Synthesis of 2 , 4-Disubstituted Thiophenols and Solid State Structures of Thiocarbamate Precursors

Uma série de tiofenóis com diferentes orto-substituintes, 2,4-dimetiltiofenol, 2-terc-butil-4metiltiofenol e 2-(1-adamantil)-4-metiltiofenol, os quais mostram diferentes graus de impedimento estérico na posição 2, foram preparados a partir dos correspondentes fenóis. Uma despronotação inicial dos fenóis foi obtida com o uso de NaH em dimetoxietano, seguido de tratamento com cloreto de N,N-dimetiltiocarbomoila, obtendo-se os O-ariltiocarbamatos. A termólise destes compostos resultou num rearranjo, obtendo-se os S-ariltiocarbamatos. Finalmente, a redução dos Sariltiocarbamatos com LiAlH 4 em THF, seguido de acidificação, levou ao isolamento dos tiofenóis. Todos os produtos foram caracterizados por técnicas espectroscópicas, e para alguns tiocarbamatos a estrutura sólida foi determinada por difração de raio X.


Introduction
Thiols represent an important class of compounds due to their relevance in organic, inorganic, and materials chemistry. 1-3Within the context of inorganic chemistry, thiols have a crucial role as thiolate ligands in coordination compounds that are relevant in both chemical and biological systems. 2,4While in many of these systems it is desirable to have bridging thiolate ligands for building multimetallic assemblies, 5 in other cases sterically demanding thiols are necessary for the preparation of monometallic complexes. 6 This latter situation requires thiols that can create a protective pocket around the metal center in order to avoid the formation of high nuclearity species.
The most common method of preparation of thiophenols that are not commercially available involves the lithiation of aromatic halides under an inert atmosphere.Subsequent reaction of the organolithium compounds with elemental sulfur produces the corresponding thiols upon hydrolysis. 1 This method is limited by the availability of halogenated aromatic compounds required for the lithium-halogen exchange reaction, with the more widely available phenols as an alternative starting material for the synthesis of thiophenols.
Newman and Karnes developed a method for the transformation of phenols into thiophenols, 7 which involves the thermal rearrangement of O-arylthiocarbamates into S-arylthiocarbamates (Scheme 1).Thus, this methodology requires the synthesis, isolation, and characterization of both O-and S-arylthiocarbamates. Given the large number of ortho-substituted phenols that are commercially available, we decided to undertake the preparation of the corresponding thiophenols.The phenols considered in this work include 2,4-dimethylphenol (1), 2-tert-butyl-4-methylphenol (2), and 2-(1-adamantyl)-4-methylphenol (3), which can be compared in terms of their reactivity based on the varying degrees of steric hindrance provided by the substituent adjacent to the hydroxy or thiol groups.

Synthesis of O-arylthiocarbamates
2 -a l k y l -4 -m e t h y l p h e n y l -N , N -d i m e t h y l -Othiocarbamates (alkyl = methyl, tert-butyl, and 1-adamantyl) were prepared from the corresponding phenols by adapting the previously described procedure. 7The phenol with the sterically encumbering 1-adamantyl group required the longest times for the reaction to proceed to completion.
The products were characterized by standard spectroscopic techniques: Nuclear Magnetic Resonance ( 1 H and 13 C NMR), infrared (IR), and electron-ionization mass spectrometry (EI-MS), as well as melting point determinations and combustion analysis.The main feature in the 1 H NMR spectra is the presence of two sharp singlets in a 1:1 ratio, which correspond to the N-methyl groups of the thiocarbamoyl moiety.The non-equivalency of the nitrogenbound methyl groups has been previously reported for related compounds. 8In this series the presence of non-equivalent N-methyl groups was observed even for 2,4-dimethylphenyl-N,N-dimethyl-O-thiocarbamate (4), which features the smallest substituent in the 2-position.It is therefore reasonable to assume that, in solution, the restriction in the rotation about the C(sp 2 )-N bond is electronic in nature.The two N-methyl resonances appear at δ 3.34 and 3.45 ppm, with those for 2tert-butyl-4-methylphenyl-N,N-dimethyl-O-thiocarbamate (5) at δ 3.39 and 3.49 ppm, and those for 2-(1-adamantyl)-4methylphenyl-N,N-dimethyl-O-thiocarbamate (6) at δ 3.42 and 3.51.
IR spectra exhibit a band for the C=S stretching at 1536, 1526, and 1553 cm -1 for compounds 4, 5, and 6.This spectroscopic technique is useful for identifying the presence of the C=S versus the C=O group of the corresponding S-arylthiocarbamates, since the disappearance of the aforementioned bands is followed by the appearance of new stretching bands at higher frequencies, which correspond to the C=O group.
The S-arylthiocarbamates were characterized by spectroscopic techniques, melting point determination, and combustion analysis.The identity of the compounds was confirmed by EI-MS, which shows the presence of the expected molecular ions.In contrast with the spectra of the O-arylthiocarbamates, in the 1 H NMR spectrum of compound 7 a pair of broad resonances that arise from the N-methyl groups was observed at δ 3.02 and 3.11.For compounds 8 and 9, the two peaks coalesce at room temperature into a single broad resonance at δ 3.08 and 3.02.As mentioned above, IR spectra clearly revealed the rearrangement of the O and S atoms.This was evidenced by the disappearance of the C=S stretching bands, and the appearance of new intense bands in the ν(C=O) region at 1654, 1653, and 1655 cm -1 for 7, 8, and 9.

