Thermal fragmentation of spirodithiohydantoins: A novel route to NHCs

Article abstract of DOI:10.1039/c2ra22487a

Spirodithiohydantoins undergo a two-step thermal fragmentation affording zwitterionic betaine intermediates and N-heterocyclic carbenes (NHCs) respectively. Such reactions are novel, occur under mild conditions and give NHCs in high yield and purity. This phenomenon was studied using various spectroscopic techniques and control experiments with elemental sulfur. Quantum chemical calculations were employed to provide a deeper understanding of such transformations.

Full text of DOI:10.1039/c2ra22487a

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Thermal fragmentation of spirodithiohydantoins: A
novel route to NHCs3
Cite this: RSC Advances, 2013, 3, 1669
Davit Jishkariani,a C. Dennis Hall,a Alexander Oliferenko,a Blake J. Tomlin,a Peter
J. Steelb and Alan R. Katritzky*ac
Received 11th October 2012,
Accepted 9th November 2012
DOI: 10.1039/c2ra22487a
www.rsc.org/advances
Spirodithiohydantoins undergo a two-step thermal fragmenta-
tion affording zwitterionic betaine intermediates and
N-heterocyclic carbenes (NHCs) respectively. Such reactions are
novel, occur under mild conditions and give NHCs in high yield
and purity. This phenomenon was studied using various spectro-
scopic techniques and control experiments with elemental sulfur.
Quantum chemical calculations were employed to provide a
deeper understanding of such transformations.
carbonyl sulfide or isothiocyanate,32 but use of such zwitterionic
adducts as intermediates may be limited by their 1,3 dipolar
nature, their stability and the temperature needed for such
transformations.32,33 By contrast, spirocyclic intermediates of type
1 are easily accessible, inert at room temperature and can be used
to generate NHC catalysts. The temperature needed for this
process (80 uC) also compares favorably with ones reported in the
literature for NHC isothiocyanate adducts.32 Herein, we report the
NMR and mass spectrometric analysis of such fragmentation
reactions as well as quantum chemical data explaining the nature
of such transformations.
Hydantoin, thiohydantoin and dithiohydantoin (Fig. 1) constitute
an important class of 5-membered heterocycles with derivatives
employed as antiepileptic drugs,1,2 anti-HIV-1,3,4 anticonvulsant,5,6
antitumor7–9 and antileishmaniasis agents,10 as well as being
important building blocks for biologically-active complex mole-
cules.11
Hydantoin libraries, created and evaluated to determine
structure–activity relationships,12 demonstrate the crucial impor-
tance of substitution at position 5 for pharmacological activity.12,13
Spiro derivatives of such heterocycles have attracted special
attention as potential aldose reductase inhibitors14 or antileish-
maniasis agents.10 Although reports of such molecules are
increasing,15–18 less than 20 reported dithiohydantoin deriva-
tives19–27 of the type shown in Fig. 1 have been located.
We previously synthesized novel spirodithiohydantoins from
N-aminobenzimidazole.22 The present study has now demon-
strated that these spirocyclic systems undergo a two-step thermal
dissociation giving zwitterionic betaines and NHCs, a phenom-
enon not previously reported. This novel phenomenon can be
utilized to generate NHCs for latent, ‘‘on demand’’ catalysis.
Previous reports of the use of NHC adducts as latent catalysts has
generally involved a transition metal,28,29 carbon dioxide,30,31
Dissociation of the spirodithiohydantoins 1a,b at 70 uC was
1
studied by H NMR (15 mg ml21 in DMSO-d6) at various time
intervals. At 70 uC, 1a,b gave zwitterionic betaines 2a,b with the
concentration of 2a,b increasing with time. Scheme 1 shows the
changes in the ratio [2a] : [1a] as the temperature was maintained
1
at 70 uC over 130 min. This phenomenon was studied by H and
13C NMR and by direct insertion probe (DIP-EI) mass spectro-
metric analysis. The formation of zwitterionic betaine 2a and
isopropyl isothiocyanate 3 was detected by a number of changes in
the NMR spectra. The singlet at 9.30 ppm, singlet at 7.81 ppm,
multiplet at 4.15–4.00 ppm, singlet at 3.87 ppm, singlet at 3.78
ppm, multiplet at 1.98–1.86 ppm, doublet at 1.31 ppm (J = 6.5 Hz)
and doublet at 1.06 ppm (J = 6.4 Hz) were used for the quantitative
determination of the [2a] : [1a] ratio (Scheme 1).
