Efficient carbamate synthesis

A method of preparing carbamates of the general formula RR&#8242;&#8212;N&#8212;CO2&#8212;R&#8243; by reacting an amine with carbon dioxide and an organic electrophile in an anhydrous solvent in the presence of a cesium base, whereby carbamate synthesis is accomplished in good yield at mild temperatures, either in solution or on a solid support, and wherein R, R&#8242;, and R&#8243; are hydrogen, alkyl of 1-18 carbon atoms, silyl, phenyl, benzyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, allyl, or heterocycle, which are widely used as industrial products, and as intermediates in organic synthesis.

1. FIELD OF THE INVENTION

The present invention relates to an efficient method for the synthesis of carbamates of the following general formula,

RR N CO 2 R

and N-alkylated derivatives thereof, wherein R, R , and R are selected from the group consisting of hydrogen, alkyl of 1-18 carbon atoms, silyl, phenyl, benzyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, allyl, and heterocycles, which are widely used as industrial products, and as intermediates in organic synthesis. In particular, the invention relates to a method providing efficient formation of carbamates from amines, carbon dioxide, and an organic electrophile, in the presence of a cesium base and, optionally, tetrabutylammonium iodide.

2. BACKGROUND OF THE INVENTION

Carbamates are widely used in industry and research, for example as fungicides, pharmaceuticals, cosmetics, and antibacterial preparations; as intermediates and cleavable protective groups in organic synthesis; and as peptidomimetic compounds.

Carbamates are prepared by a variety of methods, in particular by reaction of amines with alkyl chloroformates; by reaction of alcohols with carbamoyl chlorides or isocyanates; via reactions involving metal complexes or acyl transfer agents; and in some cases by the use of the highly toxic, and inconvenient to handle, phosgene reagent. See for example, Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis ; 1991; Wiley and Sons, p. 309-348.

The above methods suffer from certain drawbacks and limitations. Harsh reaction conditions, including elevated temperatures are often required to achieve acceptable yields of carbamate products. Use of harsh conditions complicates synthesis of compounds containing labile functional groups, requiring either additional protection/deprotection steps, or post-synthesis purification, thus lowering yields and increasing costs. Harsh reaction conditions can also promote inversion of chiral centers causing undesirable racemization of products. Furthermore, the reagents required are often toxic, for example isocyanates, or highly toxic, such as phosgene. In addition, activated compounds used in carbamate synthesis, such as acyl transfer agents, may be unstable. The latter problem is compounded when relatively unreactive aromatic amines are used. For each of these reasons, an improved method for the synthesis of carbamates has long been sought.

Carbon monoxide and certain metal catalysts can be used to synthesize carbamates from several starting compounds, including amines. Metals such as palladium, iridium, uranium, and platinum are used as catalysts. Not only are these metals expensive, but frequently a redox-active co-catalyst such as ferrous chloride is advantageous, which complicates purification and is corrosive.

Methods using carbon dioxide in place of the more toxic carbon monoxide for synthesis of carbamates have been reported, (see for example, Yoshida, Y., et al., Bull. Chem. Soc . Japan 1989, 62, 1534; and Aresta, M., et al., Tetradedron, 1991, 47, 9489) but such reactions often require harsh reaction conditions such as elevated temperatures.

Therefore, there exists a need for a method that simply and efficiently converts amines to carbamates in substantial yield. Furthermore, a desirable method would require less toxic and/or more stable reagents than are currently used. Preferably such a method could be performed under mild reaction conditions to minimize side reactions, and could provide for conversion of even poorly reactive amines, such as aromatic amines, both in solution and on solid supports.

BRIEF SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide an improved process for the conversion of amines to carbamates which avoids the aforementioned disadvantages and drawbacks.

It is a further object of the present invention to provide a process that obviates harsh reaction conditions, such as, but not limited to, reaction at high temperatures, or the presence of corrosive transition metal compounds.

It is a further object of the present invention to provide a process characterized by a three-component coupling of an amine, carbon dioxide, and an organic electrophile at mild temperatures in the presence of a cesium base.

It is a further object of the present invention to provide a simple and efficient method for the preparation of silylcarbamates.

It is yet a further object of the invention to provide methods for the synthesis of carbamate compounds upon a solid support matrix.

It is yet a further object of the invention to provide simple and efficient methods for selective synthesis of N-alkylated carbamates.

It is still a further object of the invention to provide methods for the synthesis of carbamates that avoid racemization and preserve the enantiomeric purity of the starting materials.

These and other objects of the present invention will become obvious to those skilled in the art upon review of the following disclosure.

Disclosed herein are methods for the conversion of amines that yield substantially carbamates; require reagents of lesser toxicity and higher stability than those agents set forth in the prior art; can be performed under mild reaction conditions to minimize side reactions; and provide for conversion of amines to carbamates both in solution and on solid supports. In a preferred embodiment, cesium carbonate, a source of carbon dioxide, an amine, and an alkyl halide are reacted in an anhydrous solvent. This catalytic process allows for the efficient and inexpensive preparation of various carbamates essential to industrial and research uses. Applications of the developed methodologies disclosed herewith include peptidomimetic synthesis, combinatorial library synthesis, drug design, protection of groups and the like.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the proposed mechanism for cesium-promoted carbamate synthesis in the presence of an amine RR NH, an organic electrophile R X, and CO 2 . Not to be limited by theory, the incipient in situ generated amide (2) can be formed by the reaction of an amine (1) with cesium carbonate in anhydrous DMF. The amide is free from the conjugate cesium ion; it is a naked anion , which renders it more nucleophilic. The amide (2) then rapidly reacts with carbon dioxide, giving rise to carbamate ester (3). The carbamate ester (3) further reacts with the electrophile R X, producing carbamate (4) in high yields.

