The mechanism of the reaction between amines with dimethyl carbonate (DMC) has been investigated. Whereas in the absence of bases, they give methylation and carboxymethylation reactions without selectivity (BAl2 and B Ac2 mechanisms, respectively), in the presence of bases, the B Ac2 mechanism prevails. The carbamate already formed reacts further with DMC via the BAl2 mechanism to give the corresponding N-methyl derivative. Such pronounced double selectivity has been explained in terms of Pearson's Hard-Soft Acid-Base (HSAB) theory. Accordingly, N-methylcarbamates have been prepared from primary aliphatic and aromatic amines, either at reflux temperature of DMC (90 °C) or at 230 °C in autoclave. The reaction can be carried out in one step or through the isolation of the carbamate and the subsequent methylation reaction with DMC. This method is the direct synthesis, in high yield and selectivity, of secondary N-methylamines from the corresponding primary amines.Facultad de Ciencias Exacta

Bressanello, Salima

Loris, Alessandro

Sathicq, Ángel Gabriel

Tundo, Pietro

Pure and Applied Chemistry

Servicio de Difusión de la Creación Intelectual

Pure Appi. Chem., Vol. 77, No. 10, pp. 1719-1725, 2005.DOI: 10.1351/pac200577101719©2005 IUPACDirect synthesis of /V-methy I urethanes from primary amines with dimethyl carbonate**Paper based on a presentation at the 4th International Conference of the Chemical Societies of the South-Eastern European Countries (ICOSECS-4), Belgrade. Serbia and Montenegro. 18-21 July 2004. Other presentations are published in this issue, pp. 1655-1752.^Corresponding author: Fax: +390412348620; E-mail: tundop@unive.it#On leaving from Laboratorio de Estudio de Compuestos Orgánicos (LADECOR) Facultad de Ciencias Exactas. Universitad Nacional de La Plata (B1900AJL), Argentina.1719Pietro Tundo*,  Salima Bressanello, Alessandro Loris, and Gabriel Sathicq#Dipartimento di Scienze Ambientali, Università Ca’ Foscari Venezia, Italy and Consorzio Interuniversitario Nazionale La Chimica per ¡Ambiente, Dorsoduro 2137—30123 Venezia, ItalyAbstract'. The mechanism of the reaction between amines with dimethyl carbonate (DMC) has been investigated. Whereas in the absence of bases, they give methylation and car­boxymethylation reactions without selectivity (BA12 and BAc2 mechanisms, respectively), in the presence of bases, the BAc2 mechanism prevails. The carbamate already formed reacts further with DMC via the BA,2 mechanism to give the corresponding A-methyl derivative. Such pronounced double selectivity has been explained in terms of Pearson’s Hard-Soft Acid-Base (HSAB) theory.Accordingly, 2V-methylcarbamates have been prepared from primary aliphatic and aro­matic amines, either at reflux temperature of DMC (90 °C) or at 230 °C in autoclave. The re­action can be carried out in one step or through the isolation of the carbamate and the subse­quent methylation reaction with DMC. This method is the direct synthesis, in high yield and selectivity, of secondary 2V-methylamines from the corresponding primary amines.Keywords'. Dimethyl carbonate; amines; carbamates; A-methylamines; green chemistry.INTRODUCTIONDimethyl carbonate (DMC) is a green reagent [1] whose ambident electrophilic properties have been reported [2]: its reaction with nucleophiles gives both methylation and carboxymethylation derivatives [3] (eqs. 1 and 2, respectively).We recently evidenced that the selectivity among the two reaction pathways depends on the na­ture of the nucleophile [4], In fact, harder nucleophiles react with the carbonyl of DMC (the harder elec­trophilic site) via BAc2 mechanism, while softer nucleophiles react with the methyl of DMC (the softer electrophilic site) via BA12 mechanism.Y +CH3OCOOCH3 = Y-COOCII3 + CII3() BAc2 (DY“ + CH3OCOOCH3------ > Y-CH3 + CH3()C()()' Ba12 (2)In some cases, such discrimination was shown to be complete: more than 99 % selectivity was obtained for the O-methylation of phenols and the mono-methylation of CH2 acidic compounds likeUnauthenticatedDownload Date | 8/23/19 10:51 PM1720 P.TUNDO étal.arylacetonitriles, arylacetates, aryloxyacetic esters, sulfones, sulfoxides, and lactones [5], Actually, in the latter cases, the mono-methyl derivative is the final outcome of a series of reactions that proceed se­lectively. This particular selectivity has been explained in terms of Pearson’s Hard-Soft Acid-Base (HSAB) theory [6]: operating in the presence of a base, the carbanion of a CH2 acidic compound is hard in character and