Alternative conditions for the synthesis of novel spiro[1,3-N , N -heterocyclic-adamantanes]

A series of new spiro[ N -heterocyclic-adamantanes] was synthesized through the reaction of 2-adamantanone with β -amino carboxamides. Depending on the chemical and physical characteristics of the starting compounds, the cyclocondensations proceeded under simple and mild (aqueous, solvent-free, ball-milling or/and microwave-assisted) conditions with no necessity for chromatographic purification of the products. The reaction was extended to leucinamide and salicylamide.


Introduction
The adamantane cage has been successfully utilized as a stable lipophilic scaffold 1 in the development of numerous lead compounds that demonstrate activity in the central nervous system. 2 The 1-adamantyl group is crucial for the antiparasitic activity of 1,2,4-trioxane derivatives, 3 and replacement of the 2-(adamantan-1-yl)acetyl group with other hydrophobic moieties abolished the anti-EboV activity of a new class of antiviral dipeptides. 4The incorporation of a spiroadamantane unit into 1,2,4-trioxanes 5 and 1,2,4,5-tetraoxanes 6 enhanced the antimalarial activity, together with low toxicity and high stability profiles both in vitro and in vivo.In the search for new analogues of adamantine and rimantadine, a number of six-membered spiroadamantane rings bearing one or two nitrogens, has been prepared.The in vivo antiviral activity of 3-piperidine derivative A against Japanese influenza A 2 was found to be approximately the same as that of 1-adamantanamine. 74-Piperidine derivative B proved to display significant anti-influenza A (H3N2) and trypanocidal activity, 8 while piperazine C likewise inhibited H3N2 influenza A virus replication. 9The (S)-enantiomer of acethydroxamic acid D was the most effective in a study of the trypanidical activities of hydroxamic acid-based derivatives. 10In a series of spiro[isoquinoline-3,2'-adamantanes], compound E emerged as a promising neurotropic candidate, and at the same time was not toxic towards normal cells. 11o the best of our knowledge, only the spiro[1,3-N,N-heterocyclic-adamantanes] F, 12 G 13 and H 14 have been synthetized previously; moreover pharmacological investigations have not been performed on such spiro ring systems.
In the series of spirocyclic adamantanes, we have focused mainly on the synthesis of spiro[quinazoline-2,2'-adamantanes] through green chemistry methodology and alternative forms of energy input.All of the products were prepared from commercially available adamantan-2one (1); 15 the spirocyclizations were carried out with αand β-amino acid derivatives in the presence of a catalytic amount of I 2 . 16

