Organic Chemistry Portal
Organic Chemistry Highlights

Monday, July 25, 2005
Vasco D.B. Bonifacio
New University of Lisbon

Organic Synthesis in Water

Water plays an essential role in life processes, however its use as a solvent has been limited in organic synthesis. Despite the fact that it is the cheapest, safest and most non toxic solvent in the world, its presence is generally avoided through the dehydrative drying of substrates and solvents. The use of water as a medium for organic reactions is therefore one of the latest challenges for modern organic chemists. The present Highlight presents a brief selection of different organic reactions run in an aqueous medium from the literature of the past two years. An excellent review about stereoselective organic reactions in water have been recently published (Chem. Rev. 2002, 102, 2751. DOI: 10.1021/cr010122p).

1. Oxidations

Rao and co-workers report a new methodology for a high yielding (90-96%) chemoselective oxidation of sulphides to sulphoxides using β-cyclodextrin and N-bromosuccinimide (NBS), at room temperature, and under neutral conditions. Chemoselectivity (no overoxidation to sulphones) is explained by the formation of reversible host-guest complexes between the sulphoxide and catalytic amounts of β-cyclodextrin (Tetrahedron Lett. 2005, 46, 4581. DOI: 10.1016/j.tetlet.2005.05.011).

Using a chemoenzymic oxidation methodology, Tong and co-workers successfully epoxidised water-soluble (81-93% yield) and lipophilic alkenes (60-99% yield). Commercial Glucose Oxidase (GOx) is used to produce in situ hydrogen peroxide via the enzymic oxidation of glucose. The addition of catalytic amounts of sodium bicarbonate/manganese sulphate increases the rate and the yield of the process. In the case of lipophilic alkenes, sodium dodecyl sulphate (SDS) was used as a surfactant (Tetrahedron 2005, 61, 6009. DOI: 10.1016/j.tet.2005.04.055).

a) water-soluble alkenes: Glucose (0.2 M), GOx (175 units/mL), O2, NaHCO3 (0.5 M), MnSO4 (0.1 mol%), pH 7.0 phosphate sol.; b) water-insoluble soluble alkenes: same conditions plus SDS (5 mM).

A highly efficient (88-98% yield) aerobic oxidation of benzylic alcohols, to the corresponding aldehydes or ketones, was developed by Hu and co-workers. This is a TEMPO (1)-catalysed system using DBDMH (2) and NaNO2 as co-catalysts (J. Org. Chem. 2005, 70, 729. DOI: 10.1021/jo048369k).

2. Dehydrogenation, Hydrogenation, Halogenation and Dehalogenation

Savelli and co-workers developed a mild, high yielding (90%) protocol for the dehydrogenation of primary amines to nitriles using NiSO4 as catalyst and K2S2O8 as oxidant (a stable, cheap and easy to handle salt) in an aqueous surfactant solution of dimethyldodecylamine N-oxide (DDAO) (Eur. J. Org. Chem. 2005, 3060. DOI: 10.1002/ejoc.200500047).

An asymmetric transfer hydrogenation of aromatic ketones using the Noyori-Ikariya Ru-Tsdpen catalyst (3) is now reported by Xiao and co-workers. The reaction proceeds with high yield (99%) and enantioselection (85-97% ee) using an aqueous solution of formic acid and Et3N, in which the amine acts as a pH modulator (pH 5-8). The catalyst was recycled more than 10 times without loss in enantioselectivity (Angew. Chem. Int. Ed. 2005, 44, 3407. DOI: 10.1002/anie.200500023).

a) ketone (1 mmol), 3 (0.012 mmol), H2O (0.5 mL), Et3N (2.7 mmol), HCO2H (3.3 mmol), 40C.

Nano-palladium particles (ARP-Pd) supported on an amphiphilic polystyrene-poly(ethylene glycol) (PS-PEG) resin was found to effect the hydrogenation of styrene and cinnamic derivatives in high yield (81-99% yield). Uozumi and co-workers found also that this catalytic system can be used in the hydrodechlorination of chloroarenes (81-99% yield), providing a recyclable, clean and safe protocol for the detoxification of aqueous pollutants (Org. Lett. 2005, 7, 163. DOI: 10.1021/ol047670k).

Stavber and co-workers used Selectfluor (4), a commercial, stable and water-soluble fluorinating reagent, for the selective synthesis of a series of vicinal fluorohydrins 5 (from phenyl substituted alkenes, 84-86% yield), α-fluoroketones 6 (from ketones, 85-90% yield) and 7 (from 1,3-diketones or β-ketoesters, 87-91% yield) and fluorodienones 8 and 9 (from phenols, 74-78% yield) (Org. Lett. 2004, 6, 4973. DOI: 10.1021/ol047867c).

Reaction conditions: substrate (1.05-2.1 mmol), 4 (1.1 mmol), H2O/surfactant (5 mL, 0.05%), 60 C, 2-24 h.

