Journal of Molecular Liquids 183 (2013) 45–49

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Journal of Molecular Liquids

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Protic [TBD][TFA] ionic liquid as a reusable and highly efficient catalyst forN-formylation of amines using formic acid under solvent-free condition

Seyed Meysam Baghbanian a,⁎, Maryam Farhang b

a Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iranb Faculty of Chemistry, Mazandaran University, Babolsar, 47415, Iran

⁎ Corresponding author. Tel./fax: +98 1212517071.E-mail address: S.M.Baghbanian@iauamol.ac.ir (S.M.

0167-7322/$ – see front matter © 2013 Elsevier B.V. Allhttp://dx.doi.org/10.1016/j.molliq.2013.04.001

a b s t r a c t

a r t i c l e i n f o

Article history:Received 12 February 2013Received in revised form 23 March 2013Accepted 1 April 2013Available online 13 April 2013

Keywords:Formic acidN-formylationProtic ionic liquidSolvent-free

Trifluoroacetate guanidinium salt [TBD][TFA] ionic liquid was used as a recyclable and reusable catalyst forthe synthesis of formamides. Primary and secondary amines were reacted with formic acid to affordN-formyl derivatives in high yield under solvent-free condition at room temperature.

© 2013 Elsevier B.V. All rights reserved.

R-NH-R'H

O

OH

[TBD][TFA] (cat)

r.t.;solvent-free N

R'

R

O

H

R= aryl, alkyl

1. Introduction

Formamides are important intermediates in organic synthesis andhave been widely used in the synthesis of pharmaceutically valuablecompounds [1–4]. Formamides serve as useful reagents in Vilsmeierformylation reaction [5] and in the synthesis of formamidinesand isocyanides [6]. In addition, formamides are Lewis bases thatcould be applied as catalysts in reactions such as alkylation [7]and hydrosilylation [8] of carbonyl compounds. Due to these im-portant applications of N-formyl derivative of amines, a number offormylating methods have been reported. Some of the reportedformylation reagents are chloral [9], formic acid-DCC [10], formicacid-EDCL [11], formic acid in toluene [12], ammonium formate[13], CDMT [14], 2,2,2-trifluoroethyl formate [15], KF-Al2O3 [16],formic acid in sodium formate [17], formic acid in polyethylene glycol[18], Amberlite IR120 [19] and silica supported perchloric acid [20].Recently, the N-formylation using ZnCl2, FeCl3, AlCl3, NiCl2 [21] andsulfonic acid supported hydroxyapatite encapsulated γ-Fe2O3 [22]has been introduced as efficient catalysts in N-formylation reactions.However, many of these methods suffer from drawbacks such asbeing expensive and toxic, using high reaction temperatures, havinglow thermal stability, long reaction times, formation of side productsand the use of solvents.

In recent years ionic liquids have emerged as clean alternatives toclassical conventional organic solvents or catalysts because of theirexcellent solvent power, negligible vapor pressure, high thermal,

Baghbanian).

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chemical stability and reusability [23]. Protic ionic liquids (PILs) aresubsets of ionic liquids formed by an equimolar combination of aBrønsted acid and a Brønsted base. PILs can be employed as electro-lyte for non-humidified fuel cell [24], acidic catalysts for esterification[25], protection reaction of aldehyde carbonyls [26], Mannich reac-tion [27], Biginelli condensation [28] and Friedlander annulation[29]. In line with our study on the development of new and novel syn-thetic methodologies and catalysts [30], herein we report a simple,mild, and efficient method for the N-formylation of amines usingformic acid in the presence of a catalytic amount of trifluoroacetateguanidinium salt [TBD][TFA] ionic liquid under solvent-free conditionat room temperature in high yields (Scheme 1).

2. Results and discussion

Amongst the various protic ionic liquids, the researchers were par-ticularly interested in 1,5,7-triazabicyclo[4.4.0]dec-5-ene [TBD] basedionic liquids because of their high stability, easy accessibility and

R'= aryl, alkyl, H

Scheme 1. Reaction of N-formylation of amines using formic acid in the presence of[TBD][TFA] ionic liquid.

NH

N

NH

CF3CO2NH

N

NH

BPh4NH

N

NH

Cl

I II III

Fig. 1. Structurally related TBD based protic ionic liquids.

46 S.M. Baghbanian, M. Farhang / Journal of Molecular Liquids 183 (2013) 45–49

recovery. Thus, three structurally related TBD-based ionic liquidswere prepared (Fig. 1) according to the procedure described in theliterature [31] for the activation of formic acid and allowed for theformylation of amino compounds.

