Zirconyl Chloride: An Efficient, Water-Tolerant, and Reusable Catalyst

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Zirconyl Chloride: An Efficient, Water-Tolerant, and Reusable Catalyst for the Synthesis of N-Methylamides ZirconylChlorideasCat lystfortheSynthesi ofN-Methylamides Dhrubajyoti Talukdar, Lakhinath Saikia, Ashim Jyoti Thakur* Department of Chemical Sciences, Tezpur University, Napaam 784028, India Fax +91(3712)267005/6; E-mail: [email protected] Received 10 February 2011

Abstract: ZrOCl2·8H2O is a highly effective, water-tolerant, and reusable catalyst for the direct condensation of carboxylic acids and N,N¢-dimethylurea under microwave irradiation to give the corresponding N-methylamides in moderate to excellent yields. Notably, ZrOCl2·8H2O is a potentially useful green catalyst due to its low toxicity, easy availability, low cost, ease of handling, easy recovery, good activity, and reusability. Key words: zirconium oxychloride octahydrate, carboxylic acid, N,N¢-dimethylurea, N-methyl amide

The amide is one of the most important functionalities in organic chemistry and is central in the architecture of biological systems.1 Recently, it has been shown that, in the pharmaceutical industry, amide bond formation alone accounts for 65% of all preliminary screening reactions.2 pharmaceutical round table of the ACS Green Chemistry Institute recently identified amide formation as one of the most utilized and problematic conversions in the pharmaceutical industry and as such has been identified as a high priority research area.3 Various methods are reported in the literature for amide synthesis.4 The available methods rely mainly on condensation approaches, although oxidative and free-radical approaches are the other alternatives.5 In nature, protein synthesis is achieved by straightforward dehydrative condensation of the amino acids. The main advantage of the dehydrative method over the others is the easy availability and the structural diversity of the carboxylic acids available. In this regard, the reaction of amines with the carboxylic acid or activated derivatives is the most attractive approach.6 Other methods for the synthesis of amides include Staudinger ligation,7 aminocarbonylation of aryl halides,8 oxidative amidation of aldehydes,9 Ritter reaction,10 and N-acylation of amines.11 However, the majority of such protocols involve the use of stoichiometric amounts of activated reagents, such as O

O + OH MeHN

R 1

acid anhydrides or acyl chlorides. Furthermore, an excess of these reagents is normally needed and the reaction being water-sensitive, efficient exclusion of water is necessary.12,13 Therefore, the development of new procedures for easy, clean, and simple synthesis of amides is of topical interest in medicinal chemistry. N-Methylation of peptides is a promising way rationally to improve key pharmacological characteristics of peptides14–16 and other systems such as taxanes.17 However, synthesis of N-methylamides is not well documented, the most generally useful method being to add the acid chloride very slowly dropwise, with constant stirring, into a concentrated aqueous solution of methylamine.18 Our primary objective was to develop an environmentally acceptable method for the synthesis of N-methylamides 3 from carboxylic acids 1 and N,N¢-dimethylurea (DMU, 2, Scheme 1) using zirconyl chloride (ZrOCl2·8H2O) as catalyst, under microwave irradiation (MWI) and absence of solvent. The application of ZrOCl2·8H2O as a catalyst in organic synthesis19 attracted our attention as it is relatively inexpensive, readily available, easy to handle, insensitive to air and moisture,20 and relatively nontoxic (LD50 for ZrOCl2·8H2O, oral rat) = 2950 mg/kg).21 It has been already recognized as a green catalyst for different organic conversions.20–22 In order to develop a standard experimental protocol, after screening a range of microwave power, reaction temperature, time, substrate-to-catalyst ratio, and exploring scope of various solvents, we have found that ZrOCl2·8H2O (10 mol%) is an efficient catalyst for the conversion of carboxylic acids 1 into N-methylamides 3 reacting with DMU (2) under MWI (600 W), in the absence of any solvents. DMU is an important and versatile reactant in organic chemistry.23 We than examined the efficiency of the catalyst for the synthesis of a range of amides, and the optimized results are summarized in Table 1 (entries 1–13). O

ZrOCl2⋅8H2O (10 mol%) NHMe

2

MWI

R

N 3

Me + MeNH2

H

+ CO2

4

5

where R is an aromatic or aliphatic moiety

Scheme 1

ZrOCl2·8H2O-catalyzed conversion of carboxylic acids 1 into N-methylamides 3

SYNLETT 2011, No. 11, pp 1597–1601xx. 201 Advanced online publication: 15.06.2011 DOI: 10.1055/s-0030-1260796; Art ID: D04111ST © Georg Thieme Verlag Stuttgart · New York Synthesis 2000, No. X, x–xx

