Synthesis of 3-bromotetronamides via amination of 3,4-dibromofuran-2(5H)-one

SHORT REPORT

Synthesis of 3-bromotetronamides via amination of 3,4-dibromofuran-2(5H)-one

Silvio Cunha^I,III,*; Caio C. Oliveira^I,III; José R. Sabino^II

^IInstituto de Química and Instituto Nacional de Ciência e Tecnologia - INCT em Energia e Ambiente, Universidade Federal da Bahia, Campus de Ondina, 40170-290 Salvador-BA, Brazil

^IIInstituto de Física, Universidade Federal de Goiás, CP 131, 74001-970 Goiânia-GO, Brazil

^IIIInstituto Nacional de Ciência e Tecnologia - INCT em Energia e Ambiente, Universidade Federal da Bahia, Campus de Ondina, 40170-290 Salvador-BA, Brazil

ABSTRACT

This work describes the direct synthesis of 3-bromotetronamides in good yields through the reaction of 3,4-dibromofuran-2(5H)-one, obtained from furfural, with primary and secondary amines. Aromatic amines were more tolerated than aliphatic and heteroaromatic ones. The X-ray structures of five derivatives are described.

Keywords: enaminones, tetronamides, butenolides

RESUMO

Este trabalho descreve a síntese de dez tetronamidas em bons rendimentos através da reação da 4-dibromofuran-2(5H)-ona, obtida do furfural, com aminas primárias e secundárias. As aminas aromáticas foram mais toleradas que as alifáticas e as heteroaromáticas. Foram determinadas as estruturas cristalinas de cinco derivados.

Introduction

The synthesis of functionalized tetronamides is a theme of ongoing research activity, and this interest is due to the synthetic applications of such compounds, mainly in heterocyclic synthesis.¹ A particular class of synthetically useful tetronamides are the 3-halo derivatives. However, most of the available protocols for the synthesis of 3-halotetronamides are based on the direct halogenation of a preformed enaminone, employing halogenation's reagents such as ICl, NBS, Br₂, I₂, I(py)₂BF₄ and benzyltrimetylammonium dichloroiodate (BTMA.ICl₂).²

Cyclic enaminones are especially attractive in the formation of bicyclic compounds.³ In this context, tetronamides have embedded in their structure the N-C=C-C=O enaminone moiety, and recently they have emerged as a latent acyclic enaminone in the formal aza-[3+3] cycloaddition reaction.⁴ However, the synthesis of 3-halotetronamides unsubstituted at position 5 is scarcely described, being limited to the reaction of α-halotetronic acid with an amine⁵ or by direct halogenation of tetranamides.⁶ Thus, practical synthetic approaches to this class of compound would be beneficial.

In our ongoing investigation on the chemistry of enaminones,⁷ we envisioned herein a direct route to 3-bromotetronamides (4-amino-3-bromo-2(5H)furanones), which are a special class of cyclic compound because they present both aspects mentioned above, i.e., the embedded enaminone moiety, and the bromide atom at the alpha position. Besides, this study represents an approach to 3-bromotetronamides from furfural, an attractive starting material obtained from renewable biomass. In this way, the furfural derivative of choice was the 3,4-dibromofuran-2(5H)-one 1, which is easily prepared in 70% overall yield by the reaction of furfural with bromine in water, affording mucobromic acid (commercially available also).⁸ This late was reduced affording 1 in 87-96% yield, Scheme 1, employing a recently described method by Bellina and Rossi.⁹ It should be pointed out that the reactions where 1 is employed as electrophile is scarcely described, being limited to palladium cross-coupling reactions,¹⁰ or only to morpholine as nucleophile and expensive base (Cs₂CO₃).¹¹

Results and Discussion

The amination of 1 has proved to be a difficult task due to its propensity to forming polymeric material, probably thought the corresponding homoenolate, even in the presence of weak bases. Thus, complex mixtures were formed with pyrrolidine, piperidine, pyridine, 2-aminopyridine, 2-aminothiazol, benzylamine, dibenzylamine, piperazine, cyclohexylamine and ethyl 3-aminocrotonate.

To test the possibility of a direct synthesis of 3-bromotetronamides, equimolar amounts of 1 and morpholine were reacted in diverse solvents and temperatures, but the starting material 1 was always detected by TLC. Employing 2 equiv. of morpholine in diethyl ether (24 h) or acetone (2.5 h) at room temperature complex mixture was formed, but in acetone at low temperature (0 ºC) tetronamide 3a could be obtained in modest 35% yield. However, when the reaction was carried out in methanol at room temperature, excellent yield was obtained (Table 1, entry 1). With this optimal condition in hand, it was extended to a representative spectrum of aromatic amines, and yields were good to all of them, but some ortho substituted ones (entries 6, 8 and 10). Mechanistically, formation of all 3-bromotetronamides 3a-f is a nucleophilic substitution by an addition-elimination pathway.

