Nonclassical Bergman Cyclization of Enediynes：Synthesis of Dibenzofurans and Carbazoles

Chia-Ying Lee, Chi-Fong Lin, Ching-Chen Chiu, and Ming-Jung Wu*Faculty of Medicinal and Applied Chemistry, and Graduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University, Kaohsiung,

Taiwan

Recently, we found that treatment of 2-(6-substituted 3(Z)-henxen-1,5-diynyl)phenyl t-butyldimethylsilyl ethers 1 with sodium methoxide in refluxing methanol gave dibenzofurans 2 in excellent yield.1 The aniline analogs 3 have also been carried out to test the anionic cycloaromatization of enediynes and we found that treatment of 3 with potassium t-butoxide in NMP at 60 oC gave the carbazole 4 in 45-86 % yields.2

OTBS

R

NaOCH3

CH3OHO

R

1 2

NHAc

R

KOtBu

NMP NH

R

3 4

( Eq 1 )

( Eq 2 )

OTBS

R

X

X

10b R = C5H11 10c R = C7H15 10d R = C3H6OTHP 10e R = C4H9 10f R = C5H11 10g R = C7H15 10h R = C3H6OTHP 10i R = C4H9 10j R = C5H11

O

X

X

R

Methods

reflux, 16h

11b ( 56 % )11c ( 50 % )11d ( 57 % )11e ( 93 % )11f ( 94 % )11g ( 92 % )11h ( 91 %)11i ( 75 % )11j ( 75 % )

Method A : Na, MeOH

X,X= H, H

X,X=

X,X=

Method B : K2CO3, MeOH10b 10e

11b ( 56 % )11e ( 93 % )

Table1. Generation of 5-substituted dibenzofurans and related moleculars.

Reference：1. Wu, M. J.; Lee, J. Y.; Lin, C. F. Angew. Chem., Int. Ed. 2002, 41, 40772. Lee, C.-Y.; Lin, C.-F.; Lee, J.-L.; Chiu, C.-C.; Lu, W.-D.; Wu, M.J.; J. Org. Chem.; 2004, 69, 2106-2110

R

NH2NH

R

+

NH

R

12 13 14

Entry Yield (%)

NMP, 60 oC2 h

12b. R = C5H11 13b (47%) 14b (21%)

12c R = C6H13 13c (36%) 14c (25%)

12d. R = C7H15 13d (44%) 14d (23%)

12e. R = C3H6OTHP 13e (54%) 14e (40%)

Table 2. The results for the cyclization of compounds 12a-e using t-BuOK as a base

t-BuOK

NHCOCH3

R2

15a. R2= C3H7

15b. R2= C4H9

15c. R2= C5H11

15d. R2= C6H13

15e. R2= C7H15

15f. R2= C3H6OTHP

15g. R2=C4H8OTHP

13a. ( 86% )

13b. ( 65% )

13c. ( 77% )

13d. ( 53% )

13e. ( 60% )

13f. ( 53% )

13g. ( 45% )

KOtBu

NMP NH

R2

15 13

Entry Yields (%)

Table 4. A Hernating route for the synthesis of Carbazoles.

C4H9

H

NH2

I

C4H9

NH2

NH

C4H9

Pd ( PPh3) 4, CuI

NMP, heat

n - BuNH2 , Et2O

12 a ( 57% )

13 a( 60% )

Scheme 3. Palladium-Catalyzed Coupling of 12 and subsequent cyclization of the product 13

t-BuOK

9

14

NMP, heat

t-BuOK

NH

C4H9

13 a (58 % )

+NH

C4H9

C4H9

NHAc

15a ( 58% )

Acetyl chlorideEt3N, CH2Cl2

14 a ( 21% )

Cl

Cl

+ C4H9H

Cl

C4H9SiMe3H

C4H9

R

OTBS

IC4H9

OTBSO

C4H9

Na , MeOH

Pd ( PPh3) 4, CuI

Pd ( PPh 3 ) 4 , CuI

Pd ( PPh3) 4, CuIreflux

n - BuNH2 , Et2O

n - BuNH2 , Et2O

n - BuNH2 , Et2O

5 6 7( 51%)

8 R=TMS ( 71%)K2CO3 MeOH

9 R=H ( 86%)

10a ( 57% ) 11a( 60% )

Scheme 1. Palladium-Catalyzed Coupling of 10 and subsequent cyclization of the product11

Part A Synthesis of Dibezofuran

R

OTBS

X

Xdesilylation

R

O

X

X

O

R

O

R

H

Scheme 2 Proposed Mechanism

Part B Synthesis of Carbazole

Abstract