3. Allylations

Using a recyclable electrochemical process (up to five cycles with excellent yield), Zhang and co-workers (Org. Lett. 2005, 7, 1903. DOI: 10.1021/ol050483h) developed a tin-mediated protocol for the allylation of aldehydes (95-100% yield).

a) graphite electrode (2.0 V), aldehyde (5 mmol), allyl bromide (8 mmol), SnCl2 (10 mmol), H2O (10 mL), r.t., 6-10 h.
4. Coupling of Acyl Chlorides and Alkynes

Ynones are obtained in high yields (51-99%) by coupling acyl chlorides and alkynes in a new catalytic system, reported by Liu and co-workers, which uses palladium, copper and a surfactant (sodium lauryl sulfate) in a basic aqueous medium (Org. Lett. 2004, 6, 3151. DOI: 10.1021/ol048789w).

a) acyl chloride (2 mmol), alkyne (1 mmol), PdCl2(PPh3)2 (2 mmol%), CuI (5 mmol%), K2CO3 (3 mmol), surfactant (7 mol%), H2O (1 mL), 65C, 4 h.

5. Heck Reaction

Regioselective diarylation (75-92% yield) and monoarylation of unsubstituted (69-96% yield) and substituted (42-91% yield, E/Z 70/30-100/0) α,β-unsaturated carbonyl compounds with aryl iodides is reported by Njera and Botella. Best results were obtained using the oxime-derived carbapalladacycle catalyst 9 and Cy2NMe as a base (J. Org. Chem. 2005, 70, 4360. DOI: 10.1021/jo0502551).

a) ArI (2 mmol), alkene (3 mmol), Cy2NMe (3 mmol), 9 (0.02-1 mol% Pd), H2O (3 mL), 120 C, pressure tube, 3-23 h; b) ArI (1 mmol), alkene (1.5 mmol), Cy2NMe (1.5 mmol), 9 (0.1-1 mol% Pd), H2O (2 mL) 120 C, pressure tube, 7-38 h; c) ArI (1 mmol), alkene (0.5 mmol), Cy2NMe (1.5 mmol), 9 (0.1-1 mol% Pd), H2O (2 mL), 120 C, pressure tube, 8-22 h. Cy= cyclohexyl.
6. Wittig Reaction

Bergdahl and co-workers published the first report in the literature describing that Wittig reactions of stabilised (and poorly water-soluble) ylides with aldehydes are unexpectedly accelerated in an aqueous media (Tetrahedron Lett. 2005, 46, 4473. DOI: 10.1016/j.tetlet.2005.04.105).

a) aldehyde (1 mmol), ylide (1.2-1.5 mmol), H2O (5 mL), 20-90 C, 5 min - 4 h. Troc= 2,2,2-trichloroethoxycarbonyl.
7. Mannich-type Reactions

Following an early report (J. Am. Chem. Soc. 2002, 124, 5640. DOI: 10.1021/ja026094p), Kobayashi and co-workers published an efficient (up to 94% yield) enantio- and diastereoselective (syn/anti 8-92 to 92-8, 67-95% ee) protocol for Mannich-type reactions of a hydrazono ester with silicon enolates in aqueous medium. One example of a syn adduct from an (E)-silicon enolate and two examples of anti adducts from (Z)-silicon enolates are reported (J. Am. Chem. Soc. 2004, 126, 7768. DOI: 10.1021/ja048607t).

a) acyl hydrazono ester (0.4 mmol), silyl enol ether (1.2 mmol), ZnF2 (100 mol%), 10 (10 mol%), CTAB (0.02 mmol), H2O (1.95 mL), 0 C, 20 h. CTAB= cetyltrimethylammonium bromide.
8. Intramolecular Diels-Alder Reaction

Taguchi and co-workers demonstrated that the intramolecular Diels-Alder reaction of 1,7,9-decatrienoate derivatives can be performed in an aqueous medium (H2O-iPrOH 6:1) using indium(III) triflate as a recyclable catalyst (3 runs reported without loss in yield) to give the corresponding endo cycloadducts in good yield (up to 83%) (Tetrahedron 2005, 61, 7087. DOI: 10.1016/j.tet.2005.05.062).

a) alkene (0.5 mmol), In(OTf)3 (20 mmol%), H2O (6 mL), iPrOH (1 mL), 70-80C, 8-24 h.
9. Deprotection of Functional Groups

Methods for selective deprotection of functional groups are key tools for organic chemists. The following examples, performed in water, open new possibilities for the use of this challenging medium.

9.1 Acetates, Alkyl Ethers and Acetals

Deprotection of several acetates, alkyl ethers and acetals in aqueous media were recently reviewed (Chem. Rev. 2004, 104, 199. DOI: 10.1021/cr0200769) and are summarized in Table 1.

DOI: 10.1002/anie.199620561
DOI: 10.1055/s-2001-16073
DOI: 10.1016/0040-4039(94)88373-4
DOI: 10.1016/0040-4039(94)88373-4
DOI: 10.1055/s-2001-16073

9.2 Oximes and Imines

Konwar and co-workers (J. Org. Chem. 2005, 70, 1934. DOI: 10.1021/jo0480287) reported a simple protocol for the deprotections of oximes and imines under neutral conditions (yields up to 90%) using a I2/surfactant/water system.

a) oxime or imine (1 mmol), I2 (20 mmol%), H2O (15 mL), SDS (0.2 mmol), 25-40C, 3.5-8 h.

V. D. B. Bonifacio, Org. Chem. Highlights 2005, July 25.