Saturday 29 October 2011

Wacker Oxidation (Palladium-catalysed oxidation of alkenes)


The oxidation of ethene to ethanal by oxygen and a solution of a palladium(II) salt in aqueous hydrochloric acid is an important industrial process (the Wacker reaction). The palladium(II) is simultaneously reduced to the metal, but the reaction is made catalytic by addition of copper(II) chloride in the presence of air or oxygen, whereby the palladium is continuously re-oxidized to palladium(II)

Wacker Oxidation Mechanism
TheWacker reaction has found most use for the oxidation of terminal alkenes to give methyl ketones. It is believed to take place by an initial trans hydroxypalladation of the alkene to form an unstable complex that undergoes rapid beta-elimination to the enol 112. Hydropalladation then reductive elimination completes the overall process that involves transfer of hydride ion from one carbon to the other, via the palladium atom. The hydride migration is required to explain the observation that when the reaction is conducted in deuterium oxide, no deuterium is incorporated in the aldehyde produced.

Experimental Technique
Conversion of a terminal alkene to a methyl ketone is a useful transformation in organic synthesis. The reaction is typically carried out in aqueous DMF as solvent, using palladium(II) chloride as a catalyst (commonly 10 mol%) with copper(II) or copper(I) chloride and 1 atmosphere of oxygen. Copper(I) chloride is normally preferable as this avoids the formation of chlorinated ketones. Many different functional groups are tolerated and the reaction is selective for the oxidation of terminal alkenes in the presence of di- or trisubstituted alkenes. For example, only the terminal alkene is converted to a ketone on oxidation of the dienes 113 and 114
The Wacker reaction provides a method for the preparation of 1,4-dicarbonyl compounds, by formation of an enolate, allylation with an allyl halide, followed by palladium-catalysed oxidation of the terminal alkene. The product 1,4-dicarbonyl compounds can be treated with base to promote intramolecular aldol reaction
(Robinson annulation to give cyclopentenones.


Experimental Procedure
Palladium(II) acetate (0.2 mmol), benzoquinone (9 mmol), and the inorganic acid (HCl, HClO4, HBF4, H2SO4, or HNO3, 0.1 M) were dissolved in acetonitrile/water (7:1 v/v, 50 mL). The solution was deoxygenated by purging with argon for at least 30 min and stirred vigorously until the Pd(OAc)2 had dissolved. The olefin (10 mmol) was then added to the flask (by syringe), and the reaction mixture was stirred for 10 min. The products were separated from the catalyst by extraction into hexane or diethyl ether, washed with 30% aqueous sodium hydroxide, water and concentrated to a residue.
Reference:  J. Org. Chem. 55, 2924-2927 (1990)

Natural Product Synthesis
Thus, in a synthesis of pentalenene, Wacker oxidation of the 2-allyl ketone 115 gave the 1,4- diketone 116, which was converted to the cyclopentenone 117.


Regioselectivity of Wacker Reaction
Oxidation of 1,2-disubstituted alkenes occurs more slowly than that of terminal alkenes and a mixture of the two regioisomeric products is normally formed. With certain substrates, however, very high levels of regioselectivity have been obtained. For example, oxidation of the allylic ether 118 gave only the beta-alkoxy ketone 119.

The regioselectivity in oxidation reactions of unsymmetrical 1,2- disubstituted alkenes can be explained by electronic and neighbouring group effects, the latter involving co-ordination of a heteroatom or even an allylic hydrogen atom to the palladium atom in the intermediate.

Aldehyde synthesis from alkene


Aldehydes can be synthesized from alkenes by oxidation using ozonolysis, wacker oxidation and in some cases oxidation by KMnO4 in THF can lead to formation of aldehyde.

Procedure:

Ozonolysis
To a mixture of alkene coumpound (284 mg, 0.72 mmol) in t-BuOH (1.8 mL) and THF (0.6 mL) at room temperature was added N-methylmorpholine N-oxide (337 mg, 1.44 mmol) followed by osmium tetroxide (0.027 mL, 0.022 mmol). The mixture was stirred at room temperature overnight. The reaction was then diluted with phosphate buffer (pH 7, 5 mL). Sodium periodate (693 mg, 3.24 mmol) was then added and the cloudy solution was stirred vigorously for 2 hours. Next it was diluted with water and extracted three times with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give aldehyde compound as a yellow solid (251 mg, 88%).
Patent reference: WO2010056564 (Merck)