In order to determine the optimum reaction conditions and cata-lytic activity of different ionic liquids ([TBD][TFA], [TBD][BPh4] and[TBD][Cl]) N-formylation of benzyl amine with formic acid was cho-sen as a model reaction (Table 1). Thus, benzylamine was allowedto react with formic acid (1.3 equiv) and equimolar amount of ionicliquid (IL-I) at room temperature and the reaction was completedwithin 15 min in 90% yield (Table 1, entry 3). It was also shownthat the stoichiometry of the formic acid used is very important.The use of excess formic acid under the same reaction condition re-quires a longer time and the yield of the product also falls down(Table 1, entries 1 and 2). The reason would be that some excessformic acid complexed to formic acid by hydrogen bonding with thecarbonyl group [32]. Finally, we found that the use of 5 mol% ofionic liquids (I–III) gives small differences in the yield (Table 1, en-tries 5–10), amongst them IL-I has been found to give the best results(Table 1, entry 5). The ionic liquid prepared from the reaction be-tween TBD and hydrochloric acid (IL-III) gives only 80% of the desiredformylated product (Table 1, entry 10). Again, 92% yield of theformylated product of benzyl amine was obtained when catalyticamount of IL-II was employed (Table 1, entry 9). To see the effect ofthe solvents, reactions were carried out in ethanol, acetonitrile andTHF. It was observed that with the use of any solvent, reaction timewas increased (30–45 min) and a decrease was found in the yield.From the above observations, the best yield was obtained insolvent-free condition at room temperature (Table 1, entry 5). The re-action was also studied using TBD as a catalyst for the preparation offormamides. The yields of the product with 5 and 10 mol% of TBDwere 65 and 75%, respectively (Table 1, entries 11 and 12). Encour-aged by the remarkable results, and in order to show generality and

Table 1Optimization of reaction conditions for the N-formylation of benzyl amine undersolvent free condition.

Entry Benzyl amine(equiv)

HCOOH(equiv)

Catalyst Time(min)

Yielda

(%)

1 1 9 IL I, 1 mmol 150 552 1 6 IL I, 1 mmol 40 753 1 1.3 IL I, 1 mmol 15 904 1 1.3 IL I, 10 mol% 25 875 1 1.3 IL I, 5 mol% 10 986b 1 1.3 IL I, 5 mol% 40 507c 1 1.3 IL I, 5 mol% 45 588d 1 1.3 IL I, 5 mol% 30 709 1 1.3 IL II, 5 mol% 10 9210 1 1.3 IL III, 5 mol% 10 8011 1 1.3 TBD, 5 mol% 45 6512 1 1.3 TBD, 10 mol% 25 75

a Isolated yield.b In EtOH.c In CH3CN.d In THF.

scope of this new protocol, we used various substituted primaryand secondary amines, including variously substituted aromatic,heteroaromatic and alicyclic under this procedure for N-formylationreaction (Table 2). All the amines reacted well at room temperature,although the yields were highly dependent on the substituents.Electron-donating groups in aryl amines reacted well and gave theN-formylated product a good to excellent yield (Table 2, entries 1–6),whereas, the presence of electron withdrawing groups such as chloro,bromo, carboxylic, nitrile and nitro (Table 2, entries 9–14) gave slightlylower yield with longer reaction times. Excellent chemoselectivity wasalso observed for substrates with hydroxyl functionalities providingN-formyl derivatives as the main product (Table 2, entries 7 and 8). Itis worth mentioning that even heterocyclic amine (Table 2, entries 16,17) and hindered amines (Table 2, entries 19, 20), reacted equallywell in this procedure.When a phenylenediamine derivativewas incor-porated, instead of N-formylation, cyclization occurred and produces abenzimidazole derivative as a product (Table 2, entry 21). Primary alco-hols, such as benzyl alcohol, gave the corresponding O-formylatedproduct a smoothly 90% yield (Table 2, entry 24). Cinnamyl alcoholor phenol failed to produce O-formylated products (Table 2, entries25, 26).

The possibility of recycling the catalyst was also examined. For thisreason, the reaction of benzyl amine with formic acid in the presence of[TBD][TFA] was studied. After completion of the reaction (monitored byTLC), EtOAc was added to the reaction mixture, and [TBD][TFA] wasremoved by filtration. After the removal of the solvent, the pure productwas obtained. The catalyst could be reused six times for the synthesis ofN-benzylformamide without significant loss of activity (Table 3). This[TBD] [TFA] is reusable for N-formylation reactions.

