WO2013008256A1

WO2013008256A1 - One pot acylation of aromatic amines

Info

Publication number: WO2013008256A1
Application number: PCT/IN2012/000496
Authority: WO
Inventors: Santosh Baburao MHASKE; Pankaj Shantaram MAHAJAN
Original assignee: Council Of Scientific & Industrial Research
Priority date: 2011-07-14
Filing date: 2012-07-13
Publication date: 2013-01-17

Abstract

The present invention provides a cost effective, environmental friendly and efficient, one pot decarboxylative acylation of aromatic/heteroaromatic primary /secondary amine using diethyl malonate (DEM) to obtain corresponding homologated amides in good yield with a high degree of purity.

Description

ONE POT ACYLATION OF AROMATIC AMINES

Technical field:

The present invention provides a cost effective, environmental friendly and efficient, one pot decarboxylative acylation of aromatic/heteroaromatic primary/secondary amines using diethyl malonate (DEM) to obtain corresponding homologated amides of Formula IV in good yield with a high degree of purity.

R

Formula IV

Background and Prior art:

Amide formation is a commonly used and an important reaction in organic chemistry. It is very useful in the preparation of pharmaceuticals, agrochemicals and poly amides.

Diethyl malonate, also known as DEM, is the diethyl ester of malonic acid found in fruits like grapes, pineapples and strawberries is a common ingredient of perfumes, artificial flavourings and extensively used in the famous name reaction, "Malonic Ester Synthesis (MES)". It is also being used in the preparation of CNS depressant drugs barbiturates and important vitamins like vitamin Bi & B₆. However application of DEM for "Malonic Ester Amide Synthesis (MEAS)" never emerged as general process for synthesis of amides.

Acetic acid (at high temperature/pressure), acetic anhydride (classified chemical) or acetyl chloride (lachrymatoric) are commonly used in the presence of plethora of base or acid catalysts to from corresponding amides. Long chain substituted amides are usually formed via a reaction of activated carboxylic acid with an amine. The best known method, the Schotten-Baumann reaction involves conversion of the acid to acid chlorides. A survey reveals that 44% of the amide drug candidates are prepared from acid chloride intermediates, a relatively environmentally malignant approach. Carboxylic acids are also activated with a variety of catalysts, which include Lewis acids such as metal halides, triflates, perchlorates, and solid-supported reagents or peptide coupling agents. Approximately 36% of the amide-bond forming reactions in pharmaceutical industries are carried out by means of these peptide coupling reagents, which produces a large amount of waste. Several other approaches for the. amide bond formation including enzymatic catalysis, metal catalysis, activated carboxylic esters or S-nitrosothioacids are also known. Moreover, Spanish Patent No. ES2237234 discloses the preparation of an optically pure tetramine for aza macrocycles has biocataly tic resolution of (+)-trans-cyclopentanodiamine (TC) by e.g. lipases in organic media and acylation by diethyl malonate yields optically enantiopure bisamido ester. The bisamido ester (1R,2R)-N, N'-(cyclopentane-l,2-diyl) bis (2-methyl carbamoiletanoato) II gives yield up to 60% (cf example 1 of ES'234).

Mario Sechi et al. in Molecules 2008,(13), 2442-2461 discloses general procedure for the synthesis of symmetric bis-amides (la-h), wherein dimethyl malonate (la-e and h) or diethyl malonate (lf-g) is reacted with corresponding aromatic amine under inert atmosphere and at temperature 185 °C to obtain the final product, whereas F. D. Chattaway et al. (J.Chern. Soc. 97, 339 1919) discloses conversion of unsubstituted malonic acid diethyl ester with various halo-anilines at boiling heat (199° C. for DEM) into the mono- and bis-halo-anilides.

US Patent No. 5334747 relates to the preparation of malonic mono-ester mono-anilides, wherein substituted aniline is reacted with diethyl malonate in presence of sodium methanoate in suitable organic solvent.

Further, the ammonolysis of diethyl malonate that subsequently affords malonamide, wherein ammonolysis is carried out in presence of ammonium hydroxide or ammonium chloride and other ammonium salts are known from Proc. Nat. Acad. Sci. U S A. 1937 December; 23(12): 611-615 and J. Am. Chem. Soc, 1948, 70 (7), 2596-2596.

Also there are various processes known in the literature for the preparation of amides, wherein dehydrating agents like Ν,Ν'-Dicylohexyl carbodiimide are used for preparation of amides. But such dehydrating agents are expensive and additional steps are involved in purifying the amide formed.

Also, the reaction has to be carried out in anhydrous conditions. Further the use of highly corrosive and toxic reagents like thionyl chloride or oxalyl chloride and bases like triethylamine, diisopropyl amine etc. gives undesirable side products such as HC1 in this route.

It is observed that the use of several organic/inorganic bases such as pyridine or DMAP, give either poor conversion or complex reaction mixture.

In case of excessive heating of esters with amines leads to poor or low yield and such heating also does not work for long chain esters. A simple acetylation in presence of acetic anhydride which is used in combination with toxic pyridine is known, but now acetic anhydride has been banned all over the world. In view of foregoing the prior art methods include the toxic, lachrymatoric, corrosive, harmful reagents as well as the side products, which subsequently contributes to poor yield of final amide products, therefore, there is a need for cost-effective, efficient and environmental friendly acylation process for the preparation of amides from aromatic or aliphatic amines using non-toxic, harmless, cheap and easily available acylating agent such as DEM.

Moreover, the processes known in the art are lengthy and cumbersome. The present invention has tried to obviate the drawbacks of the prior art process by employing one pot process for Malonic ester amide synthesis. Objective of the invention:

The main objective of the present invention is to provide a general methodology, which comprises improved, cost-effective and efficient catalytic decarboxylative acylation of aromatic/heteroaromatic, primary /secondary amines using malonic ester to obtain corresponding amides in good yield with high degree of purity.

The other object of the invention is to provide a simple, one pot process for the preparation of amides under optimum conditions.

