Angewandte
Chemie
Table 1: Optimization of the one-pot tandem RCM and aromatization
reaction.
[a]
[a]
Entry Acid catalyst Solvent T, t
Conv. [%]
2d/1d
1
2
3
4
5
TsOH
TsOH
TfOH
TFA
CH Cl
toluene 808C, 6 h
rt, 12 h
>99
>99 (91)
80:20
2
2
[
b]
b]
b]
0:100
0:100
0:100
70:30
[
CH Cl
458C, 10 h >99 (88)
458C, 18 h >99 (87)
458C, 12 h >99
2
2
2
2
[
CH Cl
2
BF ·Et O
3
CH Cl
2
2
1
[
a] The conversion and 2d/1d ratio were determined by H NMR
spectroscopic analysis of the crude product mixture. [b] The yield of 1d is
Scheme 6. One-pot ring rearrangement–aromatization (RRA) of spiro-
cyclic 3-oxindoles to carbazoles. Reactions conditions: 2 (0.2 mmol,
given in parentheses.
1
.0 equiv), TsOH (10 mol%), toluene (5 mL), 808C, 3 h.
the product mixture consisted mainly of the RCM product 2d
(2d/1d 80:20; Table 1, entry 1). When the substrate was
in CH Cl , no reaction occurred at room temperature, and the
heated with the same two catalysts in toluene at 808C for 6 h,
the RCM–RRA sequence proceeded efficiently to give 1d
almost exclusively in 91% yield, and when the reaction was
carried out with TfOH or TFA as the acid catalyst in CH Cl
2
2
reaction was sluggish at 458C (see Table S1). The reaction of
spirocyclic 3-oxindoles 2b–j with TsOH was then investigated
in toluene at 808C. We found that the reaction time and yield
were not influenced by the electronic character of the
substrate, and the corresponding carbazole derivatives 1b–j
were isolated in excellent yield. In this rearrangement, the
carbonyl group is probably protonated, and the nitrogen lone
pair facilitates a 1,2-shift leading to the formation of the ring-
expanded indolinium-ion intermediate E. Loss of water from
intermediate F then provides the carbazole 1 (Scheme 7).
2
2
at 458C, the carbazole derivative 1d was obtained as the sole
product in high yield (Table 1, entries 2–4). The reactivity of
Lewis acids, such as BF ·OEt , TiCl , and SnCl , was consid-
3
2
4
4
erably poorer for the rearrangement step, although they did
not interfere with the RCM step, as only the RCM product
was observed at room temperature (see Table S2).
To further explore the synthetic potential of this protocol
in natural product synthesis, we chose substituted
isatin derivatives that would provide the requisite
functionality for the construction of the carba-
zole natural products mukonal, girinimbilol,
heptaphylline, and 1,1’-bis(2-hydroxy-3-methyl-
carbazole) (Scheme 8). The carbazole alkaloids-
[
15]
mukonal and
zole)
bis(2-hydroxy-3-methylcarba-
[18]
are isolated from the stem bark of
Murraya koenigii. Girinimbilol and heptaphyl-
line are isolated from both the stem bark of
[16]
Scheme 7. Proposed mechanism for the aromatization-driven ring rearrangement.
[16]
Murraya koenigii and root bark of Clausena
[
17]
Next, we envisioned the development of a new tandem
process in which the RCM and RRA steps would be
combined in a single reaction vessel. Tandem processes,
which combine multiple steps in a one-pot process, signifi-
cantly reduce reaction sequences, time, energy, and the usage
heptaphylla. They exhibit broad pharmacological activity,
including anti-platelet-aggregation, antimycobacterial, anti-
inflamatory, anti-HIV-1, and anti-tumor-promoting activ-
[
19]
ity.
[20]
By an optimized Sandmeyer reaction,
6-hydroxy-5-
[13]
of solvents and other materials for workup and purification.
methylisatin (4l) was prepared from the aniline derivative 6 in
65% yield. Benzyl protection of 4l, followed by a Grignard
reaction, afforded the desired diallyl-3-oxindole 3l. RCM of
3l with G-II afforded the spirocyclic 3-oxindole 2l in 88%
yield. The first-generation Grubbs catalyst (G-I) was used
forthe large-scale synthesis of 2l (see the Supporting Infor-
mation). The spirocyclic compound 2l underwent one-pot
rearrangement–aromatization to afford the carbazole 1l in
95% yield. When diallyl-3-oxindole 3l was subjected to the
tandem RCM/RRA conditions (5 mol% G-II, 10 mol%
TsOH in toluene), 1l was obtained in 86% yield (as compared
to 83% in two steps). The oxidation of 1l with DDQ in
Owing to the stability of ruthenium-based metathesis cata-
lysts, several examples of tandem reactions involving olefin
[14]
metathesis have been developed. In a one-pot procedure,
the RCM/RRA was performed with 2,2-diallyl-3-oxindole 3d
as the substrate with G-II (5 mol%) and acid catalysts
[5b]
(
(
Table 1). Several acid catalysts, including Brønsted acids
TsOH, TfOH,and TFA) and Lewis acids (BF ·OEt , TiCl ,
3
2
4
and SnCl ) were explored for this orthogonal tandem reaction
4
(
see Table S2). Although the desired carbazole product 1d
was observed when 3d was treated with G-II (5 mol%) and
TsOH (10 mol%) in CH Cl at room temperature for 12 h,
2
2
Angew. Chem. Int. Ed. 2015, 54, 15831 –15835
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim