Synthesis of Carbazole Alkaloids by Ring-Closing Metathesis and Ring Rearrangement-Aromatization

Article abstract of DOI:10.1002/anie.201508746

Aprocess for the assembly of carbazole alkaloids has been developed on the basis of ring-closing metathesis (RCM) and ringrearrangement-aromatization (RRA) as the key steps. This method is based on allyl Grignard addition to isatin derivatives to provide smooth access to 2,2-diallyl 3-oxindole derivatives through a 1,2-allyl shift. The diallyl derivatives were used as RCM precursors to afford a novel class of spirocyclopentene-3-oxindole derivatives, which underwent a novel RRA reaction to afford carbazole derivatives. The synthetic sequence to carbazoles was shortened by combining the RCM and RRA steps in an orthogonal tandem catalytic process. The utility of this methodology was further demonstrated by the straightforward synthesis of carbazole alkaloids, including amukonal derivative, girinimbilol, heptaphylline, and bis(2-hydroxy-3-methylcarbazole). Just a hop, skip, and a jump away: The addition of allyl Grignard/indium reagents to isatins, ring-closing metathesis (RCM), and ring rearrangement-aromatization (RRA) provided carbazole derivatives in high overall yield (see scheme). The RCM step afforded spirocyclic 3-oxindoles, which underwent acid-catalyzed RRA to give carbazoles. A step-economical tandem RCM/RRA process was also developed and applied to the synthesis of carbazole alkaloids.

Full text of DOI:10.1002/anie.201508746

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201508746
German Edition: DOI: 10.1002/ange.201508746
Heterocycle Synthesis
Synthesis of Carbazole Alkaloids by Ring-Closing Metathesis and Ring
Rearrangement–Aromatization
Kalyan Dhara, Tirtha Mandal, Joydeb Das, and Jyotirmayee Dash*
Abstract: Aprocess for the assembly of carbazole alkaloids has
been developed on the basis of ring-closing metathesis (RCM)
and ringrearrangement–aromatization (RRA) as the key steps.
This method is based on allyl Grignard addition to isatin
derivatives to provide smooth access to 2,2-diallyl 3-oxindole
derivatives through a 1,2-allyl shift. The diallyl derivatives were
used as RCM precursors to afford a novel class of spirocyclo-
pentene-3-oxindole derivatives, which underwent a novel RRA
reaction to afford carbazole derivatives. The synthetic sequence
to carbazoles was shortened by combining the RCM and RRA
steps in an orthogonal tandem catalytic process. The utility of
this methodology was further demonstrated by the straightfor-
ward synthesis of carbazole alkaloids, including amukonal
derivative, girinimbilol, heptaphylline, and bis(2-hydroxy-3-
Scheme 1. A general approach to carbazoles.
methylcarbazole).
C
arbazoles are common motifs in natural products and
organometallic reagent to enable access to various analogues
of carbazole derivatives. Theoretically, carbazoles 1 can be
accessed from isatins by a) the addition of an allyl metal
reagent to give 3-A, b) RCM of the diallyl compound 3-A,
and c) aromatization through dehydration of the tetrahydro-
carbazole intermediate 2-A (Scheme 1).
To examine the feasibility of the proposed approach, we
prepared a variety of N-substituted isatins 4a–h (see the
Supporting Information) and treated them with an allyl
Grignard reagent. We were delighted to observe that when N-
methylisatin (4a) was treated with allylmagnesium bromide
[1]
biologically active molecules. Although diverse synthetic
routes to carbazoles have been described, a general and
[1–4]
efficient route to carbazole alkaloids is still desirable.
One
of the most commonly used synthetic methods to access
carbazole derivatives involves the Buchwald–Hartwig cou-
pling of arylamines with aryl halides, followed by oxidative
cyclization.
and iron-mediated process
the synthesis of carbazole derivatives. Approaches based on
olefin metathesis have also received considerable attention
for the construction of aromatic and heteroaromatic com-
[
1,2]
[2g]
A direct catalytic CÀH amination process
[4f,g]
have also been developed for
[
5]
in Et O–THF at 08C and the mixture was allowed to warm to
2
[
1a,5e, 6]
pounds.
Two methods have been reported for the
room temperature, the 2,2-diallyl-3-oxindole 3a was formed
in 64% yield (Scheme 2). The addition of allylmagnesium
chloride to N-methylisatin was previously reported to give
synthesis of carbazole derivatives from 3-formyl-substituted
indoles through RCM–aromatization sequences.
