Synthetic studies on indolocarbazoles: A facile synthesis of staurosporinone analogues

FULL PAPER

DOI: 10.1002/ejoc.201500939

Synthetic Studies on Indolocarbazoles: A Facile Synthesis of Staurosporinone

Analogues

Potharaju Raju,^[a]Ganesan Gobi Rajeshwaran,^[a]and Arasambattu K. Mohanakrishnan*^[a]

Keywords: Synthetic methods / Natural products / Nitrogen heterocycles / Cyclization / Insertion / Staurosporinone

Synthesis of indolocarbazoles was achieved through thermal

electrocyclization followed by triethyl phosphite-mediated

nitrene insertion reactions. Total synthesis of staurosporinone

analogues was achieved from commercially available 2-

methylindole. The CDK5/p25 kinase inhibition potential of

some representative staurosporinone analogues was ex-

plored by using the TRFRET kinase assay.

substituents on the benzene portion have been synthesized

and explored as a new class of D1/CDK4 and JAK3 in-

hibitors.^[12]Isomeric indolo[3,2-a]carbazole alkaloids,

asteropusazole A (8) and asteropusazole B (9; Figure 1) iso-

lated from marine sponges,^[13]displayed moderate cytotoxi-

city and antimicrobial activity. Recently, indolo[2,3-a]carb-

azole analogues have also been explored for optical and so-

lar-cell applications.^[14]

Introduction

The chemistry of indolo[2,3-a]carbazoles obtained from

either soil organisms or marine sources, have been widely

explored because of their promising antifungal, antimicro-

bial, antitumor, and antihypertensive activities.^[1]Omura

and co-workers reported the first isolation and discovery of

staurosporine (1; Figure 1), a metabolite from Streptomyces

staurosporeus, as a highly potent protein kinase C (PKC)

inhibitor with an IC₅₀value of 2.7 nm.^[2]Staurosporine is

also known to inhibit cyclin B/CDK1 enzymes.^[3]Thus,

staurosporine (1) has become the lead structure for the de-

velopment of new PKC inhibitors. In general, indolocarb-

azole analogues displayed antitumor properties against

different human cancer cell lines^[4]and acted as chemo-

therapeutics against Alzheimer’s disease,^[5]and other neuro-

degenerative disorders.^[6]

In particular, staurosporine analogues 2 and 3 have high

affinity for PKC and also showed prominent cytotoxicity

against various human cancer cell lines.^[7]The other most

important indolo[2,3-a]carbazole alkaloid, rebeccamycin

(4) exhibited topoisomerase I inhibitory activity.^[8]Stauro-

sporinone (5) has cytotoxic and antimicrobial properties,

and inhibits protein kinase C and platelet aggregation.^[9]Gö

6976 (6), a non-glycosidic indolo[2,3-a]carbazole, shows se-

lective inhibition of protein kinase C and acts as an antago-

nist of HIV-1.^[10]Arcyriaflavins A-D 7 showed moderate

antibiotic and antifungal activities. Arcyriaflavin C dis-

played nanomolar-range cell-cycle inhibition effects at the

G1 and G2/M stages.^[11]Over the years, a plethora of indolo-

carbazole analogues that contain halogen and methoxy

The PKC and cyclin-dependent kinase inhibitory activi-

ties of indolo[2,3-a]carbazoles prompted chemists to de-

velop elegant strategies for the synthesis of these alka-

loids.^[1,12,15]In most of the synthetic protocols outlined,

electrocyclization reaction of bisindolylmaleimides under

photochemical conditions has been utilized as a key step.^[16]

The facile transformation of bisindolylmaleimides into

indolo[2,3-a]carbazoles was also achieved through oxidative

cyclization reactions that involved a Pd catalyst,^[17]2,3-

dichloro-5,6-dicyano-1,4-benzoquinone,^[18]and phenyliod-

ine bis(trifluoroacetate).^[19]The synthesis of indolo[2,3-a]-

carbazoles has also been accomplished through carbene^[20]

and nitrene^[21]insertion reactions, and ring-closing metathe-

sis.^[22]The Diels–Alder reaction of 2,2Ј-biindoles and their

bridged analogues with maleimides have been employed for

the synthesis of indolo[2,3-a]carbazoles.^[23]The Fischer-

indolization protocol was also utilized for the synthesis of

indolo[2,3-a]carbazoles.^[24]Recently, Orito and co-workers

achieved the synthesis of staurosporinone by Pd-catalyzed

carbonylation reaction of 5-aminomethyl indolo[2,3-a]carb-

azole.^[25]Most of the indolocarbazoles that exhibit potent

biological activities have substituents on the benzene por-

tion of the core. Despite several synthetic protocols avail-

able for indolocarbazoles, a flexible and efficient route for

the synthesis of unsymmetrical indolo[2,3-a]carbazole is

still in demand. We recently reported our preliminary re-

sults on the synthesis of indolocarbazoles that involve a

thermal electrocyclization reaction as a key step.^[26]We re-

port herein the full details of the synthesis and CDK5/p25

[a] Department of Organic Chemistry, University of Madras,

Guindy Campus, Chennai 600025, Tamil Nadu, India

E-mail: mohan_67@hotmail.com

mohanakrishnan@unom.ac.in

http://ww w .unom.ac.in

Supporting Information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201500939.