FIG. 2 shows how additive TBAI can be used control the extent of N-alkylation obtained during carbamate synthesis carried out according to the present invention. 2-furanmethylamine and 2-thiophenemethylamine are converted to their corresponding carbamates by reaction with benzyl bromide and bubbling carbon dioxide in anhydrous DMF in the presence of cesium carbonate. After reaction at room temperature overnight, 85-87% yields of the respective N-alkylated carbamates are obtained. FIG. 2 A. In contrast, when an additive such as TBAI, or other quaternary amine, is included in the reaction, N-alkylation of the product carbamate is suppressed, and the carbamate is obtained in 90-92% yield. FIG. 2 B. Thus, the degree of N-alkylation of carbamates obtained using the present invention can be controlled through the addition to the reaction mixture of controlled amounts of additives such as TBAI.

FIG. 3 different organic electrophiles can be used for carbamate synthesis and for subsequent N-alkylation of the carbamate. By manipulation of the molar ratios of the organic electrophile relative to amine, and the timing of their addition, surprisingly it is possible to synthesize carbamates comprising different chemical moieties attached at the N- and O-linked positions. Thus, referring now to FIG. 3 , there are shown in FIGS. 3A and 3B two examples whereby synthesis of carbamate using a first organic electrophile is accomplished in good yield in the presence of TBAI to suppress N-alkylation, and in a subsequent step an excess of a second, chemically different organic electrophile is added, whereby N-alkylation by the second organic electrophile proceeds smoothly and in good yield. A stoichiometric excess of the second organic electrophile is preferred in this embodiment of the invention to overcome suppression of N-alkylation by TBAI. Therefore, the present invention provides a simple one-pot reaction method for the synthesis of N-alkylated carbamates with different moieties at the N- and O-linked positions.

FIG. 4 shows synthesis of peptidomimetic carbamate compounds is efficiently and simply achieved using the present invention. Referring now to FIG. 4 , synthesis of an O-methylated Leu-Ile-Leu peptidomimetic compound is shown as an illustrative example. An organic electrophile that also comprises an N-protected amine (here protected by N-butylation) is coupled in a first step via carbamate synthesis to an amine that also comprises a protected carboxylate group (here protected by O-methylation), yielding a peptidomimetic dipeptide analogue with protected N- and C-termini. Deprotection of the N-terminus (here by catalytic hydrogenation) exposes the N-terminal amine for a further cycle of carbamate synthesis through addition of a second organic electrophile that also comprises a protected amine group. Deprotection of the latter protected amine permits the synthetic process to continue. Thus, cycles of alternate carbamate coupling and deprotection steps can be used in the present invention to provide a diverse range of peptidomimetic compounds comprising natural and/or non-natural amino-acid sidechains for use in screening for biological activities, and for other applications.

FIG. 5 shows synthesis of silylcarbamates by the present invention. In this embodiment, low reaction temperatures are preferred ( 78 C. to room temperature) and TBAI may optionally be added. The organic electrophile in the present embodiment is triisopropyl silicon chloride (TIPSiCI), resulting in a novel triisopropyl silicon ester that may be cleaved, and is therefore useful in synthetic strategies requiring protection of carboxylic acids.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to providing improved methods for synthesis of carbamates, which substantially obviate the above mentioned problems of the prior art.

The present invention is based upon the inventor's discovery that the synthesis of carbamates of the general formula:

RR N CO 2 R

from the corresponding amine, organic electrophile, and carbon dioxide, is catalyzed by certain cesium bases, wherein R, R , and R are selected from the group consisting of hydrogen, alkyl of 1-18 carbon atoms, silyl, phenyl, benzyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, allyl, and heterocycles.

In the present disclosure, the term amine includes primary, secondary, aromatic, and heterocyclic amines comprising at least one carbon atom and at least one hydrogen covalently bonded to the amine nitrogen. The concentration of the amine is not critical. A concentration of about 0.2 M is advantageous.

The term organic electrophile includes organic halides such as chlorides, bromides, and iodides, as well as other organic electrophiles such as those containing mesyl (O Ms) or tosyl (O Ts) groups, silyl halides, or other organic compounds which are activated for electrophilic reaction. In preferred embodiments, chlorides and bromides are used. Most preferably, bromides are used. Organic iodides are less advantageous as electrophiles because they typically react more slowly than corresponding bromides or chlorides, and may be prone to rearrangement. The concentration of organic electrophile is advantageously from a slight molar excess to a several-fold excess, relative to amine concentration.

Advantageously, the cesium salt is cesium carbonate, cesium bicarbonate, cesium bromide, cesium hydroxide, or mixtures thereof In a most preferred embodiment, the cesium salt is cesium carbonate. Cesium carbonate is also preferred when undesirable side reactions, which may be promoted by stronger bases, must be minimized. The production of cesium halides during the reaction helps to drive the reaction to completion where the cesium halide (eg. CsBr) produced by the reaction is insoluble in the solvent used. The preferred amount of cesium salt is about a threefold excess compared to amine.

Optionally, tetrabutyl ammonium iodide (TBAI), or other material promoting halide-exchange, may be included. An advantageous amount of TBAI is from about 0.1 to 2.0 relative to amine concentration.

In the present invention, an anhydrous solvent is provided in which the cesium base is sufficiently soluble to promote carbamate synthesis. The solvent is preferably dimethyl sulfoxide, N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidinone (NMP), N,N-dimethylacetamide (DMAC), or a mixture thereof. Most preferably the solvent is DMF.

Optionally, a molecular sieve may be added to effectively sequester water produced the reaction. Preferably, a powdered molecular sieve is used that has a pore diameter of about 3-5 .

The invention will be readily understood by those of ordinary skill in the art by reference to the following examples and figures.