attacks the carbonyl of DMC via Bac2 mechanism (eq. 3); the resulting softer nucleo­phile (because of the presence of the EWG group COOCH3), now reacts with the methyl group of DMC via Bal2 mechanism (eq. 4). The anion CH3O_ so formed is hard enough to react with the carbonyl and restores the DMC molecule.The combination of the dual electrophilic character of DMC with its reaction products, allows two consecutive steps to occur selectively, to influence both reaction outcome and yields: at first, the hard-hard reaction occurs and produces a soft anion only; then, a soft-soft nucleophilic displacement leads to the final product. Since hard-soft and soft-hard interactions are inhibited by the HSAB theory, either double methylation and double carboxymethylation do not occur; as a result, the mono-methyl­ated specie is obtained in very high yield (eq. 5).ArCH“X + CH3OCOOCH3 — ArCH(COOCH3)x + CH3O“ (3)ArC“ (COOCH3) X + CH3OCOOCH3------ > ArC (CH3) (COOCH3 )x + C(), + CH,()* (4)ArC(CH3)(COOCH3)x + CH3O“ ~ ArC“(CH3)x + CH3OCOOCH3 (5)As for nitrogen nucleophiles, we have already reported that primary aromatic amines with DMC undergo mono-A-methylation under continuous-flow conditions: mono-A-methyl anilines and their ure­thanes were continuously collected at the end of a plug-flow reactor, operating under gas-liquid phase­transfer catalysis (GLPTC) conditions: A,A-dimethylated products were present in trace amounts only (Table 1) [7],Table 1 Continuous-flow reactions of aromatic primary amines with DMC under GL-PTC conditions, from ref. [7].Entry Amine ArNH, MNM DNM Carbamate NMCarbamate1 Aniline® 54.3 40.8 1.6 trace 3.32 o-Toluidineb 27.7 47.0 0.3 25.03 o-Chloroanilineb 14.6 62.7 22.74 /»-Chloro aniline® 10.1 70.0 19.9K2co3 coated with 5 wt% of PEG 6000; T= 180 °C.aDMC/anilines molar ratio = 4.0.bDMC/anilines molar ratio = 10.0. MNM = Mono /V-Methylation; DNM = AW-Dimethylation: NMCarbamate = W-Methylcarbamate.The aim of this work is to explain the connection of the reactivity of primary aliphatic and aro­matic amines with HSAB theory and the preparation of urethanes and their A-methyl derivatives, oper­ating under basic conditions. We do not refer here to the reactions carried out in the presence of zeo­lites under acidic catalysis, since in the latter case selectivity and behavior follow yet-unexplored reaction pathways [8],Different bases, temperatures, and conditions (atmospheric pressure and autoclave) have been in­vestigated in order to obtain the desired products.Actually, this method is the homologation of primary amines to the corresponding secondary A-methylamines, in high yield and selectivity, according to a one-step procedure.© 2005 IUPAC, Pure and Applied Chemistry 77, 1719-1725UnauthenticatedDownload Date | 8/23/19 10:51 PMDimethyl carbonate mechanism and application 1721RESULTS AND DISCUSSIONUnlike the mechanism that accounts for the reactions of CH2 acidic compounds, eq. 6 is shifted to the right (compare eq. 3), and eq. 7 to the left (compare eq. 5): the decarboxymethylation of .V-mcthyl ure­thanes does not occur spontaneously (eq. 8), and a successive hydrolysis is needed to produce the .V-inethylated amine.RNH2+CH3OCOOCH3^=*RNH(COOCH 3) + CH3OH BAc2 (6)RNH(COOCH3) + CH3OCOOCH3------ >RN(CH3)(COOCH3) + CO2+CH3OH Ba|2 (7)RN(CH3)(COOCH3) + CH3OH RNH(CH3)+ CH3OCOOCH3 (8)It is well known that bases significantly accelerate aminolysis and transamination reactions [9], The base removes H+ from protonated nitrogen during or after the attack, thereby increasing the nega­tive charge on the nitrogen atom [10], As we reported elsewhere [4], this behavior can be accounted in accordance with HSAB theory, since the presence of a base enhances the hardness of the nucleophile. Consequently, reactivity with harder electrophiles (the carbonyl carbon, in this case) is enhanced and aminolysis reactions proceed much faster.We report here the reactions of aliphatic and aromatic amines in the absence and presence of strong bases, and the reaction of the urethanes with DMC in the presence of bases. The corresponding .V-methyl derivatives can be obtained in one step either under atmospheric pressure at DMC reflux tem­perature (90 °C), or operating in autoclave at high temperatures. Reaction mechanisms are discussed in relation to the reaction outcomes.Reaction of amines with DMC in the absence of basesWithout a base and at reflux temperature, aliphatic amines gave both alkylation and carboxymethyla­tion reaction without appreciable selectivity (Table 