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Figure 1. Structures of biologically important indolocarbazoles.

kinase inhibition studies of staurosporinone analogues.

Synthesis of staurosporinone 13 was visualized by thermal

electrocyclization reaction^[27]of 1-(phenylsulfonyl)-2,3-di-

vinylindole (10) followed by allylic bromination and amid-

ation to give carbazole 12. 2Ј-Nitroarylcarbazole (12), upon

triethyl phosphite-mediated nitrene insertion followed by

subsequent cleavage of the phenylsulfonyl group, may af-

ford target compound 13 (Scheme 1).

Results and Discussion

The study began with preparation of required 2,3-divinyl

indole 10. The reaction of 2-methylindole (14) with methyl

acetoacetate (15) in the presence of FeCl₃(20 mol-%) in ac-

cordance with the published procedure^[28]furnished 2-

methyl-3-vinylindole (16) as a colorless solid in 93% yield.

The phenylsulfonylation of vinylindole 16 under phase-

transfer catalytic conditions^[29]gave expected 1-(phenylsulf-

onyl)indole 17 in good yield. Preferential allylic bromin-

ation of 17 with N-bromosuccinimide (NBS; 1.1 equiv.) in

the presence of a catalytic amount of 2,2-azo-bisisobutyro-

nitrile (AIBN) in CCl₄at reflux temperatures led to the iso-

lation of bromo compound 18 as a mixture of E and Z

isomers (Scheme 2). Pleasingly, the indolyl-2-methyl posi-

tion was selectively brominated, which was confirmed by

¹H NMR spectroscopy.

Upon oxidation of bromo compound 18 with bis(tetra-

butylammonium) dichromate^[30]in dry CHCl₃at reflux

temperatures for 4 h, followed by workup, afforded alde-

hyde 19 in 90% yield. Unfortunately, the expected Wittig–

Horner reaction of 3-vinyl-indole-2-carboxaldehyde (19)

with diethyl 2-nitrobenzyl phosphonate (20) with NaH as a

base in dry tetrahydrofuran (THF) at room temperature led

Scheme 1. Schematic pathway for staurosporine aglycon.

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Facile Synthesis of Staurosporinone Analogues

The Wittig–Horner reaction of indolylmethylphosphon-

ate ester 22 with 2-nitroarylaldehydes 23a–23d was facile.

However, if this reaction is performed at room temperature,

unwanted cleavage of the phenylsulfonyl unit is observed.

By heating a xylene solution of 2,3-divinylindoles 21a–

21d to reflux temperatures in the presence of 10% Pd/C

smooth electrocyclization followed by aromatization to af-

ford 2Ј-nitroarylcarbazoles 24a–24d as yellow solids in ex-

cellent yields. The remaining 2Ј-nitroarylcarbazoles 24e–24n

were also prepared by Wittig–Horner reaction of phos-

phonate ester 22 with 2-nitroarylaldehydes 23e–23n fol-

lowed by thermal electrocyclization of the resulting vinyl-

indoles (Scheme 5).

Scheme 2. Synthesis of bromo compound 18. Reagents and condi-

tions: (i) Methyl acetoacetate (15), FeCl₃(20 mol-%), 1,2-DCE,

room temp., 3 h, 93%; (ii) PhSO₂Cl, 60% NaOH/toluene,

Bu₄NHSO₄(cat.), r.t., 2 h, 92%; (iii) NBS, CCl₄, AIBN (cat.), re-

flux, 2 h, 92%.

to formation of required 2Ј-nitrophenylvinylindole 21a only

in poor yield (Scheme 3). Most of starting aldehyde 19 was

recovered unchanged possibly as a result of the low reactiv-

ity of the aldehyde carbonyl.

Scheme 5. Synthesis of 2Ј-nitroarylcarbazoles 24a–24n. Reagents

and conditions: (i) 10% Pd-C, xylenes, reflux, 24 h, 82–93%;

(ii) NaH, THF, –10 °C–0 °C, 23e–23n 2 h; (iii) 10% Pd-C, xylenes,

reflux, 24 h, 81–90% (over two steps).

With 2Ј-nitroarylcarbazoles 24a–24n in hand, further

synthetic transformation into the indolocarbazole unit was

planned. Initially, an allylic bromination of 24a was per-

formed with NBS (1.1 equiv.) in the presence of a catalytic

amount of AIBN in CCl₄at reflux temperatures. Under

these conditions, the allylic bromination reaction was not

completed and a significant amount of starting material 24a

was recovered (confirmed by ¹H NMR spectroscopy),

which was possibly a result of the poor solubility of carb-

azole in CCl₄. Subsequently, the bromination reaction was

performed in CHCl₃at reflux temperatures, which also led

to isolation of the starting material. However, by refluxing

a dilute solution of 4-methylcarbazoles 24a–24l in CCl₄

(100 mL per mmol of substrate) with NBS (2–3 equiv. in

two portions) in the presence of AIBN furnished expected

bromomethylcarbazoles 25a–25l as yellow solids in good

yields (Scheme 6). It should be noted that in the case of 4-

methyl carbazole 24n, the expected allylic bromination reac-

tion was problematic and the ¹H NMR spectra of the crude

product indicated the disappearance of the methylenedioxy

unit.