Formation of free isopropyl isothiocyanate 3 was suggested by
the appearance of a multiplet at 4.15–4.00 ppm and a doublet at
1.31 ppm (J = 6.5 Hz) (Scheme 1). The formation of isopropyl
aCenter for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, FL 32611-7200, USA. E-mail: katritzky@chem.ufl.edu;
Fax: +1-352-392-9199; Tel: +1-352-392-0554
bUniversity of Canterbury, Christchurch, New Zealand
cDepartment of Chemistry, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
Electronic supplementary information (ESI) available: NMR variation of [2a] : [1a],
3
1H and 13C spectra of 5a, b and X-ray crystal details of 5b. CCDC 901387. For ESI and
Fig. 1 Structural motifs of hydantoin, thiohydantoin, dithiohydantoin and spiro-
dithiohydantoin.
crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra22487a
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Scheme 1 Thermal fragmentation of spirodithiohydantoins; NMR variation of [2a] : [1a] ratios with time.
isothiocyanate 3 was also confirmed by 13C NMR of the heat
this case reversal was complete in 24 h, whereas reversal without
excess isopropyl isothiocyanate took more than 7 days (Fig. 2).
Dissociation of spirodithiohydantoin 1b formed zwitterionic
treated sample and by direct insertion probe (DIP-EI) mass
?
spectrometry which revealed a molecular ion M + = 101 (100%)
together with M+1 = 102 (58%) and M+2 (8%). These data are
consistent with the formation of isopropyl isothiocyanate 3 and
betaine 2a.
The formation of zwitterionic betaine is reversible. Cooling the
heated sample to room temperature formed the crystalline parent
spirocycle quantitatively. An experiment with an excess of
isopropyl isothiocyanate was found to accelerate the rate of the
reverse reaction. The control experiment was carried out with the
sample when the ratio of [2a] : [1a] had reached 0.5.
The sample was then divided in two, allowed to cool to room
temperature, and excess (10 fold) isopropyl isothiocyanate added
to one sample. Immediate 1H NMR analysis proved the ratio
[2a] : [1a] = 0.5 was unchanged in either sample. There was,
however, a significant increase in the rate of the reverse reaction
2a A 1a in the presence of excess isopropyl isothiocyanate since in
Fig. 2 Formation of parent 1a with and without the presence of excess isopropyl
isothiocyanate 3.
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betaine 2b under the same conditions. The reaction was slower
than that with 1a, but heating spirodithiohydantoins 1a and 1b at
80 uC and above resulted in the formation of two equivalents of
isopropyl isothiocyanate 3 and the formation of the corresponding
N-heterocyclic carbenes 4a,b at similar rates (Scheme 1).
The formation of N-heterocyclic carbenes (NHCs) was sup-
ported by experiments with elemental sulfur. Thus when 1a and
1b were heated with excess elemental sulfur at 80 uC for 5 h, novel
compounds 5a and 5b were obtained.
The spectra of 5a,b were found to be identical to those
obtained by the reaction of sulfur with benzimidazolium salts 6a
and 6b under basic conditions (Scheme 2). The structure of 5b was
further confirmed by X-ray crystallography (Fig. 3).
Fig. 3 X-Ray crystal structure of 5b.
