Synthesis of some Acetylenic Morpholine Derivatives via Grignard Reactions

New derivatives for acetylenic morpholine were prepared. Acetylenic amine (Npropargyl morpholine 1) was synthesized by the reaction of propargyl bromide with morpholine in aqueous medium. This compound was used as a synthone for hydroxy acetylenic compounds. Compound (1) was converted to the Grignard reagent (2) by the reaction with methyl magnesium iodide. The reaction of the intermediate (2) with different carbonyl compounds afforded hydroxy acetylenic compound (3). Finally, prepared Npropargyl ether morpholino (4a-i) was prepared by the reaction of the hydroxy acetylenic compound with chloro acetanilide, benzyl chloride via willamson reaction. The structure of the synthesized compounds has been elucidated by the available physical and spectral methods.

Antimicrobial activity (Chakrabothy, 2008), antimaterial activity (Eyong et al., 2006), as solvent in chemical reactions (George, 1996).The Grignard reaction is one of the important reactions in organic chemistry is one where a C-C bond is formed (Clevenger and Kathleen, 2007), the Grignard reagent acts as a catalyst (Gerard et al., 2007), (Terao and kamba, 2008), Grignard reagents are key building blocks for many pharmaceutical and synthesis drug (Das et al., 1993), also Grignard reagent is used to prepare tricyclic drug (Oko et al., 2001) and synthesis heterocyclic and 5-membered ring compounds (Baumann et al., 2011).

EXPERIMENTAL
Melting points were determined on an electrothermal 9300 melting point apparatus and were uncorrected.The IR spectra were determined as potassium bromide disk on Pye Unicam SP.2000 FTIR spectrophotometer.The UV spectra were recorded on Shimadzu (UV-160) UV-visible spectrophotometer using CHCl 3 as a solvent.CHN micro analyses were achieved by costech instruments elemental combustion system model 4010 international S.P.A.

Preparation of N-propargyl morpholine (1)(Mohammed, 1979):
Propargyl bromide (0.1 mole, 2g) was added solution of (0.2 mole, 1 g) morpholine in 30 ml of water with ice-cooled with stirred, the mixture was stirred for one hour at 50 ºC, the upper organic layer was separated and the aqueous layer was extracted with ether (3 ×30 ml) and the ether was evaporated under reduced pressure to give a colourless liquid, with boiling point 175 ºC in 70% yield, the IR spectrum (υ) showed the following characteristic bands: 3340 cm -1 due to ≡C-H, 2110 cm -1 for C≡C; 1455 cm -1 for C-N and 1230 cm -1 due to C-O.
The mixture was cooled to 0ºC in ice bath and dry benzene (25 ml) and aniline (2 ml, 0.033 mole) were added dropwise with shaking.The mixture was refluxed for 30 min, washed with cold water, and made alkaline with 10%, sodium hydroxide.The precipitate was filtered, washed with water and recrystalized from methanol-water to obtain the desired product as white colour crystals of 72%.Yield, mp 132-134 ºC. the IR υC=O 1685 cm -1 , υN-H 3290, λmax (CHCl 3 ) 262 nm.

Preparation of N-(1,1-disubstituted-2-butyl-ol-4-yl) morpholine (3a-i) (Zakariea and radeef, 1984).
A solution of methyl iodide (0.063 mole, 5 ml) in ether (10 ml) was added to magnesium powder (0.02 mole 0.5 g) and an iodine crystal.After magnesium was completely disappeared, the solution N-propargyl morpholine (0.02, 5 ml) in dry peroxide tetrahydrofuran (10 ml) was then added dropwise, the mixture was refluxed for 30 min., cooled and the solution of carbonyl compound (0.01 mole) in 5 ml of dry ether was added.The mixture was refluxed for 15 min., cooled and added to 10 g of crushed ice.The mixture was acidified with 10% hydrochloric acid (3 ml) and the organic layer was separated and washed, then dried over anhydrous magnesium sulfate.The evaporation of the solvent afford hydroxy acetylenic morpholine compound, as solid the precipitate was recrystallized from benzene, the physical and the spectral data of compounds (3a-i) are listed in Table (1 and 2).

Preparation of N-(1,1-disubstituted-2-propargyl ether) morpholine(4a-f) (sheat and Ali, 2006).
Sodium (0.4 g) was dissolved in absolute ethanol (25 ml). the solution was cooled and (0.33mole) hydroxy acetylenic compound and (0.048 mole) chloro acetanilide or benzyl chloride were added slowly.The reaction mixture was refluxed with stirring for 3 hours and the cooled in an ice bath .The formed precipitate was filtered, washed and recrystallized from methanol, the physical and spectral data of compounds (4a-f) are listed in Table (3 and 4).

RESULT AND DISCUSSION
Many compounds comprising both amino and ethyl functions have been reported to possess potential pharmacological values (Sharb and Jawad, 2002).Also the ether function has a pharmacological and medical value (Sheat and Ali, 2005).Therefore the acetylenic N-morpholine ether compound (4a-i) were synthesized by three stages, the first is the formation of N-propargyl morpholine (1) which accomplished simple nucleophilic substitution reaction.The second stage is the formation of the hydroxyl acetylenic morpholine compounds (3a-i) scheme (1) and the third stage is the formation of the acetylenic N-morpholine ether compounds (4a-f) scheme (1).
The synthesis of hydroxy acetylenic compounds (3a-i) were accomplished in two steps.The first is reaction of methyl magnesium iodide with N-propargyl morpholine to form N-propargyl morpholino magnesium iodide (2), which is used immediately to prepare compound (3a-i) by reaction with various carbonyl compounds.The synthesized acetylenic morpholine derivatives have been investigated according to their physical an a spectroscopic data (IR,UV) and CHN microanalysis.The other supporting evidence for the formation of compounds (3a-i) is the classifical test about the terminal acetylenic hydrogen which was obtained in the negative Tollen's test.
The IR spectra of hydroxy acetylenic compound (3a-i) indicated the presence of the characteristic absorption at (2157-2076cm -1 ) attributed to the (C≡C) bond stretching, at 3493-3297cm -1 related to the O-H bond stretching.The stretching vibration of the terminal acetylenic hydrogen in compound (1) at 3340 cm -1 was disappeared in the IR spectra of compound (3a-i).
In UV spectra of the synthesized compounds (3a-i) showed bathochromic shift (λmax 320-242 nm) due to the conjugation effect on the electronic transition (n π*) as shown in Table (2).
UV. Spectra of acetylenic N-morpholine ether compounds (4a-f) showed a bathochromic shift in λmax (331-220) nm due to the conjugation effect on the electronic transition (n π*) as showed in