Hexamethylphosphorous Triamide1

(Me2N)3P

[1608-26-0]  · C6H18N3P  · Hexamethylphosphorous Triamide  · (MW 163.24)

(strong nucleophile;2 used to synthesize epoxides from aldehydes2,3 and arene oxides from aryldialdehydes;4-7 replaces Ph3P in the Wittig reaction;8 with CCl4, converts alcohols to chlorides;9 with I2, converts disulfides to sulfides10 and deoxygenates sulfoxides and azoxyarenes;11 with dialkyl azodicarboxylate and alcohol, forms mixed carbonates;12 reduces ozonides13)

Alternate Name: tris(dimethylamino)phosphine.

Physical Data: mp 26 °C; bp 162-164 °C/760 mmHg, 50 °C/12 mmHg; n25D 1.4636; d 0.911 g cm-3.

Form Supplied in: commercially available; liquid, pure grade >97% (GC).

Preparative Methods: reaction of Phosphorus(III) Chloride with anhydrous dimethylamine; the same procedure can be used to obtain higher alkyl homologs.14

Purification: distillation at reduced pressure; exposure of hot liquid to air should be avoided.

Handling, Storage, and Precautions: very sensitive to air; best stored in nitrogen atmosphere; reacts with carbon dioxide; inhalation should be avoided. Use in a fume hood.

Synthesis of Epoxides.

Reaction of (Me2N)3P with aromatic aldehydes provides convenient direct synthetic access to symmetrical and unsymmetrical epoxides in generally high yields. A typical example is the reaction of o-chlorobenzaldehyde, which provides the corresponding stilbene oxide as a mixture of the trans and cis isomers (eq 1).2,3

The coproduct, Hexamethylphosphoric Triamide, is readily separated by taking advantage of its water solubility. A competing reaction pathway leads to formation of variable amounts of a 1:1 adduct in addition to the epoxide product (eq 2). Originally the adduct was assigned the betaine structure (1a). On the basis of more detailed NMR analysis, this was subsequently revised to the phosphonic diamide structure (1b).15

The ratio of products depends upon the electronegativity of the aldehyde and the mode of carrying out the reaction. Aromatic aldehydes with electronegative substituents, especially in the ortho position, undergo rapid exothermic reaction to yield epoxides exclusively. Conversely, aldehydes bearing electron-releasing substituents react more slowly to afford mainly 1:1 adducts. Slow addition of (Me2N)3P to the aldehyde tends to enhance the ratio of the epoxide product. These observations are compatible with a mechanism in which an initially formed 1:1 adduct reacts with a second aldehyde molecule to form a 2:1 adduct which collapses to yield the observed products (eq 3).

(Me2N)3P reacts also with saturated and heterocyclic aldehydes, but 1:1 adducts rather than epoxides are the predominant products. The reaction with Chloral takes a different course2 and yields the dichlorovinyloxyphosphonium compound Cl2C=CH-O-+P(NMe2)3 Cl-.

The scope of the reaction is considerably extended by its applicability to the synthesis of mixed epoxides.2 This is accomplished by addition of (Me2N)3P to a mixture of aldehydes in which the less reactive aldehyde predominates. For example, addition of (Me2N)3P to a mixture of o-chlorobenzaldehyde and 2-furaldehyde yields the corresponding mixed epoxide (eq 4).

An advantage of the method is that it allows the synthesis of epoxides unobtainable by the oxidation of alkene precursors with peroxides or peracids due to the incompatibility of functional groups with these reagents.

Synthesis of Arene Oxides.

Reaction of (Me2N)3P with aromatic dialdehydes provides arene oxides such as benz[a]anthracene 5,6-oxide (2a) (eq 5).4-7 These compounds, also known as oxiranes, are relatively reactive, undergoing thermal and acid-catalyzed rearrangement to phenols and facile hydrolysis to dihydrodiols. Consequently, their preparation and purification requires mild reagents and conditions. The importance of this is underlined by successful synthesis of the reactive arene oxide (2b) in 75% yield using appropriate care,7 despite a previous report of failure of the method.4 While compound (2b) is a relatively potent mutagen, it is rapidly detoxified by mammalian cells.6 The principal limitation of the method is the unavailability of the dialdehyde precursors, which are obtained through oxidation of the parent hydrocarbons, e.g. by ozonolysis.

Wittig and Horner-Wittig Reactions.

(Me2N)3P may be used in place of Triphenylphosphine in Wittig reactions with aldehydes and ketones (eq 6).8 It is advantageous because the water solubility of the byproduct, hexamethylphosphoric triamide, renders it readily removable. This method has been used for the preparation of unsaturated esters as well as alkenes (eq 7).

The phosphonic diamide products (1b) obtained from the reaction of arylaldehydes having electron-donating groups with (Me2N)3P can be deprotonated by n-Butyllithium in DME at 0 °C.15 These intermediates participate in Horner-Wittig-type reactions with aromatic aldehydes to give enamines in good yield (eq 8). In the examples studied the enamines have the (E) configuration. Mild acid hydrolysis of the reaction mixtures without isolating the intermediate enamines provides the corresponding deoxybenzoins.15 The overall procedure represents an example of reductive nucleophilic acylation of carbonyl compounds.

Conversion of Alcohols to Alkyl Chlorides and Other Derivatives.