The use of 2 equiv. of amines can be a serious drawback when expensive or no commercial amines are necessary. To circumvent this limitation, one can imagine the use of one equiv. of a trivial weak base to act as HBr scavenger. Due to the decomposition of butenolide 1 in basic medium, we investigated its stability in methanolic solution of equimolar amounts of 1 and Et₃N, Na₂CO₃ and NaHCO₃. Compound 1 was completely decomposed after 4 h to the two first bases, and after 24 h to the late. Because reaction of 1 and aromatic amines is a slow one, we choose NaHCO₃ as additive.

Fortunately, the amount of amines 2 could be reduced to 1 equiv. and comparable yields of 3 were obtained when the reaction was carried out in the presence of 1 equiv. of NaHCO₃ (entries 1, 3, 5, 7, Table 1). In general, anilines with para substituents afforded better yields and shorter reaction time than ortho substituted ones for both electron releasing and electron withdrawing groups (compare entries 3-8). Hence, a diversity of 3-bromotetronamides could be prepared, but the methodology presents some limitations, because no reaction was observed with 4-nitroaniline, diphenylaniline, 2,4-dichloroaniline and glycine, being furanone 1 quantitatively recovered.

Curiously, in the ¹H NMR spectrum of 3c, the signal of the aromatic hydrogens show up as a singlet integrated to four hydrogens, and not as the typical pair of doublets expected for para substituted aromatic rings. The structure of 3c was unambiguously confirmed by X-rays crystallography. Compounds 3a,3e and 3g also afforded single-crystals whose X-rays structures are shown in Figure 1.

During the investigation on the reactivity of butenolide 1 with benzaldehyde in Knoevenagel condition, compound 3a and 5 were obtained, and the structure of the later was corroborated by X-rays crystallography, as shown in Figure 2. Mechanistically, the formation of 3a follows the same addition-elimination pathway above mentioned, and the formation of 5 represents a three component reaction. In a control experiment, tetronamide 3a and benzaldehyde were left in the same Knoevenagel reaction condition, but the reagents were quantitatively recovered. Additionally, butenolide 1 and benzaldehyde were tentatively reacted in Knoevenagel condition with other no nucleophilic bases, being the reagents recovered or the decomposition of 1 observed. These facts ruled out 3a as the intermediate in the formation of 5, suggesting a homoaldol reaction of 1 and 4 followed by an addition-elimination and a last step of water elimination to afford 5.

In contrast of the amines' behavior with butenolide 1, which afforded tetronamides 3a-j in good yields, no reaction was observed with phenol. To gain more insight into the potential of 3-bromotetronamides 3a-j as building block, compound 3b was submitted to diverse intramolecular Mizoroki-Heck reaction conditions, but the substrate was recovered unchanged. The unique observed transformation under these condition was the debromination of the butenolide ring when dioxane was employed as solvent with compounds 3b,e, affording the two known tetronamides 6a,b,¹³ which represents a palladium catalyzed dehalogenation without a formal hydride donor font, Scheme 2. A proposed mechanism of the palladium-catalyzed dehalogenation reaction is indicated in Figure 3, which was inspired in a previously described formal hydride-free donor one,¹⁴ where DMF was employed as solvent and act as a hydride source. Thus, the intermediate formed by the insertion of palladium (0) into the C-Br bond would react with dioxane in the presence of triethylamine to yield the specie that should suffer a beta-H elimination, followed by reductive elimination of Pd⁰ from the resulting hydridopalladium complex to give C-H, Figure 3.

In conclusion, we developed a practical synthesis of 3-bromotetronamides in good yields, describing for the first time that 3,4-dibromofuran-2(5H)-one 1 can be conveniently employed as electrophile in reactions with aromatic amines, amplifying the scope of such transformation.¹¹ Efforts are underway on the application of these α-bromoenaminones in the synthesis of natural and unnatural bioactive compounds.

Experimental

Melting points were determined on a Microquímica MQAPF 301 hot plate apparatus and are uncorrected. Infrared spectra were recorded as KBr discs on a FT-IR BOMEM MB100 instrument. NMR spectra were obtained for ¹H at 300 MHz and for ¹³C at 75 MHz using a Varian Gemini 300 spectrometer. Chemical shifts are reported in ppm units downfield from reference (internal TMS).

General synthetic condition A

To a solution of 1.0 mmol of 1 in 10 mL of CH₃OH was added 2.0 mmol of amine 2. The solution was left at room temperature at the indicated time in Table 1. After this time, the solvent was evaporated and 20 mL of CHCl₃ was added, extracted with water (3 x 5 mL), and the organic layer was dried over anhydrous Na₂SO₄, filtrated and the solvent evaporated. The crude residue was recrystallized from CHCl₃/hexane affording a solid.