As a first example, carbamate (2) is prepared in a 40% yield by treatment of phenethylamine (1) in the presence of cesium carbonate, tetrabutylammonium iodide (TBAI), and n-butyl bromide in anhydrous DMF at 93 C. for 21 hours.

Efficient Cesium-Promoted Carbamate Synthesis in the Presence of a Carbon Dioxide Source

In a preferred embodiment, improved carbamate yield is obtained by supplementing the reaction with a continuous source of carbon dioxide, preferably by bubbling the reaction with a gas containing carbon dioxide. This example is a three-component coupling of amine (3) and n-butyl bromide, at room temperature and in the presence of a continuous source of carbon dioxide, to synthesize benzylcarbamate (4) in high yield. A yield of 96% of benzylcarbamate (4) is obtained in 3 hours at 23 C. from the reaction of n-butyl bromide and benzylamine (3) in anhydrous DMF in the presence of cesium carbonate and tetrabutylammonium iodide (TBAI).

Efficient Synthesis of Carbamates from Alkyl and Primary Amines

A useful feature of the present invention is that carbamates can be prepared by reactions of a very wide range of amines and organic electrophiles under mild conditions, as set forth in the following examples. In these examples, high yields of carbamates of the general formula R NH CO 2 R are produced from a range of structurally diverse primary amines reacted with organic electrophiles, preferably organic bromides or chlorides. Reactions are carried out at mild temperatures, preferably 23 C. or 0 C. Examples 3-25 demonstrate the versatility of the present invention and the syntheses are described in detail below.

Efficient Synthesis of Carbamates from Aromatic Primary and Secondary Amines

In further embodiments of the present invention, the inventor has surprisingly discovered that carbamates are synthesized in good to excellent yields from relatively unreactive aromatic amines under mild conditions in DMF in the presence of TBAI, Cs 2 CO 3 , and CO 2 . Aromatic amines are generally less reactive than corresponding alkyl amines, therefore this example significantly extends the utility of the present invention. The following examples are illustrative of the synthesis of carbamates from aromatic amines.

Preparation of carbamate A38. To a solution of p-nitroaniline (0.29 g, 2 mmol) in anhydrous N,N-dimethylformamide (10 mL), cesium carbonate (2.0 g, 6 mmol, 3 eq.) and tetrabutylammonium iodide (2.32 g, 6 mmol, 3 eq.) are added to the solution with vigorous stirring. Carbon dioxide is bubbled into the solution continuously for 1 hour before benzyl chloride (0.76 g, 6 mmol, 3 eq.) is added. The reaction is allowed to proceed at a temperature of 70 C. with constant carbon dioxide bubbling and stirring for 24 hours. The reaction mixture is quenched with water and extracted with ethyl acetate (3 30 mL). The combined organic layers were washed with water (2 30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent and subjection of the crude residue to column chromatography (1:1 hexanes:EtOAc) affords carbamate A36 (0.31 g, 60%) as a pale yellow oil.

Preparation of carbamate A37. To a solution of m-nitroaniline (0.27 g, 2 mmol) in anhydrous N,N-dimethylformamide (10 mL), cesium carbonate (1.9 g, 6 mmol, 3 eq.) and tetrabutylammonium iodide (2.16 g, 6 mmol, 3 eq.) are added to the solution with vigorous stirring. Carbon dioxide is bubbled into the solution continuously for 1 hour before benzyl chloride (0.76 g, 6 mmol, 3 eq.) is added. The reaction is allowed to proceed at a temperature of 70 C. with constant carbon dioxide bubbling and stirring for 24 hours. The reaction mixture is quenched with water and extracted with ethyl acetate (3 30 mL), water (2 30 mL), brine (30 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent and subjection of the crude residue to column chromatography (2:1 hexanes:EtOAc) affords carbamate A37 (0.334 g, 65%) as an oil.

Efficient Solid Phase Synthesis of Carbamates from Non-Aromatic Amines.

The present invention further provides a simple and mild method for the solid phase synthesis of carbamates. In the presence of TBAI, a variety of non-aromatic amines are coupled to Merrifield's resin, which in this embodiment functions as the organic electrophile. During the reaction, CO 2 is bubbled through the reaction mixture and carbamate formation is thereby facilitated, which results in coupling of the amine to the resin through formation of a CO 2 bridge. The invention produces substantially carbamates, in respectable to excellent yields. Although good results are obtained at room temperature, yields are improved if the reactions are carried out at 60 C. Surprisingly, carbamates of aniline derivatives and aminopyridines are formed successfully in moderate to excellent yields.

It will be obvious to one of ordinary skill that solid supports and resins having amine groups, instead of electrophiles, covalently attached to their surfaces can likewise be used to synthesize immobilized carbamates. In this embodiment, the electrophile is supplied in soluble form, and the resulting carbamate has the opposite orientation relative to the support compared to embodiments where the electrophile is immobilized, as in the following examples.

In a further embodiment of the present invention, resin-bound carbamates are easily released from the resin by treatment with LiAlH 4 in THF. Cleavage liberates the corresponding N-methyl secondary amine.

Preparation of carbamate AA41: Into a stirred solution of n-octylamine (0.646 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. The temperature of the reaction is then raised to 60 C., after which carbon dioxide is then passed into the suspension for 15 minutes. Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion and the reaction is allowed to further react at 60 C. for 24 hours with constant carbon dioxide bubbling. The solution is then cooled to room temperature and filtered through a coarse fitted disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield the desired carbamate AA41 (1.04 g, 44%) as a solid. Data for AA41: IR (KBr pellet) 3400, 3320, 2980, 2950, 2930, 2915, 2825, 1729, 1710, 1595, 1500, 1480, 1450, 1400, 1230, 1040, 1020, 740, 695 cm 1 .