2).Table 2 Reaction of amines and DMC in the absence of a base.Entry Amine T (°C) Time (h) MNM (%) DNM (%) Carbamate (%)1 Benzylamine 90 6 12 6 42 Aniline 200 24 15 37 9Conditions: Amine/DMC molar ratio: 1/40. MNM = Mono W-Methylation; DNM = N,N- Dimethylation.As expected, aliphatic amines react faster, while aromatic ones need high temperature (and auto­clave) to react in a reasonable time. They react via both BA12 and BAc2 pathways, and demonstrate the intermediate character of amine nitrogen toward DMC, in terms of hardness and softness.Urethanes from amines in the presence of strong basesStrong bases (potassium ieri-butylate or sodium methoxide) catalyze the reaction of aliphatic and aro­matic amines to give the corresponding carbamates quantitatively at 90 °C (eq. 9).RNH2 + CH3OCOOCH3 base > RNHCOOCH3 + CH3OH (9)©2005 IUPAC, Pure and Applied Chemistry 77, 1719-1725UnauthenticatedDownload Date | 8/23/19 10:51 PM1722 P.TUNDO étal.In these conditions, high yields of carbamates are obtained in few minutes (Table 3). Since aliphatic amines are harder nucleophiles than aromatic ones, they react faster with the carbonyl of DMC (entries 3-7). No 2V,2V-dimethyl dérivâtes were observed.Table 3 Reaction of amines and DMC in the presence of a base.Entry /Amine Time (min) Base Carbamate (%)1 /j-Aiiisidine“ 25 c4h9ok 772 p -Chloro anilineb 20 c4h9ok 86.53 Benzylamine0 1 c4h9ok 1004 /7-Decylamined 3 CH,ONa 1005 Hexane-1.6-diamine 10 CH,ONa 1006 n-Octylamine 5 CH,ONa 1007 Phenethylamine 5 CH,ONa 100Conditions: Reflux temperature. 90 °C; amine/base/DMC molar ratio: 1/1.2/40. “After 18 h. 73 % of W-methylcarbamate.bAfter 18 h. 87 % of W-methylcarbamate.cAfter 0.5 h. 70 % of W-methylcarbamate.dAfter 6 h. 78 % of W-methylcarbamate./V-methylurethanes from amines in the presence of strong basesIf the reaction is protracted, the initially formed carbamates undergo further reaction with DM and give the corresponding N-methylurethanes (eq. 10 and Table 3). The base is necessary: no reaction occurs in its absence, as verified in an independent experiment.rnhcooch3 + ch3ocooch3 base > rn(ch3)COOCH3 + CO2 + CH3OH (10)However, the reaction needs to be carried out in the absence of atmospheric carbon dioxide, as it reacts with the base and methylation reactions come to a stop. Under the conditions of entry 4, Table 3, n-decylamine was reacted with DMC under nitrogen atmosphere: after 3 min, 100 % of the carbamate was produced.Ninety-nine percent of n-C10H21N(CH3)COOCH3 was obtained only after 21 h at reflux temper­ature (20 % after 2 h, and 46 % after 5 h).The behavior of amines in the presence and in the absence of a base reported on Tables 2 and 3 confirms that, since the hardness of the nucleophile is increased while operating in the presence of a base, the BAc2 rate is dramatically accelerated, and carboxymethyl derivatives are quantitatively ob­tained. Once formed, the urethanes need the presence of a base to further react with DMC. In these con­ditions, their RN_COOCH3 anions, softer nucleophiles than RNH2, undergo solely BA12 reactions. No RN(COOCH3)2 products—deriving from a double BAc2 reaction—were observed under such condi­tions./V-methylurethanes from amines in the presence of K2CO3Weaker bases like potassium carbonate can be used instead of alkoxides. Higher temperatures must be used, and the reaction is performed in an autoclave; at that temperature, the direct formation of mono­methyl and dimethyl derivatives cannot be totally avoided (eqs. 11 and 12); they come from two con­secutive BAc2 mechanisms.RNH2 + CH3OCOOCH3------ > RNHCH3 + CO2 + CH3OH (11)© 2005 IUPAC, Pure and Applied Chemistry 77, 1719-1725UnauthenticatedDownload Date | 8/23/19 10:51 PMDimethyl carbonate mechanism and application 1723RNHCH3 + CH3OCOOCH3------ >RN(CH3)2 + C02 + CH3OH (12)In these conditions, harder amines react in 22 h and give the corresponding carbamates and A-methylcarbamates, while mono- and dimethyl derivatives, if any, are present in lower amount (entries 3 and 4, Table 4); anilines react slower, and their softness is responsible for the formation of mono- and dimethylated products in higher amount.Table 4 Reactions of aliphatic and aromatic amines in the presence of K ,('(), after 22 h.Entry Amine Substrate MNM DNM Carb amate NMCarbamate1 Aniline 41.8 6.2 2.6 8.3 41.02 /»-Chloro aniline 38.4 6.3 2.1 5.7 47.53 /»-Anisidine 0.5 1.3 13.4 1.8 83.04 /7-Octylamine — — 1.2 53.7 45.05 Phenethylamine — — — 77.0 23.0Conditions: T = 180 °C; amine/DMC/K2CO3 molar ratio: 