Dimethylaluminum Amide

(R1 = Me, R2 = H, R3 = H)

[24758-44-9]  · C2H8AlN  · Dimethylaluminum Amide  · (MW 73.07) (R1 = Me, R2 = Me, R3 = Me)

[7398-63-2]  · C4H12AlN  · Dimethylaluminum Dimethylamide  · (MW 101.13) (R1 = Me, R2 = Et, R3 = Et)

[51706-28-6]  · C6H16AlN  · Dimethylaluminum Diethylamide  · (MW 129.18) (R1 = Et, R2 = Me, R3 = Me)

[13154-82-0]  · C6H16AlN  · Diethylaluminum Dimethylamide  · (MW 129.18) (R1 = Et, R2,R3 = -CMe2(CH2)3CMe2-)

[54159-47-6]  · C13H28AlN  · Diethylaluminum 2,2,6,6-Tetramethylpiperidide  · (MW 225.35)

(mild, nonbasic amine transfer reagents, compatible with many functional groups1)

Physical Data: dialkylaluminum amides2 are commonly prepared in situ. Dimethylaluminum amide exists as a six-membered ring trimer in the solid state.2c

Solubility: sol dichloromethane, benzene, toluene, xylene.

Preparative Methods: dialkylaluminum amides are conveniently prepared in situ from the appropriate trialkylaluminum and amine3 or amine hydrochloride.4

Handling, Storage, and Precautions: dialkylaluminum amides are hydrolytically unstable. 1 M stock solutions can be prepared and stored in the freezer, although best results are usually obtained with freshly prepared reagents.3,5

Preparation of Dialkylaluminum Amides.

Although in early studies dialkylaluminum amides were isolated,6 in practice the reagents are either made in situ from primary and secondary amines or ammonia and a trialkylaluminum, or stock solutions are prepared and stored.3,5 Diethylaluminum amides often show reduced reactivity compared to dimethylaluminum amides,3 which are less reactive than dialkylhaloaluminum-amine complexes.4b,6d,7 Dialkylaluminum amides that have been used in organic synthesis include dimethylaluminum amide, dimethylaluminum anilide, dimethylaluminum o-bromoanilide, dimethylaluminum 2-(diethylamino)ethylamide, dimethylaluminum N-methoxy-N-methylamide, diethylaluminum diethylamide, diethylaluminum n-propylamide, diethylaluminum 2,2,6,6-tetramethylpiperidide (DATMP), diethylaluminum N-methylanilide, and dimethylaluminum N-methyl-N-trimethylsilylamide.

Conversion of Esters to Amides.

The reaction of dimethylaluminum amides with a variety of esters to produce amides in high yields has been widely used (eq 1).1,3

In general, aminolysis of esters requires high temperatures and/or long reaction times,8 and the strong alkali metal catalysts sometimes used9 are often not compatible with sensitive functionality. The use of dimethylaluminum amides has the advantages of low temperatures and moderate reaction times. The aluminum amides are conveniently prepared in situ and appear to be mild, nonbasic reagents, compatible with many functional groups. The isolation of the product is simple, since hydrolysis of the aluminum reagents and products affords only methane and acid-soluble aluminum salts. For example, this procedure has been used to prepare the oxindole portion of gelsemine (eq 2).10

This method has also been used to prepare N-substituted 4-(1H-imidazol-2-yl)benzamides from the corresponding methyl ester and N-substituted amine in the presence of Trimethylaluminum (eq 3).11

Lactones undergo acyl-oxygen bond cleavage when treated with dialkylaluminum amides to produce hydroxy amides upon hydrolysis.3,6a A hindered lactone was converted to the corresponding hydroxy amide upon treatment with dimethylaluminum amide (eq 4). Sodium amide in liquid ammonia was unsuccessful at performing the same transformation.3

The aluminum amide reagent derived from N,O-dimethylhydroxylamine (see also N,O-Dimethylhydroxylamine) was used to achieve lactone ring-opening in the total syntheses of (+)-actinobolin and (-)-bactobolin (eq 5).12

An alternative procedure involves the use of Dimethylaluminum Chloride-amine complexes in the same transformations. These reagents, prepared from the reactions of trimethylaluminum with conveniently handled, readily available amine hydrochloride salts, provide efficient means for the aminolysis of esters (eq 6).4,13

The use of these alternative aluminum reagents avoids the necessity of having to condense and measure volatile low molecular weight amines and ammonia. In a diastereospecific synthesis of the C-20-C-34 segment of the immunosuppressant FK-506, a lactone is converted to the hydroxy amide when subjected to the complex from trimethylaluminum and N,O-Dimethylhydroxylamine hydrochloride (eq 7).14

This type of reaction can also be done intramolecularly, affording lactams (eq 8).15 b-Lactams can also be synthesized, as in Woodward's synthesis of cephalosporin C (eq 9).16

Bifunctional units such as 1,2-diaminoethane are effectively coupled with trimethylaluminum to produce reagents that can be treated with esters to give 2-imidazolines and benzimidazoles directly (eq 10).17

Transaminations can also be achieved using dialkylaluminum amides. For example, Schreiber used dimethylaluminum N-methoxy-N-methylamide to convert an oxazolidone auxiliary to the N-methyl-N-methoxy amide (eq 11).18 This transformation gives a key intermediate corresponding to the C-22-C-28 segment of rapamycin in a form suitable for alkylative coupling.