Preparation of carbamate AA33: Phenethylamine (0.61 g, 5 mmol, 2.5 eq.) is dissolved in N,N-dimethylformamide (40 mL) to make a 0.2 M solution. Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added to the solution under vigorous stirring. Dry carbon dioxide is allowed to pass into the stirred suspension at room temperature for 1 hour. The temperature of reaction is then raised to 60 C., after which Merrifield's resin (1 g, 2 mmol, 1 eq.) is added and the reaction is allowed to continue with stirring at 60 C. for 24 hours with constant carbon dioxide bubbling. The reaction is subsequently cooled to room temperature and filtered through a coarse fitted filter funnel. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield the desired carbamate AA33 (1.10 g, 51%) as a solid. Data AA33: IR (KBr pellet) 3400, 3080, 3060, 3040, 2920, 2850, 1940, 1729, 1710, 1595, 1525, 1485, 1450, 1210, 1130, 1000, 840, 695 cm 1 .

Preparation of carbamate AA31: Into a stirred solution of p-methoxyphenethylamine (0.76 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. The temperature of the reaction is then raised to 60 C., after which carbon dioxide is passed into the suspension for 2 hours. Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion and the reaction is further allowed to continue at 60 C. for 20 hours with constant carbon dioxide bubbling. The reaction is then cooled to room temperature and filtered through a coarse fitted disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield desired carbamate AA31 (1.20 gm, 68%) as a solid. Data for AA31: IR (KBr pellet) 3080, 3060, 3020, 2920, 2860, 1950, 1875, 1825, 1722, 1595, 1510, 1495, 1440, 1210, 1150, 1020, 815, 740, 695 cm 1 .

Cleavage of solid phase support of carbamate AA31: Under a nitrogen atmosphere resin bound carbamate AA31 (1.02 g, 1.12 nunol) is placed in a flame dried flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (377 mg, 10 mmol) is then added in portions to the resulting suspension over a period of 20 minutes, and the reaction is refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL) followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 mL). The reaction mixture is filtered through a coarse filtration frit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield the desired N-methylated product AA32 (0.039 g, 21%).

Preparation of carbamate AA27: Into a stirred solution of benzylamine (0.536 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. Carbon dioxide is then passed into the reaction at room temperature for 1 hour. The temperature of the reaction is then raised to 60 C., after which Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion and the reaction was further continued at 60 C. for 24 hours with constant carbon dioxide bubbling. The suspension is then cooled to room temperature and filtered through a coarse flitted disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield desired carbamate AA27 (1.09 g, 55%) as a solid. Data for AA27: IR (KBr pellet) 3400, 3350, 3080, 3060, 3020, 3040, 2920, 2840, 1950, 1870, 1780, 1722, 1590, 1520, 1505, 1495, 1465, 1210, 1120, 1020, 750, 695 cm 1 .

Preparation of carbamate AA35: Into a stirred solution of allylamine (0.29 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. The temperature of reaction is raised to 90 C., after which carbon dioxide is bubbled into the stirred suspension for 3 hours. The suspension is then cooled to 60 C. and Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion and the mixture is stirred at the same temperature for 24 hours with constant carbon dioxide bubbling. The solution is then cooled to room temperature and filtered through a coarse fitted filter disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order. and then dried in vacuo to yield desired carbamate AA36 (1.10 gm, 85%) as a solid. Data for AA36: IR (KBr pellet) 3420, 3320, 3080, 3060, 3020, 2935, 2850, 1722, 1712, 1650, 1595, 1525, 1500, 1450, 1215, 750, 695 cm 1 .

Preparation of carbamate AA34: To a solution of 2-methoxyethylamine (0.37 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. Carbon dioxide is then bubbled into the reaction at room temperature for 1 hour. The temperature of reaction is raised to 60 C., after which, Merrifield's resin (1 g, 2 mmol, 1 eq.) is added and reaction is allowed to further react at 60 C. for 24 hours with continuous CO 2 bubbling. The reaction mass was cooled to room temperature and filtered through a coarse fitted filter disc. The insoluble resin is then washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield desired carbamate AA34 (1.06 g, 89%) as a solid. Data for AA34: IR (KBr pellet) 3420, 3320, 3080, 3060, 3040, 2925, 2840, 1722, 1590, 1525, 1495, 1450, 1220, 1110, 1020, 830, 740, 695 cm 1 .

Preparation of carbamate AA1: Into a stirred solution of furfurylamine (0.47 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g; 7.5 mmol, 3.75 eq) and tetrabutylammonium iodide (2.8 g, 7.5 mmol, 3.75 eq) are added. The temperature of the suspension is raised to 90 C., after which carbon dioxide (flow rate 25-30 mL/min) is bubbled into the stirred suspension at 90 C. for 3 hours. The reaction is then cooled to 60 C. and Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion and the mixture is stirred at 60 C. for 24 hours with constant carbon dioxide bubbling. The suspension is then cooled to room temperature and filtered through a coarse fitted filter funnel. The resin is subsequently washed with 20 ml aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield the desired carbamate AA1 (1.2 g, 92%) as a solid. Data for AA1: IR (KBr pellet) 3475, 3360, 3080, 3060, 3030, 2915, 2865, 1701, 1600, 1530, 1450, 1345, 1225, 1120, 1010, 998, 850, 730, 695 cm 1 .

Cleavage of solid phase support for carbamate AA1: Under a nitrogen atmosphere, resin bound carbamate AA1 (1.07 g, 1.65 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.377 g, 10 mmol) is added in portions to the resulting slurry over a period of 20 minutes. The reaction is then refluxed under nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% aqueous sodium hydroxide solution (0.4 mL), and finally water (1.1 mL). The reaction mixture is then filtered through a coarse filtration frit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product was then purified by flash chromatography (1:1 hexanes:ethyl acetate) to yield the desired N-methylated product AA2 (0.21 g, 11%).