1/3/40.MNM = Mono-MMethylation; DNM = N,N-Dimethylation; NMCarbamate = MMethylcarbamate.Two steps preparation of /V-methylurethanesAnother route to the A-methylcarbamate is the standard two-step procedure: first, the synthesis of the carbamate at reflux temperature, according to the condition of Table 2, is completed; then, the subse­quent methylation is carried out in autoclave at 230 °C with K2C03 as a base (Table 5). Because of the high temperature, reaction time is reduced, while A,A-dimethylation products were not observed.Table 5 Reactions of carbamates with DMC in the presence of K ,( '( ),. after 4 h.Entry Carbamate A-Methylcarbamate (%)1 /»-CH,OPhNHCOOCH, 952 PhNHCOOCH, 1003 n-C8H17NHCOOCH, 974 PhCH,CH,NHCOOCH, 100Conditions: Temperature: 230 °C, Carbamate/K2CO3/DMC molar ratio: 1/3/40.CONCLUSIONSThe reactivity of amines with DMC can be explained according to the HSAB theory, since DMC mol­ecule presents an ambident electrophilic character: it reacts with hard nucleophiles (amines in the pres­ence of strong bases) according to a BAc2 mechanism, and the carbonyl group is involved. The anions of the so-produced urethanes, being softer in character, react now according to a BA12 mechanism with the softer part of the molecule, the methyl group, and give the A-methyl derivatives.The combination of the dual electrophilic character of DMC with its reaction products allows two consecutive steps to occur in a selective way. Since hard-soft and soft-hard interactions are inhibited, either double methylation and double carboxymethylation do not occur. Accordingly, primary amines give the corresponding A-methyl secondary derivatives in high yield and selectivity, without apprecia­ble production of A,A-dimethyl compounds.The results of Tables 4 and 5 compared with those already described on Table 1 [7] show that op­erating under batch conditions it is not possible to complete in one step the transformation of primary ©2005 IUPAC, Pure and Applied Chemistry 77, 1719-1725UnauthenticatedDownload Date | 8/23/19 10:51 PM1724 P.TUNDO étal.amines into secondary amines. In fact, reaction 8 is prevented and a further hydrolysis procedure is needed for obtaining pure .V-mcthyl amines. However, selectivity is high and work-up easy; moreover, once the reason of the mechanism according to the HSAB theory is understood, one can perform car­boxylation reaction and alkylation reaction with different alkyl carbonates and alkylating agents, re­spectively, in order to get the desired product in the easier way.EXPERIMENTAL SECTIONAll used compounds were ACS grade and were employed without further purification.GC analyses were performed using a 30-m, CP-sil 24 CB capillary column. GC-MS analyses were performed on a mass detector at 70 eV coupled to a gas chromatograph fitted with a 30-m capil­lary column. All reaction compounds were compared with authentic samples.Preparation of carbamates with strong bases at reflux temperature (Table 3): The reactions were carried out in a three-necked, 100-mL round-bottomed flask with a reflux condenser and a mag­netic bar. Amines (9.3 10-3 mol: p-anisidine, p-chloroaniline, benzylamine, n-decylamine, hexane-1,6- diamine, n-octylamine, and phenethylamine), the base and DMC were charged in a 1.0/1.2/40 molar ratio respectively, under a flux of N2 to remove the possible CO2 formed as by-product (DMC is the solvent of the reaction). The bases employed were sodium methylate or potassium iert-butoxide. Temperature was 90 °C (reflux of DMC).Preparation of A-methylcarbamates in the presence of K2CO3 (Table 4): The amine (9.3 10-3 mol), K2CO3, and DMC were charged in a 1.0/3.0/40 molar ratio respectively and were charged in a 250-mL autoclave equipped with a sample tube and a magnetic bar. The autoclave was heated with an electric mantle at 180 °C.Two steps preparation of A-methylcarbamates (Table 5): The carbamates (9.3 10-3 mol) pre­pared and isolated according to the above-described procedure, were introduced in stainless steel auto­clave (250 mL) equipped with a sample tube and a magnetic bar; K2CO3 and DMC were charged in a 1.2 and 40 molar ratio with respect to the carbamate.The reaction temperature was 230 °C (DMC is the solvent of the reaction).ACKNOWLEDGMENTSContributions from the Consorzio Interuniversitario Nazionale “La Chimica per I'Ainbiente", INCA (Interuniversity National Consortium “Chemistry for the Environment’’) are gratefully acknowledged.REFERENCES1. (a) P. Tundo, P. Anastas, D. Black, J. Breen, T. Collins, S. Memoli, J. Miyamoto, M. Polyakoff, W. Tumas. PureAppl. Chem. 72, 1207 (2000); (b) P. Anastas and J. C. Warner. Green Chemistry: Theory and Practice, p. 30, Oxford University Press, New York (1998); (c) R. A. Sheldon. Pure Appl. Chem. 72, 1233 (2000); (d) B. M. Trost. Science 254, 1471 (1991).2. (a) P. Tundo, M. Selva, A. Bomben. Org. Synth. 