Summary of the Invention:

R

Formula IV

Accordingly, the present invention provides a one pot catalytic decarboxylative acylation of amine of formula (I) to obtain amides of formula (IV) in high yield and purity; wherein,

R is selected from the group consisting of hydrogen, substituted /unsubstituted alkyl, substituted/ unsubstituted phenyl, substituted/unsubstituted alkylaryl and substituted/unsubstituted heteroaryl; Ar is selected from the group consisting of substituted or unsubstituted phenyl, substituted/unsubstituted alkylaryl or substituted/unsubstituted heteroaryl; and

R' is selected from the group consisting of hydrogen, substituted/unsubstituted alkyl, substituted/unsubstituted phenyl, substituted/unsubstituted alkylaryl or substituted/unsubstituted heteroaryl , and the said process comprising the steps of;

a) heating the mixture of amine (Formula I) and malonic ester (Formula II) in mole ratio ranging between (1: 10-20) for a period ranging between 0.5-3 hrs at a temperature ranging between 100-130 °C to obtain intermediate (III), cooling the reaction mixture;

Formula-I Formula-II Formula-HI

wherein;

Ar = substituted/unsubstituted alkylaryl or substituted/unsubstituted heteroaryl;

R=hydrogen, substituted/unsubstituted alkyl, substituted/unsubstituted phenyl, substituted/unsubstituted alkylaryl and substituted/unsubstituted heteroaryl; R'= hydrogen, substituted/unsubstituted alkyl, substituted unsubstituted phenyl, substituted/unsubstituted alkylaryl or substituted/unsubstituted heteroaryl. b) catalytic decarboxylation of the intermediate (III) as obtained in step (a) optionally in presence of alkali metal carbonate and a polar organic solvent at 80-120 °C until complete disappearance (1-3 h) of intermediate (III) to obtain crude amide product; c) evaporating the organic solvent of step (b) followed by dissolving in another polar organic solvent, subsequently washing the organic layer with brine, drying and concentrating followed by washing with a non-polar solvent, filtering, drying to obtain the desired amide (Formula IV) in good yield and purity.

In one embodiment of the present invention alkali metal carbonate used in step (b) is CS₂CO3.

In another embodiment of the present invention the decarboxylation may be self- catalyzed.

In another embodiment of the present invention the catalyst is amine substrate, preferably hetero- aromatic amine.

In another embodiment of the present invention malonic ester used in step (a) is substituted or unsubstituted diethyl malonate.

In another embodiment of the present invention the purification of crude product obtained in step (b) optionally comprises evaporating the dialkyl malonate under vacuum, dissolving the residue in polar solvent followed by filtration and drying.

In another embodiment of the present invention polar organic solvent used in step (b) and (c) is selected from the group consisting of halo alkanes, aliphatic esters, ethers, acids either alone or mixtures thereof, selected from the group consisting of dichloromethane, ethylacetate, dichloroethane, dietheyl ether or mixtures thereof.

In another embodiment of the present invention non-polar organic solvent used in step ( c) is selected from petroleum ether, hexane, heptane, carbon tetrachloride, benzene and like thereof.

In another embodiment of the present invention yield of amides of formula (IV) is in the range of 57- 98%.

In another embodiment of the present invention purity of amides of formula (IV) is in the range of 92- 97%.

Abbreviations:

DEM: Diethyl Malonate

ME AS: Malonic Ester Amide Synthesis

CS2CO3: Cesium carbonate

DMAP: 4-Dimethylaminopyridine

DEPT Spectra: Distortionless Enhancement by Polarization Transfer

Ac: Acetyl i.e. (-COCH3) group

DCC- N, N'-Cyclohexyl carbodiimide

Description of drawings:

Fig A depicts the plausible mechanism for the MEAS methodology

Fig.l: a) depicts ¾, Spectra of Ethyl 3-((2-chlorophenyl)amino)-3-oxopropanoate

Fig 1: b) depicts ¹³C Spectra of Ethyl 3-((2-chlorophenyl)amino)-3-oxopropanoate

Fig 1: c) DEPT Spectra of Ethyl 3-((2-chlorophenyl)amino)-3-oxopropanoate

Fig-2: Ή NMR Spectra of N-phenylacetamide

Fig-3: ¾ NMR Spectra of N-(p-tolyl)acetamide

Fig-4: *H NMR Spectra of N-(4-nitrophenyl)acetamide

Fig-5: a) ¾ NMR Spectra of N-(3,4,5-trimethoxyphenyl)acetamide

Fig-5: b) ¹ C NMR Spectra of N-(3,4,5-trimethoxyphenyl)acetamide Fig-5 c) DEPT Spectra of N-(3,4,5-trimethoxyphenyl)acetamide

Fig-6: H NMR Spectra of N-(2-chlorophenyl)acetamide

Fig-7: *H NMR Spectra of N-(2-iodophenyl)acetamide

Fig-8: Ή NMR Spectra of N,N'-(l,4-phenylene)diacetamide

Fig-9: ¾ NMR Spectra of teit-butyl (4-acetamidophenyl)carbamate

Fig-10: Ή NMR Spectra of N-(4-hydroxyphenyl)acetamide

Fig-11: Ή NMR Spectra of N-(4-(3-hydroxypropyl)phenyl)acetamide

Fig-12: Ή NMR Spectra of N-(pyridin-2-yl)acetamide

Fig-13: a) ¾ NMR Spectra of N-(3-cyano-5-propylthiophen-2-yl)acetamide

Fig-13: b) ¹³C NMR Spectra of N-(3-cyano-5-propylthiophen-2-yl)acetamide

Fig-13: c) DEPT Spectra of N-(3-cyano-5-propylthiophen-2-yl)acetamide

Fig-14: Ή NMR Spectra of N,N-diphenylacetamide

Fig-15: Ή NMR Spectra of N-methyl-N-phenylacetamide

Fig-16: Ή NMR Spectra of N-phenylpropionamide

Fig-17: ^lH NMR Spectra of N-(p-tolyl)propionamide

Fig- 18: a) ^l NMR Spectra of N-(4-nitrophenyl)butyramide

Fig-18: b) ) ¹³C NMR Spectra of N-(4-nitrophenyl)butyramide

Fig-18: c) DEPT Spectra of N-(4-nitrophenyl)butyramide

Fig-19: ^lH NMR Spectra of N-(4-chlorophenyl)hexanamide

Fig-20: Ή NMR Spectra of N-(pyridin-2-yl)dodecanamide

Fig-21: Ή NMR Spectra of N,3-diphenylpropanamide

Fig-22: Ή NMR Spectra of N,2-diphenylacetamide

Detailed description of invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

In the preferred embodiment, the present invention provides a cost effective and improved one pot catalytic decarboxylative acylation of aromatic/heteroaromatic, primary/secondary amine formula (I) using malonic ester of formula (II) to obtain carbon homologated aromatic/heteroaromatic, primary/secondary amides of formula (IV) in high yield and purity;