ISSN 0039-7881

© Thieme Stuttgart · New York

is a copy of the author's personal reprint l

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1598 Table 1 Entry

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D. Talukdar et al. ZrOCl2·8H2O-Catalyzed Conversion of Carboxylic Acids 1a–m into the Corresponding N-Methylamides 3a–m Carboxylic acids 1

Amides 3

MWI (min) OH

O

H N

O

Thermal (h) MWI

Thermal

Me

1

1a

Yield (%)a,b

Reaction time

3

8

98

48

5

9

90

45

6

10

92

47

10

12

55

20

15

17

50

18

18

17

90

44

15

15

90

38

8

10

75c

30c

3a O

OH

H N

O

Me

2 O2N

NO2

1b

O2N

NO2

3b

O

OH

H N

O

Me

3 Cl

Cl

1c

3c

O

OH

H N

O

Me

4 OH

OH

1d O

3d OH

H N

O

Me

5 NH2

NH2

1e

3e

O

OH

H N

O

Me

6 NO2

1f

NO2

3f

O

OH

H N

O

Me

7 I

1g

I

3g COOH

CONHMe

8 COOH

1h

Synlett 2011, No. 11, 1597–1601

CONHMe

3h


LETTER Table 1 Entry

1599

Zirconyl Chloride as Catalyst for the Synthesis of N-Methylamides

ZrOCl2·8H2O-Catalyzed Conversion of Carboxylic Acids 1a–m into the Corresponding N-Methylamides 3a–m (continued) Carboxylic acids 1

Amides 3

MWI (min) O

Yield (%)a,b

Reaction time

Thermal (h) MWI

Thermal

9

12

50

15

10

15

90

45

5

5

45

7

30

20

65

33

20

20

69

25

O OH

9

N Me

OH O

O

1i 10

3i

O

O

HO

HN Me

1j

3j O

11

O

H2C

OH

H2C

H2C

OH

H2C

O

O

3k

1k O

12

N Me

O OH

HO

NHMe

MeHN

O

1l

O

3l O

O

O

13

NHMe

OH

1m

O

3m

a

Yields referred to isolated yields Characterized using 1H NMR, 13C NMR, and IR spectroscopy, mass spectrometry, and elemental analysis. c Acid 1h/DMU (2) = 1:2 (molar ratio) was used. b

The generality and the scope of the reaction were evaluated for a wide spectrum of carboxylic acids, bearing both electron-withdrawing and electron-donating substituents at various positions as well as dicarboxylic acids. As is evident from Table 1, the reaction has a broad scope for aromatic, alkyl, and a,b-unsaturated carboxylic acids. Various mono- and dicarboxylic acids 1a–m (aliphatic and aromatic) reacted efficiently with DMU (2) to give the corresponding N-methylamides 3a–m in moderate to excellent yields (45–98%). It is noteworthy that these reactions proceed efficiently without solvent. This may be due to the selective absorption of microwaves by the reactants, intermediates or the catalyst, which accelerates the reaction rate.24 This reaction also proceeded under conventional heating in an oil bath under solvent-free conditions, but took much longer (5–20 h) and the yields (7– 48%) were less satisfactory. In the absence of the catalyst, the reaction did not provide any product, and the reactants were recovered. N,N¢-diphenylurea (DPU), urea, N-phenylurea, N-p-tolylurea, and N-benzylurea failed to react under the reaction conditions possibly due to lower nucleophilicity of the systems, in accordance with the proposed mechanism (Scheme 2). The method is advantageous in the sense that the reaction does not generate water. So, the problem of