Preparation of carbamate AA3: To a solution of 2-Thiophenemethylamine (0.56 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. The temperature of reaction is raised to 90 C., after which carbon dioxide (flow rate 25-30 mL/min) is bubbled into the stirred suspension at 90 C. for 3 h. The reaction mass is then cooled to 60 C., and Merrifield's resin (1 g, 2 mmol, 1 eq.) is added into the reaction and stirred at 60 C. for 24 hours with constant carbon dioxide bubbling. The reaction mass is subsequently cooled to room temperature and filtered through a coarse fitted filter disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield desired carbamate AA3 (1.15 g, 71%) as a solid. Data for AA3: IR (KBr pellet) 3430, 3325, 3080, 3040, 3020, 2930, 2850, 1705, 1600, 1510, 1465, 1360, 1210, 1150, 1110, 1020, 950, 830, 750, 690, 530 cm 1 .

Cleavage of solid phase support for carbamate AA3: Under a nitrogen atmosphere, resin bound carbamate AA3 (1.02 g, 1.25 mmol) is placed in a flame dried round-bottomed flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.377 g, 10 mmol) is added in portions to the resulting suspension over a period of 20 minutes. The reaction mass is then refluxed under nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched by dropwise addition of water (0.4 mL), followed by 15% aqueous sodium hydroxide solution (0.4 mL), and finally water (1.1 mL). The reaction mixture is filtered through a coarse filtration frit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes: ethyl acetate) to yield the desired N-methylated product AA4 (0.55 g, 34%). Data for AA4: 1 H NMR (360 MHz, CDCl 3 ) 2.01 (bs, N H ), 2.35 (s, 3H), 3.82 (s, 2H), 6.83-7.11 (m, 3H).

Preparation of carbamate AA5: Tetrahydrofurfurylamine (0.51 g, 5 mmol, 2.5 eq.) is dissolved in N,N-dimethylformamide (40 mL) to make a 0.2 M solution. Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added to the solution with vigorous stirring. The temperature of reaction is then raised to 60 C., after which carbon dioxide (flow rate 25-30 mL/min) is allowed to pass into the stirred suspension for 3 hours. Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in into the reaction and the mixture is stirred at 60 C. for 24 h with constant carbon dioxide bubbling. The reaction mass is subsequently cooled to room temperature and filtered through a coarse fitted filter disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield desired carbamate AA5 (1.17 g, 84%) as a solid. Data for AA5: IR (KBr pellet) 3475, 3360,3080, 3065, 3025, 2915, 2865, 1722, 1600, 1510, 1490, 1470, 1375, 1225, 1070, 1020, 815, 775, 695, 530 cm 1 .

Preparation of carbamate AA36: Into a stirred solution of cyclooctylamine (0.64 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. The temperature of the reaction is raised to 90 C., after which carbon dioxide is bubbled into the stirred suspension at 90 C. for 3 hours. The suspension is then cooled to 60 C. and Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion into the reaction and the mixture is stirred at the same temperature for 24 hours with constant carbon dioxide bubbling. The reaction is then cooled to room temperature and filtered through a coarse fitted disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield desired carbamate AA36 (1.23 g, 88%) as a solid. Data for AA36: IR (KBr pellet) 3450, 3370, 3080, 3060, 3035, 2915, 2820, 1722, 1595, 1500, 1480, 1440, 1205, 1030, 820, 770, 695 530 cm 1 .

Preparation of carbamate AA39: Into a stirred solution of D,L- -methylbenzylamine (0.61 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. The temperature of reaction is then raised to 60 C., after which carbon dioxide is passed into the reaction for 15 minutes. Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion and the reaction is fturther continued at 60 C. for 24 hours with constant carbon dioxide bubbling. The suspension is then cooled to room temperature and filtered through a coarse flitted disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield desired carbamate AA39 (1.17 g, 73%) as a solid. Data for AA39: IR (KBr pellet) 3400, 3320, 3080, 3060, 3020, 2980, 2825, 1900, 1850, 1735, 1722, 1595, 1480, 1440, 1330, 1210, 1040, 1015, 720, 695 cm 1 .

Cleavage of solid phase support of carbamate AA39: Under a nitrogen atmosphere, resin bound carbamate AA39 (1.06 g, 1.31 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.38 g, 10 mmol) is added in portions to the resulting suspension over a period of 20 minutes. The reaction is then refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 mL). The reaction mixture is then filtered through a coarse filtration frit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield desired N-methylated product AA39 (0.118 g, 66%).

Preparation of carbamate AA28: Leucine methyl ester (0.508 g, 5 mmol, 2.5 eq.) was dissolved in N,N-dimethylformamide (40 mL) to make a 0.2 M solution. Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added to the solution with vigorous stirring. Carbon dioxide is then allowed to pass into the stirred suspension at room temperature for 1 hour. The temperature of reaction is then raised to 60 C., after which Merrifield's resin (1 g, 2 mmol, 1 eq.) is added and the reaction was continued with stirring at 60 C. for 24 hours with constant carbon dioxide bubbling. The reaction is subsequently cooled to room temperature and filtered through a coarse fitted disc. The resin is washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield desired carbamate AA28 (1.13 g, 46%) as a solid. Data AA28: IR (KBr pellet) 3420, 3360, 3080, 3040, 3020, 2935, 2840, 1950, 1722, 1595, 1515, 1495, 1450, 1240, 1190, 1160, 810, 750, 695 cm 1 .

Cleavage of solid phase support of carbamate AA28: Under nitrogen atmosphere, resin bound carbamate AA28 (1.06 g, 0.865 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.38 g, 10 mmol) is then added in portions to the resulting suspension over a period of 20 minutes, and the reaction is refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 mL). The reaction mixture is then filtered through a coarse filtration fit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 rnL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield the desired N-methylated product AA29 (0.103 g, 80%).

