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Microwave-mediated reduction of selected functional groups employing: N,N-dimethylaniline.borane.

1. INTRODUCTION

Over the decades, amine.borane complexes have gained wide applications in organic synthesis [1], dye industry as well as in various other industrial applications [2-5]. The utilization of these complexes was reported in [H.sub.2] storage fuel cells, due to its stability and high gravimetric content of hydrogen [6a, 6b]. The scope and uses of amine.borane in organic synthesis was limited because of stability [7 a], lack of reactivity towards functional group [7b]. In order to activate the stable amine.borane complexes like triethylamine.borane, pyridine.borane high reaction temperature [9], addition of acetic acid [10], mineral acid [11] and lewis acid [12] are required. One set of amine.borane complexes derived from N,N-dialkyl anilines and N,N -dialkyl amines is significantly more reactive than most amine.boranes [1, 13, 4]. The steric effects and electronic property of the groups attached to nitrogen atom of amines influence their reducing property [1, 15a, 15b]. The main drawback from are their laborious synthesis [1], [7b, 17]. The procedure involves the alkylation of aniline or mono alkyl aniline, which is very delicate and time consuming. But diethyl aniline.borane complex is commercially available, properties are well documented [16]. Instead of aiming to prepare a new reactive amine.borane complex, we choose the novel technique like microwave irradiation, 'Corresponding author. E-mail: svikumar70@gmail.com sonication to activate the moderately reactive amine.borane complexes towards the reduction of functional groups. On the other hand very few reports were available on the use of (DMANB) [8] as reducing agent as compared to N,N-diethyl aniline.borane [18]. Therefore, we intended to study the reduction potential of DMANB under microwave condition for the functional group reduction.

It has been well known that the activation of various chemical reactions by microwave irradiation is not only enhances the selectivity and product yield [19] but also shorten the reaction time, decreases the side products [20] and it is providing quite successful in the formation of a variety of carbon-heteroatom bonds [21]. By taking advantage of this efficient source of energy, compound libraries for lead generation and optimization can be assembled in a fraction of the time required by classical thermal methods [22]. Microwave-induced Organic Reaction Enhancement (MORE) chemistry has gained popularity as a non-conventional technique for rapid organic synthesis [23]. It can be termed as 'echemistry' because it is easy, effective, economical and eco-friendly and believed to be a step towards green chemistry. Furthermore, with the ease of recovery and recycling of N,N-dimethylaniline after the reaction makes amine.borane complex environmentally benign reagent.

We encouraged by the previous results [24] on hydroboration of alkenes to alcohols with DMANB under microwave irradiation and further expand its utility as a hydride source, we undertook a series of compounds for functional group reduction by DMNAB under microwave irradiation.

2. MATERIAL AND METHODS

All chemicals were purchased from Fluka and Aldrich. Melting point of compounds were measured using a differential scanning calorimeter (Shimadzu DSC-50) and are uncorrected. Liquid substrates were distilled prior to use. Proton nuclear magnetic resonance ([sup.1]H NMR) spectra were recorded using 400 MHz equipment, Bruker AVANCE. For [sup.1]H NMR spectra, chemical shifts ([delta]) are referenced from TMS (0.00 ppm) and the samples were dissolved in an appropriate deuterated solvent. Carbon nuclear magnetic resonance ([sup.13]C NMR) spectra were recorded using a NMR spectrometer at 100 MHz. For [sup.13]C NMR spectra, chemical shifts ([delta]) are given from reference signal of the deuterated solvent used. IR spectra were recorded on FTIR Shimadzu spectrometer. The mass spectra were recorded on EI-Shimadzu-GC-MS spectrometer. Elemental analyses were measured on a HERAEUS (CHNO, Rapid) analyzer.

Microwave specification

Microwave experiments were conducted using a CEM discover monomode oven operating at 2450MHz monitored by a PC computer and temperature was maintained at a constant value by power modulation (0-300W). Stirring was provided by an in situ magnetic stirrer. Reactions were performed under nitrogen atmosphere. Reaction conditions: power 300 Watts; ramp time 3min; hold time 10 min; stirring on; temperature 145[degrees]C.

3. RESULTS AND DISCUSSION Preparation and stability of DMANB complex:

The VW-dimethyl aniline.borane complex was prepared by two methods [25, 26]. The complexing ability of amine towards borane was monitored by [sup.11]B-NMR spectroscopy. This reagent could be maintained under nitrogen atmosphere and it is apparently stable indefinitely at room temperature. In [sup.11]B NMR the amine.borane complex showed a peak at -4 ppm (decoupled) and -4 to -9 ppm (coupled).

