Microwave-assisted synthesis of cycloalkanespirohydantoins and piperidinespirohydantoins as precursors of restricted  -amino acids

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Introduction
The imidazolidine-2,4-dione ring or hydantoin has been extensively studied.This five-membered heterocyclic ring containing a reactive cyclic urea core is present in a wide range of biologically active compounds. 1For example, Phenetoin 1 (5,5-diphenylhydantoin) 2 was synthesized in 1908 and is the drug of choice for the treatment of certain types of epileptic seizures. 3The biological activities that have shown some of their derivatives are mainly as anticonvulsant and antimuscarinic, antiviral, antiulcer and antiarrythmic agents.Also, penicillamine hydantoin 2, a prodrug form of D-penicillamine, and its thiazolidine-2,4-dione derivatives have shown insulinotropic effects in INS-1 cells. 4Some hydantoin compounds are potent inhibitors of muscle and liver glycogen phosphorylase, metalloproteinase and HIV protease enzymes.Hydantoins are also used as herbicides, antibiotics and as DNA binding compounds. 5The observed activities arise from the hydantoin heterocycle, but the different ligands attached to it are determinant in these properties. 6he first synthesis of cycloalkanespirohydantoins was developed by Bucherer and Lieb in 1934  by the reaction of a cycloalkanone with sodium cyanide and ammonium carbonate refluxed in a mixture of ethanol/water. 7Recently, Naydoneva and coworkers reported the synthesis of a series of cycloalkanespirohydantoins 3 with n = 0, 1, 2, 3, and 7 and yields of 89-95% using the Bucherer-Lieb conditions. 8However, there is an inconvenience for this synthetic method from an experimental point of view.The use of cyanide ion and the high temperature required to obtain higher yields in the cyclization process can promote hydrogen cyanide and must be controlled to prevent the risk of intoxication or contamination.
In this sense, microwave irradiation in chemical reactions has been recognized for increased reaction rates, better yields and cleaner products. 9,10Additionally, working with sealed vessels for shorter times reduces the exposure to toxic substances.Several methods for the preparation of diverse hydantoins have been reported using microwave-assisted conditions, 11 but to the best of our knowledge, the synthesis of cycloalkanespirohydantoins 3 and piperidinespirohydantoins 4 has not been reported under microwave-assisted conditions.
Restricted -amino acids, i.e. 1-aminocycloalkane-1-carboxylic acids with three, five, or sixmembered rings have attracted considerable attention due to the variety of synthetic applications 12 and the conformational restriction induced for these molecules when they are incorporated into peptides reducing the flexibility of peptide chains. 13In this sense, spirohydantoins are important intermediates in the synthesis of restricted -amino acids as well as in the evaluation of conformational properties of rigid cyclic glutamic acid analogues. 14For example, the first synthesis of 1-aminocyclopropanecarboxylic acid 5 reported in 1922, 15 was accomplished by alkaline hydrolysis of cyclopropanespirohydantoin 6, which was obtained by Hofmann degradation of the amide functionality in cyclopropane-1,1-dicarboxamide.Treatment of the resulting hydantoic acid 7 with nitrous acid furnished carbamic acid 8, which upon spontaneous loss of carbon dioxide formed aminocyclopropanecarboxylic acid 5 in 60% yield (Scheme 1).Scheme 1.First synthesis of 1-aminocyclopropanecarboxylic acid 5.
The traditional synthetic method for almost all restricted amino acids includes the conversion of a ketone into spirohydantoins via the classical Bucherer-Bergs reaction.Hydrolysis of spirohydantoins leads to crude amino carboxylic acids. 16The same methodology is used for the synthesis of 1-aminocyclobutane carboxylic acid.The most common approaches include the Strecker synthesis starting from cyclobutanone. 17n recent years, the cycloalkanespirohydantoins 3 were used as synthetic intermediates to generate restricted -amino acids in mild conditions. 18The Bucherer-Berg approach is still the most convenient method to prepare simple restricted -amino acids in good yields. 19