Results and Discussion
We have previously described ecofriendly methods for the preparation of quinazolin-4(1H)-ones in aqueous 17 or solvent-free medium from a 2-aminobenzamide (2a) 18 or 2-amino-benzhydrazides (2b and 2c) 19 and a number of aldehydes 20 or ketones. 21Inspired by the excellent results of the mechanochemical synthesis (e.g., 3a, Table 1, conversion ~ 99%), we decided to extend the ring closure of 1 with the reactions of a number of amides and hydrazides under either aqueous or ball-milling conditions.
The idea for our initial mechanochemical experiment stemmed from the study by Oliveira et al., 22 in which a series of hydrazones was synthetized by the ball-milling of aldehydes with hydrazines in the solid state at rt. Conversions of 85-99% were obtained, depending on the aldehyde/hydrazide used.These observations on the mechanical solvent-free and solid-state procedures led us to investigate the solid-solid reactions of equimolar amounts of hydrazides 2b and 2c with 1, catalyzed by I 2 (5 mol%) in a vibrational ball-mill.The progress of the reactions was monitored by TLC, and the conversions of the mechanochemical reactions were determined by 1 H NMR.
[°C] After grinding for 4 h, the 1 H NMR spectrum revealed that the conversion of 1 and 2b to quinazoline 3b was almost complete (95%).The use of ZrO 2 balls insteated of stainless-steel balls was essential in order to avoid the paramagnetic impurity effects in the NMR determination of the conversions of the crude products in our further mechanochemical studies. 21,24When it was necessary to eliminate I 2 from the crude products 3a-3i, a simple aqueous work-up technique was applied (Tables 1 and 2 c ). Analytically pure samples of ball-milled 3a-3i were prepared by crystallization from a suitable solvent.
For a comparison of the reactivities of 2b and 2c, the mixture of 1 and 2c were mixed in the presence of iodine at 25 Hz for 1 h.NMR analysis demonstrated the presence of hydrazone 3c in a conversion of 98%.The rearrangement of 3c to the thermodynamically favored quinazolinone 17 was not observed on heating at reflux hydrazone 3c in EtOH or in water, or on the application of microwave (MW) irradiation in the same solvents at 160 °C either without a catalyst or in the presence of I 2 or p-TSA as catalyst.It is presumed that rearrangement through the transimination of 3c did not occur because of the steric hindrance of the adamantane moiety.On the other hand, the presence of the phenyl substituent on the benzhydrazide component led to regioselective ring closure of 1 with 2b. 25 Since (cyclo)aliphatic amines are usually good nucleophiles, we extended the ball-milling methodology to the spirocyclizations of β-aminoamides 2d-2h with 1. First, a mixture of 1 and 2d was milled at 25 Hz for 1 h in the absence of the I 2 catalyst.The .1 H NMR spectrum of the reaction mixture showed that product 3d was obtained in a yield of 8-10% [Figure 2 (I)].When 5 mol% of solid I 2 was added to the mixture and the mechanical treatment was continued for an additional 1 h under the same conditions, crude 3d was formed with a conversion of 85% (Figure 2 II).The results shown in Figure 2 can be explained by the fact that I 2 promotes activation of the imine (Schiff base) in the intramolecular cyclization. Temp.
[°C] Encouraged by this result, we investigated the reactions of 1 with alicyclic amides 2e−2h and α-amino acid derivative 2i under the application of mechanical forces (entries 2−5).The reactions were complete in 2−4 h at 25 Hz, leading to powdery products; a liquid phase 27 was not observed.Surprisingly, under such reaction conditions the N-methylamide derivatives 2a, 2d and 2e did not give spirocyclic products.During the ball-milling procedure, melt mixtures were seen; perhaps because of the steric effects of the methyl group, mainly imine formation occurred.
In the light of our work on spirocyclization in/on water [17][18][19] and reported aqueous protocols for the synthesis of nitrogen heterocycles by several research groups, [32][33][34] we were motivated to attempt the preparation of 3a-3h in aqueous medium.For the condensation reactions followed by intramolecular cyclizations, an I 2 /KI catalyst was used. 21,26e first re-examined the reaction of 1 with 2a, after the addition of 1 mol% (0.5 mL of 1% aqueous solution) of I 2 /KI 35 to a stirred suspension of stoichiometric amounts (2 mmol) of 1 and 2a in water (10 mL).After stirring for 24 h at rt, 3a was filtered off in a yield of 86%.The spectroscopic data and the mp of 3a corresponded well with the literature values. 21ble 3. Synthesis of adamantane derivatives 3a-3i in aqueous media (ii)
[°C]  (ii) A mixture of 2 mmol of each of the reactants and 0.5 mL of 1% I 2 /KI solution was stirred in 10 mL (3a-3c) or in 3 mL (3d-3i) of water for 24 h at rt.The precipitates were filtered off, washed with 3 mL of water, and dried; a isolated yields from aqueous suspension; b melting points of filtered and dried products.
We further employed this ecofriendly protocol for the preparation of 3b and 3c (Table 3, entries 1-3).It is important to note that condensations of 1 with the more water-soluble (cyclo)alkyl amides 2d-2h were carried out in 3 mL of water (Entries 4-8).The moderate yield and longer reaction time of 3i can be explained by the higher solubilities of 2i and 3i in water.The 1 H NMR data on the crude products isolated from aqueous media corresponded well with those on the analytically pure samples of 3a-3i.
Heterocycle 3j was synthesized in an analogous manner to spiro[cyclohexane-1,2'pyrido [2,3-d]pyrimidine] 38 through the use of MW irradiation.When a mixture of 1 and 2j with 1 mol% of I 2 was irradiated (100 W) in a sealed vial, 3j was obtained in good yield with excellent purity (Entry 1).Melzig reported the synthesis of photochromic 3k when a reaction mixture of 1, 2k and polyphosphate ethyl ester was refluxed in CHCl 3 .The pale-yellow crystalline product melted at 220-225 °C, 39 but its IR and NMR data were not published.In view of the lack of a spectroscopic analysis, we decided to attempt to prepare 3k by a greener procedure.An equimolar ratio of 1 and 2k with 1 mol% of I 2 was refluxed in EtOH under conventional heating for 8 h.Water was added to the cooled solution, and 3k separated out as a colourless precipitate in a yield of 71%.For a route to the preparation of biologically and pharmaceutically important pyrazolo [3,4d]pyrimidines 40 with avoidance of the formation of a pyrazolopyridine, we used 2l rather than oaminopyrazolcarbonitrile. 41 Methods (i) and (ii) led to insufficient yields, and we catalyzed the MW-induced reaction of 1 with 2l with various Lewis acids and solvents.We found that 1.3 equiv. of AlCl 3 in DCM was the best of the traditional Lewis acids.When the reaction was carried out at 110 °C (60 W) for 2 h, crude 3l was isolated in a yield of 81%.
In conclusion, various conditions have been examined for the condensation of 2-adamantanone with hydrazides or amides 2a-2l, including solvent-free ball-milling, in/on water or in EtOH solution, and MW irradiation in EtOH solution or in DCM.The relative reactivities, solubilities in water and melting points of the nucleophiles all influenced the above protocols.These methods have a number of advantages over other methods: the reaction techniques are very simple, and the syntheses proceed under mild reaction conditions without the need for costly catalysts and chromatographic purification.