[3]
[8]
Herein, we disclose a facile synthetic approach to
naturally occurring carbazole alkaloids from isatin derivatives
by the use of RCM and a novel rearrangement as the key
steps. We anticipated that carbazole derivatives 1 could be
constructed by the ring rearrangement–aromatization of
spirocyclic isatin derivatives 2, which could be derived from
compound 3a in low yield (20%). The scope of this
Grignard reaction was then explored. Both electron-rich
and electron-deficient N-substituted isatins 4 afforded the
corresponding 2,2-diallylindolin-3-ones 3 in acceptable yields.
The Grignard addition presumably proceeds by the formation
of an intermediate A, which further reacts with excess
allylmagnesium bromide to form the intermediate B. The
elimination of OMgBr may lead to the indolinium intermedi-
ate C, which undergoes a 1,2-shift of the allyl group with the
elimination of OMgBr to afford the diallyl compound 3
[7]
2
3
,2-diallyl 3-oxindoles 3 by RCM (Scheme 1). The 2,2-diallyl
-oxindoles 3 could be readily prepared by the addition of
allyl metal reagents to the readily available isatin derivatives.
Substituted allyl bromides 5 could be used to form the allylic
(Scheme 3).
We next prepared unsymmetrical diallyl 3-oxindoles 3i–k
[
+]
[+]
[
*] K. Dhara, T. Mandal, J. Das, Prof. Dr. J. Dash
Department of Organic Chemistry
by sequential allyl metal addition to isatins 4 (Scheme 4).
Allyl indium addition took place chemoselectively at the C3
position of isatin derivatives. The reaction of isatins 4 with
allyl bromides 5a–c in the presence of indium metal and
sodium iodide in DMF at room temperature afforded 3-allyl
Indian Association for the Cultivation of Science
Jadavpur, Kolkata-700032 (India)
E-mail: ocjd@iacs.res.in
+
[
] These authors contributed equally.
3
-hydroxy-2-oxindole derivatives 6a–c in excellent yield
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508746.
[9]
(Scheme 4). The subsequent addition of allylmagnesium
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Scheme 2. Exploration of the allyl Grignard addition to isatin deriva-
tives. Reactions conditions: 4 (2.0 mmol, 1.0 equiv), allylmagnesium
bromide solution (1m in Et O, 5.0 equiv), Et O–THF (10 mL), room
2
2
temperature, 3 h. Bn=benzyl.
[a]
[b]
Scheme 4. Sequential addition of allylindium and Grignard reagents
to isatin derivatives.[a] Reaction conditions: 4 (2.0 mmol, 1.0 equiv),
allyl bromide (1.6 mmol), NaI (1.6 mmol), indium metal (1 mmol),
DMF, room temperature. [b] Reaction conditions: 6 (2.0 mmol,
1
.0 equiv), allylmagnesium bromide solution (1m in Et O, 3.0 equiv),
2
Et O–THF (10 mL), room temperature, 3 h. DMF=N,N-dimethyl-
2
formamide.
Scheme 3. Proposed rearrangement pathway for the formation of 2,2-
diallyl 3-oxindoles 3.
bromide to the monoallyl 2-oxindoles 6a–c afforded 2,2-
diallyl 3-oxindoles 3i–k in good yield through the 1,2-allyl-
shift pathway (Scheme 3).
Ring-closing metathesis (RCM) of the synthesized 2,2-
diallyl 3-oxindole precursors 3 was next explored (Scheme 5).
RCM of the dialkene 3a with the Grubbs second-generation
catalyst (G-II; 5 mol%) in CH Cl2 at room temperature
2
provided the desired 2-spirocyclopentene-3-oxindole deriva-
tive 2a in 78% yield. Electron-rich and electron-deficient
dialkenyl 3-oxindoles 3 were converted into the correspond-
ing spirocyclic compounds 2 in excellent yield. The structure
of the spirocyclic compound 2e was confirmed by single-
crystal X-ray analysis (see Figure S1 in the Supporting
Information). RCM of 2-allyl-2-cinnamyl-3-oxindole 3k
afforded the spirocyclic compound 2b in 85% yield. Several
synthetic methods have been reported for the preparation of
[
10]
3
-spirocyclic 2-oxindole derivatives, but few methods are
Scheme 5. Ring-closing metathesis of diallyl 3-oxindole derivatives.
Reaction conditions: 3 (0.3 mmol, 1.0 equiv), G-II catalyst (5 mol%),
[11]
known to give spirocyclic 3-oxindole derivatives.