Scheme 3. Wittig–Horner reaction of indole-2-carboxaldehyde 19.

Reagents and conditions: (i) (Bu₄N)₂Cr₂O₇, CHCl₃, reflux, 2 h,

90%; (ii) NaH, THF, 0 °C, o-nitrobenzyl phosphonate ester 20, 2 h.

Next, the Michaelis–Arbuzov reaction of bromo com-

pound 18 with triethyl phosphite at reflux temperatures fol-

lowed by usual workup afforded 3-vinyl-2-indolylmethyl-

phosphonate ester 22 in 91% yield. As expected, Wittig–

Horner reaction of indolylmethyl phosphonate ester 22

with 2-nitroarylaldehydes 23a–23d with NaH as a base in

dry THF at 0 °C followed by workup and trituration of the

crude products with methanol furnished 2,3-divinylindoles

21a–21d as yellow solids in 75–82% yields (Scheme 4).

Next, interaction of bromomethylcarbazoles 25a–25l

with aq. NH₃in THF at reflux temperatures resulted in

amides 26a–26l as colorless solids. The further reaction of

2Ј-nitroarylcarbazoles 26a–26k with triethyl phosphite in

1,2-dichlorobenzene (o-DCB) at reflux temperatures for

12 h effected final ring closure to afford indolocarbazoles

Scheme 4. Synthesis of 2Ј-nitrophenylvinylindoles 21a–21d. Rea-

gents and conditions: (i) P(OEt)₃, 140 °C, 2 h, 91%; (ii) NaH, THF,

–10 °C to 0 °C, 2-nitroarylaldehydes 23a–23d, 2 h, 75–82%.

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Initially, cleavage of the phenylsulfonyl unit of indolo-

carbazole 27a was carried out with NaOH (50%) in di-

methyl sulfoxide (DMSO) for 12 h. However, the usual

work-up led to the formation of the lactam ring-opened

1

product, which was identified by its H NMR spectrum.

Finally, expected cleavage of the phenylsulfonyl unit of

indolocarbazoles 27a–27k proceeded smoothly without af-

fecting the amide unit with K₂CO₃in MeOH/THF at reflux

temperatures to afford staurosporine aglycons 28a–28k as

brown solids in good yields (Scheme 6).

After having completed the synthesis of indolo[2,3-a]-

carbazoles 28a–28k, the synthesis of an isomeric indolo-

[3,2-a]carbazole analogue was planned by means of a sim-

ilar protocol. Recently, an indolo[3,2-a]carbazole alkaloid,

asteropusazole A 8 has been identified as a potential candi-

date for targeting neurological and psychiatric disorders.^[13]

Known phosphonate ester 29,^[27]upon Wittig–Horner reac-

tion with 2-nitrobenzaldehydes (23a/23e) with K₂CO₃as a

base in dry dimethylformamide (DMF) at room tempera-

ture for 14 h followed by workup and purification by col-

umn chromatography, afforded divinyl compounds 30a/30b

as yellow solids.

As expected, divinyl compounds 30a/30b upon thermal

electrocyclization in the presence of Pd/C (10%) in dry xyl-

enes at reflux temperatures afforded carbazoles 31a/31b in

excellent yield. However, 3-(2Ј-nitrophenyl)carbazole com-

pound 31a/31b upon triethyl phosphite-mediated nitrene in-

sertion at reflux temperatures for 6 h followed by workup

and purification by column chromatography led to the iso-

lation of indolocarbazole 32a/32b and quinocarbazoles 33a/

33b in a 3:1 ratio (Scheme 7). The formation of quinocarb-

azoles 33a and 33b can be visualized through the intermedi-

acy of corresponding 3-(2Ј-nitrosophenyl)carbazoles 34a

and 34b (Scheme 8). The latter, upon triethyl phosphite-me-

diated condensation^[31]followed by subsequent reduction of

quinocarbazole N-oxides 36a and 36b, may lead to quino-

carbazoles 33a and 33b.

Scheme 6. Synthesis of staurosporine aglycon 28a–28k. Reagents

and conditions: (i) NBS, CCl₄, AIBN (cat.), reflux, 4 h, 80–92%;

(ii) aq. NH₃, THF, reflux, 2 h, 83–92%; (iii) P(OEt)₃, o-DCB, re-

flux, 12 h, 85–92%; (iv) K₂CO₃, MeOH/THF, reflux, 10 h, 83–

91%.