Results and Discussion
We report the synthesis of cycloalkanespirohydantoins 3 and piperidinespirohydantoins 4 under microwave irradiation.Figure 1 depicts the study of yields for spirohydantoin 3b depending on time and temperature.The best yields were obtained at 8 minutes for all temperatures; longer irradiation lowers the yields.The higher yields were obtained between 110 and 130 °C; yields were moderate at lower temperatures and poor at higher temperatures.Similar results were observed for the other spirohydantoins.At the reaction time of 8 min, the maximum yield for spirohydantoins 3b,c was found at 120 °C (Figure 2); for spirohydantoin 3d the yield was 68% between 100-130 °C, but increased to 97% at 140 °C (Figure 2).At lower temperatures yields were low; higher temperatures caused decomposition.For the synthesis of cylcloalkanespirohydantoins 3, the cycloalkanones 9a-f were treated with potassium cyanide and ammonium carbonate under thermal and microwave irradiation conditions (Table 1).Under thermal conditions, low yields (16-59%) were obtained with five-and sixmembered cycloalkanones (entries 1-4), while with seven-and eight-membered cyclo-alkanones, the yields increased to 87 and 100%, respectively (entries 5, 6).
The same reactions under microwave irradiation gave the opposite result: higher yields were obtained with five-and six-membered cycloalkanones (77-97%), and lower yields from seven-and eight-membered cycloalkanones (50 and 85%, respectively).Moreover, a methyl group at C2 of the cyclohexanone in 9c lowers the electrophilicity of the carbonyl group more than a methyl group in position C3 as in 9d.Also, steric hindrance by the methyl group at C2 in 9c may explain the low yield of 3c as compared to that of 3d.
Compounds 3c and 3d are expected to form a mixture of diastereomers (-form A and -form B, Figure 3), but only one stereoisomer was apparent by NMR.It is well documented that the-form A of hydantoins predominates when prepared from substituted cycloalkanones by the Bucherer synthesis, whereas the -isomer B predominates when the Strecker synthesis is used. 21It is generally assumed that alkyl-substituted cycloalkanones form exclusively the -form of cycloalkanespirohydantoins. 22,23his is confirmed by the ORTEP structure of spirohydantoin 3d obtained by X-ray analysis (Table 2).Figure 4 shows the X-ray diffraction structures; Table 3 gives the geometry of the intermolecular hydrogen bonds.Symmetry transformations used to generate equivalent atoms: #1 -x,-y+2,-z #2 -x,-y+2,-z+1.
Under thermal conditions, piperidones 10a-c were treated with KCN and (NH4)2CO3 to give moderate yields of piperidinespirohydantoins 4a-c (Table 4).Piperidinespirohydantoins 4a-c were obtained by maintaining the time at 8 min at different temperatures (Figure 5); maximum yields were obtained at 120, 140, and 130 °C, respectively (Table 4).Under microwave irradiation conditions spirohydantoin 4c was obtained quantitatively under same conditions.Finally, cycloalkanespirohydantoins 3a-e were converted into restricted amino acids 12 by protecting with di-tert-butyl dicarbonate to obtain N,N'-diprotected spirohydantoins 11a-e, which were hydrolyzed under basic conditions followed by strong acidification (Scheme 3).Scheme 3. Synthesis of restricted amino acids 12 from cycloalkanepirohydantoins 3.
Hydantoins require harsh conditions for hydrolysis, thus compromising the ability to generate side-chain protected polyfunctional amino acids.This problem was partially overcome by Rebek and coworkers, 24 who discovered that N,N'-bis(tert-butyloxycarbonyl)hydantoins can be hydrolyzed under milder conditions.
Without prior isolation, compounds 11 were hydrolyzed in a biphasic mixture of THF and aqueous 2.0 M KOH solution at room temperature to promote the clean separation of the restricted amino carboxylate 12 (in the aqueous phase) from the hydrolysis byproduct di-tertbutyliminodicarboxylate (in the THF layer).
Amino acids 12a-c were obtained in quantitative yields, while the -amino acids 12d and 12e gave 80% and 89% yields, respectively (Table 5).The identity of the restricted -amino acids 12 was confirmed by NMR and by electrospray ionization mass spectrometry (ESIMS).