Formula IV

wherein, R is selected from the group consisting of hydrogen, substituted /unsubstituted alkyl, „ substituted/ unsubstituted phenyl, substituted unsubstituted alkylaryl and substituted unsubstituted heteroaryl;

Ar is selected from the group consisting of substituted or unsubstituted phenyl, substituted/unsubstituted alkylaryl or substituted/unsubstituted heteroaryl; and

R' is selected from the group consisting of hydrogen, substituted/unsubstituted alkyl, substituted/unsubstituted phenyl, substituted/unsubstituted alkylaryl or substituted/unsubstituted heteroaryl.

Accordingly the present invention provides cost effective and improved one pot decarboxylative acylation of aromatic/heteroaromatic primary/secondary amine to obtain corresponding carbon homologated amide (IV) comprises;

a. heating the mixture of aromatic/heteroaromatic primary/secondary amine (Formula I) and malonic ester (Formula II) for 0.5-3 hrs till TLC indicates complete consumption of amine and formation of the intermediate (III), cooling the reaction mixture;

b. catalytic decarboxylation of the intermediate (III) in presence of alkali metal carbonate under optimum conditions until complete disappearance of intermediate (III); (In the case of a-substituted DEM, to avoid the use of excess a-substituted DEM (from economical point of view), only 10 - 20 eq. can be used and in the second step a small amount of polar solvent such as 1,4-dioxane can be added to avoid thick slurry formation. The results of both the ways are comparable)

c. reaction mixture of step (b) is then dissolved in another polar organic solvent, subsequently washing the organic layer with brine, drying and concentrating followed by addition of a non- polar solvent, filtering the formed solid, drying to obtain the desired amides (Formula IV) in high yield and purity.

The one pot process of decarboxylative acylation of aromatic/heteroaromatic, primary or secondary amine is given below in Scheme 1:

Scheme 1: Schematic representation of decarboxylative acylation of aromatic amines

Formula ! Formula-Π FormuEa-HI Formula-TV wherein, Ar = substituteaVunsubstituted alkylaryl or substituted/unsubstituted heteroaryl; R= hydrogen, substituted/unsubstituted alkyl, substituted/unsubstituted phenyl, substituted /unsubstituted alkylaryl and substituted/unsubstituted heteroaryl;

R'=hydrogen, substituted/unsubstituted alkyl, substituted/unsubstituted phenyl, substituted /unsubstituted alkylaryl or substituted/unsubstituted heteroaryl.

The malonic ester of formula II of the instant invention is selected from substituted or unsubstituted dialkyl malonate, more preferably substituted or unsubstituted diethyl malonate.

Further the aromatic/heteroaromatic primary/secondary amine (Formula I) and malonic ester (Formula II) is used in the mole ratio 1:20.

The catalytic decarboxylation of the intermediate may be self- catalyzed i.e. the decarboxylation may be effected by the amine substrate used in the reaction, preferably when the substrate is hetero-aromatic amine.

The heating is achieved by conventional or microwave heating. The temperature is maintained in the range of 50°C to 250°C, preferably 100°C to 150°C for a period of 0.5 to 3 hrs till the complete consumption of amine.

In the process of the instant invention, the polar organic solvent is selected from the group consisting of halo alkanes such as Dichloromethane (DCM) , aliphatic esters such as Ethyl acetate, ethers such as 1,4-dioxane, diethyl ether, Tetrahydrofuran (THF) , ketones such as Acetone and other polar solvents such as Dime thy If ormamide (DMF), Acetonitrile, Dimethyl sulfoxide (DMSO), water, either alone or mixtures thereof. The non-polar solvent is selected from petroleum ether, hexane, heptane, benzene and like thereof.

In accordance with scheme 1, the one pot process includes reacting a mixture of amine of Formula I and malonic ester of Formula II for 0.5 to 3 hrs at optimum temperature (100-150 °C) till TLC indicated complete consumption of the amine and formation of intermediate of formula (III). The reaction mixture is cooled at 100°C, whereas in the case of a-substituted DEM, to avoid the use of excess -substituted DEM (from economical point of view), only 10 - 20 eq. can be used followed by addition of small amount of first polar organic solvent such as 1,4-dioxane, to avoid thick slurry formation and Cs2C03 was added to the intermediate product, maintained at the same temperature for another 1-3 hrs until complete disappearance of the intermediate. The reaction mixture is further cooled to room temperature, the first polar solvent is evaporated off and the residue is dissolved in a second polar solvent. The second polar solvent is washed with brine, followed by drying and evaporation. Further, a non-polar solvent is added to the crude reaction product obtained after concentration and triturated until it forms free flowing solid. The non-polar solvent is filtered off and the solid amide product obtained is further dried under vacuum.

Alternatively, the crude amide product of step (b) can also be purified by evaporating off the dialkyl malonate under vacuum and dissolving the residue in polar solvent, followed by filtration through a bed of celite™. The concentration of the filtrate provides the expected amide product in comparable yields and more than 94-97% purity. The process of the present invention results in carbon homologated aromatic/heteroaromatic, primary/secondary amides of formula (IV) in high yield and purity; wherein the yield of amides of formula (IV) is in the range of 57-98% and the purity of amides of formula (IV) is in the range of 92- 97%.

The present process provides easy access to amides with odd/even chain lengths and array of substituents on the alkyl/aryl part.