The cyclin-dependent kinase (CDK) activity of the ind-

olocarbazole analogues^[3,12]prompted us to explore the ac-

tivity of some representative staurosporinones. It should be

noted that among CDKs, CDK5 represents an attractive

pharmacological target as its deregulation is implicated in

27a–27k in excellent yields (Scheme 6). Expected nitrene in- various neurodegenerative diseases such as Alzheimer’s and

sertion of 2Ј-nitroarylcarbazoles 26l that are substituted at Parkinson’s. Hence, the CDK5 inhibition assay for repre-

position 6 failed to produce expected indolocarbazole 27l sentative indolocarbazoles 28a–28d were performed with a

possibly as a result of atropisomerism, which may hinder LANCE® Ultra high-throughput screening technology

the proximal position of the nitro group required for the platform optimized for homogeneous time-resolved fluores-

insertion reaction. It is noteworthy to mention that the tri- cence resonance energy transfer (TRFRET) kinase assays

ethyl phosphite-mediated nitrene insertion of 2Ј-nitroaryl- (see the Experimental Section for details). Staurosporine 1

carbazoles 26a–26k proceeded in excellent yields relative to and roscovitine 37 were used as standards for the CDK5/

the work by Moody in which a similar reaction afforded p25 assay of staurosporinones 28a–28d.

only a low yield for indolocarbazole.^[21g]In addition, no N-

The CDK5/p25 IC₅₀values (0.05–1.5 μm) of indolo-

ethylation products were observed as reported by Moody carbazoles 28a–28d are lower relative to parent alkaloid

and co-workers. Excellent yields of indolocarbazoles ob- staurosporine 1 (IC₅₀4 nm). However, the indolocarbazole

tained herein might be a result of the nitrene insertion reac- CDK5/p25 IC₅₀values (0.05–1.5 μm) are similar to that of

tion that takes place at the electron rich meta-position to roscovitine (IC₅₀≈ 0.5–0.2 μm).^[32]Among the four indolo-

the amide carbonyl unlike in the work by Moody in which carbazoles, chloro- and fluoro-indolocarbazole analogues

the reaction occurred at the electron deficient para-position. 28c (Figure 2) and 28d (Figure 3), respectively, inhibit

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Facile Synthesis of Staurosporinone Analogues

Scheme 7. Synthesis of indolo[2,3-c]carbazoles 32a and 32b, and quinocarbazoles 33a and 33b. Reagents and conditions: (i) K₂CO₃, dry

DMF, 2-nitroarylaldehydes (23a, 23e), r.t, 14 h, 75%, 78% (ii) 10% Pd/C, xylenes, reflux, 24 h, 92%, 93%; (iii) P(OEt)₃, reflux, 6 h, 80–

93%.

Scheme 8. Plausible mechanism for quinocarbazoles 33a and 33b.

Figure 3. TRFRET CDK5/p25 assay of staurosporinone 28d.

CDK5/p25 enzyme at relatively low concentrations

(0.05 μm & 0.12 μm). Similar to roscovitine,^[33]staurospori-

nones may also inhibit kinase by competing with ATP at

the ATP-binding site of the kinase.

Conclusions

In summary, an efficient synthesis of staurosporinone

and its analogues was achieved from commercially available

2-methylindole that involved multiple steps. Relative to exi-

sting syntheses of staurosporinone analogues, the present

protocol is general and widely applicable.

By using this protocol, the synthesis of indolo[3,2-a]carb-

azole derivatives was also achieved. A mechanistic rationale

for the formation of quinocarbazole during triethyl phos-

phite-mediated nitrene insertion of 3-(2Ј-nitrophenyl)carb-

azole has been reported. Among, the four staurosporinone

analogues explored for CDK5/p25 inhibition studies, chloro

and fluoro analogues inhibit the enzyme at relatively lower

Figure 2. TRFRET CDK5/p25 assay of staurosporinone 28c.

concentrations.

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7.81 (m, ArH), 7.49–7.44 (m, ArH), 7.38–7.26 (m, ArH), 7.20–7.06

(m, ArH), 6.18 (s, 0.3 H, Vinylic CH), 6.02 (d, J = 1.2 Hz, 0.7 H,

Vinylic CH), 4.95 (s, 1.4 H, CH₂Br), 4.80 (s, 0.7 H, CH₂Br), 3.74

(s, 1 H, OMe), 3.69 (s, 2 H, OMe), 2.45 (s, 2 H, Me), 2.25 (s, 1 H,

Me) ppm. (¹H signals show a 2:1 E/Z isomeric mixture).

Experimental Section

General Methods: All the experiments were carried out under a

nitrogen atmosphere unless otherwise stated. The progression of all

reactions was monitored by TLC with ethyl acetate/hexanes mix-

tures. Column chromatography was carried out with Silica gel

(230–400 mesh, Merck) by increasing polarity. ¹H NMR, ¹³C

NMR, and DEPT 135 spectra were recorded in CDCl₃and [D₆]-

DMSO with tetramethylsilane as an internal standard with a

Bruker 300 MHz spectrometer at room temperature. Chemical shift

values were quoted in parts per million (ppm) and coupling con-

stants were quoted in Hertz (Hz). Elemental analysis data was re-

corded with a Elementar Vario Series Analyzer instrument. HRMS

data was recorded with a JEOL GC Mate II (EI). Required 2-

nitrobenzaldehydes 23a–23n were prepared by using reported pro-

cedures.