76, 169 (1999); (b) P. Tundo and M. Selva. Acc. Chem. Res. 35, 706 (2002).3. (a) F. Rivetti. In Green Chemistry: Challenging Perspectives, P. Tundo and P. Anastas (Eds.), p. 201, Oxford University Press, Oxford (2001); (b) D. Delledonne, F. Rivetti, U. Romano. J. Organomet. Chem. 448, C15-C19 (1995); (c) U. Romano, F. Rivetti, N. Di Muzio. U.S. Patent 4,318,862 (1979); (d) P. Tundo. Continuous Flow Methods in Organic Synthesis, Chap. 4, p. 190, E. Horwood, Chichester (1991).4. P. Tundo, L. Rossi, A. Loris. J. Org. Chem. 70, 2219 (2005).5. P. Tundo, M. Selva, A. Perosa, S. Memoli. J. Org. Chem. 67, 1071 (2002).© 2005 IUPAC, Pure and Applied Chemistry 77, 1719-1725UnauthenticatedDownload Date | 8/23/19 10:51 PMDimethyl carbonate mechanism and application 17256. (a) R. G. Pearson. J. Am. Chem. Soc. 85, 3533 (1963); (b) R. G. Pearson and J. Songstad. J. Am.Chem. Soc. 89, 1827 (1967); (c) H. Tse-Lok. Chem. Rev. 75, 1 (1975); (d) G. Klopman. J. Am.Chem. Soc. 90, 223 (1968); (e) G. Klopman (Ed.). Chemical Reactivity and Reaction Paths, John Wiley, New York (1974).7. F. Trotta, P. Tundo, G. Moraglio. J. Org. Chem. 52, 1300 (1987).8. M. Selva, P. Tundo, A. Perosa. J. Org. Chem. 62, 7374 (2003).9. J. F. Bunnett and G. T. Davis. J. Am. Chem. Soc. 82, 665 (1960).10. W. P. Jencks and J. Carriuolo. J. Am. Chem. Soc. 82, 675 (1960).©2005 HJ PAC, Pure and Applied Chemistry 77, 1719-1725UnauthenticatedDownload Date | 8/23/19 10:51 PM

Direct synthesis of N-methylurethanes from primary amines with dimethyl carbonate

SEDICI - Repositorio de la UNLP

Pure Appi. Chem., Vol. 77, No. 10, pp. 1719-1725, 2005.
DOI: 10.1351/pac200577101719
©2005 IUPAC
Direct synthesis of /V-methy I urethanes from 
primary amines with dimethyl carbonate*
*Paper based on a presentation at the 4th International Conference of the Chemical Societies of the South-Eastern European 
Countries (ICOSECS-4), Belgrade. Serbia and Montenegro. 18-21 July 2004. Other presentations are published in this issue, 
pp. 1655-1752.
^Corresponding author: Fax: +390412348620; E-mail: tundop@unive.it
#On leaving from Laboratorio de Estudio de Compuestos Orgánicos (LADECOR) Facultad de Ciencias Exactas. Universitad 
Nacional de La Plata (B1900AJL), Argentina.
1719
Pietro Tundo*,  Salima Bressanello, Alessandro Loris, and 
Gabriel Sathicq#
Dipartimento di Scienze Ambientali, Università Ca’ Foscari Venezia, Italy and 
Consorzio Interuniversitario Nazionale La Chimica per ¡Ambiente, Dorsoduro 
2137—30123 Venezia, Italy
Abstract'. The mechanism of the reaction between amines with dimethyl carbonate (DMC) 
has been investigated. Whereas in the absence of bases, they give methylation and car­
boxymethylation reactions without selectivity (BA12 and BAc2 mechanisms, respectively), in 
the presence of bases, the BAc2 mechanism prevails. The carbamate already formed reacts 
further with DMC via the BA,2 mechanism to give the corresponding A-methyl derivative. 
Such pronounced double selectivity has been explained in terms of Pearson’s Hard-Soft 
Acid-Base (HSAB) theory.
Accordingly, 2V-methylcarbamates have been prepared from primary aliphatic and aro­
matic amines, either at reflux temperature of DMC (90 °C) or at 230 °C in autoclave. The re­
action can be carried out in one step or through the isolation of the carbamate and the subse­
quent methylation reaction with DMC. This method is the direct synthesis, in high yield and 
selectivity, of secondary 2V-methylamines from the corresponding primary amines.
Keywords'. Dimethyl carbonate; amines; carbamates; A-methylamines; green chemistry.
INTRODUCTION
Dimethyl carbonate (DMC) is a green reagent [1] whose ambident electrophilic properties have been 
reported [2]: its reaction with nucleophiles gives both methylation and carboxymethylation derivatives 
[3] (eqs. 1 and 2, respectively).
We recently evidenced that the selectivity among the two reaction pathways depends on the na­
ture of the nucleophile [4], In fact, harder nucleophiles react with the carbonyl of DMC (the harder elec­
trophilic site) via BAc2 mechanism, while softer nucleophiles react with the methyl of DMC (the softer 
electrophilic site) via BA12 mechanism.
