Synthesis of 5-Substituted a,b-Unsaturated g-Lactams from

N-Sulfinyl Azadienes by Iron-mediated Reaction Cascades and Palladium-catalyzed Cyclocarbonylation Strategies

        Patrick Amrhein and Karola Rück-Braun*

Institut für Organische Chemie, Johannes Gutenberg-Universität,

Duesbergweg 10-14, 55099 Mainz, Germany

E-mail: [email protected]

Received: 1 August 2000 / Uploaded: 2 August 2000

 

Introduction:

A new synthesis of 5-substituted a,b-unsaturated g-lactams is reported. b-[Cp(CO)₂Fe]-Substituted N-sulfonyl¹ and N-sulfinyl azadienes 1 react with Grignard reagents or organolithium compounds furnishing 5-substituted a,b-unsaturated g-lactams 3.^2,3 These reaction cascades occur by initial attack of the organometallic reagent at the imine functionality followed by an intramolecular cyclocarbonylation step. In a number of cases non-N-protected lactams are obtained from N-sulfonyl azadienes besides the desired N-sulfonyl g -lactams 3. Moreover, chiral b-[Cp(CO)₂Fe]-substituted N-sulfinyl azadienes 1 react with the organometallic reagents to furnish exclusively 5-substituted non-N-protected g -lactams 3.^2,3

In addition, the synthesis of 5-substituted a,b-unsaturated g-lactams 3 by palladium-catalyzed cyclocarbonylations of chiral bromo-substituted sulfinamides 2, derived from the corresponding azadiene precursors and organometallic reagents, is described.⁴

 

 

Reactions of b-[Cp(CO)₂Fe]-substituted N-Sulfonyl Azadienes with C-Nucleophiles:

a,b-Unsaturated imines 1 are synthesized e.g. from b-[Cp(CO)₂Fe]-substituted (Z)-alkenals 4 and electron poor primary amino compounds in CH₂Cl₂ in the presence of TiCl₄ and NEt₃ in dichloromethane (66-100 %).^1,4

The g-lactams 3 are accessible by treatment of the a,b-unsaturated imines 1 with organolithiums in THF at -78°C or 0°C followed by prolonged stirring at room temperature (39-56 %). Reactions with Grignard-reagents carried out in dichloromethane at room temperature furnished the g-lactams 3 in 37-62 % yield.

Examples:

The reaction of imine 5 with Grignard reagents is found to furnish the allyliron complexes 6. The structure of the allyl-substituted product was elucidated by X-ray analysis. Therefrom an anti-orientation of the metal fragment and the allyl residue at carbon-5 is concluded.

 

Influence of the temperature on the carbonylation step:

When the cyclohexene-derivative shown below is treated with allyl Grignard reagent at room temperature the N-sulfonyl g -lactam is isolated in only 19% yield. However, the yield could be increased by raising the reaction temperature after the initial 1,2-addition for the cyclocarbonylation key step. Thereby, in 1,2-dichloroethane at 50°C complete turnover to the desired product is achieved. The N-sulfonyl g -lactam is isolated in 75 % yield after flash chromatography.

 

Unexpected Deprotection: What role does the iron play in this game?

Reactions of compound 1a with either organolithium or Grignard reagents led to the non-N-protected lactams 3f, 3h, 3j besides the lactams 3e, 3g, 3i. At the current stage the cleavage of the N-S bon is not conclusive. Iron-mediated redox processes my be involved in the formation of the non-N-protected g -lactams 3f, 3h, 3j.

Mechanistic Considerations:

After 1,2-additon of the organometallic reagents to the N-sulfonyl azadienes, furnishing the metallated amides (B), the carbonylation steps may proceed via an acyl iron intermediate or a ferrilactam intermediate.^1-4

For the formation of the allyliron complexes presented above it seems reasonable to propose an anionic p -alkene-iron complex as intermediate (C) being formed after the reductive elimination step leading to the five-membered ring system. In an intramolecular nucleophilic substitution reaction the attack of the iron moiety at the neighboring methylene group could lead to a phenolate prior aqueous work-up yielding the allyliron complexes.

Application of Iron-substituted N-Sulfinyl Azadienes:

Chiral sulfinimines react with Grignard- or organolithium reagents to give exclusively non-N-protected a,b-unsaturated g-lactams. Only the N-tert-butyl sulfinyl imines can be treated with organolithiums and alkyl Grignard reagents since the sulfur atom is effectively shielded by the tert-butyl residue leading to exclusive attack at the imine carbon atom. For the reactions summarized in the Table, the enantioselectivities were determined by shift experiments to range from 10% ee up to 62% ee.

Iron-mediated redox processes during aqueous work-up seem to be responsible for the N-S bond cleavages observed.

 

For the addition of organolithiums and Grignard reagents to sulfinimines six-membered ring transition state models have been proposed by Davis and Ellman to predict the diastereofacial selectivity. ^5,6

Palladium-catalyzed Cyclocarbonylations:

Enantiopure g-lactams 3 are accessible by palladium(0)-catalyzed cyclocarbonylation reactions of chiral sulfinamides. The chiral sulfinyl amides used are synthesized from the corresponding imines by 1,2-addition of organolithium or Grignard-reagents in 50-100 % yield. The diastereoselectivity obtained ranged from 51:49 up to 91:9. Fortunately, the diastereomers are easily separated by chromatography. The absolute configuration of an allyl-substituted and a methyl-substitued optically pure sulfinamide was elucidated by X-ray analysis. In the palladium-catalyzed cyclocarbonylation reactions surprisingly N-sulfinyl-substituted (B) and non-N-protected derivatives (A) are formed. The reactions are carried out with Pd(PPh₃)₄ and n-Bu₃N as base in acetonitrile at reflux for 5-28 h. The N-S bond cleavage can be attributed to attack of hydrogen bromide formed from the palladium hydride intermediate within the catalytic cycle.

The palladium-catalyzed cyclocarbonylation of allyl-substituted sulfinamides gave the desired lactam derivatives in less than 5% yield. The chiral amines shown below are found to be formed instead by Heck-reaction. In the presence of LiCl compound A is exclusively obtained.

From the optically pure sulfinamide shown below the amine derivative is prepared by treatment with HCl in dioxane/methanol for cyclocarbonylation studies, yielding the non-N-protected a , b -unsaturated g -lactam quantitatively.

In summary, 5-substituted a , b -unsaturated g -lactams were obtained in novel reaction cascades starting from iron-substituted N-sulfonyl or N-sulfinyl azadienes and organometallic reagents. Enantiomerically pure derivatives were prepared from chiral sulfinamides by a palladium-catalyzed cyclocarbonylation strategy starting from b -bromo-substituted N-sulfinyl azadienes.

References:

1. K. Rück-Braun, Angew. Chem. Int. Ed. Engl. 1997, 36, 509.
2. P. Amrhein, D. Schollmeyer, K. Rück-Braun Organometallics 2000, in press.
3. K. Rück-Braun , P. Amrhein Eur. J. Org. Chem. 2000, in press.
4. P. Amrhein, D. Schollmeyer, K. Rück-Braun Org. Lett. 2000, submitted for publication.
5. F. A. Davis, W. McCoull J. Org. Chem. 1999, 64, 3396.
6. D. A. Cogan, G. Liu, J. A. Ellman Tetrahedron 1999, 55, 8883.