Methyl 3-[2-Formyl-1-(phenylsulfonyl)-1H-indol-3-yl]but-2-enoate

(19): To the solution of bromo compound 18 (1 g, 2.23 mmol) in

dry CHCl₃(20 mL), tetrabutyl ammonium dichromate (2.34 g,

3.3 mmol) was added and heated to reflux for 2 h. After consump-

tion of the bromo compound (monitored by TLC), the reaction

mixture was concentrated under reduced pressure and the crude

product was purified by flash column chromatography (EtOAc/hex-

anes, 1:99) to afford indole 2-aldehyde 19 as a colorless solid. 1.12 g

(90%). M.p. 110–112 °C. ¹H NMR (300 MHz, CDCl₃): δ = 10.5 (s,

1 H, CHO), 8.26 (d, J = 8.7 Hz, 2 H, ArH), 7.82 (d, J = 8.1 Hz, 1

H, ArH), 7.60–7.29 (m, 8 H, ArH), 5.83 (d, J = 1.5 Hz, 1 H, vinylic

CH), 3.75 (s, 3 H, CO₂Me), 2.45 (s, 3 H, Me) ppm.

Methyl (E)-3-(2-Methyl-1H-indol-3-yl)but-2-enoate (16): To a solu-

tion of 2-methylindole (14; 1 g, 7.63 mmol) and methyl acetoacetate

(0.98 mL, 9.16 mmol) in dry 1,2-dichloroethane (DCE; 5 mL) un-

der N₂was added FeCl₃(0.24 g, 1.52 mmol) and stirred for 3 h.

After consumption of 14, the solvent was removed under reduced

pressure. Then, the residue was dissolved in ethyl acetate (30 mL)

and water (10 mL). The organic layer was separated and washed

with brine solution (2ϫ 5 mL) and dried (Na₂SO₄). The solvent

was removed under reduced pressure and the solid obtained was

triturated with MeOH to afford vinyl indole 16 as a brown solid.

Diethyl {3-[1-(Methoxycarbonyl)prop-1-en-2-yl]-1-(phenylsulfonyl)-

indol-2-yl}methylphosphonate (22): A solution of crude bromo com-

pound 18 (1 g, 2.23 mmol) and triethyl phosphite (0.63 g,

3.79 mmol) was heated to reflux under N₂for 2 h. After consump-

tion of bromo compound 18 (monitored by TLC), the reaction

mixture was poured over crushed ice (100 g) that contained conc.

HCl (2 mL), and extracted with CHCl₃(50 mL). The organic layer

was washed with brine (2ϫ 25 mL) and dried (Na₂SO₄). The sol-

vent was removed under reduced pressure to give phosphonate es-

ter 22 as a brown thick liquid. 1.03 g (91%). The crude product

was used in the next step without further purification. ¹H NMR

(300 MHz, CDCl₃): δ = 8.02–7.99 (m, 1 H, ArH), 7.99–7.70 (m, 4

H, ArH), 7.49–7.44 (m, 1 H, ArH), 7.38–7.33 (m, 2 H, ArH), 7.25–

7.20 (m, 1 H, ArH), 6.51 (d, J = 16.2 Hz, 1 H, vinylic CH), 4.08

(q, J = 7.2 Hz, 4 H, OCH₂), 3.98 (d, J = 23.1 Hz, 2 H, CH₂-P),

3.75 (s, 3 H, -OCH₃), 3.25 (s, 3 H, CH₃), 1.22 (t, J = 7.1 Hz, 6 H,

CH₃) ppm.

1.63 g (93%). M.p. 136–138 °C. IR (KBr): ν = 3251, 1651 cm^–1. ¹H

˜

NMR (300 MHz, CDCl₃): δ = 8.11 (br. s, 1 H, NH), 7.64 (d, J =

8.1 Hz, 1 H, ArH), 7.30–7.26 (m, 1 H, ArH), 7.18–7.12 (m, 2 H,

ArH), 5.95 (s, 1 H, vinylic CH), 3.76 (s, 3 H, CO₂Me), 2.67 (s, 3

H, Me), 2.50 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ

= 167.8, 152.6, 135.1, 133.0, 127.0, 121.8, 120.4, 119.6, 116.7, 116.6,

110.5, 50.9, 20.5, 13.5 ppm.