The reagent combination (Me2N)3P and CCl4 can be used in place of Triphenylphosphine-Carbon Tetrachloride for the conversion of alcohols to alkyl chlorides (eq 9).9 An advantage is the ease of removal of the water-soluble coproduct (Me2N)3P=O. The mechanism entails initial rapid formation of a quasiphosphonium ion, followed by reaction with an alcohol with displacement of chloride, and nucleophilic attack by the chloride ion on the carbon atom of the alcohol in a final rate-determining step to yield an alkyl chloride.

This reagent reacts more rapidly with primary than with secondary alcohols. This property has been made use of to transform the primary hydroxy groups of sugars to salts, which then may be converted to halides (Cl, Br, I), azides, amines, thiols, thiocyanates, etc. by reaction with appropriate nucleophiles (eq 10).16 Arylalkyl ethers and thioethers may also be prepared by appropriate modification of this method.17 These reactions generally proceed with high stereoselectivity. Thus reaction of chiral 2-octanol with this reagent afforded 2-chlorooctane with complete inversion of configuration. Also, conversion of the salt prepared from reaction of (R)-(-)-2-octanol with (Me2N)3P/CCl4 at low temperature to the corresponding hexafluorophosphate salt, followed by reaction of this with potassium phenolate in DMF, gave optically pure (S)-(+)-2-phenoxyoctane in 93% yield (eq 11).17

(Me2N)3P/CCl4 may also be employed for the selective functionalization of primary long-chain diols.17 Reactions of diols of this type with (Me2N)3P and CCl4 in THF followed by addition of KPF5 gives mono salts in high yield (eq 12).18 THF serves to precipitate the mono salts as they are formed, thereby blocking their conversion to bis salts. Reactions of the mono salts with various nucleophiles provides the corresponding monosubstituted primary alcohols.

Conversion of Disulfides to Sulfides.

Alkyl, aralkyl, and alicyclic disulfides undergo facile desulfurization to the corresponding sulfides on treatment with (Me2N)3P or (Et2N)3P (eq 13).10 For example, reaction of methyl phenyl disulfide with (Et2N)3P in benzene at rt for ~1 min furnishes methyl phenyl sulfide in 86% yield. The desulfurization process is stereospecific, in that inversion of configuration occurs at one of the carbon atoms a to the disulfide group. Thus desulfurization of cis-3,6-dimethoxycarbonyl-1,2-dithiane affords a quantitative yield of trans-2,5-dimethoxycarbonylthiolane (eq 14). It is worthy of note that the rates of these reactions are markedly enhanced by solvents of high polarity.

Deoxygenation of Sulfoxides and Azoxyarenes.

Sulfoxides are deoxygenated to sulfides under mild conditions with (Me2N)3P activated with Iodine in acetonitrile (eq 15).11 Equimolar ratios of the sulfoxide, (Me2N)3P, and I2 are generally employed. Yields are superior to those obtained with either (Me2N)3P/CCl4 or Ph3P/I2. Reaction time is reduced by addition of Sodium Iodide. Azoxyarenes, such as azoxybenzene, are converted to azoarenes with this reagent combination under similar mild conditions (eq 16).11

Preparation of Mixed Carbonates.

The reaction of (Me2N)3P with alcohols and dialkyl azodicarboxylates proceeds smoothly at rt to provide mixed dialkyl carbonate esters in moderate to good yields (eq 17).12 An advantage of the method over the chloroformate method is the neutrality of the conditions employed. It should be noted that the related system Triphenylphosphine-Diethyl Azodicarboxylate converts alcohols into amines.

Reduction of Ozonides.

In the synthesis of ecdysone from ergosterol, the ozonide product produced from (5) was reduced with (Me2N)3P under mild conditions to the aldehyde (6) without isomerization (eq 18).13 The scope of this method has not been investigated.


1. Wurziger, H. Kontakte (Darmstadt) 1990, 13.
2. Mark, V. JACS 1963, 85, 1884.
3. Mark, V. OSC 1973, 5, 358.
4. Newman, M. S.; Blum, S. JACS 1964, 86, 5598.
5. Harvey, R. G. S 1986, 605.
6. Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and Carcinogenesis; Cambridge University Press: Cambridge, 1991; Chapter 12.
7. Harvey, R. G.; Goh, S. H.; Cortez, C. JACS 1975, 97, 3468.
8. Oediger, H.; Eiter, K. LA 1965, 682, 58.
9. Downie, I. M.; Lee, J. B.; Matough, M. F. S. CC 1968, 1350.
10. Harpp, D. N.; Gleason, J. G. JACS 1971, 93, 2437.
11. Olah, G. A.; Gupta, B. G. B.; Narang, S. C. JOC 1978, 43, 4503.
12. Grynkiewicz, G.; Jurczak, J.; Zamojski, A. T 1975, 31, 1411.
13. Furlenmeier, A.; Fürst, A.; Langemann, A.; Waldvogel, G.; Hocks, P.; Kerb, U.; Wiechert, R. HCA 1967, 50, 2387.
14. Mark, V. OSC 1973, 5, 602.
15. Babudri, F.; Fiandanese, V.; Musio, R.; Naso, F.; Sciavovelli, O.; Scilimati, A. S 1991, 225.
16. Castro, B.; Chapleur, Y.; Gross, B. BSF(2) 1973, 3034.
17. Downie, I. M.; Heaney, H.; Kemp, G. AG(E) 1975, 14, 370.
18. Boigegrain, R.; Castro, B.; Selve, C. TL 1975, 2529.

Ronald G. Harvey

University of Chicago, IL, USA



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