Wacker oxidation (general procedure)
 Palladium(II) acetate (0.2 mmol), benzoquinone (9 mmol), and the inorganic acid (HCl, HClO4, HBF4, H2SO4, or HNO3, 0.1 M) were dissolved in acetonitrile/water (7:1 v/v, 50 mL). The solution was deoxygenated by purging with argon for at least 30 min and stirred vigorously until the Pd(OAc)2 had dissolved. The olefin (10 mmol) was then added to the flask (by syringe), and the reaction mixture was stirred for 10 min. The products were separated from the catalyst by extraction into hexane or diethyl ether, washed with 30% aqueous sodium hydroxide, water and concentrated to a residue.
Reference:  J. Org. Chem. 55, 2924-2927 (1990)


KMnO4 in THF oxidation
 4-Formyl-2,2-dimethyl-1H-1,5-benzodiazepine (2, R1=R4)
To a solution of 10 g (0.036 mol) of 1 in 300 mL of THF was added 10 g (0.063 mol) of KMnO4 dissolved in 100 mL of water, over a period of 3.5 h in small portions. The reaction mixture was allowed to warm up to 40 °C. After the addition was finished, the brown precipitate was filtered, and the filtrate was concentrated and extracted with diethyl ether. After drying, the organic phase was concentrated and the resulting oil crystallized from diisopropyl ether: 7 g (78.7%); mp 102-104°C.

Above procedure can be used to synthesize all of the other aldehydes listed in Table I. Solubility of the starting material determines the THF/H2O ratio. In case of low solubility, a few preliminary tests should be made to determine the minimum amount of THF.

Attention: Usage of neat THF or addition of solid KMnO4 may lead to an explosion and therefore must be avoided.

4-(2-Phenylvinyl)-2,2-dimethyl-1H-1,5-benzodiazepine (1, R1=R4, R2=H, R3=Ph)
A solution of 10 g (0.053 mol) of 2,2,4-trimethyl-1H-1,5-benzodiazepine, 5.63 g (0.053 mol) of benzaldehyde, and 0.5 g of ammonium acetate in 100 mL benzene was refluxed for 4 h and then concentrated. The resulting oil is crystallized from diisopropyl ether: 12.1 g (82.4%); mp 134-136°C.
Refrence: P. Viski, Z. Szeverenyi, and L. I. Simandi J. Org. Chem. 51, 3213-3214 (1986)

Reduction of Acid Chlorides to Aldehydes using Sodium Borohydride and Pyridine


By use of sodium borohydride in N,N-dimethylformamide solution containing a molar excess of pyridine as a borane scavenger, direct conversion of both aliphatic and aromatic acid chlorides to the corresponding aldehydes can be achieved in >70% yield with minimal (5-10%) alcohol formation.

Procedure:
To a solution of 129 mg (3.4 mmoles) of sodium borohydride and 2.0 mL of pyridine in 5.0 mL of DMF and 3.0 mL of anhydrous THF cooled to approximately 0°C (external bath temperature) was added rapidly (<5 seconds) a solution of 4.0 mmoles of an acyl chloride in 2.0 mL of anhydrous THF. This mixture was subsequently stirred at 0°C for 1 minute before 0.50 mL of water was added to the flask to hydrolyze the excess acid chloride. Stirring of this mixture was continued at 0°C for an additional 60 seconds, after which 50 mL of 4:1 (v/v) hexane: solvent ether was quickly introduced into the flask. The globules of pyridine borane which appeared at this point can be separated from the reaction product by rapid filtration of the reaction mixture through a small column of Florisil (25 mL). An additional 25 mL portion of 4:1 (v/v) hexane: solvent ether was used to rinse out the reaction flask and ensure quantitative elution of the desired aldehyde (and any of the corresponding alcohol17) from the Florisil column18. 25 mL of ether was added to the combined filtrate, and this organic phase was washed successively with 15% aqueous NaCl (2x100mL), 1:1 (v/v) 2M aqueous hydrochloric acid:brine (1x100mL), 4:1 (v/v) 1M aqueous NaOH:brine (2x100mL), and saturated brine (100 ml). The organic layer was then dried (MgSO4) and the solvent removed in vacuo.

