GB2258653A - Crystalline lithium di-isopropylamide and preparation therof - Google Patents

Abstract

The invention relates to a monoclinic crystalline lithium di-isopropylamide (LDA), wherein the crystal structure comprises a polymeric LDA structure consisting of a helical backbone of alternating 2 co-ordinate Li<+> centres and substantially tetrahedral, 4 co-ordinate N<+> centres, each 2 co-ordinate Li<+> centre being joined to two 4 coordinate N<+> centres, thereby to make up a series of asymmetrical, substantially linear N-Li-N units forming the backbone of the polymer, and to which are attached via the said N-atoms the isopropyl groups grouped in pairs extending radially outward from the core of the helix. The crystalline (LDA) is obtained by crystallising LDA from solution in the presence of a Lewis base.

Description

METHOD FOR THE PREPARATION OF CRYSTALLINE LITHIUM DIISOPROPYbAMIDE This invention concerns a novel method for the production of crystalline lithium diisopropylamide (LDA).

LDA is an extremely important chemical reagent and is extensively used in organic syntheses as a reagent to effect proton abstraction.

Existing methods for the production of LDA by the reaction of a lithium alkyl, such as n-butyllithium or t-butyllithium, with diisopropylamine are disadvantageous in that the product LDA is a highly pyrophoric, microcrystalline material, with extremely low solubility in hydrocarbon solvents, which restricts its utility and purification by conventional recrystallisation procedures.

In accordance with the present invention, a method of recrystallising LDA has been found which yie]ds a macrocrystalline form of LDA which, although still sensitive to atmospheric moisture and oxygen, is substantially non-pyrophoric in the form as isolated, i.e.

in macrocrystalline form.

This method comprises suspending microcrystalline LDA in a hydrocarbon solvent, preferably n-hexane, containing an organic nitr-ogen-containing donor 1 igand (Lewis base), eg.

tetramethylethylenediamine (TMEDA), heating the suspension under an inert atmosphere (argon, nitrogen etc) to obtain a solution of LDA in the hydrocarbon solvent and cooling the solution to re-precipitate the iDA. Surprisingly, the IDA re-precipitates in a macro-crystalline fonn with litt.le or no complex formation with the Lewis base.

In one technique, the LDA may be for-med in~situ by the reaction of a lithium alkyl with diisopropylamine in the presence of the suspension medium, thereby to form an initial LDA precipitate, which is then redissolved and recryst:allised by adding the donor i igand to the reaction mixture.

Alternatively, the macrocrystalline LDA may be prepared by reacting a lithium alkyl with diisopropylamine in a hydrocarbon solvent, the reaction being carried out under an inert atmosphere in the presence of the Lewis base, and cooling the reaction mixture to precipitate the product LDA.

In either method, the product LDA crystals may be recovered from the mother liquor by filtration, washed with fresh solvent and dried, preferably in vacuo.

As the organic solvent, a variety of different hydrocarbons may be used both aliphatic and aromatic. Preferred are aliphatic straight or branched chain, saturated hydrocarbons such as n-hexane.

As the Lewis base TMEDA is preferred, but other nitrogen containing donor ligands (Lewis base) known in the art may also be used.

The proportion of Lewis base present in the reaction mixture is not narrowly critical and amounts may range from about equimolar, (relative to I.DA) or less, to a 5:1 molar excess or more. Preferably the molar proportion of Lewis base to LDA is from about 1:1 to about 2:1.

EXAMPLE 1 10 mniol of t-butyllithium were reacted with 10 mmol of diisopropylamine in n-hexane at 295 K under an inert atmosphere of argon. A conventional powdery deposit of lithium diisopropylamide was obtained. 20 mmol TMEDA were then added to the reaction mixture without further separation of the LDA precipitate from the mother liquor, and the mixture, still under argon, heated gently until the LDA powder redissolved.

Following dissolution of the LDA crystals, the reaction mixture was cooled by refrigeration for 24 hours to provide weti formed, almost colourless (but with a slight brown tinge) crystals of I.,DA, yield 59%, based on t-butyllithium consumed.

'H NMR spectroscopic analysis of the crystals showed only traces of TMEDA and diisopropylamine in the crystalline product.

X-ray diffraction data confirms that the product is an uncomplexed LDA polymer, which in the solid phase adopts a helical geometry with backbone of near linear N-Li-N units in which the lithium shows a 2-co-ordination and the nitrogen a 4-coordination, with four such units to each turn of the helix.