Y +CH3OCOOCH3 = Y-COOCII3 + CII3() BAc2 (D
Y“ + CH3OCOOCH3------ > Y-CH3 + CH3()C()()' Ba12 (2)
In some cases, such discrimination was shown to be complete: more than 99 % selectivity was 
obtained for the O-methylation of phenols and the mono-methylation of CH2 acidic compounds like
Unauthenticated
Download Date | 8/23/19 10:51 PM
1720 P.TUNDO étal.
arylacetonitriles, arylacetates, aryloxyacetic esters, sulfones, sulfoxides, and lactones [5], Actually, in 
the latter cases, the mono-methyl derivative is the final outcome of a series of reactions that proceed se­
lectively. This particular selectivity has been explained in terms of Pearson’s Hard-Soft Acid-Base 
(HSAB) theory [6]: operating in the presence of a base, the carbanion of a CH2 acidic compound is hard 
in character and attacks the carbonyl of DMC via Bac2 mechanism (eq. 3); the resulting softer nucleo­
phile (because of the presence of the EWG group COOCH3), now reacts with the methyl group of DMC 
via Bal2 mechanism (eq. 4). The anion CH3O_ so formed is hard enough to react with the carbonyl and 
restores the DMC molecule.
The combination of the dual electrophilic character of DMC with its reaction products, allows two 
consecutive steps to occur selectively, to influence both reaction outcome and yields: at first, the 
hard-hard reaction occurs and produces a soft anion only; then, a soft-soft nucleophilic displacement 
leads to the final product. Since hard-soft and soft-hard interactions are inhibited by the HSAB theory, 
either double methylation and double carboxymethylation do not occur; as a result, the mono-methyl­
ated specie is obtained in very high yield (eq. 5).
ArCH“X + CH3OCOOCH3 — ArCH(COOCH3)x + CH3O“ (3)
ArC“ (COOCH3) X + CH3OCOOCH3------ > ArC (CH3) (COOCH3 )x + C(), + CH,()* (4)
ArC(CH3)(COOCH3)x + CH3O“ ~ ArC“(CH3)x + CH3OCOOCH3 (5)
As for nitrogen nucleophiles, we have already reported that primary aromatic amines with DMC 
undergo mono-A-methylation under continuous-flow conditions: mono-A-methyl anilines and their ure­
thanes were continuously collected at the end of a plug-flow reactor, operating under gas-liquid phase­
transfer catalysis (GLPTC) conditions: A,A-dimethylated products were present in trace amounts only 
(Table 1) [7],
Table 1 Continuous-flow reactions of aromatic primary amines with DMC under 
GL-PTC conditions, from ref. [7].
Entry Amine ArNH, MNM DNM Carbamate NMCarbamate
1 Aniline® 54.3 40.8 1.6 trace 3.3
2 o-Toluidineb 27.7 47.0 0.3 25.0
3 o-Chloroanilineb 14.6 62.7 22.7
4 /»-Chloro aniline® 10.1 70.0 19.9
K2co3 coated with 5 wt% of PEG 6000; T= 180 °C.
aDMC/anilines molar ratio = 4.0.
bDMC/anilines molar ratio = 10.0. MNM = Mono /V-Methylation; DNM = AW-Dimethylation: 
NMCarbamate = W-Methylcarbamate.
The aim of this work is to explain the connection of the reactivity of primary aliphatic and aro­
matic amines with HSAB theory and the preparation of urethanes and their A-methyl derivatives, oper­
ating under basic conditions. We do not refer here to the reactions carried out in the presence of zeo­
lites under acidic catalysis, since in the latter case selectivity and behavior follow yet-unexplored 
reaction pathways [8],
Different bases, temperatures, and conditions (atmospheric pressure and autoclave) have been in­
vestigated in order to obtain the desired products.
Actually, this method is the homologation of primary amines to the corresponding secondary 
A-methylamines, in high yield and selectivity, according to a one-step procedure.
© 2005 IUPAC, Pure and Applied Chemistry 77, 1719-1725
Unauthenticated
Download Date | 8/23/19 10:51 PM
Dimethyl carbonate mechanism and application 1721
RESULTS AND DISCUSSION
Unlike the mechanism that accounts for the reactions of CH2 acidic compounds, eq. 6 is shifted to the 
right (compare eq. 3), and eq. 7 to the left (compare eq. 5): the decarboxymethylation of .V-mcthyl ure­
thanes does not occur spontaneously (eq. 8), and a successive hydrolysis is needed to produce the 
.V-inethylated amine.
RNH2+CH3OCOOCH3^=*RNH(COOCH 3) + CH3OH BAc2 (6)
RNH(COOCH3) + CH3OCOOCH3------ >RN(CH3)(COOCH3) + CO2+CH3OH Ba|2 (7)
RN(CH3)(COOCH3) + CH3OH RNH(CH3)+ CH3OCOOCH3 (8)
It is well known that bases significantly accelerate aminolysis and transamination reactions [9], 
The base removes H+ from protonated nitrogen during or after the attack, thereby increasing the nega­
tive charge on the nitrogen atom [10], As we reported elsewhere [4], this behavior can be accounted in 
accordance with HSAB theory, since the presence of a base enhances the hardness of the nucleophile. 
Consequently, reactivity with harder electrophiles (the carbonyl carbon, in this case) is enhanced and 
aminolysis reactions proceed much faster.
We report here the reactions of aliphatic and aromatic amines in the absence and presence of 
strong bases, and the reaction of the urethanes with DMC in the presence of bases. The corresponding 
.V-methyl derivatives can be obtained in one step either under atmospheric pressure at DMC reflux tem­
perature (90 °C), or operating in autoclave at high temperatures. Reaction mechanisms are discussed in 
relation to the reaction outcomes.