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Encouraged by the results of our preliminary exploratory observations we undertook a study of the reduction of aldehydes, ketone, carboxylic acid, amide, ester, amino acid, Schiff base with DMANB under MWI. The results are summarized in Table 1.

The Aldehydes shown in entries 1, 13 and 14 from Table 1 were comfortably reduced to the corresponding alcohols by DMANB in a short period of time (4 minutes) under MWI and quantitative yields were obtained. 1:3 stoichiometry ratio was followed for the reduction. The halo aldehyde in entry 3 was reduced to the corresponding alcohol without affecting the halogen. Reduction of cyclohexanone is slow at room temperature (24 h with only 80% completion as shown by TLC and Gas-burette analysis), however under microwave irradiation the reduction was completed in just 5 minutes and a 96% yield of the corresponding alcohol was isolated (entry 5, Table 1). The same was observed in the case of acetophenone in 4 minutes (entry 4, Table 1).

Aliphatic and aromatic carboxylic acids (entries 1 and 13, Table 1) were readily reduced by DMANB to the corresponding alcohols in very good yields in a short period of time (5minutes). A one to one ratio of reagents was used since one hydride is utilized for acid hydrolysis and further two hydrides are required for the carbonyl reduction. Tandem reduction/hydroboration was observed with undecenoic acid and cinnamic acid (entries 8-9, Table 1) and a mixture of products was formed based on GC analysis (tandem reduction/hydroboration of carboxyl group and double bond; the reduction of carboxyl group alone and the hydroboration of double bond alone).

DMANB conveniently reduced amides to amines in very good yields within 6minutes under microwave irradiation. According to literature reports [8], the reduction of Benzamide, Acetanilide with W-diethyl aniline.borane requires 7-13hours under conventional methods. 1:2 stoichiometry ratio was followed for the reduction, because the reduced amine forms a complex with borane, hence excess borane needed to make the reduction convenient.

The reduction of amino acids [25, 26] is considered important transformation in organic synthesis, the amino alcohol obtained in this transformation plays vital role in asymmetric synthesis [1] and peptide synthesis. In the present study the reduction of three amino acids were focused namely valine, proline and leucine (entries 14-16, Table 1). Amine.borane reagent conveniently reduces the amino acid to amino alcohol within 6 minutes in good yields. 1:2 stoichiometry ratio was followed, the specific rotation value [o,]d matches with the literature value [27].

The reduction of imine esters (Schiff base) to amine esters [17] in THF was facile with amine.borane under microwave irradiation within 4 minutes in good yields.

It is noteworthy to mention that the reagent DMANB did not reduce ester functionality up to 30 min of microwave irradiation. This observation led us further to the study on chemoselectivity aspects from reduction process.

Chemoselectivity studies

Encouraged by the results we under took a study of chemoselective reduction of 4-nitro benzaldehyde, nonomethyl hydrogen phthalate, 4-carbomethoxy acetanilide and imine esters with DMNAB. Reagent selectively reduces the aldehyde, acid, amide and imine functionality within 4-6 minutes under MWI condition and the ester group remains intact.

In the case of ethyl-10-undecenoate selective hydroboration of double bond was observed, further confirmed by corresponding signal in [sup.11]B NMR at 75 ppm and supported by the oxidation of trialkyl boron species with NaOH/[H.sub.2][O.sub.2].

Experimental procedure for functional group reduction: [1, 7b, 13, 14, 25]

An oven dried, 50 mL flask fitted with a sidearm capped by a rubber septum (to permit introduction and removal of material with a hypodermic syringe) was equipped with microwave reflux condenser connected to a mercury bubbler by means of take-off adapter. DMANB in dry THF 10 mL (5.3M, 8.3 mmol) was added to the flask by syringe followed by compound in dry THF (5.00 mL, 6.25 mmol) slowly during 5 minutes under nitrogen atmosphere. The contents were stirred for about 4-6 minutes under microwave irradiation. At appropriate time intervals, samples were withdrawn and hydrolyzed using HCl (2M)-glycerol-water mixture, the hydrogen evolved was measured using the gasimeter. Progress of the reaction was cross checked by GC, TLC analysis. In a number of cases, the reduction was carried out as described above to establish yield and stoichiometry. However, the reaction mixtures were then worked up depends on nature of substrate and to isolate and characterize the reaction products.