Conversion of Esters to Nitriles.

Esters are converted to nitriles in a one-pot procedure when heated with 2 equiv of dimethylaluminum amide in refluxing xylene (eq 12).5 This reaction, which is thought to proceed through a carboxamide or aluminum derivative of a carboxamide as an intermediate, is the first direct conversion of an ester to a nitrile.

In studies toward the total synthesis of tetronomycin, Yoshii and co-workers used this procedure to directly convert a lactone to a hydroxy nitrile (eq 13).19

Conversion of Nitriles to Amidines.

Often methods used for amidine synthesis are moderate to poor yielding, multistep processes.20 In early studies, dimeric aluminum amidine derivatives resulting from the addition of diethylaluminum dimethylamide to benzonitriles were isolated for spectroscopic study,6b,c but the synthetic scope of the reaction in preparing amidines was not demonstrated. However, it was recently found that the addition of a dimethylchloroaluminum-amine complex4 to a nitrile produces the corresponding amidine directly (eq 14).7

Dialkylaluminum amides react sluggishly with nitriles compared to the corresponding dialkylchloroaluminum-amine complexes.4b,6d,7 Alkyl, benzyl, and aryl amidines are prepared in high yield (78-96%) from the corresponding nitriles using this method. Mono- and disubstituted amidines are obtained from N-substituted amine complexes. This transformation can also be achieved intramolecularly. By generating the dimethylchloroaluminum-amine complex in situ from 6-aminocapronitrile hydrochloride and trimethylaluminum, caprolactamidine was prepared (eq 15).

Additionally, guanidines can be prepared from the corresponding N-substituted cyanamide (eq 16).7

Epoxide and Oxetane Cleavage.

Diethylaluminum amides react stoichiometrically with epoxides at rt to give, after hydrolysis, b-amino alcohols in good yield (eq 17).21 The classical method of reacting epoxides directly with amines is limited by the poor reactivity of nonnucleophilic or bulky amines and the high temperatures often necessary. This procedure avoids these problems.

The reaction of 1-hexene oxide with diethylaluminum diethylamide occurs exclusively at the terminal carbon (eq 18). In contrast, the reaction of isoprene oxide with diethylaluminum n-propylamide gives a mixture of products in which the tertiary carbinyl amine predominates (eq 19). This can be compared to the direct reaction of isoprene oxide with n-propylamine, which gives the tertiary allylic alcohol.22

Epoxides can be converted to allylic alcohols using Diethylaluminum 2,2,6,6-Tetramethylpiperidide (DATMP),23 which is readily prepared from diethylaluminum chloride and the corresponding lithium amide.24 On reaction with DATMP in benzene, (E)-cyclododecene oxide is converted quantitatively in 1 h at 0 °C into (E)-2-cyclododecen-1-ol (eq 20).23 In contrast, under the same reaction conditions, the (Z)-isomer affords only 8% of the alcohol. DATMP seems virtually unreactive toward all cis-2,3-disubstituted epoxides.

DATMP is very reactive towards 2,2,3-trisubstituted epoxides (eqs 21 and 22).24 The observed selectivity is consistent with a cyclic syn-elimination mechanism, in which the organoaluminum compound adds to the epoxide preferentially on the same side as hydrogen at C-3. The proton required for elimination is supplied by the alkyl group on C-2 which is cis to the hydrogen atom on C-3.23 The resulting double bond generally prefers the (E) configuration.

Similarly, homoallylic alcohols can be made by rearrangement of oxetane rings using an organoaluminum amide. Reaction of oxetanes with diethylaluminum methylanilide in boiling benzene gives the corresponding homoallylic alcohols in high yields (eqs 23 and 24).25 Again the (E) configuration of the product is preferred.

Substitution of Allylic Phosphates.

Nucleophilic substitution of allylic phosphates can be accomplished using dialkylaluminum amides. For example, the reaction of cis- or trans-5-isopropenyl-2-methyl-2-cyclohexenyl diethyl phosphate with dimethylaluminum phenylamide results in the corresponding allylic amines (eq 25).26 Substitution occurs with predominant inversion of configuration.27

Conversion of Ketones to N-Methyl Imines.

N-Methyl imines28 can be formed from the reaction between ketones and (trimethylsilyl)(dimethylalumino)methylamine (eq 26).29 Imine yields are fair using this method. The aluminum reagent is prepared by treating the corresponding trimethylsilylalkylamine with trimethylaluminum in benzene.


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Steven M. Weinreb, Glen T. Anderson & Christine S. Nylund

The Pennsylvania State University, University Park, PA, USA



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