Preparation of carbamate AA38: To a solution of diisopropylamine (0.51 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. Carbon dioxide is then bubbled into the reaction at room temperature for 1 hour. The temperature of reaction is raised to 60 C., after which, Merrifield's resin (1 g, 2 mmol, 1 eq.) is added and reaction is allowed to react further at 60 C. for 24 hours with continuous CO 2 bubbling. The reaction is cooled to room temperature and filtered through a coarse fitted disc. The insoluble resin is then washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield the desired carbamate AA38 (1.08 g, 50%) as a solid. Data for AA38: IR (KBr pellet) 3400, 3080, 3050, 3020, 2950, 2925, 2850, 1703, 1580, 1490, 1450, 1360, 1290, 1275, 1030, 770, 695, 530 cm 1 .

Preparation of carbamate AA8: Quinoline (0.67 g, 5 mmol, 2.5 eq.) is dissolved in N,N-dimethylformamide (40 mL) to make a 0.2 M solution. Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added to the solution under vigorous stirring. The temperature of reaction is then raised to 60 C., after which carbon dioxide is allowed to pass into the stirred suspension at the same temperature for 10 hours. Merrifield's resin (1 g, 2 mmol, 1 eq.) is added and the reaction is continually stirred at 60 C. for 12 hours with constant carbon dioxide bubbling. The reaction mass is then cooled to room temperature and filtered through a coarse fitted filter disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield desired carbamate AA8 (1.27 g, 96%) as a solid. Data for AA8: IR (KBr pellet) 3440, 3075, 3045, 2920, 2850, 1900, 1875, 1740, 1695, 1590, 1560, 1505, 1450, 1395, 1320, 1250, 1220, 1170, 1115, 1010, 950, 905, 830, 820, 740, 695, 530 cm 1 .

Cleavage of solid phase support for carbamate AA8: Resin bound carbamate AA8 (1.21 g, 1.83 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL) under nitrogen atmosphere. Lithium aluminum hydride (0.38 g, 10 mmol) is added in portions to the resulting suspension over a period of 20 minutes. The reaction is then refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 mL). The reaction mixture is then filtered through a coarse filtration frit to remove insoluble aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield the desired N-methylated product AA9 (0.154 g, 54%). Data for AA9: 1 H NMR (360 MHz, CDCl 3 ) 1.99 (m, 2 H), 2.78 (t, 2 H, J 6.48 Hz), 2.88 (s, 3 H), 3.22 (t, 2 H, J 5.76 Hz), 6.58-7.26 (m, 4 H).

Cleavage of solid phase support of carbamate AA42: Under a nitrogen atmosphere, resin bound carbamate AA10 (1.16 g, 1.39 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.38 g, 10 mmol) is added in portions to the resulting suspension over a period of 20 minutes. The reaction is then refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 ml). The reaction mixture is then filtered through a coarse filtration frit to remove aluminum salts, and the residual salts were washed diethyl ether (4 8 mL). The combined filtrate and washings were dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield the desired N-methylated product AA42 (0.43 g, 16%).

Efficient Solid Phase Synthesis of Carbamates from Aromatic Amines

Under substantially similar conditions to those above, the inventor has surprisingly found that solid-phase carbamates are also synthesized in good yields from comparatively unreactive aromatic amines by the methods of the present invention. Furthermore, these carbamates can also be cleaved to yield corresponding secondary N-methyl amines.

Preparation of carbamate AA13: Aniline (0.54 g, 5 mmnol, 2.5 eq.) is dissolved in N,N-dimethylformamide (40 mL) to make a 0.2 M solution. Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added to the solution with vigorous stirring. The temperature of reaction mass is then raised to 60 C., after which carbon dioxide is allowed to pass into the stirred suspension for 1 hour. Merrifield's resin (1 g, 2 mmol, 1 eq.) is added into the reaction and the stirring is continued at 60 C. for 24 hours with constant carbon dioxide bubbling. The reaction mass is subsequently cooled to room temperature and filtered through a coarse fitted disc. The resin is subsequently washed with 20 ml aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield desired carbamate AA13 (1.12 g, 70%) as a solid. Data for AA13: IR (KBr pellet) 3420, 3300, 3080, 3060, 3040, 2925, 1730, 1600, 1510, 1485, 1445, 1210, 1120, 995, 695 cm 1 .

Preparation of carbamate AA14: Into a stirred solution of p-toluidine (0.54 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. Carbon dioxide is passed into the reaction at room temperature for 1 hour. The temperature of the reaction mass is then raised to 60 C., after which Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion and the reaction is further continued at 60 C. for 24 hours with constant carbon dioxide bubbling. The reaction mass is then cooled to room temperature and filtered through a coarse fitted disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield desired carbamate AA14 (1.18 g, 81%) as a solid. Data for AA14: IR (KBr pellet) 3420, 3330, 3080, 3060, 3020, 2915, 2850, 1950, 1900, 1722, 1605, 1525, 1445, 1405, 1315, 1200, 1035, 1010, 815, 740, 695 cm 1 .

Cleavage of solid phase support for carbamate AA14: Under a nitrogen atmosphere, resin bound carbamate AA14 (1.13 g, 1.57 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.38 g, 10 mmol) is added in portions to the resulting suspension over a period of 20 minutes. The reaction is refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 mL). The reaction mixture is filtered through a coarse filtration frit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield the desired N-methylated product AA15 (0.54 g, 49%). Data for AA15: 1 H NMR (360 MHz, CDCl 3 ) 2.26 (s, 3 H), 2.84 (s, 3 H), 6.65-7.27 (m, 4 H).