reversibility of the equilibrium and destroying of amide does not arise. Functional groups such as OH (1d), NO2, Cl (1c), NH2 (1e), I (1g), and double bonds (1j and 1l) remained intact, thus showing their tolerance to the reaction conditions. Succinic acid (1k) and phthalic acid (1i) reacted with 1 equivalent of DMU to provide cyclic N-methylamides 3k and 3i, respectively, instead of dimethylated amides. Using 2 equivalents of DMU (2) also did not give the dimethylated product. Dicarboxylic acids 1l and terephthalic acid (1h) provided dimethylated amides 3l and 3h. The effect of the amount of the catalyst on the yield of the N-methylamide (3c) was studied for the model reaction between p-chlorobenzoic acid (1c, 1 mmol) and DMU (2, 1 mmol). It was found that the yield increased up to to 15 mol% but further increases in catalyst did not provide any improvement in yield, and 10 mol of the catalyst was found to be the optimum amount. We also varied the microwave power wherein the yield increased with an increase in MW power from 140 W to 560 W but at 700 W the reactants decomposed. Hence, 560 W power was chosen for our study. To investigate the versatility of the catalyst for reuse, after the reaction, the product was extracted with ethyl acetate, and the catalyst was recovered by filtration. After filtration the catalyst was washed

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D. Talukdar et al.

with CH2Cl2 or CHCl3, dried at 60 °C (at 75 °C, dehydration from ZrOCl2·8H2O to ZrOCl2·6H2O occurrs25) and subjected to reaction again. The recovered catalyst could be further used for at least four times without appreciable loss in activity.

The catalyst has the advantage of being readily available at low cost, moisture stable, environmentally benign, and reusable, giving this methodology good utility.

ZrOCl2·8H2O is known to be an ionic cluster [Zr4(OH)8(H2O)16]Cl8·12H2O.25 Generally, the cationic cluster [Zr4(OH)8(H2O)16]8+ is regarded as the active species. This cationic cluster may have high coordinating ability to ligands such as DMU through ligand exchange. Examination of the XRD spectrum of our fresh catalyst revealed it to be a mixture of ZrOCl2·8H2O and ZrOCl2·6H2O. The XRD spectrum of the recovered catalyst showed it to be amorphous material.22a The FT-IR spectra of the catalyst and the recovered catalyst were recorded in the range 500 cm–1 to 4000 cm–1 (Figure 1). A peak at 1621 cm–1 was characteristic for ZrOCl2·8H2O.22a There was a broad absorption in the range 3400–3520 cm–1 observed both in the initial and recovered catalyst. However, a new peak at 1029.91 cm–1 was observed for the recovered catalyst. A plausible mechanism for the reaction is depicted in Scheme 2.

Typical Procedure for the Synthesis of N-Methylamides 3 A 1:1 mixture of DMU (2, 0.088 g, 1 mmol), carboxylic acid 1a (0.122 g, 1 mmol, R = Ph), and ZrOCl2·8H2O (0.032 g, 10 mol%) were ground in a mortar, placed in a 50 mL conical flask and irradiated in a microwave oven. The progress of the reaction was monitored by TLC. After completion of the reaction, the contents were extracted with EtOAc (3 × 10 mL) and filtered to remove the catalyst. To remove unreacted acid the organic layer was washed with aq NaHCO3 followed by H2O. Evaporating the organic solvent provided the product in essentially pure form. Column chromatography was used when required. In this instance, recrystallization from EtOH afforded the pure product N-methylbenzamide (3a). White solid; mp 77 °C. MS: m/z = 225 [M+]. IR (KBr): nmax = 3289, 3105, 1646, 1540, 1411, 715 cm–1. 1H NMR (400 MHz, CDCl3): d = 3.02 (s, 3 H, NMe), 6.85 (br s, 1 H, NH, exchangeable with D2O), 8.83– 9.03 (m, 5 H). 13C NMR (100 MHz, CDCl3): d = 27, 127.5, 134.3, 136.4, 149.5, 168.3. Anal. Calcd (%) for C8H9NO: C, 71.09; H, 6.71; N, 10.36. Found: C, 71.18; H, 6.68; N, 10.63.

Acknowledgment The authors wish to thank Council of Scientific and Industrial Research (CSIR), New Delhi, India for financial support (grant no. 01(2147)/07/EMR-II) and referees for valuable suggestions. DT thanks Tezpur University for the institutional fellowship to him during his work.

References

Figure 1 ZrOCl2 δ–

ZrOCl2

δ–

O δ+

MeHN

δ+

Scheme 2

NHMe MeN

O C

ZrOCl2 RCOO–

O H Me N

NHMe R

C O C

H

NHMe

N Me R

C

O

O

Plausible mechanism for the synthesis of N-methylamides 3

In conclusion, the procedure as described above is an efficient, novel, fast (3–30 min), and greener method for the direct synthesis of N-methylamides from carboxylic acids and DMU in the presence of ZrOCl2·8H2O as a catalyst.

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