The present invention provides one pot decarboxylative acylation of 2-chloroaniline (1) using DEM (2) to afford corresponding phenylacetamide (4) in 98% yield with more than 97 % purity (Scheme 2). Scheme 2:

I 200 °C without Cs₂0₃

5-24 h, - 60%

In accordance with scheme 2, the one pot decarboxylative acylation is illustrated with 2-chloroaniline (1), wherein diethyl malonate (2) and 2-chloroaniline (1) are heated together up to temperature ranging from 100°C-200°C for 1 hour to obtain approximately 1:1 mixture of intermediate amide (3) (*H NMR provided below-refer Figure 1) and final product (4). When the reaction mixture is heated further for longer hours (5-24 hrs.) the ratio shifts to the final product, with the formation of several other side products, result into a poor quality of dark coloured final product (60%), but when mixture containing (3), (4) and DEM is heated up to 100 °C in the presence of Cs₂C0₃ the product, N-(2- chlorophenyl) acetamide (4) is obtained in quantitative yield (98%).

Table- 1 represents the formation of various corresponding amides from different aromatic/heteroaromatic amines.

Table 1: Amide formation of various amines using DEM

Reaction condition = Step 1: amine (1.00 equiv.), DEM, 100 - 130 °C, 0.5 - 3 h and Step 2: Cs₂C0₃ (3.00 equiv.), 100 °C, 1 - 3 h; ^aexpected product was not observed; "after completion of the reaction, methanol was added and the reaction mixture was stirred at rt for 0.5 h; 'single step, 120 °C, 1 h (Cs₂C0₃ was not necessary, self-catalyzed).

As seen from Table 1, quantitative yield of corresponding amide in the case of 4-nitroaniline (Table 1, entry 3) and 70-75% yield in the case of aniline (Table 1, entry 1), p-toludine (Table 1, entry 2) and 3,4,5-trimethoxy aniline (Table 1, entry 4) indicates that aromatic amine with electron deficient substituent is better substrate most probably because in the second step it facilitates the attack of the base as well as provides an extra stability to the anion formed after decarboxylation. In the case of halogen substituted substrates, it is observed that 2-chloroaniline (Table 1, entry 5) gives better yield than 2-iodoaniline (Table 1, entry 6) plausibly because of the steric reasons and tenacity of iodo compounds to decompose at higher temperature. p-Phenylenediamine (Table 1, entry 7) gives good yield as expected. Application of the protocol to an acid labile substrate (Table 1, entry 8) provides very good yield which shows that this protocol can be used for such substrates too. However, in case of base labile substrate (Table 1, entry 9) there is no expected compound formation, but a trace amount of product same as observed in case of entry 7 (Table 1) is detected. Amide formation of aromatic amine in the presence of competing phenolic -OH moiety (Table 1, entry 10) shows 100% selectivity and the expected only iV-acetamide product which is obtained in good yields. The product of entry 10 (Table 1) is a widely used over-the-counter antipyretic and analgesic drug "Paracetamol", which is industrially prepared by acetylation of 4-aminophenol using acetic anhydride. In the case of amino-alcohol (Table 1, entry 11) along with the expected amide product a DEM trans esterified (but not decarboxylated) product is also observed hence after completion of the reaction methanol is added and the reaction mixture is stirred at room temperature for 0.5 h to obtain exclusively the expected product in 57% yield. Further, acetylation reaction on hetero-aromatic amines such as 2-aminopyridine (Table 1, entry 12) give an interesting result, wherein amide is obtained directly in a short time without the need of using Cs₂C0₃. This indicates that the substrate itself catalyzed the further decarboxylation reaction. The present invention provides the MEAS methodology using a-substituted DEM and aromatic/heteroaromatic amines (Table 2). Table 2. Amide formation using a-substituted DEM

Reaction condition = Same as used for Table 1; ^aStep 1: 12 h, Step 2: 5 h;

bsingle step. 120 °C, 1 h (CS2CO3 was not necessary, self catalyzed). Commercially available a-substituted DEM were used, which otherwise also can be prepared^11,14 easily starting from DEM.

Similar to the reaction pattern observed with DEM (Table 1, entry 1 & 2), aniline and p-toluidine is reacted with a-methyl DEM providing satisfactory yields (Table 2, entry 1 & 2). Contrary to the observation in Table 1 (entry 3), reaction of 4-nitro aniline with a-ethyl DEM provides lower yield. The reaction of 4-chloro aniline with -butyl DEM (Table 2, entry 4) provides the expected amide in 68% yield. The plausible side reaction malondiamide formation might have contributed to the lower yield. Further, the present inventors are experimented the process using longer chain a-substituted DEM. Since very good yield (Table 1, entry 13) using 2-amino pyridine and DEM is obtained , without the need of Cs₂C0₃, reaction using the same amine with a-decyl DEM is carried out which also gives excellent yields (Table 2, entry 5). The reaction of aniline with a-benzyl DEM (Table 2, entry 6) and a-phenyl DEM (Table 2, entry 7) gives excellent yields as compared to a-methyl DEM (Table 2, entry 1), probably because of the extended electron withdrawing resonance and inductive effect of the benzene ring.

In yet another embodiment, the present invention also provides MEAS methodology for the preparation of polyamide, which is illustrated in Scheme 3.

H₂N-R -NH₂

O O O O

Polyamide

Where R = alkyl, aryl etc.

wherein n is 1,2,3,4

Scheme 3

The MEAS method may potentially be useful for the preparation of polyamides, wherein diamine reacts with diester under neat heating gives final product with repeated units of amide bond i.e. polyamide in yield greater than 50% with purity levels greater than 50%.

In an embodiment, the present invention provides the spectral data for the array of carbon homologated amides synthesized by the process described above. Accordingly, the IR spectra are recorded on an FT- IR spectrometer. The 1H and 13C NMR spectra are recorded on 200/400/500 MHz and 50/100/125 MHz NMR spectrometer respectively in CDCl₃/CD₃OD/DMSO-d6 solvents. Mass spectra are taken on LC-MS (ESI) mass spectrometer. Analytically pure compounds are obtained by column chromatographic purifications are on neutral alumina. The structures of known compounds are further confirmed by their ^XH NMR and melting points.

The process of the instant invention comprising cost effective, improved one pot catalytic decarboxylative acylation provides easy access to amides with odd/even chain lengths and array of substituents on the alkyl/aryl part. The synthesis of odd chain lengths is noteworthy and important because most of the naturally occurring long chain alcohols/acids (which are commonly used as starting materials in the prior art) have even chain lengths. Therefore MEAS methodology of the current invention is a suitable alternative in industries for easy preparation of various aromatic amines to diverse amides.