Cleavage of solid phase support of carbamate AA16: Under a nitrogen atmosphere, resin bound carbamate AA16 (1.14 g, 1.38 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.38 g, 10 mmol) is added in portions to the resulting suspension over a period of 20 minutes. The reaction is then refluxed under av nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 mL). The reaction mixture is filtered through a coarse filtration frit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield desired N-methylated product AA17 (0.198 g, 73%). Data for AA17: 1 H NMR (360 MHz, CDCl 3 ) 2.20 (s, 3 H), 2.25 (s, 3 H), 2.81 (s, 3 H), 6.80-7.25 (m, 3 H).

Preparation of carbamate AA19: o-nitroaniline (0.69 g, 5 mmol, 2.5 eq.) is dissolved in N,N-dimethylformamide (40 mL) to make a 0.2 M solution. Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added to the solution with vigorous stirring. Carbon dioxide is then allowed to pass into the stirred suspension at room temperature for 1 hour. The temperature of the reaction is then raised to 60 C., after which Merrifield's resin (1 g, 2 mmol, 1 eq.) is added, and the reaction is continued with stirring at 60 C. for 24 hours with constant carbon dioxide bubbling. The reaction is subsequently cooled to room temperature and filtered through a coarse fitted disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield desired carbamate AA19 (1.11 g, 44%) as a solid. Data for AA19: IR (KBr pellet) 3085, 3065, 3030, 2925, 2850, 1722, 1570, 1520, 1495, 1450, 1385, 1340, 1220, 1180, 1110, 1020, 695 cm 1 .

Preparation of carbamate AA22: Into a stirred solution of 3-aminoacetophenone (0.69 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. The temperature of the reaction is raised to 90 C., after which carbon dioxide is bubbled into the stirred suspension at 90 C. for 3 hours. The reaction mass is then cooled to 60 C. and Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion into the reaction, and the mixture is stirred at the same temperature for 24 hours with constant carbon dioxide bubbling. The reaction is then cooled to room temperature and filtered through a coarse fitted disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield desired carbamate AA22 (1.15 g, 62%) as a solid. Data for AA22: IR (KBr pellet) 3370, 3080, 3060, 3035, 2915, 2835, 1920, 1870, 1830, 1710, 1690, 1595, 1530, 1495, 1450, 1385, 1335, 1270, 1240, 1205, 1050, 775, 695 cm 1 .

Cleavage of solid phase support of carbamate AA43: Under a nitrogen atmosphere, resin bound carbamate AA43 (1.07 g, 1.15 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.38 g, 10 mmol) is added in portions to the resulting suspension over a period of 20 minutes. The reaction is refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% sodium hydroxide solution (0.4 mL), and finally water (1.1 mL). The reaction mixture is then filtered through a coarse filtration fit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield desired N-methylated product AA43 (0.109 g, 63%). Data for AA43: 1 H NMR (360 MHz, CDCl 3 ) 1.38 (d, 3 H, J 6.44 Hz), 2.73 (s, 3 H), 3.02 (bs, N H , O H ), 4.69 (q, 1 H, J 6.44 Hz 6.42-7.10 (m, 4 H).

Preparation of carbamate AA23: 2-aminopyridine (0.470 g, 6 mmol, 2.5 eq.) is dissolved in N,N-dimethylformamide (40 mL) to make a 0.2 M solution. Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added to the solution under vigorous stirring. Carbon dioxide is then allowed to pass into the stirred suspension at room temperature for 1 hour. The temperature of reaction is then raised to 60 C., after which Merrifield's resin (1 g, 2 mmol, 1 eq.) is added and the reaction is allowed to proceed with stirring at 60 C. for 24 hours with constant carbon dioxide bubbling. The reaction is subsequently cooled to room temperature and filtered through a coarse fitted disc. The resin is then washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield the desired carbamate AA23 (1.11 g, 66%) as a solid. Data AA23: IR (KBr pellet) 3400, 3085, 3065, 3025, 2930, 2850, 1920, 1722, 1570, 1520, 1490, 1415, 1385, 1300, 1210, 1180, 1170, 1080, 1010, 720, 695 cm 1 .

Cleavage of solid phase support of carbamate AA24: Under a nitrogen atmosphere, resin bound carbamate AA24 (1.05 g, 1.25 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.378 g, 10 mmol) is added in portions to the resulting suspension over a time period of 20 minutes. The reaction is then refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 mL). The reaction mixture is then filtered through a coarse filtration frit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield the desired N-methylated product AA24 (0.93 g, 30%). Data for AA24: 1 H NMR (360 MHz, CDCl 3 ) 3.52 (s, 3H), 4.50 (bs, N H ), 7.50-7.62 (m, 1H), 7.80-7.89 (m, 1H), 8.60-8.80 (m, 2H).

Preparation of carbamate AA25: 3-aminopyridine (0.47 g, 6 mmol, 2.5 eq.) is dissolved in N,N-dimethylformamide (40 mL) to make a 0.2 M solution. Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added to the solution under vigorous stirring. Carbon dioxide is then allowed to pass into the stirred suspension at room temperature for 1 hour. The temperature of reaction mass was then raised to 60 C., after which Merrifield's resin (1 g, 2 mmol, 1 eq.) is added and the reaction is continued with stirring at 60 C. for 24 hours with constant carbon dioxide bubbling. The reaction is subsequently cooled to room temperature and filtered through a coarse fitted disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane, and methanol in the given order and then dried in vacuo to yield the desired carbamate AA25 (1.13 g, 72%) as a solid. Data AA25: IR (KBr pellet) 3400, 3080, 3060, 3040, 2915, 2860, 1722, 1595, 1575, 1490, 1480, 1410, 1210, 1050, 1020, 740, 695 cm 1 .

