Cryogenics Report of Kumamoto University, 2006, 17, 1-4.

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Cryogenics Report of Kumamoto University, 2006, 17, 1-4.

Manganese(III)-Based Oxidative Dual Cyclization of Cyclic Triketones with 1,1-Disubstituted Alkenes

Kentaro Asahi and Hiroshi Nishino

^*

Department of Chemistry, Graduate School of Science and Technology, Kumamoto University Kurokami 2-39-1, Kumamoto 860-8555, Japan

Abstract: Manganese(III)-based oxidation of a mixture of 3-(2-oxoethyl)piperidine-2,4-diones 5 and 1,1-diarylethenes 6 in acetic acid at reflux temperature gave structurally unique heterocyclic [4.3.3]propellanes 7 in high yields. Whereas a similar reaction using a catalytic amount of manganese(III) acetate at room temperature in air selectively yielded propellane-type endoperoxides 8 in moderate to good yields. The reaction using cyclic triketones 11 also afforded similar results.

However, the manganese(III)-based dual cyclization of 2-(3-oxopropyl)-substituted cyclic diketones 15 was suppressed and most of the reaction stopped at the monocyclization stage. The mechanism for the formation of the propellanes and their derivatives was discussed.

Some biologically active furopyridinones are known as antifungal and antibacterial heterocycles.

For example, cladobotryal and an isomeric furopyridinone, which are metabolites of the fungus Caldobotrium varium, have an inhibitory effect on the growth of plant pathogens and moderate activity against some drug-resistant bacteria.

¹

Recently, we reported that the reaction of 1,1-disubstituted ethenes 1 with 2-(2-oxoethyl)malonates 2 in the presence of a stoichiometric amount of manganese(III) acetate in boiling acetic acid produced 2,8-dioxabicyclo[3.3.0]oct-3-enes 3 via the cycloaddition-tandem cyclization (Scheme 1).

²

The 2,8-dioxabicyclo[3.3.0]oct-3-ene skeleton is found in biologically and pharmacologically active compounds, such as the insect antifeedant clerodin isolated from Clerodendrum infortunatum.

³

Me Ar O O

Ac R

¹

R

¹

O R

¹

O

R

¹

Me

Ac Ar

O Ar

Ac Mn(OAc)

₃

AcOH reflux

1 2 3 (53-78%) 4 (11-24%)

Scheme 1

R

¹

R

¹

Propellanes are compounds in which a bond between two carbon atoms forms the axis of three linked bridges, and the structures are found in a lot of different categories of natural products. The synthesis of heterocyclic propellanes is attractive from the standpoint of the challenging molecular framework and finding potent biological and pharmacological activities. In connection with our study, we tried to synthesize nitrogen-containing heterocyclic propellanes using manganese(III)-based tandem cyclization of 3-(2-oxoethyl)piperidine-2,4-diones. A mixture of 3-(2-oxoethyl)piperidine-2,4-dione 5 (R

¹

= Bn, R

²

= Ph) and 1,1-diphenylethene (6: R

³

= Ph) was allowed to react with manganese(III) acetate in acetic acid at reflux temperature. The reaction finished within 1 min, and after usual work-up, azadioxa[4.3.3]propellane 7 together with a small amount of azatrioxa[4.4.3]propellane 8 and inseparable acetates 9 and 10 were obtained (Scheme 2).

⁴

The structure of the products 7-10 was determined by IR, NMR, positive FAB mass, and elemental analysis. A similar reaction of other 3-(2-oxoethyl)piperidine-2,4-diones 5 (R

¹

= Me, Et, Pr, i-Pr, Ph, R

²

= 4-MeC

6

H

4

, 4-ClC

6

H

4

) with various alkenes 6 (R

³

= 4-MeC

6

H

4

, 4-MeOC

6

H

4

, 4-ClC

6

H

4

, 4-FC

6

H

4

) was carried out and the corresponding azadioxa[4.3.3]propellanes 7 were mainly obtained in moderate to good yields along with azatrioxa[4.4.3]propellanes 8 and the

*

e-mail: [email protected] Fax: +81-96-342-3374

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Cryogenics Report of Kumamoto University, 2006, 17, 1-4.

inseparable acetates 9 and 10 as by-products. We assumed that the azadioxa[4.3.3]propellanes 7 and the acetates 9, 10 must be formed from the same intermediate. Therefore, when a mixture of acetates 9 and 10 (R

¹

= Bn, R

²

= Ph, R

³

= 4-Cl-C

6

H

4

) was heated under reflux in acetic acid for 10 min, they could be converted into the corresponding propellane 7 in high isolated yield (92%).