With aldehydes, ketone, carboxylic acid and ester reaction mixture was quenched with HCl (3N, 10 mL) and product was extracted with ether. The combined ether extracts were washed with HCl 3N, water and brine and dried over anhydrous sodium sulphate, removal of solvent under vacuum gives crude product, which on purification by column chromatography yields pure product. In the case of amide, amino acid, imine, imine ester reaction mixture was quenched with potassium carbonate aqueous solution and product was extracted with ether. The crude product was obtained by simple acid/base manipulation, which was further purified by column chromatography, purity of the final product was obtained by HPLC method.

4. CONCLUSION

We have demonstrated the successful utilization of DMNAB towards the reduction of functional groups. Reagent DMANB has certain advantages over the currently available borane reagents such as borane.tetrahydrofuran (BTHF) and borane.dimethylsulfide (BMS). Pure DMANB is 1) quite concentrated at 5.6M, 2) thermally stable, 3) convenient and comfortable to handle, 4) environment friendly, not disagreeable odour, 5) DMANB makes available all three hydrides for the reduction. In comparison with conventional methods microwave technique is a novel and efficient method to activate the DMANB complex towards the reduction of functional groups. Studies on the stoichiometry, applications and limitations of this methodology are undergoing and will be reported in due course.

5. ACKNOWLEDMENTS

We express gratitude to our respected Rev. Fr. Dr. Arulraj Founder, DMI Group of Institutions, East Africa & India, Dr. T. X. A. Ananth, Director (International Operations), DMI group of Institutions, Mr.Ignatius Herman, Director (Academic), DMI group of Institutions, also we acknowledge the support provided by Rev. Sr. Fatima Mary, Vice Principal (Administration), and Mr. N. Ressel Raj, Vice Principal (Academic), DMI. St. Joseph University, Tanzania.

6. REFERENCE AND NOTES

[1] Kanth, J. V. B. Aldrichim. Acta 2002, 35, 57.

[2] Lane, C. F. Aldrichim. Acta 1973, 6, 51.

[3] Masui, M.; Shiorii, T. Tetrahedron Lett. 1998, 39, 5199. [CrossRef]

[4] Akahoshi, H. US patent. 1987, 4, 642, 161.

[5] a) Mallory, G,O.; Hajdu, J. B. (eds.) Electroless plating, Fundamentals and Applications, Am. electroplaters and surface finishers society, Orlando, Florida, 1990; b) Meller, A.; In: Gmelin Handbook of Inorganic and Organometallic Chemistry, Springer: Berlin, 1992; 4th Supplement, Vol. 3, 1.

[6] a) Follet, M. Chem. Ind. 1986, 1, 123; b) Lane, C.F.; N-B-H Survey, Contract # DE-FC3605GO 15060 Northern Arizona University, 2006.

[7] a) Hutchins, R. O.; Learn, K.; Nazer, B.; Pytiewski, D.; Pelter, A. Organic preparations and procedures Int. 1984, 16, 335; b) Brown, H. C.; Kanth, J. V. B.; Dalvi, P. V.; Zaidlewicz, M. J. Org. Chem. 1999, 64, 6263.[CrossRef]

[8] Brown, H. C.; Murray, L. T. Inorg.chem. 1984, 23, 2746. [CrossRef]

[9] Barnes, R. P.; Graham, J. H.; Taylor, M. D. J. Org. Chem. 1958, 23, 1561. [CrossRef]

[10] Kelly, H. C.; Giusto, M. B.; Marchelli, F. R. J. Am. Chem. Soc. 1994, 59, 6470.

[11] Wuts, P. G. M.; Cabaj, J. E.; Havens, J. L. J. Org. Chem. 1994, 59, 6470. [CrossRef]

[12] Periasamy, M.; Kanth, J. V. B.; Prasad, A. S. B. Tetrahedron 1994, 50, 6411. [CrossRef

[13] Brown, H.C.; Zaidlewicz, M.; Dalvi, P. V. Organometallics 1998, 17, 4202. [CrossRef]

[14] Brown, H. C.; Kanth, J. V. B.; Zaidlewicz, M, M. J. Org. Chem. 1998, 63, 5154.

[15] Long, L. H.; In A Comprehensive Treatise on Inorganic and Theoretical Chemistry; Mellor, W.J., Ed.; Longman: London, 1981; Supplement Vol.5, Part B1; b) Kanth, J. V. B.; Periasamy, M. Chem.Commun. 1990, 1, 1145.

[16] Salunkhe, A, M.; Burkhardt, E. R. Tetrahedron Lett. 1997, 38, 1519. [CrossRef]

[17] Periasamy, M.; Kanth, J. V. B.; Reddy. C. K. Perkin Trans. A. 1995, 1, 427. [CrossRef

[18] Salunkhe, A, M.; Burkhardt, E. R. Tetrahedron Lett. 1997, 38, 1523. [CrossRef]

[19] Loupy, A., Ed.; Microwaves in organic synthesis, Wiley-VCH: Weinheim, 2002. [CrossRef!