Reference: Synthetic Communications 12(11), 839-846 (1982)

Other reagents which can be used for partial reduction of acyl chlorides to aldehydes are:
  • bis(Triphenylphosphine)cuprous borohydride [Fleet, G.W.J., Fuller, C.J., and Harding, P.J.C.,Tetrahedron Lett., 1437 (1978); Sorrell, T.N. and Spillane, R.J., Tetrahedron Lett., 2473 (1978); Sorrell, T.N. and Pearlman, P.S., J. Org. Chem., 45, 3449 (1980)]
  • Lithium tri-tert-butoxyaluminum hydride [Brown, H.C. and Subba Rao, B.C., J. Am. Chem. Soc., 80, 5377 (1958)]
  • Complex copper cyanotrihydridoborate salts [Hutchins, R.O. and Markowitz, M., Tetrahedron Lett., 21, 813 (1980)]
  • Anionic iron carbonyl complexes [Watanabe, Y., Mitsudo, T., Tanaka, M., Yamamoto, K., Okajima, T., and Takegami, Y., Bull. Chem. Soc. Jpn., 44, 2569 (1971); Cole, T.E. and Pettit, R., Tetrahedron Lett., 781 (1977)]
  • Tri-n-butyltin hydride in the presence of tetrakis(triphenylphosphine)palladium(0) [Four, P. and Guibe, F., J. Org. Chem., 46, 4439 (1981)]



Aldehydes from Acyl chlorides, Esters, Nitriles



Aldehydes  can be prepared by mild reduction of acyl chlorides, esters, nitriles. The reducing agents of choice are usually lithium tri-tert-butoxy aluminum hydride (LATB—H) and diisobutylaluminum hydride (DIBAL—H).  low temperature is very crucial for aldehyde conversion otherwise you may end getting an alcohol (over reduced).

Acyl chloride reduction

Acyl chlorides can be reduced by reacting them with lithium tri-tert-butoxyaluminum hydride at −78°C.




Ester and nitrile reduction
You can use diisobutylaluminum hydride to reduce both esters and nitriles to aldehydes.

The mechanism for both of these reactions is very similar to the mechanism for the reduction of acyl chlorides by LATB—H. The first step is an acid-base reaction between an unshared electron pair on oxygen or nitrogen with the aluminum atom of the DIBAL—H. The second step is the transfer of a hydride ion from the DIBAL—H to the carbon atom of the carbonyl or nitrile group. The last step is the hydrolysis of the aluminum complex to form the aldehyde.

Ester reduction mechnaism

Nitrile reduction mechanism

Procedures
Aldehyde synthesis (via cyanide):

A 200 mL round bottom flask was charged with a magnetic stir bar, 3-ethoxy-2- fluorobenzonitrile (1.000 g, 6.05 mmol), and anhydrous toluene (12.92 ml). The solution was placed under argon and cooled to 0°C with an ice bath. DIBAL-H (7.27 ml, 7.27 mmol) (1M in PhMe) was then added drop wise via syringe and the reaction was allowed to stir to rt overnight. To this mixture was added 10 % HCl until the solution reached a pH of ~ 2. The resulting mixture was then left to stir for 0.5 h. and was then poured into a separatory funnel and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was dried with MgSO4, filtered, and concentrated in vacuo to yield the crude product which was purified via silica gel chromatography (80 g) using ethyl acetate/hexanes (1:4) as eluent to provide pure 3-ethoxy-2-fluorobenzaldehyde (0.810 g, 80 %).
Patent reference: WO2010001169 (Astrazeneca)

Aldehyde synthesis (via ester):
Dissolve the ester (1 equiv) in CH2Cl2. The temperature of the solution should be -78oC. Add DIBAL in THF (1.2 equiv.) to the solution dropwise with a N2 inlet. Stir the resulting mixture at -78oC for 1 hour. Quench the mixture with methanol slowly, and then add brine into the mixture. Separate the organic layer, dry and concentrate. In many cases the residue needs to be purified by column chromatography.


Saturday 22 October 2011

Bodroux-Chichibabin aldehyde synthesis

Bodroux-Chichibabin aldehyde synthesis

The Bodroux-Chichibabin aldehyde synthesis is a chemical reaction whereby a Grignard reagent is converted to an aldehyde one carbon longer.