General synthetic condition B

To a solution of 1.0 mmol of 1 in 10 mL of CH₃OH were added 1.0 mmol of NaHCO₃ and 1.0 mmol of amine 2. The solution was left at room temperature at the indicated time in Table 1. After this time, the solvent was evaporated and 20 mL of CHCl₃ was added, extracted with water (3 x 5 mL), and the organic layer was dried over anhydrous Na₂SO₄, filtrated and the solvent evaporated. The crude residue was recrystallized from CHCl₃/hexane affording a solid.

Synthesis of 3a and 5

To a solution of 1 (0.613 g, 2.54 mmol) and benzaldehyde (0.531 g, 5 mmol) in 20 mL of methanol, was added 0.356 mL of morpholine (0.349 g, 4 mmol) under magnetic stirring at room temperature. After 16 h the solvent was evaporated and the crude residue purificated by column chromatography (hexane:ethyl acetate 4:1), affording 0.162 g (19% yield) of 5 as a yellow solid, and 0.210 g (34% yield) of yellow solid 3a after recrystallization in ethyl acetate.

Compound 3a

mp 128-129 ºC; IR (KBr) v_max/cm^-1: 1766, 1029, 990; ¹H NMR (CDCl₃) δ 3.63-3.66 (m, 4H), 3.78-3.81 (m, 5H), 4.71 (s, 2H); ¹³C NMR (CDCl₃) δ 171.41, 159.26, 72.80, 67.52, 66.17, 47.10.

Compound 5

mp 149-154 ºC; IR (KBr) v_max/cm^-1: 2867, 1742, 1727, 1621, 1450; ¹H NMR (CDCl₃) δ 3.69-3.72 (t, 4H, J 9.3 Hz), 3.85-3.88 (t, 4H, J 9.3 Hz), 6.13 (s, 1H), 7.32-7.41 (m, 3H), 7.71-7.44 (m, 2H); ¹³C NMR (CDCl₃) δ 50.85, 67.07, 85.33, 111.10, 128.80, 129.18, 130.54, 132.17, 157.11, 165.43.

Synthesis of 6a,b

A suspension of 3b,e (0.5 mmol), PdCl₂(PPh₃)₂ (0.035 g, 0.05 mmol) and triethylamine (0.15 g, 1.5 mmol) in dry, degassed dioxane was refluxed until total substrate consume (15 and 68 h for 3b and 3e, respectively). The solvent was evaporated and the crude residue purificated by column chromatography (ethyl acetate:hexane 7:3).

Compound 6a

Pale brown solid, mp 201-203 ºC (lit.¹³ 220-221 ºC); ¹H NMR (DMSO-D₆) δ 4.92 (s, 2H), 5.30 (s, 1H), 7.05 (t, 1H, J 7 Hz); 7.19 (d, 2H, J 7 Hz), 7.38 (t, 2H, J 7 Hz), 9.68 (s, 1H).

Compound 6b

Pale brown solid; ¹H NMR (CDCl₃) δ 4.94 (s, 2H), 5.19 (s, 1H), 7.05 (d, 2H, J 10 Hz); 7.21 (d, 2H, J 10 Hz), 9.60 (s, 1H).

X-ray analysis

Single-crystals of the compounds 3a,3c and 3g were mounted on a Bruker KappaCCD diffractometer, using graphite filtered Mo-Kα, single-crystals the compounds 3e and 5 were mounted on an Enraf-Nonius CAD-4 diffractometer,¹⁵ using graphite filtered Cu-Kα radiation, all using room temperature. The structure solutions were obtained by Direct Methods using ShelxS97.¹⁶ Non hydrogen atoms were refined with anisotropic displacement parameters and hydrogen atoms were refined isotropic with riding constraints to their parent atoms using ShelxL97.¹⁶ Refinement using Full-matrix least-squares on F².

Supplementary Information

CCDC 767789 (compound 5), CCDC 767791 (3g), CCDC 767790 (3e), CCDC 643308 (3c) and CCDC 643307 (3a) contains the supplementary crystallographic data for this paper. It can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone]. Supplementary data is available free of charge at http://jbcs.sbq.org.br, as PDF file.

Acknowledgments

We acknowledge the financial support of Conselho Nacional de Desenvolvimento Científico e Tecnológico/CNPq, Fundação de Amparo à Pesquisa do Estado da Bahia/FAPESB, and IFSC/USP and IF/UFF for the access to the KappaCCD. We also thank CNPQ for fellowship to C. C. O., and research fellowship to S. C.

References

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Submitted: July 22, 2010

Published online: October 26, 2010

Supplementary Information

General information

Melting points were determined on a Microquímica MQAPF 301 hot plate apparatus and are uncorrected. Infrared spectra were recorded as KBr discs on a FT-IR BOMEM MB100 instrument. NMR spectra were obtained for ¹H at 300 MHz and for ¹³C at 75 MHz using a Varian Gemini 300 spectrometer. Chemical shifts are reported in ppm units downfield from reference (internal TMS).

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Publication Dates

• Publication in this collection
  24 Mar 2011
• Date of issue
  Mar 2011

History

• Accepted
  26 Oct 2010
• Received
  22 July 2010