DH2 = (DENHC + DEITC) 2 DEbeta
Quantum chemical calculations were employed to elucidate the
reversible thermolysis mechanism of the spirodithiohydantoins,
with 1a taken as an example. A 3D structure of 1a was resolved in
our previous paper22 using X-ray diffraction analysis. Based on this
X-ray structure, structures of the products and intermediates were
drawn with Chem3D Pro software. Geometry optimization and
calculation of the total energies was achieved using the Hartree–
Fock method with the 6-31G* basis set, as implemented in the
Firefly/GAMESS program.34
Although the zwitterionic betaine 2a appears to be a kinetic
product, the reversible process of the original spirodithiohydan-
toin formation infers a significant extent of thermodynamic
control. The apparently asymmetric reaction profile (the direct
reaction goes faster than the reverse one) visualized in Scheme 1
and Fig. 2 can be explained by the liquid-to-solid phase transition
which arrests many degrees of freedom and thus slows down the
reverse process.
where DEbeta, DEITC, DEspiro and DENHC are the total energies of
zwitterionic betaine 2a, isopropyl isothiocyanate 3, spirodithiohy-
dantoin 1a, and N-heterocyclic carbene 4a, respectively. The
calculated enthalpies were close with DH1 = 13.32 kcal mol21 and
DH2 = 12.80 kcal mol21. The positive sign of both DH1 and DH2
confirms the endothermic character of the reaction, which is in
line with the observed reaction profile. The small difference
between DH1 and DH2 is also consistent with the small rise of the
reaction temperature (only 10 uC) to initiate further thermolysis of
the zwitterionic intermediate 2a to N-heterocyclic carbene 4a.
Another mechanistic question that may arise from Scheme 1 is
whether the formation of 1a and 1b is concerted or step-wise. The
step-wise unimolecular pathway may be contemplated as the spiro
system 1a undergoing C–N bond rupture, with no other changes
and preservation of the number of nuclei and electrons. However,
this pathway seems to be too energy demanding, as the calculated
reaction enthalpy for this process (defined as DH3 = DEopen
2
The reaction enthalpies of the two-step reaction shown in
Scheme 1 were calculated using the following equations:
DEspiro) is 27.3 kcal mol21, twice the value of DH1 for the concerted
pathway.
DH1 = (DEbeta + DEITC) 2 DEspiro
Conclusions
We have shown that spirodithiohydantoins, conveniently synthe-
sized from N-aminobenzimidazoles, undergo a two-step reversible
thermolysis to afford N-heterocyclic carbenes through the forma-
tion of zwitterionic betaine intermediates. The NHC formation
was confirmed by reaction with elemental sulfur that irreversibly
trapped the nascent carbenes to give the corresponding thiones.
Quantum calculated reaction enthalpies showed that the two steps
are both endothermic and require very similar amounts of energy.
A concerted mechanism (an inverse of the [3 + 2] dipolar
cycloaddition) was justified, as the step-wise unimolecular path-
way was calculated to be two times less favorable in terms of
reaction enthalpy. This novel facile reaction can be utilized to
generate NHC ‘‘on demand’’ for use in latent catalysis.
Experimental section
Melting points were determined on a capillary point apparatus
equipped with a digital thermometer. NMR spectra were recorded
1
in CDCl3 or DMSO-d6 with TMS for H (300 MHz) and 13C (75
MHz) NMR as internal reference. Elemental analyses were
performed on a Carlo Erba-1106 instrument. All solvents were
Scheme 2 The synthesis of novel 5a,b from spirodithiohydantoins.
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J. Lineberger, W. A. Schleif and E. A. Emini, Bioorg. Med. Chem.
Lett., 2001, 11, 3103.
freshly distilled before use and all reactions carried out under a
nitrogen atmosphere.
5 E. Rydzik and A. Szadowska, Acta Pol. Pharm., 1978, 35, 537.
6 E. Rydzik, A. Szadowska and A. Kaminska, Acta Pol. Pharm.,
1979, 36, 167.
7 S. Suzen and E. Buyukbingol, Farmaco, 2000, 55, 246.
8 A. M. Al-Obaid, H. I. El-Subbagh, A. I. Khodair and M. M.
A. Elmazar, Anti-Cancer Drugs, 1996, 7, 873.
9 M. Blanc, M. Cussac, A. Boucherle and G. Leclerc, Eur. J. Med.
Chem., 1992, 27, 839.