Methyl

(E)-3-[2-Methyl-1-(phenylsulfonyl)indol-3-yl]but-2-enoate

(17): To a solution of (E)-methyl 3-(2-methyl-1H-indol-3-yl)but-2-

enoate 16 (1 g, 4.36 mmol) in toluene (10 mL), PhSO₂Cl (0.61 mL,

4.80 mmol) and NaOH solution (50%, 10 mL) were added along

with Bu₄NHSO₄(100 mg, 0.29 mmol). The two-phase system was

stirred at room temperature for 2 h, and then diluted with water

(10 mL) and the organic layer was separated. The aqueous layer

was extracted with toluene (10 mL) and the combined organic ex-

tract was dried (Na₂SO₄). The solvent was removed under reduced

pressure and the solid obtained was washed with MeOH to afford

General Procedure for Wittig–Horner Reaction of the Phosphonate

Ester with 2-Nitroarylaldehydes: To a solution of phosphonate ester

22 (1.93 mmol) in dry THF (5 mL), a suspension of hexane-washed

NaH (0.07 g, 2.91 mmol, 5 mL of hexane) in dry THF (5 mL) at

–10 °C under N₂was slowly added and stirred for 15 min. Then, a

solution of 2-nitroarylaldehyde 23a–23n (2.32 mmol) in dry THF

(2 mL) was added and allowed to stir for an additional 2 h. Once

the reaction was complete (monitored by TLC), it was poured over

crushed ice (100 g) that contained conc. HCl (3 mL). The solid

formed was filtered and washed with MeOH to afford vinylindoles

21a–21d and 21n. Crude vinylindoles 21e–21m were used in the

next step (thermal electrocyclization reaction) without further char-

acterization.

compound 17 as brown crystals. 1.48 g (92%). M.p. 118–120 °C.

1

IR (KBr): ν = 1685, 1609, 1365, 1174 cm^–1. H NMR (300 MHz,

˜

CDCl₃): δ = 8.22 (d, J = 8.1 Hz, 1 H, ArH), 8.79 (d, J = 7.5 Hz, 2

H, ArH), 7.57–7.53 (m, 1 H, ArH), 7.47–7.35 (m, 3 H, ArH), 7.33–

7.21 (m, 2 H, ArH), 5.82 (s, 1 H, Vinylic CH), 3.75 (s, 3 H,

CO₂Me), 2.57 (s, 3 H, Me), 2.48 (s, 3 H, Me) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 166.7, 149.8, 139.2, 136.3, 133.8, 132.8,

129.4, 128.5, 126.3, 124.7, 124.5, 123.8, 121.1, 119.3, 114.6, 51.1,

20.3, 13.6 ppm. C₂₀H₁₉NO₄S (369.43): C 65.02, H 5.18, N 3.79;

found C 65.28, H 5.31, N 3.93.

Methyl (2E)-3-[2-(2Ј-Nitrostyryl)-1-(phenylsulfonyl)indol-3-yl]but-2-

enoate (21a): Bright yellow solid. 0.77 g (80%). M.p. 138–140 °C.

IR (KBr): ν = 1705, 1610, 1500, 1371, 1162 cm^–1. ¹H NMR

˜

(300 MHz, CDCl₃): δ = 8.25 (d, J = 8.1 Hz, 1 H, ArH), 8.06 (d, J =

7.5 Hz, 1 H, ArH), 7.85–7.68 (m, 4 H, ArH), 7.63 (d, J = 15.9 Hz, 1

H, Vinylic CH), 7.53–7.36 (m, 6 H, ArH), 7.31–7.26 (m, 1 H, ArH),

7.21 (d, J = 16.2 Hz, 1 H, Vinylic CH), 5.99–5.98 (m, 1 H, Vinylic

CH), 3.75 (s, 3 H, CO₂Me), 2.44 (d, J = 0.9 Hz, 3 H, Me) ppm.

¹³C NMR (75.4 MHz, CDCl₃): δ = 166.5, 149.2, 147.8, 37.6, 136.5,

134.1, 133.7, 132.5, 131.5, 129.4, 129.2, 129.0, 128.9, 127.2, 126.8,

126.0, 124.9, 124.5, 123.2, 122.0, 120.0, 115.4, 51.2, 20.0 ppm.

HRMS (ESI): calcd. for C₂₇H₂₂N₂NaO₆S [M + Na]⁺525.1096;

found 525.2391.

Methyl 3-[2-Bromomethyl-1-(phenylsulfonyl)indol-3-yl]but-2-enoate

(18): A mixture of 1-(phenylsulfonyl)-2-methylindole (17; 1 g,

2.71 mmol) and NBS (0.53 g, 2.98 mmol) in dry CCl₄(25 mL) that

contained a catalytic amount of AIBN (20 mg, 0.12 mmol) was

heated to reflux for 2 h. The reaction mixture was then cooled to

room temperature. The insoluble succinimide was filtered off and

the filtrate was concentrated under reduced pressure to afford

bromo compound 18 as a thick brown liquid. 1.12 g (92%). The

crude product was used in the next step without further purifica-

tion. H NMR (300 MHz, CDCl₃): δ = 8.05–8.00 (m, ArH), 7.87– yl)indol-3-yl]but-2-enoate (21b): Bright yellow solid. 0.80 g (80%).

Methyl (2E)-3-[2-(4Ј,5Ј-Dimethoxy-2Ј-nitrostyryl)-1-(phenylsulfon-

1

7136

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7131–7145

Facile Synthesis of Staurosporinone Analogues

M.p. 150–151 °C. IR (KBr): ν = 1707, 1628, 1510, 1372, 1175 cm^–1.