A plausible mechanism for the reaction was depicted in Fig. 2.We postulate that the guanidinium core of salts could form doublyH-bonded motifs with carbonyl of formic acid thus enhancing theirelectrophilicity when followed by the nucleophilic attack by amineon the carbonyl carbon. The protonation and subsequent dehydrationcould produce formamide and regenerate catalyst.

In order to show the accessibility of the present work in compari-son with the reported results in the literature, we summarized someof results for the N-formulation of benzylamine in Table 4, whichshowed that [TBD][TFA] ionic liquid is the more efficient catalystwith respect to the reaction time, lower catalyst content, temperatureand exhibited broad applicability in terms of yields.

3. Conclusion

In conclusion, the present study described the N-formylation ofamines with formic acid in the presence of protic [TBD][TFA] ionic liq-uid. The reported protocol is efficient, inexpensive, chemoselectiveand the ionic liquid is reusable. In comparison with earlier studiesthe advantages of the present method were as follows: (i) the useof easy to handle ionic liquid; (ii) simplicity in the extraction of theproduct/substrate from ionic liquid; (iii) no significant loss of activity byemploying reused catalyst; (iv) chemoselectivity and finally (v) solvent-free condition.

47S.M. Baghbanian, M. Farhang / Journal of Molecular Liquids 183 (2013) 45–49

Acknowledgment

This research is supported by the Islamic Azad University, AyatollahAmoli Branch.

Table 2N-formylation of amines at room-temperature under solvent-free conditionsa.

Entry Substrate Time (min)

1 10

2 10

3 10

4 10

5 10

6 10

7 10

8 10

9 10

10 10

11 10

12 10

13 20

14 15

15 10

16 30

17 30

18 30

19 35

20 35

21 10

22 30

23 30

Appendix A. Supplementary data

Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.molliq.2013.04.001.

Product Yieldb (%) Ref.

98 [17]

95 [16]

90 [15]

92 [17]

92 [17]

94 [34]

85 [16]

88 [16]

93 [16]

88 [17]

88 [16]

90 [16]

90 [16]

92 [16]

88 [17]

75 [17]

80 [16]

82 [17]

75 [16]

80 [17]

95 [33]

85 [35]

75 [16]

(continued on next page)

Table 2 (continued)

Entry Substrate Time (min) Product Yieldb (%) Ref.

24 30 90 [36]

25 – No reaction – –

26 – No reaction – –

a Reaction conditions: amine (1.0 mmol), formic acid (1.3 mmol) and [TBD][TFA] ionic liquid (5 mol%).b Yield refers to the pure isolated product.

Table 3Reusability studies of catalysts for the synthesis ofN-benzylformamide (Table 2, entry 1)a.

Number of experiments Fresh 1 2 3 4 5

Isolated yield (%)b 98 97 95 92 92 90

a Reaction condition: benzyl amine 1 mmol, formic acid 1.3 mmol, [TBD][TFA] as acatalyst 5 mol%, solvent-free, r.t.

b Isolated yield.

NH

N

NH

CF3CO2

O

HO H

N

N

N

CF3CO2

H H

O

HO H

R-NH2

O

N

N

N

CF3CO2

H H

HNH2R

HO

O

N

N

N

CF3CO2

H H

HNHR

H2O

H2O

RNHCHO

Fig. 2. Catalytic cycle of protic ionic liquid ([TBD][TFA] ionic liquid) promoted formylationof amines.

Table 4Comparison of the catalytic efficiency of [TBD][TFA] ionic liquid with some reportedcatalysts in the N-formylation of benzylamine.

Entry Formylating method Solvent Temp. (°C) Time(min)

Yield(%)

Ref.

1 γ-Fe2O3@HAp-SO3H Solvent-free r.t. 40 92 [22,38]2 HCOOH, sulfated

tungstateSolvent-free 70 °C 10 99 [37]

3 HCOOH, HClO4–SiO2 Solvent-free r.t. 40 92 [38]4 HCOOH, imidazolium

trifluoroacetate ionicliquids

Solvent-less 70 °C 60 96 [39]

5 HCOONa Solvent-free r.t. 150 85 [17]6 HCOOH, amberlite

IR-120Solvent-free Microwave,

320 W95 92 [40]

7 HCOOH, PEG Solvent-free r.t. 360 42 [41]8 HCOOH, H2O2, copper

saltMeOH r.t. 75 80 [42]

9 Methylformate PhMe r.t. 120 94 [43]10 Ammonium formate CH3CN Reflux 360 88 [44]13 [TBD][TFA] ionic liquid Solvent-free r.t. 10 98 –

48 S.M. Baghbanian, M. Farhang / Journal of Molecular Liquids 183 (2013) 45–49

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