The
protocol described herein provides facile access to a novel
class of spirocyclic 3-oxindole derivatives. Previously, we
reported RCM-based approaches for the synthesis of spiro-
CH
Cl (4 mL), room temperature, 8 h. Cy=cyclohexyl, Mes=2,4,6-
2 2
trimethylphenyl.
[12]
cyclic thiazolidine diones and hydantoins.
Table S1 in the Supporting Information). The rearrangement
also proceeded with Brønsted acids such as triflic acid (TfOH)
and trifluoroacetic acid (TFA) in CH Cl at 458C. When the
To our delight, oxindole 2a reacted with p-toluenesulfonic
acid (TsOH; 10 mol%) in toluene at 808C to afford the
carbazole derivative 1a in 88% yield (Scheme 6; see also
2
2
Lewis acids BF ·OEt , TiCl , and SnCl were used as catalysts
3
2
4
4
1
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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
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Communications
6
7% yield. Girinimbilol (11) was further con-
[23]
verted into heptaphylline
(12) in 85% yield
through oxidation with DDQ.
In summary, the described method makes use
of rearranged 2,2-diallyl-3-oxindole products,
obtained by allyl Grignard addition to isatin
derivatives, as precursors of ring-closing meta-
thesis. The RCM afforded a novel class of
spirocyclic 3-oxindoles that undergo a novel aro-
matization-driven ring rearrangement to provide
facile access to carbazole derivatives. Further-
more, we have demonstrated an orthogonal
tandem process that combines the RCM and
RRA processes in a single reaction vessel. The
carbazole derivatives can be synthesized in just
two steps from isatin derivatives in improved
yield. The method has been used for the synthesis
of carbazole natural products in a concise and
especially straightforward manner.
Experimental Section
Typical procedure for one-pot RCM/RRA: G-II
(8.48 mg, 0.01 mmol, 5 mol%) and TsOH (3.5 mg,
0
.02 mmol, 10 mol%) were added to a solution of
oxindole 3d (50 mg, 0.15 mmol) in toluene, and the
reaction mixture was heated at 808C for 6 h and then
concentrated. Purification of the residue by column
chromatography (EtOAc–hexane, 10:90–20:80) on silica
gel afforded the carbazole 1d (37 mg, 86%) as a white
solid.
Scheme 8. Synthesis of naturally occurring carbazole alkaloids. a) 1. CCl CH(OH) ,
3
2
NH OH–HCl, Na SO , 608C, 12 h; 2. H SO , 808C, 30 min, 65%; b) 1. BnBr, K CO ,
2
2
4
2
4
2
3
DMF, room temperature, 8 h, 95%; 2. allylMgBr, THF, room temperature, 2 h, 75%;
c) G-II (5 mol%), CH Cl , 8 h, room temperature, 88%, or G-I (10 mol%), CH Cl ,
2
2
2
2
1
(
3
8 h, room temperature, 78%; d) TsOH (10 mol%), toluene, 808C, 3 h, 95%; e) G-II
5 mol%), TsOH (10 mol%), 808C, 6 h, 86%; f) DDQ, MeOH, room temperature,
0 min, 91%; g) 10% Pd/C, H , MeOH, 36 h, room temperature, 98%; h) CuCl2
Acknowledgements
2
(
10 mol%), DBU, MeCN, 1008C, 26 h, 51%; i) 10, DIPEA, CH Cl , 12 h, room
2 2
This research was funded by the DST and the
CSIR, India. We thank Professor Dr. Hans-Ulrich
Reissig for useful discussions. K.D. thanks UGC,
T.M. and J. Das thank the CSIR, India for research
fellowships.
temperature, 67%; j) DDQ, MeOH, room temperature, 30 min, 85%. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone,
DIPEA=N,N-diisopropylethylamine.
Keywords: allylation · carbazole alkaloids · rearrangement ·
ring-closing metathesis · tandem catalysis
MeOH provided the N- and O-benzyl-protected mukonal
[15b]
derivative 7 in 91% yield.
Hydrogenolysis of the benzyl
protecting groups in 1l provided the 2-hydroxy-3-methylcar-
bazole (8), a common intermediate for the synthesis of
a variety of naturally occurring carbazole alkaloids.
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15831–15835
Angew. Chem. 2015, 127, 16057–16061
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Received: September 18, 2015
Published online: November 19, 2015
Angew. Chem. Int. Ed. 2015, 54, 15831 –15835
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 15835