Cleavage of solid phase support of carbamate AA25: Under nitrogen atmosphere resin bound carbamate AA25 (1.13 g, 1.4 mmol) is placed in a flame dried round-bottom flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.38 g, 10 mmol) is added in portions to the resulting suspension over a period of 20 minutes. The reaction mass is refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL), followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 mL). The reaction mixture is filtered through a coarse filtration frit to remove aluminum salts, and the residual salts are washed diethyl ether (4 8 mL). The combined filtrate and washings were dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield the desired N-methylated product AA26 (0.082 g, 54%). Data for AA26: 1 H NMR (360 MHz, CDCl 3 ) 2.73 (s, 3H), 4.81 (bs, N H ), 6.72-8.91 (m, 4H).

Preparation of carbamate AA18: Into a stirred solution of N-ethylaniline (0.61 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. Carbon dioxide is passed into the reaction at room temperature for 1 hour. The temperature of the reaction is then raised to 60 C., after which Merrifield's resin (1 g, 2 mmol, 1 eq.) is added in one portion and the reaction is further continued at 60 C. for 24 hours with constant carbon dioxide bubbling. The suspension is then cooled to room temperature and filtered through a coarse flitted filter disc. The resin is subsequently washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield desired carbamate AA18 (1.22 g, 89%) as a solid. Data for AA18: IR (KBr pellet) 3090, 3050, 3020, 2915, 1930, 1795, 1722, 1699, 1600, 1490, 1450, 1395, 1300, 1275, 1140, 1120, 1040, 1010, 810, 780,695 cm 1 .

Cleavage of solid phase support of carbamate AA19: Under a nitrogen atmosphere, resin bound carbamate AA19 (1.01 g, 0.806 mmol) is placed in a flame dried round-bottomed flask containing anhydrous tetrahydrofuran (20 mL). Lithium aluminum hydride (0.38 g, 10 mmol) is added in portions to the resulting suspension over a period of 20 minutes. The reaction mass is then refluxed under a nitrogen atmosphere for 8 hours. The reaction is subsequently cooled to 0 C. and quenched with dropwise addition of water (0.4 mL) followed by 15% sodium hydroxide solution (0.4 mL) and finally water (1.1 mL). The reaction mixture is then filtered through a coarse filtration frit to remove aluminum salts, and the residual salts were washed diethyl ether (4 8 mL). The combined filtrate and washings are dried over sodium sulfate and concentrated in vacuo. The crude product is then purified by flash chromatography (1:1 hexanes:ethyl acetate), to yield the desired N-methylated product AA20 (0.30 g, 31%).

Preparation of carbamate AA26: To a solution of diphenylamine (0.85 g, 5 mmol, 2.5 eq.) in anhydrous N,N-dimethylformamide (40 mL), Cesium carbonate (2.44 g, 7.5 mmol, 3.75 eq.) and tetrabutylammonium iodide (2.77 g, 7.5 mmol, 3.75 eq.) are added. Carbon dioxide is then bubbled into the reaction at room temperature for 1 hour. The temperature of reaction is raised to 60 C., after which, Merrifield's resin (1 g, 2 mmol, 1 eq.) is added and the reaction is allowed to further react at 60 C. for further 24 hours with continuous CO 2 bubbling. The reaction is then cooled to room temperature and filtered through a coarse fitted disc. The insoluble resin is then washed with 20 mL aliquots of water, methanol/water (1:1 v/v), water, tetrahydrofuran, dichloromethane and methanol in the given order and then dried in vacuo to yield desired carbamate AA26 (1.02 g, 21%) as a solid.

Overalkylation of Carbamates Using Activated Halides

In a further embodiment of the present invention, N-alkylated carbamates (dialkyl carbamates) are produced in a one-pot reaction. Omission of TBAI, provision of excess organic electrophile, and longer reaction times, promote synthesis of N-alkylated carbamates in good yields. Table 1. In other respects, conditions are substantially similar to those in the preceding Examples. In this embodiment, the N-linked and O-linked moieties that derive from the organic electrophile are necessarily identical.

N-alkylation of Carbamates

In an alternative embodiment to that set forth in examples above, chemically different organic electrophiles are used sequentially to first effect carbamate synthesis, and subsequently effect N-alkylation of the preformed carbamate. In this embodiment the N-linked and O-linked moieties that derive from the organic electrophiles are different. As disclosed in FIG. 3 , purification of the carbamate prior to N-alkylation is not essential; a one-pot carbamation is permitted to proceed essentially to completion, and addition of an excess amount of a second organic electrophile with a further reaction period results in good yield of the N-alkylated carbamate.

Synthesis of Silylcarbamates

In a further embodiment of the present invention, organic electrophiles are used that provide carbamates in which the ester oxygen bridges to an element other than carbon. Use of silicon-based organic electrophiles in the present invention, such as tri-isopropylsilicon chloride (TIPS), result in facile silylcarbamate formation in good yield under mild reaction conditions (FIG. 5 ).

In Summary, a method is disclosed for the mild and simple syntheses of carbamates, both in solution and on solid phases, utilizing a three component coupling of an amine, carbon dioxide, and an electrophile. This methodology provides a general synthesis scheme for carbamates for a variety of applications, including peptidomimetic synthesis, combinatorial library synthesis, drug design, protection of groups, and the like.

It should be apparent to those of ordinary skill that the examples disclosed herein adequately support the use of cesium bases to promote synthesis of carbamates in general, including silylcarbamates.

It should also be apparent that other embodiments of the present invention can be readily contemplated by those of ordinary skill in the art after reviewing the present specification and teachings. The present invention is not limited, however, to the specific embodiments disclosed herein and should not be construed so narrowly as to exclude embodiments that fall within the scope and spirit of the invention, which invention is limited solely by the scope of the following claims.