This synthesis involves the treatment of ethyl orthoformate with corresponding Grignard reagents to form of aliphatic or aromatic aldehydes is generally referred to as Bodroux-Chichibabin reaction. Other orthoformates have also been used for this reaction. When ethyl orthoformate is applied in this reaction, the replacement of the first ethoxyl group is a slow reaction, but the yields can be improved by refluxing the mixture of Grignard reagent and orthoformate. The yields of the reaction have been improved by refluxing the mixture of Grignard reagent and orthoformate. In this reaction the acetals with axial 2-alkoxy groups react rapidly with a variety of Grignard reagents.

Reaction of a Grignard reagent with triethyl orthoformate gives an acetal, which can be hydrolyzed to an aldehyde.


Mechanism

Nucleophillic attack by the Grignard on the electrophillic triacetal is followed by acid catalyzed hydrolysis of the diacetal to give the aldehyde.

Literature
  • F. Bodroux, Compt. Rend. 138, 92 (1904)
  • E. Chichibabin, Ber. 37, 186, 850 (1904)
  • F. Bohlmann, Ber. 86, 63, 657 (1933)
  • L. I. Smith et al., J. Org. Chem. 6, 437, 489 (1941)
  • H. W. Post, The Chemistry of the Aliphatic Orthoesters, p 96 (New York, 1943)
  • E. H. Rodd, Chemistry of Carbon Compounds 1, 614 (New York, 1951)
  • O. Bayer, Houben- Weyl-Muller 7 65 (1951)
  • L. I. Smith, J. Nichols, J. Org. Chem. 6, 489 (1941)
  • J. Sicé J. Am. Chem. Soc. 75, 3697 (1953)
  • E. R. H. Jones et al., J. Chem. Soc. 1958, 1054
  • Use of lithio derivatives instead of Grignard reagents: E. A. Evans, Chem. & Ind. (London) 1957, 1596
  • Synthetic applications using modified conditions: C. Pétrier et al., Tetrahedron Letters 23, 3361 (1982).
  • J. Einhorn, J. L. Luche, ibid. 27, 1791 (1986)
  • H. Meier, H. Aust, J. Prakt. Chem. 341, 466 (1999)


Thursday 20 October 2011

Bouveault aldehyde synthesis

Bouveault Aldehyde Synthesis

The reaction for synthesis of aldehydes by the treatment of N, N-disubstituted formamides with either Grignard reagent or organic lithium reagent in an ether solvent is generally known as Bouveault aldehyde synthesis or you in a simple way it is a one-pot chemical reaction that converts a primary alkyl halide to an aldehyde one carbon longer.  This reaction has been reported to work only in certain cases and occasionally this reaction produces tertiary amines as the main products. The study finds that the greater the R group in the Grignard reagent, the more aldehyde is yielded. This reaction has been improved by either running in a co-solvent of ether-HMPA or irradiating with high-frequency ultrasound in THF or tetahydropyran. This reaction has general application in the preparation of aldehydes.

Reaction mechanism
  
The first step of the Bouveault aldehyde synthesis is the formation of the Grignard reagent. Upon addition of a N,N-disubstituted formamide (such as DMF) a hemiaminal is formed, which can easily be hydrolyzed into the desired aldehyde .

Literature

  • L. I. Smith, J. Nichols, J. Org. Chem. 6, 489 (1941);
  • J. Sicé J. Am. Chem. Soc. 75, 3697 (1953);
  • E. R. H. Jones et al., J. Chem. Soc. 1958, 1054.
  • Use of lithio derivatives instead of Grignard reagents: E. A. Evans, Chem. & Ind. (London) 1957, 1596.
  • Synthetic applications using modified conditions: C. Pétrier et al., Tetrahedron Letters 23, 3361 (1982);
  • J. Einhorn, J. L. Luche, ibid. 27, 1791 (1986); ]
  • H. Meier, H. Aust, J. Prakt. Chem. 341, 466 (1999).
  • Smith, L. I.; Nichols, J. (1941). "The Synthesis of Aldehydes from Grignard Reagents. II. Polymethylbenzaldehydes". J. Org. Chem6 (4): 489.
  • Sice, Jean (1953). "Preparation and Reactions of 2-Methoxythiophene". J. Am. Chem. Soc. 75 (15): 3697.
  • Comins, D.L.; Brown, J.D. J. Org. Chem. 1984, 49, 1078 (region selective control)
  • Meier, H.; Aust, H. J. Prakt. Chem. 1999, 341, 466 (uses DMA for ketone and DMF for aldehyde synthesis)
  • L. Bouveault, Bull. Soc. Chim. France 31, 1306, 1322 (1904).