtrate was concentrated in vacuo and the residue was purified either by crystallization from EtOH (for solid compounds 5, 7, 8, 11) or by column chromatography (for liquid compounds 3, 9, 10).Analytical Data for Compound 3: Yield: 80%; yellow oil; MS (EI): m/z (%) = 221 (5%) [M]+, 163 (100%) [Ad]+; 1H NMR (500 MHz, CDCl3): δ = 2.17 (s, 1 H), 1.81 (s, 2 H), 1.62 (dd, J = 13.0, 12.0 Hz, 4 H), 1.32 (dd, J = 16.0, 12.5 Hz, 4 H), 1.15 (s, 2 H), 0.87 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ = 129.92 (s, 1 C, NCS), 59.75 (s, 1 C, C-NCS), 49.88 (s, 1 C, Ad), 49.61 (s, 2 C, Ad), 42.26 (s, 1 C, Ad), 41.89 (s, 2 C, Ad), 32.58 (s, 1 C, Ad), 29.90 (s, 2 C, Ad), 29.62 (s, 2 C, 2CH3). Elemental analysis calcd for C13H19NS: C, 70.54; H, 8.65; N, 6.33; S, 14.48; found: C, 70.59; H, 8.67; N, 6.29; S, 14.44.Analytical Data for Compound 9: Yield: 78%; yellow oil; MS (EI): m/z (%) = 221 (15) [M]+, 135 (100) [Ad]+. 1H NMR (500 MHz, CDCl3): δ = 3.51 (t, J = 7.5 Hz, 2 H, CH2-NCS), 1.96 (s, 3 H), 1.67 (dd, J = 32.0, 12.0 Hz, 4 H), 1.54–1.49 (m, 10 H). 13C NMR (125 MHz, CDCl3): δ = 128.99 (s, 1 C, NCS), 43.89 (s, 1 C, CH2-NCS), 41.88 (s, 3 C, Ad), 40.19 (s, 1 C, Ad-CH2), 36.79 (s, 3 C, Ad), 28.38 (s, 3 C, Ad), 27.54 (s, 1 C, quaternary C in Ad). Elemental analysis calcd for C13H19NS: C, 70.54; H, 8.65; N, 6.33; S, 14.48; found: C, 70.50; H, 8.66; N, 6.33; S, 14.45.Analytical Data for Compound 10: Yield: 86%; brown oil; MS (EI): m/z (%) = 221 (12) [M]+, 163 (8) [Ad-CH(CH3]+, 135 (100) [Ad]+. 1H NMR (500 MHz, CDCl3): δ = 3.35 (q, J = 6.5 Hz, 1 H, CH), 2.03 (s, 3 H), 1.74–1.46 (m, 12 H), 1.27 (d, J = 6.5 Hz, 3 H, CH3). 13C NMR (125 MHz, CDCl3): δ = 128.50 (s, NCS), 63.68 (s, 1 C, CH), 38.22 (s, 3 C, Ad), 36.90 (s, quaternary C in Ad), 36.72 (s, 3 C, Ad), 28.17 (s, 3 C, Ad), 15.13 (s, 1 C, CH3). Elemental analysis calcd for C13H19NS: C, 70.54; H, 8.65; N, 6.33; S, 14.48; found: C, 70.51; H, 8.66; N, 6.32; S 14.45

Zoom Image
Scheme 1 Reaction in which the functional group metathesis was ­discovered. Reagents and conditions: (a) Ph-NCS (ratio 1:1 with 1), DMF, r.t., overnight, 12% (3).
Zoom Image
Scheme 2 Reagents and conditions: (a) Ph-NCS (ratio 1:1 with 4), p-xylene, reflux, 3 h, 47%.
Zoom Image
Scheme 3 Reagents and conditions: (a) Ph-NCS (ratio 1:1 with 6), p-xylene, reflux, 3 h, 95%; (b) Ph-NCS (ratio 1:2 with 4), p-xylene, reflux, 3 h, 95%.
Zoom Image
Scheme 4 Proposed mechanism of the functional group metathesis reaction