Reaction of amines with DMC in the absence of bases
Without a base and at reflux temperature, aliphatic amines gave both alkylation and carboxymethyla­
tion reaction without appreciable selectivity (Table 2).
Table 2 Reaction of amines and DMC in the absence of a base.
Entry Amine T (°C) Time (h) MNM (%) DNM (%) Carbamate (%)
1 Benzylamine 90 6 12 6 4
2 Aniline 200 24 15 37 9
Conditions: Amine/DMC molar ratio: 1/40. MNM = Mono W-Methylation; DNM = 
N,N- Dimethylation.
As expected, aliphatic amines react faster, while aromatic ones need high temperature (and auto­
clave) to react in a reasonable time. They react via both BA12 and BAc2 pathways, and demonstrate the 
intermediate character of amine nitrogen toward DMC, in terms of hardness and softness.
Urethanes from amines in the presence of strong bases
Strong bases (potassium ieri-butylate or sodium methoxide) catalyze the reaction of aliphatic and aro­
matic amines to give the corresponding carbamates quantitatively at 90 °C (eq. 9).
RNH2 + CH3OCOOCH3 base > RNHCOOCH3 + CH3OH (9)
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1722 P.TUNDO étal.
In these conditions, high yields of carbamates are obtained in few minutes (Table 3). Since 
aliphatic amines are harder nucleophiles than aromatic ones, they react faster with the carbonyl of DMC 
(entries 3-7). No 2V,2V-dimethyl dérivâtes were observed.
Table 3 Reaction of amines and DMC in the presence of a base.
Entry /Amine Time (min) Base Carbamate (%)
1 /j-Aiiisidine“ 25 c4h9ok 77
2 p -Chloro anilineb 20 c4h9ok 86.5
3 Benzylamine0 1 c4h9ok 100
4 /7-Decylamined 3 CH,ONa 100
5 Hexane-1.6-diamine 10 CH,ONa 100
6 n-Octylamine 5 CH,ONa 100
7 Phenethylamine 5 CH,ONa 100
Conditions: Reflux temperature. 90 °C; amine/base/DMC molar ratio: 1/1.2/40. 
“After 18 h. 73 % of W-methylcarbamate.
bAfter 18 h. 87 % of W-methylcarbamate.
cAfter 0.5 h. 70 % of W-methylcarbamate.
dAfter 6 h. 78 % of W-methylcarbamate.
/V-methylurethanes from amines in the presence of strong bases
If the reaction is protracted, the initially formed carbamates undergo further reaction with DM and give 
the corresponding N-methylurethanes (eq. 10 and Table 3). The base is necessary: no reaction occurs in 
its absence, as verified in an independent experiment.
rnhcooch3 + ch3ocooch3 base > rn(ch3)COOCH3 + CO2 + CH3OH (10)
However, the reaction needs to be carried out in the absence of atmospheric carbon dioxide, as it 
reacts with the base and methylation reactions come to a stop. Under the conditions of entry 4, Table 3, 
n-decylamine was reacted with DMC under nitrogen atmosphere: after 3 min, 100 % of the carbamate 
was produced.
Ninety-nine percent of n-C10H21N(CH3)COOCH3 was obtained only after 21 h at reflux temper­
ature (20 % after 2 h, and 46 % after 5 h).
The behavior of amines in the presence and in the absence of a base reported on Tables 2 and 3 
confirms that, since the hardness of the nucleophile is increased while operating in the presence of a 
base, the BAc2 rate is dramatically accelerated, and carboxymethyl derivatives are quantitatively ob­
tained. Once formed, the urethanes need the presence of a base to further react with DMC. In these con­
ditions, their RN_COOCH3 anions, softer nucleophiles than RNH2, undergo solely BA12 reactions. No 
RN(COOCH3)2 products—deriving from a double BAc2 reaction—were observed under such condi­
tions.
/V-methylurethanes from amines in the presence of K2CO3
Weaker bases like potassium carbonate can be used instead of alkoxides. Higher temperatures must be 
used, and the reaction is performed in an autoclave; at that temperature, the direct formation of mono­
methyl and dimethyl derivatives cannot be totally avoided (eqs. 11 and 12); they come from two con­
secutive BAc2 mechanisms.
RNH2 + CH3OCOOCH3------ > RNHCH3 + CO2 + CH3OH (11)
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Dimethyl carbonate mechanism and application 1723
RNHCH3 + CH3OCOOCH3------ >RN(CH3)2 + C02 + CH3OH (12)
In these conditions, harder amines react in 22 h and give the corresponding carbamates and 
A-methylcarbamates, while mono- and dimethyl derivatives, if any, are present in lower amount (entries 
3 and 4, Table 4); anilines react slower, and their softness is responsible for the formation of mono- and 
dimethylated products in higher amount.
Table 4 Reactions of aliphatic and aromatic amines in the presence of K ,('(), after 22 h.