Furthermore, the acylation process involved in present disclosure avoids use of toxic, harmful or banned chemicals such as acyl chlorides, acetic anhydride, organic bases as well as expensive peptide coupling reagents or metal catalysts, whereas the one pot preparation obviates the existing cumbersome process steps such advantages make the current process cost-effective, environment friendly and efficient.

The invention will now be illustrated with help of examples. The aforementioned embodiments and below mentioned examples are for illustrative purpose and are not meant to limit the scope of the invention. Various modifications of aforementioned embodiments and below mentioned examples are readily apparent to a person skilled in the art. All such modifications may be construed to fall within the scope and limit of this invention as defined by the appended claims.

Examples

Example 1: General procedure for the preparation of carbon homologated amides

A two neck round bottom flask (equipped with a distillation condenser and a magnetic stirring bar) containing a mixture of amine (leq.) and DEM / a-substituted DEM was heated (100-130°C) until complete consumption (0.5-3 h) of the starting amine. The reaction mixture was allowed to cool down to 100°C and Cs₂C0₃ (3 eq.) was added. Heating at 100°C was continued until (1-3 h) complete disappearance of the intermediate. Reaction progress was monitored by TLC. A suitable polar solvent was added to the reaction mixture at room temperature and CS2CO3 was filtered off. The organic layer was washed with water and brine and dried over Na₂S0₄. To the crude reaction product obtained after concentration was added a non-polar solvent and triturated until it forms free flowing solid. The non-polar solvent was then filtered off and the solid product obtained was characterized. Alternatively the product can also be purified by evaporating off the dialkyl malonate under vacuum and dissolving the residue in polar solvent, followed by filtration through a bed of celite™. Concentration of the filtrate provides the expected product in comparable yields and purity. The products obtained by both methods of purification were more than 92-97% pure.

Example 2: preparation of N-(2-chlorophenyl) acetamide (4)

The mixture containing 2-chloroaniline 1 (1 g, 7.84 mmol) and diethyl malonate 2 (2.51 g, 15.68 mmol) was heated at 130 °C for 3 h. After complete consumption of the starting amine, as followed by TLC, the reaction mixture was cooled to 100 °C and Cs₂C0₃ (7.66 g, 23.52 mmol) was added and then maintained at the same temperature for another 3 h. The reaction mixture was then cooled to room temperature, DEM was evaporated off and the residue was dissolved in 50 mL dichloromethane (DCM). The DCM layer was washed once with 25 mL brine, followed by drying over Na₂S0₄ and evaporation. To the obtained crude residue was added petroleum ether and triturated until it forms free flowing solid. Petroleum ether was filtered off and the product obtained was dried under vacuum to obtain amide 4 (1.3 g, 7.67mmol) in 98% yield and in more than 97% purity.

Example 3: General procedure for preparation of iV-(pyridin-2-yl) acetamide (Table 1, entry 12) and N-(pyridin-2-yl)dodecanamide (Table 2, entry 5).

iV-(pyridin-2-yl) acetamide : A two neck round bottom flask (equipped with a distillation condenser and a magnetic stirring bar) containing a mixture of 2-amino pyridine (200 mg, 2.12 mmol) and DEM (3 mL) was heated (120 °C) for lh. Reaction progress was monitored by TLC. Purification as mentioned in example 2 provided the expected acylated products in 87% (250 mg) yield and more than 97% purity.

iV-(pyridin-2-yl)dodecanamide: A two neck round bottom flask (equipped with a distillation condenser and a magnetic stirring bar) containing a mixture of 2-amino pyridine (100 mg, 1.06 mmol) and cr-decyl DEM (2 mL) was heated (120 °C) for lh. Reaction progress was monitored by TLC. Purification as mentioned in example 2 provided the expected acylated products in 97% purity and 92% (255 mg) In both these entries Cs₂C0₃ (i.e. Table 1, entry 12 and Table 2, entry 5) was not required and substrate itself catalyzes the decarboxylation.

Example 4: Spectral data and characterization of the array of carbon homologated amides

The characterization of the amides is performed by using FT-IR spectrometer, and *H and ¹³C NMR spectrometer respectively in CDCl₃/CD₃OD/DMSO-d6 solvents. Further the mass spectra are taken on LC-MS (ESI) mass spectrometer. Analytically pure compounds are obtained by column chromatographic purifications on neutral alumina. The structures of known compounds are further confirmed by their ¾ NMR and melting points.

Example 4a: Ethyl 3-((2-chlorophenyl) amino)-3-oxopropanoate (3, CAS: 15270-54-9).

2-Chloroaniline (200 mg, 1.56 mmol) and DEM (3 mL). Mp. 61-63 °C; IR (Nujol) v_max 1698, 1712, 1731, 3291 cm ¹; ¾ NMR (CDC1₃, 200 MHz, ppm): δ 1.34 (t, J = 7.0 Hz, 3H), 3.53 (s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 7.06 (t, J = 7.4 Hz, 1H), 7.27 (t, J = 7.71 Hz, 1H), 7.39 (d, J = 8 Hz, 1H), 8.38 (d, J = 8.2 Hz, 1H), 9.75 (bs, 1H); ¹³C NMR (CDC1₃, 125MHz, ppm): δ 14.1, 41.9, 62.0, 121.8, 123.3, 124.9, 127.6, 129.2, 134.6, 163.1, 169.5; ESIMS (m/z): 264 (M+Na). Purity 97%, Yield 163 mg, 43%.

Example 4b: N-phenylacetamide (CAS: 103-84-4, Table-1, Entry-1).

Aniline (100 mg, 1.07 mmol), DEM (2 mL), Cs₂CO₃ (1.05 g, 3.22 mmol). (Mp. 112-114 °C; ¾ NMR (CDC1₃, 200 MHz, ppm): δ 2.16 (s, 3H), 7.09 (t, J = 7.3 Hz, 1H), 7.30 (t, J = 7.3 Hz, 2H), 7.51 (d, J = 7.7 Hz, 2H), 7.81 (bs, 1H). Purity 96%, Yield 102 mg, 70%.