124.3, 123.0, 115.3, 113.7, 52.0, 18.3 ppm. C₂₇H₂₀N₂O₆S (500.52):

˜

¹H NMR (300 MHz, CDCl₃): δ = 8.23 (d, J = 8.4 Hz, 1 H, ArH), calcd. C 64.79, H 4.03, N 5.60; found C 65.01, H 4.18, N 5.99.

7.77 (d, J = 7.5 Hz, 2 H, ArH), 7.68 (s, 1 H, ArH), 7.57–7.50 (m,

2 H, ArH), 7.46–7.27 (m, 6 H, ArH), 7.18 (s, 1 H, ArH), 5.99 (s, 1

H, Vinylic CH), 4.09 (s, 3 H, OMe), 4.00 (s, 3 H, OMe), 3.75 (s, 3

Methyl 2-(4Ј,5Ј-Dimethoxy-2Ј-nitrophenyl)-4-methyl-9-(phenylsulf-

onyl)carbazole-3-carboxylate (24b): 0.90 g (90%). M.p. 190–192 °C.

IR (KBr): ν = 1731, 1592, 1517, 1372, 1175 cm^–1. ¹H NMR

˜

H, OMe), 2.46 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 166.5, 153.5, 149.3, 149.0, 140.2, 137.5, 136.4, 134.0, 133.9,

132.6, 129.4, 129.2, 127.7, 126.9, 126.8, 125.9, 124.5, 122.0, 121.9,

119.9, 115.3, 109.9, 107.9, 56.5, 56.5, 51.2, 19.9 ppm. MS: m/z =

563 [M]⁺.

(300 MHz, CDCl₃): δ = 8.43 (d, J = 8.4 Hz, 1 H, ArH), 8.24 (s, 1

H, ArH), 8.07 (d, J = 7.8 Hz, 1 H, ArH), 7.78–7.75 (m, 2 H, ArH),

7.72 (s, 1 H, ArH), 7.57–7.52 (m, 1 H, ArH), 7.49–7.44 (m, 2 H,

ArH), 7.40–7.32 (m, 2 H, ArH), 6.81 (s, 1 H, ArH), 4.03 (s, 3 H,

OMe), 3.95 (s, 3 H, OMe), 3.59 (s, 3 H, OMe), 2.75 (s, 3 H,

Methyl (2E)-3-[2-(4Ј-Chloro-2Ј-nitrostyryl)-1-(phenylsulfonyl)indol- Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 169.2, 152.3, 148.4,

3-yl]but-2-enoate (21c): Bright yellow solid. 0.85 g (82%). M.p.

141.2, 139.1, 138.5, 137.1, 135.9, 134.1, 131.3, 129.8, 129.5, 129.2,

1

140–142 °C. IR (KBr): ν = 1711, 1632, 1512, 1376, 1183 cm^–1. H 127.5, 126.7, 126.5, 124.9, 124.4, 123.0, 115.3, 113.7, 113.6, 107.6,

˜

NMR (300 MHz, CDCl₃): δ = 8.24 (d, J = 8.4 Hz, 1 H, ArH), 8.06 56.6, 56.5, 52.2, 18.2 ppm. C₂₉H₂₄N₂O₈S (560.57): calcd. C 62.13,

(d, J = 2.1 Hz, 1 H, ArH), 7.81–7.73 (m, 3 H, ArH), 7.69–7.61 (m, H 4.32, N 5.00; found C 62.33, H 4.61, N 5.27.

2 H, ArH), 7.55–7.50 (m, 1 H, ArH), 7.45–7.37 (m, 4 H, ArH),

Methyl

2-(4Ј-Chloro-2Ј-nitrophenyl)-4-methyl-9-(phenylsulfonyl)-

7.30 (d, J = 7.2 Hz, 1 H, ArH), 7.16 (d, J = 16.2 Hz, 1 H, Vinylic

CH), 5.97 (s, 1 H, Vinylic CH), 3.75 (s, 3 H, OMe), 2.43 (s, 3 H,

Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 166.4, 149.0, 147.8,

137.5, 136.5, 134.7, 134.1, 133.7, 133.2, 130.9, 130.0, 129.9, 129.3,

129.2, 127.4, 126.7, 126.1, 125.0, 124.6, 123.7, 122.1, 120.0, 115.3,

51.2, 19.9 ppm. HRMS (EI): calcd. for C₂₇H₂₁ClN₂O₆S [M]⁺

536.0809; found 536.0819.

carbazole-3-carboxylate (24c): 0.93 g (93%). M.p. 225–226 °C. IR

(KBr): ν = 1719, 1580, 1379, 1174 cm^–1. ¹H NMR (300 MHz,

˜

CDCl₃): δ = 8.37 (d, J = 8.1 Hz, 1 H, ArH), 8.14 (s, 1 H, ArH),

8.02–8.00 (m, 2 H, ArH), 7.70 (d, J = 7.8 Hz, 2 H, ArH), 7.56 (dd,

J = 2.1, 8.1 Hz, 1 H, ArH), 7.49 (t, J = 8.1 Hz, 1 H, ArH), 7.43–

7.35 (m, 2 H, ArH), 7.32–7.18 (m, 2 H, ArH), 7.07–7.01 (m, 1 H,

ArH), 3.51 (s, 3 H, OMe), 2.69 (s, 3 H, Me) ppm. ¹³C NMR

Methyl (2E)-3-[2-(4Ј-Fluoro-2Ј-nitrostyryl)-1-(phenylsulfonyl)indol- (75.4 MHz, CDCl₃): δ = 167.6, 149.1, 139.3, 139.1, 137.0, 135.1,