Synthesis of hydantoins (3) and (4) under microwave conditions. General method A
10 mL pressure-rated vial was charged with the ketone (1.0 equiv), ammonium carbonate (2.15 equiv), methanol (2 mL), and deionised water (1 mL).The mixture was stirred at room temperature until the solid was dissolved.A solution of potassium cyanide was added (2.10 equiv) in water (1 mL).The vial was sealed and irradiated at 100 watts for 8 min to rise to the desired temperature.The conversion of cycloalkanone into spirohydantoin was monitored by IR.Excess of solvent was eliminated under reduced pressure and the yellow solid was washed with deionised water (4 × 25 mL).The product was dried at reduced pressure to obtain the pure spirohydantoin.

1-Aminocyclopentanecarboxylic acid (12a). Typical procedure
A round bottom flask equipped with an argon inlet adapter, glass stopper and an overhead mechanical stirrer was charged with a suspension of the 1,3-diazaspiro[4.5]decane-2,4-dione3a (1.0 g, 6 mmol) in 30 mL of dry THF. 24,25Triethylamine (0.60 g, 6 mmol) was added in one portion and the resulting white suspension was stirred for 30 min.di-tert-butyl dicarbonate (6.5 g, 29 mmol) was added dropwise, followed by 4-dimethylaminopyridine (DMAP) (7.08 mg, 0.06 mmol).Six additional portions of DMAP were added at 12 h intervals during the course of the reaction.The reaction mixture was stirred vigorously for 72 h.Then, potassium hydroxide solution (2.0 M, 30 mL) was added in one portion.The reaction mixture was stirred for 6 h and then poured into a 125 mL separatory funnel.The layers were allowed to separate over 45 min, and the aqueous layer was then drained into a 250-mL round-bottomed flask.This solution was cooled to 0 °C, the pH was adjusted to 8.0 by the slow addition of 6.0 N HCl solution.The resulting mixture was further acidified to pH 6.5 by slow addition of 2.0 N HCl solution.The white precipitate, which appeared was collected by filtration on a Buchner funnel, and the filtrate was concentrated to a volume of 60 mL to furnish additional precipitate, which was collected by filtration.The portions of white solid were combined, dried at room temperature under reduced pressure to obtain the -amino acid 12a as a pure white solid (0.77 g, 6.0 mmol, ~99%); mp 300 °C, lit. 19

Figure 1 .
Figure 1.Study of the time dependence of yields for spirohydantoins 3.

Figure 2 .
Figure 2. Study of temperature dependence of yields for spirohydantoins 3.

Figure 5 .
Figure 5. Study of temperature and yields for spirohydantoins 4.

Table 1 .
Synthesis of cycloalkanespirohydantoins 3 from cycloalkanones 9 a Obtained at classic Bucherer-Berg condition. 20b Optimum temperature for microwave assisted synthesis.c Conditions of synthesis by microwave: 8 min, 100 Watts.

Table 5 .
13elds of restricted amino acids 12 All reagents were used in the highest quality available without further purification.The solvents for column chromatography were used as obtained from commercial suppliers.Infrared spectra (FTIR) were recorded on a Perkin Elmer FT-IR 1600 spectrophotometer.1Hand13CNMR spectra (at 200 and 50 MHz, respectively) of CDCl3 solutions with TMS as internal standard were recorded on a Varian Mercury 200 MHz Spectrometer.Liquid chromatograms were obtained on an Agilent 1100 Series LC with a reverse phase ZORBAX s-C18 column (5 mm, 3 x 150 mm) and MSD Trap.Electrospray ionization mass spectra (ESIMS) were obtained with an ion trap.HRMS were obtained in an Agilent LCTOF (2006), a high resolution TOF analyzer with Windows XP based OS and APCI/ESI ionization.Melting points were obtained with an Electrothermal 88629 apparatus.Microwave assisted synthesis was carried out in a CEM Discover TM Focused Synthesizer.