Solvent-free preparation of primary carbamates using silica sulfuric acid as an efficient reagent

A simple and efficient method for the conversion of structurally diverse compounds containing a hydroxyl group to primary carbamates is described by grindstone chemistry. The transformation was done at room temperature with high yield and purity, and without any epimerization in the absence of solvent. Silica sulfuric acid was used as a solid acid and as a mild, convenient and effective reagent for this transformation


Introduction
Carbamates (urethanes) are compounds of growing interest because of their applications in the agrochemicals industry [1][2][3][4][5] as herbicides, fungicides and pesticides, in the pharmaceuticals industry 1,2,6 as drug intermediates and in the polymer industry, 1,2,7 in the synthesis of polyurethane and peptides.In addition, among the various amine-protecting groups, carbamates are commonly used due to their chemical stability towards acids, bases and hydrogenation. 82][3] These procedures seem to be efficient, pose environmental and operational concerns since highly harmful and corrosive reagents are used.Efforts have been continuously made for the replacement of the phosgene with carbon dioxide and organic carbonates. 9However these methods cannot produce N-unsubstituted (primary) carbamates.Synthesis of N-unsubstituted carbamates 1 from alcohols has been also accomplished by several-pot reaction methods such as; trichloroacetyl isocyanate, 10,11 chloroformates (starting from toxic phosgene), 12 chlorosulfonyl isocyanate 13 and cyanogen chloride. 14oev and coworkers reported the synthesis of N-unsubstituted carbamates from alcohols by treatment with sodium cyanate and trifluoroacetic acid in certain organic solvents such as benzene, methylene chloride and carbon tetrachloride without any spectral data such as IR and NMR. 15 These solvents are toxic and are not eco-friendly.In addition, trifluoroacetic acid is very expensive.From the standpoint of 'green chemistry', significant efforts have been made to find an alternative to organic solvents.][18][19][20][21] Grindstone Chemistry is a branch of green chemistry for solvent-free chemical reactions which can be probably conducted in high yield by just grinding solid/solid, solid/liquid, or even liquid/liquid together. 22Required activation energy is provided from friction of the reactive molecules in solvent-free conditions.
In attempts to synthesize primary carbamates from phenols and alcohols under solvent-free conditions, we have recently reported a method for the conversion of compounds containing hydroxyl group to primary carbamates at room temperature in the absence of solvent using trichloroacetic acid as well as spectra data such as IR, NMR and their dynamic NMR. 23,2426][27][28][29] The use of solid acids such as silica sulfuric acid (SSA) for synthesizing organic intermediates and fine chemicals is gaining awareness increasingly, also, making a field of intense research activity. 30Furthermore, in the past decade the development of new technologies have been expedited to strive to eliminate the need for chromatographic separation of mixtures, especially impurities and this itself has led to the development of new technologies in synthetic organic chemistry. 31n this paper, a simple and efficient solvent-free methodology was performed to prepare primary carbamates 1 in high yield and purity from compounds 2, sodium cyanate and silica sulfuric acid (Scheme 1 and 2).However, to the best of our knowledge there has been no report on the use of silica sulfuric acid for primary carbamates synthesis.