The detailed crystal structure of the polymeric LDA is illustrated in the accompanying drawing, wherein the hydrogen atoms have been omitted for the sake of clar-ity. In this structure each 2co-ordinate Lit centre is joined by one short bond (ax.1.937.X) and one longer bond (av.1.9570) to two substantially tetrahedral, 4 co-ordinate N-centres making up a series of asymmetrical substantially linear, N Li-N units (av. N-Li-N bond angle 176") forming the backbone of the polymer. Each 360 turn of the helix comprises four such units with a repeat distance along the helix of 9.567.

The bulky isopropyl groups are attached in pairs to the nitrogen atoms forming the backbone of the polymer and project radially outward from the core of the helix.

The centrosymmetric crystal structure comprises equal numbers of left handed and right handed helices, the drawing illustrating the right handed helix.

Other Crystal data: C6HliNLi, M = 107.1,monoclinic, P21/n, a = 9.146(3), b = 9.567(3), c = 17.740(7)A, ss = 92.91(3)R, V 1550. 4 , Z = 8, Dt = 0.918 g cm-3 \(CuKa) = 1.54184A, ii = 0.354 mm -l F(000) = 480. Measurements were made at 240 K on a Stoe-Siemens diffractometer with an Oxford Cryostream cooler from a crystal of size 0.50 X 0.58 X 0.61 mm. 1880 unique observed reflections were used for structure determination by direct methods and least-squares refinement on F, with weighting w = 1/o2(F).

H atoms were constrained, other atoms were assigned anisotropic thermal parameters. At convergence, R = 0.0562, R1 = 0.0673, goodness of fit = 1.01 for 170 parameters. All features in a final difference synthesis were within +0.18 -3.

EXAMPLE 2 Similar macrocrystalline LDA was obtained by adding diisopropylamine (20 mmol) of n-butyllithium (20 mmol) in solution in cyclohexane (10 ml) under nitrogen. tipon addition of TMI.DA (20 mmol) the initially clear solution became cloudy, but clarified after heating gently for 14 to 15 minutes. After filtering, the product LDA solution was cooled by refrigeration (-12"C) for 24 hours. A first crop (58% yield) of macrocrystalline transparent, colourless LDA crystals were obtained showing the same NMR spectrum as described above.

The stability and reactivity of the novel macrocrystalline LDA prepared as above was compared with that of a commercially available microcrystalline LDA (source: Aldrich).

Reactivity: Selective Enolate Formation Using Lithium Dialkylamides in the Presence of Trimethylsilyl Chloride (Corey Reaction: Tetrahedron Lett. 25. 495.1984) To a solution of LDA (5.5 mmol) in THF (7 ml) at -78 C were added a solution of trimethylsilyl chloride (TMSCl) in THF (7 ml), followed by the dropwise addition of 2-octanone (5 mmol) in THF (7 ml). After ca. 1 minute, triethylamine (50 to 70 mmol) was added. The cooling bath was removed and aqueous NaHCO3 added. The product was extracted into petroleum ether and the combined organic extracts washed, first with water and then with 0.1M nitric acid. Drying over sodium sulphate and concentration in vacuo afforded a mixture of kinetic (I) and thermodynamic (II) silyl and ethers (SEE) which was analysed by GC/MS.

The reaction involved (the Corey Reaction) is as follows:

2-octanone SEE (I) kinetic (II) thermodynamic The product analysis was as follows:

Run Reagent Age Age K:T Ratio 1 SEE:SM ratio2 1 LDA (in situ)3 LDA I Fresh 93.5:6.5 2 LDA (in situ)3 LDA Fresh 93:7 97:3 3 LDA (in situ)3 LDA Fresh 90:10 > 99:15 4 5 Macrocrystalline4 LDA 1 week 89:11 95::56 6 Macrocrystalline4 LDA 2 months 92.2:7.8 90.1:9.97 I 7 Macrocrystalline- LDA 2 months 93.9:6.1 86.6:13.4 Footnotes: 1 mole ratio kinetic:thermodynamic SEE.

2 mole ratio SEE:starting material.

3 prepared in situ by adding diisopropylamine to n butyllithium in THF.

4 product of Example 2.

1.5 eq LDA, reverse addition, product work up with EtZO and MgSO.

6 reverse addition, Et2O plus MgSOi work up.

t reverse addition, Et20 work up.

Runs 4 to 7 show that the reactivity and selectivity of the macrocrystalline LDA of this invention is maintained substantially unchanged over periods up to 2 months, and is comparable with that of freshly prepared LDA.