Entry Amine Substrate MNM DNM Carb amate NMCarbamate
1 Aniline 41.8 6.2 2.6 8.3 41.0
2 /»-Chloro aniline 38.4 6.3 2.1 5.7 47.5
3 /»-Anisidine 0.5 1.3 13.4 1.8 83.0
4 /7-Octylamine — — 1.2 53.7 45.0
5 Phenethylamine — — — 77.0 23.0
Conditions: T = 180 °C; amine/DMC/K2CO3 molar ratio: 1/3/40.
MNM = Mono-MMethylation; DNM = N,N-Dimethylation; NMCarbamate = MMethylcarbamate.
Two steps preparation of /V-methylurethanes
Another route to the A-methylcarbamate is the standard two-step procedure: first, the synthesis of the 
carbamate at reflux temperature, according to the condition of Table 2, is completed; then, the subse­
quent methylation is carried out in autoclave at 230 °C with K2C03 as a base (Table 5). Because of the 
high temperature, reaction time is reduced, while A,A-dimethylation products were not observed.
Table 5 Reactions of carbamates with DMC in the presence of 
K ,( '( ),. after 4 h.
Entry Carbamate A-Methylcarbamate (%)
1 /»-CH,OPhNHCOOCH, 95
2 PhNHCOOCH, 100
3 n-C8H17NHCOOCH, 97
4 PhCH,CH,NHCOOCH, 100
Conditions: Temperature: 230 °C, Carbamate/K2CO3/DMC molar ratio: 
1/3/40.
CONCLUSIONS
The reactivity of amines with DMC can be explained according to the HSAB theory, since DMC mol­
ecule presents an ambident electrophilic character: it reacts with hard nucleophiles (amines in the pres­
ence of strong bases) according to a BAc2 mechanism, and the carbonyl group is involved. The anions 
of the so-produced urethanes, being softer in character, react now according to a BA12 mechanism with 
the softer part of the molecule, the methyl group, and give the A-methyl derivatives.
The combination of the dual electrophilic character of DMC with its reaction products allows two 
consecutive steps to occur in a selective way. Since hard-soft and soft-hard interactions are inhibited, 
either double methylation and double carboxymethylation do not occur. Accordingly, primary amines 
give the corresponding A-methyl secondary derivatives in high yield and selectivity, without apprecia­
ble production of A,A-dimethyl compounds.
The results of Tables 4 and 5 compared with those already described on Table 1 [7] show that op­
erating under batch conditions it is not possible to complete in one step the transformation of primary 
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1724 P.TUNDO étal.
amines into secondary amines. In fact, reaction 8 is prevented and a further hydrolysis procedure is 
needed for obtaining pure .V-mcthyl amines. However, selectivity is high and work-up easy; moreover, 
once the reason of the mechanism according to the HSAB theory is understood, one can perform car­
boxylation reaction and alkylation reaction with different alkyl carbonates and alkylating agents, re­
spectively, in order to get the desired product in the easier way.
EXPERIMENTAL SECTION
All used compounds were ACS grade and were employed without further purification.
GC analyses were performed using a 30-m, CP-sil 24 CB capillary column. GC-MS analyses 
were performed on a mass detector at 70 eV coupled to a gas chromatograph fitted with a 30-m capil­
lary column. All reaction compounds were compared with authentic samples.
Preparation of carbamates with strong bases at reflux temperature (Table 3): The reactions 
were carried out in a three-necked, 100-mL round-bottomed flask with a reflux condenser and a mag­
netic bar. Amines (9.3 10-3 mol: p-anisidine, p-chloroaniline, benzylamine, n-decylamine, hexane-1,6- 
diamine, n-octylamine, and phenethylamine), the base and DMC were charged in a 1.0/1.2/40 molar 
ratio respectively, under a flux of N2 to remove the possible CO2 formed as by-product (DMC is the 
solvent of the reaction). The bases employed were sodium methylate or potassium iert-butoxide. 
Temperature was 90 °C (reflux of DMC).
Preparation of A-methylcarbamates in the presence of K2CO3 (Table 4): The amine (9.3 10-3 
mol), K2CO3, and DMC were charged in a 1.0/3.0/40 molar ratio respectively and were charged in a 
250-mL autoclave equipped with a sample tube and a magnetic bar. The autoclave was heated with an 
electric mantle at 180 °C.
Two steps preparation of A-methylcarbamates (Table 5): The carbamates (9.3 10-3 mol) pre­
pared and isolated according to the above-described procedure, were introduced in stainless steel auto­
clave (250 mL) equipped with a sample tube and a magnetic bar; K2CO3 and DMC were charged in a 
1.2 and 40 molar ratio with respect to the carbamate.
The reaction temperature was 230 °C (DMC is the solvent of the reaction).
ACKNOWLEDGMENTS
Contributions from the Consorzio Interuniversitario Nazionale “La Chimica per I'Ainbiente", INCA 
(Interuniversity National Consortium “Chemistry for the Environment’’) are gratefully acknowledged.
REFERENCES
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Dimethyl carbonate mechanism and application 1725
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Direct synthesis of N-methylurethanes from primary amines with dimethyl carbonate

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