Synthesis of thiophenols
Reduction of the S-arylthiocarbamates with excess LiAlH 4 in anhydrous THF, followed by acidic workup yielded 2,4-dimethylbenzenethiol (10) methylbenzenethiol (11), and 2-(1-adamantyl)-4methylbenzenethiol (12).The thiols were obtained as yellow or colorless liquids upon evaporation of the organic solvents.Compound 10 was only prepared by this method to prove the feasibility of the reaction since it is a commercially available substance.An alternative synthetic procedure for 10 has been reported which minimizes the formation of the corresponding disulfide, although it requires the sulfonyl chloride as a starting material. 9 In the 1 H NMR spectra of the fully characterized thiols 11 and 12, the characteristic resonance of the thiol group was observed at δ 3.52 and 3.57.Likewise, the most prominent feature of the IR spectrum of 11 was the stretching band of the S-H group at 2567 cm -1 .In the case of 12, although the corresponding S-H band appeared at 2564 cm -1 with low intensity, both the 1 H NMR and the mass spectrometry data confirm its identity.Thus, the expected molecular ions in the mass spectra of the two thiols were observed, as well as the ions of the corresponding disulfides [ArSSAr] + , which are probably formed in the ionization chamber.
The thiocarbamoyl moiety is diverted from the orthosubstituent, such that the aromatic and thiocarbamoyl fragments are not coplanar.This results in a close C1-S1 contact (3.00 Å), which is a requisite for the thermal rearrangement to occur.An ORTEP view of 4 at the 40% probability level is presented in Figure 1.Selected bond lengths and angles for compounds 4, 5, and 8 are listed in Table 2. Short intramolecular contacts, which are attributed to the planarity of the thiocarbamoyl group, are also present in the solid state structure of 5 [H14a-O1 2.20 Å, and H13c-S1 2.52 Å].As in 4, the thiocarbamoyl fragment of 5 is directed away from the tert-butyl substituent.This allows the S1 atom to make a close contact with the C1 atom (3.05 Å), which is directly involved in the rearrangement reaction.
In compound 8, the carbonyl C12-O1 bond length of 1.210(2) Å is comparable to that of related S-arylthiocarbamates, and it further proves the thermal rearrangement of the O and S atoms.As in the case of 5, the S-thiocarbamoyl fragment is planar, and directed away from the bulky ortho-substituent.A considerable amount of steric repulsion arises from the presence of the sulfur atom O( 1) S( 1) N( 1) C( 9)  2)°], which correspond to sp 2 -hybridization, the contribution of the S atom to the π-system does not appear to be significant based on the small bond angle [C1-S1-C12 99.9(1)°].Short intramolecular contacts are once again present due to the planarity of the thiocarbamoyl moiety [H13c-O1 2.29 Å, and H14c-S1 2.37 Å], which enforces the proximity of C13 and C14 to the O1 and S1 atoms, respectively.A list of selected bond lengths and angles for all compounds is presented in Table 2, and ORTEP diagrams of 5 and 8 are shown in Figures 2 and 3, respectively.

Conclusions
We have prepared and characterized new O-aryl and S-arylthiocarbamates which provide the entry point into O(1) S( 1) N( 1) C( 12)  the synthesis of 2,4-disubstituted thiols.Of the latter compounds, 11 and 12 are thiophenols that feature bulky substituents in the 2-position, which have not previously been reported perhaps due to the difficulty in their preparation.These thiols may prove useful as sterically encumbered thiolate ligands towards transition metals, and thus we are currently undertaking their synthesis on a larger scale.Having one of the activated ortho-positions available, this series of thiophenols can be incorporated into more complex structures in polydentate sulfur-based ligands with varying degrees of steric hindrance, depending on the identity of the substituent on the 2-position. 11

General methods
THF and dimethoxyethane were dried with sodium/ benzophenone, and distilled under a nitrogen atmosphere.All other solvents were used as received from commercial suppliers.2,4-dimethylphenol (1), 2-tert-butyl-4methylphenol (2), 2-(1-adamantyl)-4-methylphenol (3), sodium hydride, and N,N-dimethylthiocarbamoyl chloride were purchased from Aldrich Chemical Co., and were used without further purification.IR spectra were obtained as chloroform solutions with a Perkin-Elmer 203-B spectrophotometer in the range 4000-400 cm -1 . 1 H and 13 C NMR spectra were recorded on a JEOL Eclipse spectrometer at 20 °C operating at 300 and 75 MHz respectively.Chemical shifts were reported using Si(CH 3 ) 4 as an internal standard.Electron-ionization mass spectrometry measurements were obtained with a JEOL JMS-AX505HA spectrometer.Elemental analyses were performed by Galbraith Laboratories (Knoxville, TN).

Synthesis of organosulfur compounds
For each kind of compound, i. e. O-arylthiocarbamate, S-arylthiocarbamate, and thiophenol, a detailed synthetic procedure is exemplified.The peaks that were specifically assigned in the NMR spectra are based on the numbering presented in Scheme 2.

Table 1 .
Crystal and refinement data for compounds 4, 5 and 8