Example 4c: N-(p-tolyl) acetamide (CAS: 103-89-9, Table-1, Entry-2).

p-Toludine (500 mg, 4.66 mmol), DEM (5 mL), Cs₂C0₃ (4.56 g, 13.99 mmol). Mp. 151-153 °C; ¾ NMR (CDC1₃, 200 MHz, ppm): δ 2.15 (s, 3H), 2.31 (s, 3H), 7.11 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H) 7.53 (bs, 1H). Purity 92%, Yield 522 mg, 75%.

Example 4d: N-(4-nitrophenyl)acetamide (CAS: 104-04-1, Table-1, Entry-3).

4-Nitroaniline (100 mg, 0.72 mmol), DEM (3 mL), Cs₂CO₃ (702 mg, 2.15 mmol). Mp. 215-217 °C; Ή NMR (CDCl₃+DMSO-d₆ (9:1), 200 MHz, ppm): δ 2.04 (s, 3H), 7.66 (d, J = 9.2 Hz, 2H), 8.00 (d, J = 9.2 Hz, 2H), 9.82 (bs, 1H); ¹³C NMR (DMSO-d₆, 50 MHz, ppm): δ 24.3, 118.6, 124.9, 142.1, 145.6, 169.4. Purity 97%, Yield 127 mg, 98%.

Example 4e: N-(3,4,5-trimethoxyphenyl)acetamide (CAS: 4304-24-9, Table-1, Entry-4).

3,4,5-trimethoxyaniline (100 mg, 0.54 mmol), DEM (0.16 mL, 1.09 mmol), Cs₂C0₃ (533 mg, 1.63 mmol). Mp. 140-142 °C; IR (Nujol) v_max 1212, 1695, 1758, 3395 cm l; ¾ NMR (DMSO-d₆, 200 MHz, ppm): δ 2.00 (s, 3H), 3.60 (s, 3H), 3.72 (s, 6H), 6.94 (s, 2H), 9.84 (bs, 1H); ¹³C NMR (DMSO-d₆, 50 MHz, ppm): δ 24.3, 55.9, 60.3, 97.0, 133.5,135.8, 153.0, 168.5; ESIMS (m/z): 248 (M+Na). Purity 96%, Yield 91 mg, 74%.

Example 4f: N-(2-chlorophenyl) acetamide (CAS: 533-17-5, Table-1, Entry-5).

2-Chloro aniline (100 mg, 0.7 mmol), DEM (2 mL), Cs₂C0₃ (766 mg, 2.35 mmol). Mp. 90-92 °C; ¾ NMR (CDCI3, 200 MHz, ppm): δ 2.24(s, 3H), 7.04 (t, J = 7.8 Hz, lH), 7.27 (t, J = 9.3 Hz, 1H), 7.37 (d, J = 8.1 Ηζ,ΙΗ), 7.63 (bs, 1H), 8.34 (d, J = 7.7 Hz, 1H); ¹³C NMR (CDC1₃, 50 MHz, ppm): δ 24.6, 121.8, 122.7, 124.6, 127.5, 128.9, 134.4, 168.3. ESIMS (m/z): 192 (M+Na). Purity - 97%, Yield- 129 mg, 98%.

Example 4g: N-(2-iodophenyl) acetamide (CAS: 19591-17-4, Table-1, Entry-6).

2-Iodo aniline (500 mg, 2.28 mmol), DEM (5 mL), Cs₂C0₃ (2.23 g, 6.84 mmol). Mp. 112-113 °C; ¾ NMR (CDCI₃, 200 MHz, ppm): δ 2.25(s, 3H), 6.86 (t, J = 8.1 Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.43 (bs, 1H), 7.77 (d, J = 8.1 Hz, 1H), 8.19 (d, J = 8.1 Hz, 1H). Purity -93%, Yield- 397 mg, 66%.

Example 4h: N,N'-(l,4-phenylene)diacetamide (CAS: 140-50-1, Table-1, Entry- 7).

p-Phenylenediamine (100 mg, 0.92 mmol), DEM (3 mL), Cs₂C0₃ (1.8 g, 5.54 mmol). Mp. 302-304 °C; ¾ NMR (DMSO-de, 500MHz, ppm): δ 2.00 (s, 6H), 7.46 (s, 4H), 9.85 (bs, 2H); ¹³C NMR (DMSO-d₆, 125MHz, ppm): δ 24.1, 119.6, 134.8, 168.2. Purity -92%, Yield- 126 mg, 71%.

Example 4i: iert-butyl (4-acetamidophenyl) carbamate (CAS: 769121-30-4, Table-1, Entry-8). tert-butyl (4-aminophenyl)carbamate (200 mg, 0.96 mmol), DEM (4 mL), Cs₂C0₃ (938 mg, 2.88 mmol). Mp. 183-185 °C; ¾ NMR (CDC1₃, 200 MHz, ppm): δ 1.51 (s, 9H), 2.14 (s, 3H), 6.57 (bs, 1H), 7.28 (d, J = 8.9 Hz, 2H), 7,40 (d, J = 8.9 Hz, 2H), 7.49 (bs, 1H). Purity -94%, Yield- 209 mg, 87%. Example 4j: N-(4-hydroxyphenyl)acetamide (CAS: 103-90-2, Table-1, Entry-10).

4-Amino Phenol (200 mg, 1.83 mmol), DEM (5 mL), Cs₂C0₃ (1.79 g, 5.49 mmol). Mp. 166-168 °C; Ή NMR (CDCI3+ DMSO-d₆(9:l), 200MHz, ppm): δ 1.87 (s, 3H), 6.53 (d, J = 8.7 Hz, 2H), 7.12 (d,-J = 8.7 Hz, 2H), 8.50 (bs, 1H), 8.77 (bs, 1H). Purity -94%, Yield- 154 mg, 72%.

Example 4k: N-(4-(3-hydroxypropyl)phenyl)acetamide (CAS: 184001-14-7, Table-1, Entry-11). 3- (4-aminophenyl)propan-l-ol (200 mg, 1.32 mmol), DEM (3 mL), Cs₂C0₃ (1.29 g, 3.96 mmol). Mp. 105-107 °C; ^lH NMR (CD₃OD, 200MHz, ppm): δ 1.47-1.81 (quint., J = 6.8Hz, 2H), 2.10 (s, 3H), 2.64 (t, J = 7.7, 2H), 3.56 (t, J = 6.5, 2H), 7.15 (d, J = 8.5, 2H), 7.43 (d, J = 8.3, 2H). Purity -95%, Yield- 145 mg, 57%. Example 41: N-(pyridin-2-yl)acetamide (CAS: 5231-96-9, Table- 1, Entry-12).