10 A.-S. S. Hamad Elgazwy, S. R. Atta-Allha and S. M. A. S. Keshk,
Monatsh. Chem., 2009, 140, 243.
11 A. A. El-Barbary, A. Z. Abou El-Ezz, A. M. Sharaf and C. Nielsen,
Phosphorus, Sulfur Silicon Relat. Elem., 2007, 182, 1621.
12 P. Dang and A. K. Madan, J. Chem. Inf. Comput. Sci., 1994, 34,
1162.
Spirodithiohydantoins 1a,b and benzimidazolium salts 6a,b
were prepared according to the procedure developed by our
group.22
General procedure for the preparation of benzimidazole-
thiones 5a,b from spirodithiohydantoins 1a,b
Spirodithiohydantoin 1a,b (1 mmol) and elemental sulphur (8.0
mmol) were mixed and heated at 80 uC for 5 h without solvent.
After 5 h, the residue was purified by flash chromatography using
EtOAc/hexanes to afford the corresponding benzimidazole-thiones
5a,b.
General procedure for the preparation of benzimidazole-
thiones 5a,b from benzimidazolium salts 6a,b
13 S. Cortes, Z. K. Liao, D. Watson and H. Kohn, J. Med. Chem.,
1985, 28, 601.
Sodium hydride (1.3 mmol) was added to a mixture of the
benzimidazolium iodide 6a,b (1.0 mmol) and elemental sulfur (8.0
mmol) in dry THF (30 mL) and stirred for 5 h at room temperature
under an argon atmosphere. After 5 h the solution was filtered, the
filtrate was concentrated under reduced pressure and purified by
flash chromatography using EtOAc/hexanes to afford pure
benzimidazole-thione 5a,b.
14 R. Sarges, R. C. Schnur, J. L. Belletire and M. J. Peterson, J. Med.
Chem., 1988, 31, 230.
15 A. R. Katritzky and A. F. Pozharskii, Handbook of Heterocyclic
Chemistry, 2nd edn, 2000.
16 A. F. Pozharskii, A. T. Soldatenkov and A. R. Katritzky,
Heterocycles in Life and Society: An Introduction to Heterocyclic
Chemistry, 1997.
(E)-1-butyl-3-((4-methoxybenzylidene)amino)-1H-benzo[d]i-
midazole-2(3H)-thione 5a. White solid (90%): m.p. 120–122 uC;
1H NMR (CDCl3): d 10.07 (s, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.50–7.46
(m, 1H), 7.27–7.18 (m, 3H), 6.99 (d, J = 8.7 Hz, 2H), 4.35 (t, J = 7.5
Hz, 2H), 1.89–1.79 (m, 2H), 1.53–1.41 (m, 2H), 0.99 (t, J = 7.4 Hz,
3H); 13C NMR (CDCl3): d 163.6, 162.4, 161.1, 131.5, 130.1, 129.8,
125.6, 123.2, 122.8, 114.1, 109.9, 108.5, 55.4, 44.1, 29.9, 20.2, 13.8;
Anal. Calcd. for C19H21N3OS: C, 67.23; H, 6.24; N, 12.38. Found: C,
67.26; H, 6.38; N, 12.33.
17 I. Shinkai, Five-Membered Rings with Two Heteroatoms and
Fused Carbocyclic Derivatives, Comprehensive Heterocyclic
Chemistry II, 1996, vol. 3.
18 M. C. Bellucci, T. Marcelli, L. Scaglioni and A. Volonterio, RSC
Adv., 2011, 1, 1250.
19 G. Herrmann and G. Suess-Fink, Synthesis, 1986, 422.
20 W. Kantlehner, Science of Synthesis, 2005, 22, 795.
21 H. Heitz, G. Herrmann and G. Suess-Fink, Chem. Ber., 1986,
119, 2895.