ReactiyAy: Conversion of 2-Methylcyclohexanone into the Corresponding Lithium Enolate and Subsequent Trimethylsilylation (Brandsma Reaction: Preparative Polar Organic Metallic Chemistry 2, pub. Springer-Verlag 1990, p 190) To a solution of LDA (11 mmol) in THF (7 ml) at -78 C was added a solution of 2-methylcyclohexanone (10 mmol) in THF (2 ml) dropwise over 5 to 10 minutes. The cooling bath was removed and the temperatul-e was allowed to rise to -50aC. TMSCl (13 roniol) was added and the temperature was allowed to rise to -15 C.Triethylamine (4.1 mmol) was added and stirring was continued for 5 mintil es at RT. The reaction mixture was poured into ice water (20 ml) and then the product wds extracted into hexane (3 x 20 ml). The combined organic extracts wee washed with saturated ammonium chloride solution and dried over MgSO4.

The products were analysed by GC/MS.

The reaction involved is as follows:

kinetic thermodynamic (I) (II) The product analysis was as follows:

Run Reagent Age K:T Ratio SEE:SM 1 LDA (in situ) Fresh 94:6 2 LDA (in situ) Fresh 94.9:5.1 96.5:3.5 3 LDA (in situ)3 Fresh 95.6:4.4 98.6:1.44 4 Macrocrystalline LDA5 3 days 95.9:4.1 79.7:20.36 5 Macrocrystalline LDA5 3 days 95.4:4.6 73.9:26.16 6 Macrocrystalline LDA5 1 months 93.5:6.5 60.2:39.8 Footnotes: 1 molar ratio kinetic (I)::thermodynamic (II).

2 molar ratio SEE:Starting Material.

3 prepared by adding diisopropylamine to n-butyllithium in THF.

alternative method: after- addition of methylcyclohexanone to LDA in THF, stir 20 mins. at -70 C, add TMSCl (11 mmol), warm to room temperature and stir for 30 to 40 mins. before quenching with NaHC03.

5 Example 2.

2-MCH added neat. Diethylamine used in p]ace of triethylamine.

Again, runs 4 to 6 show little change in selectivity over time, compared with fresh LDA, but some loss of yieLd.

Pyrophoricity Freshly prepared, microcrystalline LDA obtained by reacting diisopropylamine with n-butyllithium immediately turns black upon exposure to air. Large samples ignite spontaneously.

When the macrocrystalline product of Example 2 is exposed to air, no immediate effect is noted, although there is some weight loss with time:

Sample Initial Mass after Mass after 2 Mass after 66 (mg) 45 mins (mg) hours (mg) hours (mg) 1 145 138 128 133 2 94 86.5 - 87.2

Claims (9)

1. CLAIMS 1. Amonoclinic, crystalline lithium diisopropylamide (LDA), wherein the crystal structure comprises a polymeric LDA structure consisting of a helical backbone of alternating 2 co-ordinate Lit centres and substantially tetrahedral, 4 co-ordinate N centres, each 2 co-ordinate Lit centre being joined to two 4 co-ordinate N centres, thereby to make up a series of asymmetrical, substantially linear N-Li-N units forming the backbone of the polymer, and to which are attached via the said Natoms the isopropyl groups grouped in pairs extending radially outward from the core of the helix.
2. 2. A method for the preparation of crystalline lithium diisopropylamide LDA which comprises forming a suspension of LDA in a hydrocarbon solvent, adding a nitrogen-containing donor ligand (Lewis base) to the suspension, heating the suspension under an inert atmosphere to dissolve the LDA in the presence of the donor ligand, cooling the solution to recrystallise the LDA, and recovering the recrystallised LDA from the mother liquor.
3. 3. A method according to claim 1, wherein the LDA is formed in situ by reacting a lithium alkyl with diisopropylamine in the suspension medium to form an initial LDA product, the said rea(tiol1 being performed under an inert atmosphere, adding the donor ligalu lo the reaction mixture to redissolve the initial LDA product, te-cooling the mixtur-e to recrystallise the LDA, and recovering the recrystal 1 ised product from the mother liquor.
4. 4. A method For the preparation of crystalline lithium diisopropylamide LDA which comprises reacting a lithium alkyl with diisopropylamine in a hydrocarbon solvent containing à nitrogen containing donor ligand (Lewis base), the reaction being performed under an inert atmosphere, cooling the reaction mixture to crystallise the product LDA, and recovering the crystallised LDA from the mother liquor.
5. 5. A method according to any one of claims 2 to 4, wherein the lithium alkyl reactant is t-butyllithium or n-butyllithium.
6. 6. A method according to any one of claims 2 to 5, wherein the donor ligand is tetramethylethylenediamine.
7. 7. A method according to any one of claims 2 to 6, wherein the hydrocarbon solvent is a saturated aliphatic hydrocarbon.
8. 8. A method according to claim 7, wherein the hydrocarbon solvent is n-hexane or cyclohexane.
9. 9. Crystalline lithium diisopropylamide when prepared by a method according to any one of claims 2 to 8.