N R

¹

O

O R

²

O

N R

¹

O

O O R

³

R

³

N R

¹

O

O R

²

R

³

O R

³

AcO

N R

¹

O

O R

³

R

³

R

²

O

OAc Mn(OAc)

₃

AcOH reflux, 1 min

5 7 (53-28%) 8 (4-10%) 9 (13-39%) 10 (8-21%)

N O

R

¹

O

R

²

O O R

³

R

³

R

³

R

³

6 R

¹

= Bn, Me, Et, Pr, i-Pr, Ph R

²

= Ph, 4-Me-C

₆

H

₄

, 4-Cl-C

₆

H

₄

R

³

= Ph, 4-Me-C

₆

H

₄

, 4-MeO-C

₆

H

₄

, 4-Cl-C

₆

H

₄

, 4-F-C

₆

H

₄

AcOH, reflux, 10 min

(92%) R

¹

= Bn, R

²

= Ph, R

³

= 4-Cl-C

₆

H

₄

Scheme 2 R

²

+ + +

The formation of the azatrioxa[4.4.3]propellanes 8 deserves comment. In our previous study, it was suggested that the endoperoxide ring was derived from the molecular oxygen dissolved in the solvent acetic acid.

⁵

In order to avoid the formation of the minor by-product 8, the complete degassing under reduced pressure for 30 min using an ultrasonicator followed by argon displacement before the reaction could control the formation of 8, and the sole production of azadioxa[4.3.3]propellanes 7 was accomplish (Scheme 3, left).

N O

O R

¹

R

²

Mn(OAc)

₃

O AcOH, under Ar reflux for10 min

5 R

¹

= Aryl or alkyl, R

²

, R

³

= Aryl

7 (62-98%) 8 (53-75%)

Scheme 3

cat. Mn(OAc)

₃

AcOH, under air

r.t. for 7 h then 100

^o

C for 30 min N R

¹

O

O O R

³

R

³

R

²

N

O R

¹

O

R

²

O O R

³

R

³

R

³

R

³

6 R

³

R

³

6 The endoperoxide framework has been important for the synthesis of naturally occurring bioactive 1,2-dioxanes.

⁶

For example, naturally occurring artemisinin isolated from Artemisia annua is a well-known potent antimalarial agent.

⁷

In addition, chemically synthesized azaartemisinin has much stronger antimalarial activity than its natural product.

⁸

Therefore, we next investigated the synthesis of minor by-product, azatrioxa[4.4.3]propellanes 8.

The autoxidation of 3-(2-oxoethyl)piperidine-2,4-diones 5 (R

¹

= Bn, Me, Et, Pr, i-Pr, Ph, R

²

= Ph, 4-MeC

6

H

4

, 4-ClC

6

H

4

) with alkenes 6 (R

³

= Ph, 4-MeC

6

H

4

, 4-MeOC

6

H

4

, 4-ClC

6

H

4

4-FC

6

H

4

) was carried out in acetic acid at room temperature in air using a catalytic amount of manganese(III) acetate, giving the desired azatrioxa[4.4.3]propellanes 8 in good yields. The optimized reaction conditions were that the mixture was stirred for 7 h under air in the presence of a catalytic amount of manganese(III) acetate followed by heating at 100 °C for 30 min (Scheme 3, right).

In order to apply the manganese(III)-based propellane formation, the reaction of

2-(2-oxoethyl)cycloalkane-1,3-diones 11 with alkenes 6 was examined under similar reaction

conditions (Scheme 4). When the reaction was conducted using a stoichiometric amount of

manganese(III) acetate at reflux temperature, the corresponding propellanes 12 were obtained in

good yields. Furthermore, the ring size of the cycloalkanediones 11 is larger, the yield of the

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Cryogenics Report of Kumamoto University, 2006, 17, 1-4.

propellanes 12 is lower, and spiroalkanes 13 were also formed (Scheme 4, left). On the other hand, the reaction in air at room temperature gave trioxapropellanes 14 as a sole product (Scheme 4, right).

However, the oxidation of cycloheptane-1,3-dione 11 (R

¹

= H, R

²

= H, n = 2) gave an intractable mixture and the corresponding trioxapropellanes 14 were not isolated.

O Ph

Ph

O O R

³

Mn(OAc)

₃

O AcOH, under Ar

reflux

11 O

O R

³

Ph

R

¹

, R

²

= H, Me, R

³

= Ph, 2-Naphtyl 12 (27-80%)

Ph Ph cat. Mn(OAc)

₃

AcOH, under air

r.t.