Results and Discussion
As mentioned in the literature, 30 silica sulfuric acid (SSA) was obtained from silica gel and chlorosulfonic acid (Scheme 1).Primary carbamates 1a-o were prepared in high yields and in high purity from reaction of either alcohol or phenol 2 with sodium cyanate 3 in the presence of SSA at room temperature or 55-65 o C for the appropriate time, as showed in Table 1 and Scheme 2.
As indicated in Table 1 some substrates with various structures were used to synthesize primary carbamates 1a-o purely and cleanly through this easy procedure.Primary, secondary, tertiary, allylic, benzylic alcohols and phenols showed a smooth conversion to the corresponding carbamates.It is high important to mention that (-)-menthol 2a the reaction produced the corresponding (-)-menthyl carbamate 1a while no epimerization took place.The crude product, in most cases, was completely pure and did not require to be purified or worked up anymore.Since the activation energy is low for alcohols 1a-i then their carbamates formation is very easy.The activation energy is provided from friction of available molecules in solid phase (alcohols 1a-i, sodium cyanate and silica sulfuric acid).However activation energy of phenols 1j-o is higher than alcohols 1a-i, so the yield and purity of aromatic compounds 1j-o (entries 10-15) was modified by heating at 55-65 o C for 1h.The low nucleophilicity of the phenol oxygen is a reason of this difference.Phenols which carried electron-withdrawing substituents (CN, COOR and CHO) did not react successfully in our experimental conditions.These substituents very probably reduce the nucleophilicity of the phenol oxygen, so they fail to attack intermediate 5 and/or 7 (Scheme 3).This might have caused low yield (60%) of compound 1l (entry 12).Moreover, we found that the reaction conditions could tolerate such moieties as O-i-propyl (1h, entry 8) which often undergoes cleavage in strongly acidic media.In addition, it is remarkable to note that reaction of α-and β-naphthol (entries 14 and 15) proceeded effectively in the present experimental conditions, while it did not work completely in trichloroacetic acid (the latest reported procedure 23,24 ).Indeed, the amount of remained starting material after long times and/or at high temperatures was really considerable.Moreover, regarding removal of trichloroacetic acid and reaction time, the present procedure was more effective than what recently reported, 23,24 because the time was shortened from 12 hr to 1 hr (Table 1).
By comparing the IR and physical properties of the products with those of authentic samples, 23,25,[32][33][34][35][36] carbamates 1a-o were easily identified.Also; they were characterized by 1 H-NMR (500 MHz) and 13 C-NMR (125 MHz).The signals of carbonyl carbon of aliphatic or aromatic carbamate is displayed in 13 C-NMR spectra in the range of δ 146-157 ppm.
The present feasible reaction mechanism resembles the recently reported one 23,25 which is illustrated in Scheme 3. The reaction of sodium cyanate 3 with an acid (SSA) to produce isocyanic acid 5 could be the first step. 23,37,38Next, for the generation of the intermediate 7, the proton of SSA is added to isocyanic acid 5 that the proton is perfectly added to nitrogen rather than oxygen. 39Finally, carbamate 1 is likely to be formed when either alcohol or phenol 2 attack to the carbon of the intermediate 7 (Scheme 3).
In conclusion, this simple solvent free method affords various primary carbamates at room temperature in short reaction times, with high yields and purity, without involvement of toxic solvents, expensive starting materials, formation of any undesirable side products and epimerization.Also, we have revealed that silica sulfuric acid is a highly effective reagent for synthesizing primary carbamates.Furthermore, this method does not require purification or separation techniques (column chromatography).Further studies are in progress.

Experimental Section
General Procedures. 1 H-NMR and 13 C-NMR spectra were recorded by BRUKER AVANCE DRX500 (500 MHz).The IR spectra were obtained on a SHIMADZU-470.Melting points were recorded by Electro thermal 9100 and were uncorrected.Thin layer chromatography (TLC) was carried out using plastic sheets precoated with silica gel 60 F. All starting materials such as alcohols, phenols, NaOCN and solvents were purchased from Fluka, Merck and Aldrich chemical companies and were purified with the proper purification techniques before use. 40,413][34][35][36] Silica sulfuric acid (SSA) was prepared from silica gel and chlorosulfonic acid according to literature. 30

General preparative procedure
In a typical procedure, to a mixture of sodium cyanate (2 mmol) and SSA (0.77 g, 2 mmol), alcohol or phenol (1.0 mmol) was added and the mixture was pulverized in a mortar (or the mixture can be also stirred by a magnet in a test tube) at room temperature or 55-65 o C for appropriate time (Table 1).The reaction was monitored in TLC.After completion of reaction, CHCl 3 was added and the mixture was filtered for separating of reagent.The solvent (CHCl 3 ) evaporated to give product.Pure products were obtained in high yields, as summarized in Table Scheme 1 Scheme 3