[20] Hayes, L. B. Aldrichim. Acta 2004, 37, 66.

[21] Madhvi, A. S.; Smita, J.; Desai K. R. Arch. Appl. Sci. Res. 2012, 4, 645.

[22] Jacob, J. Int. J. Chem. 2012, 4, 29. [CrossRef

[23] Varma, S. Green Chem. 1999, 1, 43. [CrossRef

[24] Jayakumar, V. S.; Srinivas, A. K.; Hiriyana. G.; Pati. H. Rasayan J. Chem. 2008, 1, 326.

[25] Pelter, A.; Smith, K.; Brown, H. C. Borane reagents, Academic press, London, 1988.

[26] Brown, H. C.; Organic synthesis via boranes vol.1; Aldrich chemical company, Inc.; Milwaukee, WI, 1997. [CrossRef]

[27] McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58, 3568.

S. Venkatesan Jaya kumar (a),*, S. Mothilal Krishna Ganesh (b)

(a) Chemistry department, College of Natural Sciences, P.O.Box 378, Jimma University, Jimma, Ethiopia.

(b) Department of Computer Science & Engineering, St. Joseph University, Dar Es Salaam, Tanzania.

Article history: Received: 07 May 2013; revised: 07 February 2014; accepted: 30 March 2014. Available online: 02 April 2014.
Table 1. Reduction of representative functional groups with DMNAB
complex.

Entry   Substrate               Time     Stoichiometry
                                (min.)   ratio (DMANB:Sub)

1       Benzaldehyde            4        1:3
2       2-Fluoro-4-Bromo        4        1:3
        benzaldehyde
3       p-Anisaldehyde          4        1:3
4       Acetophenone            4        1:2
5       Cyclohexanone           5        1:2
6       Benzoic acid            6        1:1
7       Azealic acid            6        1:1
                                         2:1
8       Undecenoic acid         6        1:1 & 2:1
                                         1:2
9       Cinnamic acid           6        1:1 & 2:1
                                         1:2
10      Benzamide               6        1:1
11      Acetanilide             6        1:1
13      4-Bromo acetanilide     6        1:1
14      L-Valine                6        1:1
15      L-Leucine               6        1:1
16      L-Proline               6        1:1
17      n-Butyl acetate         25       1:1 & 2:1
18      Ethyl benzoate          25       1:1 & 2:1
19      Methyl salicylate       25       1:1
20      Tyrosine methyl ester   25       1:1

Entry   Product                   Yield

1       Benzyl alcohol            90
2       2-Fluoro-4-Bromo          1
        benzyl alcohol
3       p-Anisyl alcohol          94
4       sec-Phenethyl alcohol     98
5       Cyclohexyl alcohol        96
6       Benzyl alcohol            93
7       Diol                      95

8       Mixture of products       96 (crude)

9       Mixture of products       95 (crude)

10      Benzyl amine              96
11      N-Ethyl aniline           94
13      4-Bromo-N-Ethyl aniline   93
14      L-Valinol                 95
15      L-Leucinol                95
16      L-Prolinol                96
17      No reaction               __
18      No reaction               __
19      No reaction               __
20      No reaction               __

Table 2. Chemoselective reduction of selected functional groups with
N, N-Dimethyl aniline.borane (DMANB).

Entry   Substrate                       Time
                                        (min.)

1       p-Nitro benzaldehyde            4
2       Monomethyl hydrogen phthalate   6
3       4-Carbomethoxy acetanilide      6
4       N- [(4-chlorophenyl)            4
          methylene]aniline
5       Methyl 2-[(2-hydroxy            4
          phenyl)methylene] amino-3-
          methylbutanoate
6       Ethyl- 10-undecenoate           6

Entry   Stoichiometry       Product
        ratio (DMANB:Sub)

1       1:3                 p-Nitro benzyl alcohol
2       1:1                 Methyl(2-hydroxy methyl) benzoate
3       1:1                 4-Carbomethoxy-N-Ethyl aniline
4       1:1                 N-(4-chlorobenzyl) aniline

5       1:1                 Methyl 2-[(2-hydroxybenzyl)
                              amino]-3-methylbutanoate

6       1:1                 No reduction of ester group,
                              hydroboration of double bond.
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Author:Kumar, S. Venkatesan Jaya; Ganesh, S. Mothilal Krishna
Publication:Orbital: The Electronic Journal of Chemistry
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Date:Jan 1, 2014
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