2-Amino Pyridine (200 mg, 2.12 mmol), DEM (3 mL). Mp. 163-165 °C; ¾ NMR (CDC1₃, 200 MHz, ppm): δ 2.19 (s, 3H), 6.95-7.10 (in, 1H), 7.60-7.80 (m, 1H), 8.15-8.35 (m, 2Ή), 9.48 (bs, 1H); ¹³C NMR (CDCla, 125MHz, ppm): δ 24.6, 114.4, 119.6, 138.5, 147.3, 151.8, 169.0. Purity -97%, Yield- 250 mg, 87%.

Example 4m: N-(3-cyano-5-propylthiophen-2-yl)acetamide (Table-1, Entry-13).

2-amino-5-propylthiophene-3-carbonitrile (200 mg, 1.20 mmol), DEM (3 mL), Cs₂C0₃ (1.18 g, 3.60 mmol). Mp. 108-110 °C; IR (Nujol) v_max 1693, 2220, 3225, 3280 cm ¹; Ή NMR (CDC1₃, 400MHz, ppm): δ 0.96 (t, J = 7.1 Hz, 3H), 1.62-1.73 (m, 2H), 2.29 (s, 3H), 2.68 (t, J = 7.5 Hz, 2H), 6.61 (s, 1H), 9.11 (bs, 1H); ¹³C NMR (CDC1_¾ 100MHz, ppm): δ 13.5, 22.9, 24.3, 31.4, 91.2, 115.0, 119.6, 137.6, 148.1, 167.2; ESIMS (m/z): 207 (M-l). Anal. Calcd. for Ci₀H₁₂N₂OS: C, 57.67; H, 5.81; N, 13.45. Found: C, 57.95; H, 5.68, N, 13.24. Purity -96%, Yield- 163 mg, 65%.

Example 4n: Ν,Ν-diphenylacetamide (CAS: 519-87-9, Table-1, Entry-14).

N,N-diphenylamine (300 mg, 1.77 mmol), DEM (10 mL), Cs₂C0₃ (1.73 g, 5.31 mmol). Mp. 102-104 °C; ¾ NMR (CDCI3, 200 MHz, ppm): δ 2.06 (s, 3H), 7.10-7.50 (m, 10H). Purity -97%, Yield- 384 mg, 92%.

Example 4o: N-methyl-N-phenylacetamide (CAS: 579-10-2, Table-1, Entry-15).

N-methylaniline (200 mg, 1.86 mmol), DEM (5 mL), Cs₂C0₃ (1.82 g, 5.6 mmol). Mp. 101-103 °C; ¾ NMR (CDCI₃, 200 MHz, ppm): δ 1.89 (s, 3H), 3.28 (s, 3H), 7.20 (d, J = 6.8 Hz, 2H), 7.29-7.50 (m, 3H). Purity -96%, Yield- 250 mg, 90%.

Example 4p: N-phenylpropionamide (CAS: 620-71-3, Table-2, Entry-1).

Aniline (300 mg, 3.22 mmol), diethyl 2-methyl malonate (5 mL), Cs₂C0₃ (3.14 g, 9.66 mmol). Mp, 105-107 °C; IR (Nujol) v_max 1664, 3194, 3254 cm ¹; ¾ NMR (CDC1₃, 200 MHz, ppm): δ 1.24 (t, J = 7.5 Hz, 3H), 2.38 (q, J = 7.4 Hz, 2H), 7.09 (t, J = 7.33 Hz, 1H), 7.30 (t, J = 7.7 Hz, 2H), 7.40 (bs,lH), 7.50 (d, J = 8.0 Hz, 2H); ESIMS (m z): 172 (M+Na). Purity -96%, Yield- 297 mg, 62%.

Example 4q: N-(p-tolyl) propionamide (CAS: 2759-55-9, Table-2, Entry-2).

p-Toludine (200 mg, 1.86 mmol), diethyl 2-methyl malonate (5 mL), Cs₂C0₃ (1.82 g, 5.59 mmol). Mp. 123-125 °C; Ή NMR (CDC1₃, 200 MHz, ppm): δ 1.24 (t, J = 7.6 Hz, 3H), 2.31 (s, 3H), 2.37 (q, J = 7.5 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H and s, 1H). Purity -96%, Yield- 213 mg, 70%. Example 4r: N-(4-nitrophenyl) butyramide (CAS: 54191-12-7, Table-2, Entry-3).

4-Nitroaniline (500 mg, 3.6 mmol), diethyl 2-ethyl malonate (2.04 g, 0.1 mmol), Cs₂C0₃ (3.53 g, 0.1 mmol). Mp. 143-145 °C; IR (Nujol) v_max 1676, 3148, 3269 cm ¹; ¾ NMR (CDC1₃, 500MHz, ppm): δ

1.03 (t, J = 7.32 Hz, 3H), 1.75-1.79 (sext., J = 7.5, 2H), 2.41 (t, J = 7.33 Hz, 2H), 7.62 (bs, 1H), 7.73 (d, J = 9.1 Hz, 2H), 8.21 (d, J = 9.1 Hz, 2H); ¹³C NMR (CDC1₃, 125MHz, ppm): δ 13.7, 18.8, 39.7,

119, 125.1, 143.4, 143.8, 171.6; ESIMS (m/z): 207 (M-l). Purity -96%, Yield- 452 mg, 60%.

Example 4s: N-(4-chlorophenyl) hexanamide (CAS: 95843-76-8, Table-2, Entry-4).