14 (75-83%) O

O R

³

O O Ph

Ph R

¹

R

¹

R

¹

R

¹

R

¹

R

¹

n n n

(n = 1) (n = 1-3)

13 (0-31%)

n

R

²

R

²

R

²

R

²

R

²

R

²

Scheme 4 O

Ph PhO

R

¹

R

¹

R

²

R

²

O R

³

A similar reaction of 3-oxopropyl-substituted cycloalkanediones 15 at reflux temperature gave the desired dioxapropellanes 16 in moderate yields together with oxabicyclo[4.3.0]nonanes 17 (Scheme 5, left). In this case, the continuous heating after finishing the oxidation did not increase the yield of 16. On the other hand, the autoxidation of 15 at room temperature did not give trioxapropellanes, but dioxabicyclo[4.4.0]decanes 18 were obtained (Scheme 5, right). The substituent effect of 4-chlorophenyl group at R

¹

in 15 was not observed.

O Ph

Ph

O O

Mn(OAc)

₃

AcOH, under Ar

reflux

15 O

O Ph Ph

R

¹

= Ph, 4-Cl-C

₆

H

₄

n = 0, 1

16 (21-49%)

Ph Ph cat. Mn(OAc)

₃

AcOH, under air

r.t.

18 (94-99%)

n

R

¹ n

O R

¹

O

n

R

¹

O

O O Ph Ph

OH O

n

R

¹

O

O Ph Ph

OH 17 (27-37%)

Scheme 5

The proposed mechanism for the formation of dioxapropellanes and trioxapropellanes is outlined in Scheme 6. The manganese(III)-based propellane formation would start the production of the maganese(III)-piperidinedione enolate complex A. It is known that the generation of enolate complex such as A in the manganese(III) acetate oxidation of 1,3-dicarbonyl compounds is the rate-determining step.

^9,10

When an electron-rich alkene 6 exists in the reaction system, easy electron transfer from 6 to A with loss of manganese(II) acetate would occur and give the corresponding tertiary carbon radical B via an electron donor-acceptor-like complex between the electron-rich alkene 6 and the electron-poor enolate complex A.

¹⁰

When the reaction was carried out at room temperature in air using a catalytic amount of manganese(III) acetate, the carbon radicals B could trap molecular oxygen dissolved in the solvent to produce the peroxy radicals C during the reversible fashion. The peroxy radicals C should be reduced by the manganese(II)-enolate complex D formed by the ligand-exchange reaction of manganese(II) acetate with other piperidinediones 5 during the reaction, followed by cyclization to give the corresponding azabicyclic peroxides E.

⁵

As a result, the manganese(III) species should be reproduced, and the autoxidation reaction system would be completely established by use of Mn(III)-Mn(II) catalysts.

Subsequently, the thermodynamically stable azatrioxa[4.4.3]propellanes 8 would be obtained by the

intramolecular cyclization between the 2-oxoethyl side chain and the hydroxyl group in the

azabicyclic peroxides E. In contrast, when the reaction was carried out at reflux temperature

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Cryogenics Report of Kumamoto University, 2006, 17, 1-4.

under argon using a stoichiometric amount of manganese(III) acetate, the carbon radicals B would be quickly oxidized by manganese(III) species to afford the corresponding tertiary carbocations F because of the absence of dissolved molecular oxygen and the presence of sufficient metal oxidant.

As a result, the carbocations F should cyclize at the keto carbonyl oxygen of the piperidinedione to produce thermodynamically more stable carbocations G, which would be allowed to intramolecular cyclize at the carbonyl oxygen of the most appropriate position to finally produce the desired dioxapropellanes 7 with deprotonation. The by-products 9 and 10 must be formed by the attack of the acetate ion on the cations F and G, however, the reaction should be reversible. The dioxapropellanes 7 could be solely obtained when the dissolved molecular oxygen in the solvent was completely removed by degassing before the oxidation and the heating of the reaction mixture was continued for 10 min after the oxidation.

Scheme 6 6

5 N O

O

R

³

R

²

O Mn

^III

N O

O

R

³

R

²

O Mn

^II

N

O

R

³

R

²

R

¹

R

¹

N O

O

R

³

O

R

²

R

¹

R

¹

O O N O

O

R

³

R

²

R

¹

R

¹

O O

R

¹

R

¹

Mn(OAc)

₂

AcOH

N O

R

³

O

R

²

R

¹

R

¹

O O OH O

₂

/r.t. 8

-H

₂

O

A

B C

D

E N

O

R

³

R

²

R

¹

R

¹

Mn(III)

heat

9 N O

R

³

O

R

²

O R

¹

R

¹

10 AcOH

AcOH

7 -H

F

G

Mn

O O O

In summary, we have accomplished the unique synthesis of heterocyclic propellanes 7, 8, 12, 14, and 16 using the manganese(III)-based oxidative dual cyclization of 3-(oxoethyl)piperidine-2,4-diones 5, 2-(2-oxoethyl)cycloalkane-1,3-diones 11, and 3-oxopropyl-substituted cycloalkanediones 15 with 1,1-diarylethenes 6. In addition, we have also proposed the mechanism for the formation of heterocyclic propellanes.