Experimental Section
General.The reaction courses and the purities of products were monitored by TLC. 1 H NMR spectra of the dried crude mixtures were recorded in DMSO-d 6 or CDCl 3 to confirm the conversion to 3a-3i.Analytically pure samples of 3a-3l were prepared by crystallization and their 1 H NMR (400 Hz) and 13 C NMR (100 MHz) spectra were recorded on a Bruker Avance DRX 400 spectrometer with TMS as internal reference.Melting points were determined on a Kofler apparatus.FT-IR spectra were recorded in KBr pellets on a Perkin-Elmer 100 FT-IR spectrometer.Elemental analyses were carried out on a Perkin-Elmer 2400 elemental analyzer.The MW-promoted reactions were performed in sealed reaction vials (10 mL) through use of the MW reactor (CEM, Discover) cavity.The ball-milling experiments were carried out in a Retsch MM400 mixer mill with two ZrO 2 balls 15 mm in diameter in a stainless-steel jar (25 mL) at 25 Hz at rt.

Preparation of spiroadamantanes (3a,3b and 3d-3l) and hydrazone (3c)
A. 2b-2i (2.0 mmol), 1 (0.30 g, 2.0 mmol), 25 mg (5 mol%) of I 2 and two ZrO 2 balls 15 mm in diameter were placed in a stainless-steel jar.The vessel was vibrated at 25 Hz for the appropriate length of time.The reaction progress was monitored by TLC.The products were recovered as solids (directly from the jar) and dried.The conversions to 3b-3i were determined by 1 H NMR. In the aqueous work-up procedure, 2 or 3 mL of 2% Na 2 S 2 O 5 solution and 3 or 5 mL of water were added to the reaction mixture in the jar.The aqueous suspension was mixed at 25 Hz for 5 min, filtered off, washed with water (3 or 5 mL) and dried.The isolated yields and melting points of crude 3b-3i were determined.Analytically pure samples of compounds 3b-3i were recrystallized from a suitable solvent.B. To a stirred mixture of 1 (0.30 g, 2.0 mmol) in 0.5 mL of 1% I 2 /KI (1 g of I 2 and 1.6 g of KI in 100 mL of water) and 3-10 mL of water in a round-bottomed flask (25 mL), 2a-2c (2 mmol) was added in portions.The flask was sealed with a Teflon cap.After vigorous stirring at rt for 24 h, 3a-3i precipitated.The product was filtered off, washed with water (3 mL) and dried.The purities of 3a-3i were established by 1 H NMR measurements.C. A stirred mixture of 5 mg (1 mol%) of I 2 , 2k (0.27 g, 2 mmol) and 1 (0.30 g, 2 mmol) in EtOH (5 mL) was refluxed for 8 h.To the cooled mixture, 5 mL of water was added.The solid product was separated by filtration and dried.For 3j, I 2 (5 mg, 1 mol%), 2j (0.28 g, 2 mmol) and 1 (0.30 g, 2 mmol) were placed in a MW test-tube (10 mL) (which was subsequently sealed with a Teflon cap) which contained a magnetic stirrer and EtOH (2 mL).The test-tube was placed in the CEM Discover MW reactor.The solution was irradiated for 6 h at 160 °C (100 W).To the cooled solution, water (4 mL) was added, and the precipitated product was filtered off and dried.The melting points of both the crude and the recrystallized 3j and 3k were determined.D. 0.30 g (1.5 mmol) of 2l, 0.23 g (1.5 mmol) of 1 and 0.26 g (2 mmol) of AlCl 3 were placed in a MW test-tube (10 mL) (sealed with a Teflon cap) containing a magnetic stirrer and 2 mL of DCM.The test-tube was placed in the MW reactor (CEM, Discover) cavity, microwaved at 110 °C (60 W) for 2 h and then cooled to room temperature.The reaction mixture was poured onto water (50 mL) and extracted with DCM (3 × 10 mL), and the extract was evaporated in vacuo.The residue was recrystallized from EtOAc.Analytical and spectroscopic data on 3b-3l are given below.

Figure 2 . 1 H
Figure2.1  H NMR spectra of (I) a catalyst-free reaction mixture of 2d and 1 after ball-milling for 1 h, (II) the reaction mixture after the addition of 5 mol% I 2 followed by mechanochemical treatment for 1 h, and (III) the mixture of I 2 , 1 and 2d after milling for 2 h.
216) f (i) 2 mmol of reactants, 25 mg (5 mol%) of I 2 , stainless-steel jar (25 mL) with two ZrO 2 balls (15 mm) at 25 Hz; a on the basis of 1 H NMR; b from aqueous suspension; c isolated yields from aqueous work-up (2 mL of 2% Na 2 S 2 O 5 and 3 mL of water, 25 Hz for 5 min, filtration, and washing with 3 mL of water); d from EtOAc; e from EtOH; f from i-Pr 2 O.

Table 4 .
Synthesis of adamantane derivatives 3j-3l in EtOH (iii) or in DCM (iv) (iii) A mixture of 2 mmol of each of the reactants, and 5 mg (1 mol%) of I 2 was irradiated or refluxed in EtOH; (iv) a mixture of 1.5 mmol of 1, 2l and AlCl 3 (2 mmol), MW in DCM; a isolated yield of crude products; b mp-s from EtOH-H 2 O; c from EtOAc; d from EtOH.