4-Chloroaniline (100 mg, 0.78 mmol), diethyl 2-butyl malonate (3.38 g, 15.8 mmol), Cs₂C0₃ (766 mg,

2.35 mmol). Mp. 101-103 °C; IR (Nujol) v_max 1654, 1706, 3302, 3412 cm ¹; H NMR (CDC1₃, 500MHz, ppm): δ 0.91 (t, J = 7.0 Hz, 3H), 1.30-1.40 (m, 4H), 1.69-1.78 (m, 2H), 2.35 (t, J = 7.8 Hz, 2H), 7.28 (d,

J = 8.8 Hz, 2H), 7.27 (s, 1H), 7.46 (d, J = 8.86 Hz, 2H); ¹³C NMR (CDC1₃, 125MHz, ppm): δ 13.9, 22.4,

25.2, 31.4, 37.7, 121.0, 128.9, 129.1, 136.5, 171.5. Purity -97%, Yield- 120 mg, 68%.

Example 4t: N-(pyridin-2-yl) dodecanamide (CAS: 70933-08-3, Table-2, Entry-5).

2-Amino pyridine (100 mg, 1.06 mmol), diethyl 2-decyl malonate (2 mL). Mp. 191-193 °C; ¾ NMR (DMSO-de, 400MHz, ppm): δ 0.83 (t, J = 7.0 Hz, 3H), 1.12-1.44 (m, 18H), 2.39 (t, J = 7.5 Hz, 2H),

7.30 (t, J = 6.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 8.01 (t, J = 7.4, 1H), 8.92 (d, J = 6.8 Hz, 1H), 12.04

(bs, 1H). Purity -97%, Yield- 255 mg, 92%.

Example 4u: N,3-diphenylpropanamide (CAS: 3271-81-6, Table-2, Entry-6).

Aniline (100 mg, 1.07 mmol), diethyl 2-benzyl malonate (538 mg, 2.14 mmol), Cs₂CO₃ (1.04 g, 3.22 mmol). Mp. 97-99 °C; ^JH NMR (CDC1₃, 400MHz, ppm): δ 2.67 (t, J = 7.4 Hz, 2H), 3.06 (t, J = 7.4 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 7.18 (bs, 1H), 7.20-7.35 (m, 7H), 7.44 (d, J = 7.7 Hz, 2H). Purity -96%, Yield- 205 mg, 85%.

Example 4v: N,2-diphenylacetamide (CAS: 621-06-7, Table-2, Entry- 7). Aniline (500 mg, 5.36 mmol), diethyl phenyl malonate (5 mL), Cs₂C0₃ (5.24 g, 16.1 mmol). Mp. 116-119 °C; ¾ NMR (CDC1₃, 200 MHz, ppm): δ 3.74 (s, 2H), 7.08 (t, J = 7.3 Hz, 2H), 7.20-7.48 (m, 9H). Purity -97%, Yield- 1.02 mg, 90%.

Advantages of the invention:

The process of the instant invention comprising cost effective, improved one pot catalytic decarboxylative acylation provides easy access to amides with odd/even chain lengths and array of substituents on the alkyl/aryl part. The synthesis of odd chain lengths is noteworthy and important because most , of the naturally occurring long chain alcohols/acids (which are commonly used as starting materials in the prior art) have even chain lengths. Therefore MEAS methodology of the current invention is a suitable alternative in industries for easy preparation, of various aromatic amines to diverse amides.

Moreover the process can be utilized for synthesis of polyimides with tailored material characteristics.

Claims

We claim:

1. One pot catalytic decarboxylative acylation of amine of formula (I)

Ar_{Xi i} ,H

^■ R Formula I

to obtain amide of formula (IV) in high yield and purity; wherein,

R

Formula IV

R is selected from the group consisting of hydrogen, substituted /unsubstituted alkyl, substituted /unsubstituted phenyl, substituted/unsubstituted alkylaryl and substituted/unsubstituted heteroaryl;

R' is selected from the group consisting of hydrogen, substituted/unsubstituted alkyl, substituted/unsubstituted phenyl, substituted/unsubstituted alkylaryl or substituted/unsubstituted heteroaryl and the said process comprising the steps of:

(a) heating the mixture of amine (Formula I) and malonic ester (Formula II) in mole ratio ranging between (1: 10-20) for a period ranging between 0.5-3 hrs at a temperature ranging between 100-130 °C to obtain intermediate (III), cooling the reaction mixture;

Formula-I Formula-II Formula-Ill

wherein;

R= hydrogen, substituted/unsubstituted alkyl, substituted/unsubstituted phenyl, substituted/unsubstituted alkylaryl and substituted/unsubstituted heteroaryl; R'= hydrogen, substituted/unsubstituted alkyl, substituted/unsubstituted phenyl, substituted/unsubstituted alkylaryl or substituted/unsubstituted heteroaryl.

(b) catalytic decarboxylation of the intermediate (III) as obtained in step (a) optionally in presence of alkali metal carbonate and a polar organic solvent at 80-120 °C until complete disappearance (1-3 h) of the intermediate (III) to obtain crude amide product;

(c) evaporating the organic solvent of step (b) followed by dissolving in another polar organic solvent, subsequently washing the organic layer with brine, drying and concentrating followed by washing with a non-polar solvent, filtering, drying to obtain the desired amide (Formula IV) in good yield and purity.

2. The process as claimed in claim 1, wherein alkali metal carbonate used in step (b) is Cs₂C0₃.

3. The process as claimed in claim 1, wherein the decarboxylation is optionally self- catalyzed.

4. The process as claimed in claim 3, wherein the catalyst is the amine substrate, preferably hetero-aromatic amine.

5. The process as claimed in claim 1, wherein malonic ester used in step (a) is substituted or un substituted di ethyl malonate.

6. The process as claimed in claim 1, wherein the purification of crude product obtained in step (b) optionally comprises evaporating the di alkyl malonate under vacuum, dissolving the residue in polar solvent followed by filtration and drying.

7. The process as claimed in claim 1, wherein polar organic solvent used in step (b) and (c) is selected from the group consisting of halo alkanes, aliphatic esters, ethers, acids either alone or mixtures thereof, selected from the group consisting of dichloromethane, ethylacetate, dichloroethane, diethyl ether or mixtures thereof.

8. The process as claimed in claim 1, wherein non-polar organic solvent used in step (c) is selected from petroleum ether, hexane, heptane, carbon tetrachloride, benzene and like thereof. .

9. The process as claimed in claim 1, wherein yield of amides of formula (IV) is in the range of 57-98%.

10. The process as claimed in claim 1, wherein purity of amides of formula (IV) is in the range of 92-97%.