22 A. R. Katritzky, D. Jishkariani, R. Sakhuja, C. D. Hall and P.
J. Steel, J. Org. Chem., 2011, 76, 4082.
(E)-1-(benzylideneamino)-3-butyl-1H-benzo[d]imidazole-
2(3H)-thione 5b. Colorless crystals (88%): m.p. 106–108 uC, H
1
23 H. E. Winberg and D. D. Coffman, J. Am. Chem. Soc., 1965, 87,
2776.
24 Y. Cheng, M.-F. Liu, D.-C. Fang and X.-M. Lei, Chem.–Eur. J.,
2007, 13, 4282.
25 M. Regitz and J. Hocker, Synthesis, 1970, 301.
26 A. Sudo, K. Igarashi and T. Endo, J. Polym. Sci., Part A: Polym.
Chem., 2000, 38, 4200.
NMR (CDCl3): d 10.36 (s, 1H), 7.97–7.94 (m, 2H), 7.54–7.45 (m,
4H), 7.29–7.18 (m, 3H), 4.35 (t, J = 7.5 Hz, 2H), 1.89–1.79 (m, 2 H),
1.51–1.41 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3): d
163.8, 160.3, 133.3, 131.7, 130.0, 128.8, 128.5, 123.5, 123.0, 110.2,
108.7, 44.0, 29.8, 20.2, 13.9. Anal. Calcd. for C18H19N3S: C, 69.87;
H, 6.19; N, 13.58. Found: C, 69.98; H, 6.42; N, 13.43.
27 M. Regitz, J. Hocker, W. Schoessler, B. Weber and
A. Liedhegener, Justus Liebigs Ann. Chem., 1971, 748, 1.
28 B. R. Van Ausdall, J. L. Glass, K. M. Wiggins, A. M. Aarif and
J. Louie, J. Org. Chem., 2009, 74, 7935.
29 H. A. Duong, T. N. Tekavec, A. M. Arif and J. Louie, Chem.
Commun., 2004, 112.
References
1 E. A. Swinyard, J. A. Madsen and L. S. Goodman, J. Pharmacol.
Exp. Ther., 1954, 111, 54.
2 T. C. Butler and W. J. Waddell, J. Pharmacol. Exp. Ther., 1954,
110, 120.
30 A. M. Voutchkova, L. N. Appelhans, A. R. Chianese and R.
H. Crabtree, J. Am. Chem. Soc., 2005, 127, 17624.
31 H. Zhou, W.-Z. Zhang, C.-H. Liu, J.-P. Qu and X.-B. Lu, J. Org.
Chem., 2008, 73, 8039.
32 B. C. Norris, D. G. Sheppard, G. Henkelman and C.
W. Bielawski, J. Org. Chem., 2011, 76, 301.
3 D. Kim, L. Wang, C. G. Caldwell, P. Chen, P. E. Finke, B. Oates,
M. MacCoss, S. G. Mills, L. Malkowitz, S. L. Gould, J.
A. DeMartino, M. S. Springer, D. Hazuda, M. Miller,
J. Kessler, R. Danzeisen, G. Carver, A. Carella, K. Holmes,
J. Lineberger, W. A. Schleif and E. A. Emini, Bioorg. Med. Chem.
Lett., 2001, 11, 3099.
33 M. Hans, J. Wouters, A. Demonceau and L. Delaude, Eur. J. Org.
Chem., 2011, 7083.
34 Firefly/GAMESS: Dr Alexander Granovsky, http://classic.chem.
msu.su.
4 D. Kim, L. Wang, C. G. Caldwell, P. Chen, P. E. Finke, B. Oates,
M. MacCoss, S. G. Mills, L. Malkowitz, S. L. Gould, J.
A. DeMartino, M. S. Springer, D. Hazuda, M. Miller,
J. Kessler, R. Danzeisen, G. Carver, A. Carella, K. Holmes,
1672 | RSC Adv., 2013, 3, 1669–1672
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