3-yl]but-2-enoate (21d): Bright yellow solid. 0.75 g (75%). M.p. 134.9, 134.4, 133.6, 133.1, 132.7, 130.8, 129.4, 128.5, 126.6, 125.0,

1

160–162 °C. IR (KBr): ν = 1712, 1635, 1500, 1371, 1176 cm^–1. H 124.6, 124.5, 124.1, 116.3, 115.3, 52.4, 27.6 ppm. C₂₇H₁₉ClN₂O₆S

˜

NMR (300 MHz, CDCl₃): δ = 8.24 (d, J = 8.4 Hz, 1 H, ArH),

(534.97): calcd. C 60.62, H 3.58, N 5.24; found C 60.83, H 3.75, N

7.56–7.75 (m, 4 H, ArH), 7.58 (d, J = 15.9 Hz, 1 H, ArH), 7.53– 5.38.

7.36 (m, 6 H, ArH), 7.31–7.26 (m, 1 H, ArH), 7.17 (d, J = 16.2 Hz,

Methyl

2-(4Ј-Fluoro-2Ј-nitrophenyl)-4-methyl-9-(phenylsulfonyl)-

1 H, Vinylic CH), 5.95 (s, 1 H, Vinylic CH), 3.75 (s, 3 H, OMe),

2.44 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 166.4,

149.1, 137.5, 136.4, 134.1, 133.3, 130.7, 130.4, 129.3, 129.2, 128.3,

127.2, 126.7, 126.0, 124.6, 123.3, 122.0, 121.4, 121.1, 120.0, 115.3,

112.7, 112.3, 51.2, 20.0 ppm.

carbazole-3-carboxylate (24d): 0.83 g (82%). M.p. 221–222 °C. IR

(KBr): ν = 1720, 1615, 1381, 1177 cm^–1. ¹H NMR (300 MHz,

˜

CDCl₃): δ = 8.37 (d, J = 8.4 Hz, 1 H, ArH), 8.15 (s, 1 H, ArH),

8.01 (d, J = 8.1 Hz, 1 H, ArH), 7.76 (d, J = 8.1 Hz, 1 H, ArH),

7.70 (d, J = 7.8 Hz, 2 H, ArH), 7.51–7.26 (m, 7 H, ArH), 3.50 (s,

Methyl (2E)-3-[2-(4Ј,5Ј-Methylenedioxy-2Ј-nitrostyryl)-1-(phenyl- 3 H, OMe), 2.69 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

sulfonyl)indol-3-yl]but-2-enoate (21n): Bright yellow solid. 0.78 g

δ = 168.8, 161.64 (d, J = 251.8 Hz), 149.3, 139.0, 138.4, 137.1,

134.2, 133.7, 133.6, 131.7, 131.5, 129.4, 129.2, 127.6, 126.6, 126.5,

125.2, 124.5, 123.0, 119.7 (d, J = 21.1 Hz) 115.3, 113.8, 112.0 (d, J

= 26.39 Hz), 52.1, 18.2 ppm. C₂₇H₁₉FN₂O₆S (518.51): calcd. C

(80%). M.p. 144–146 °C. IR (KBr): ν = 1708, 1626, 1619, 1375,

˜

1

1172 cm^–1. H NMR (300 MHz, CDCl₃): δ = 8.24 (d, J = 9 Hz, 1

H, ArH), 7.77 (d, J = 7.5 Hz, 2 H, ArH), 7.58–7.35 (m, 8 H, ArH),

7.30–7.25 (m, 2 H, ArH), 7.19 (s, 1 H, ArH), 6.18 (s, 2 H, ArH), 62.54, H 3.69, N 5.40; found C 62.82, H 3.83, N 5.71.

5.97 (s, 1 H, Vinylic CH), 3.75 (s, 3 H, OMe), 2.43 (s, 3 H,

Methyl

2-(5Ј-Fluoro-2Ј-nitrophenyl)-4-methyl-9-(phenylsulfonyl)-

Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 166.4, 152.2, 149.2,

148.0, 137.5, 136.4, 134.0, 133.7, 132.2, 129.6, 129.3, 129.2, 127.0,

126.8, 125.9, 124.5, 122.2, 121.9, 119.9, 115.3, 107.3, 105.63,

103.21, 51.19, 20.00 ppm. MS: m/z = 547 [M + 1]⁺.

carbazole-3-carboxylate (24e): 0.84 g (84%). M.p. 202–203 °C. ¹H

NMR (300 MHz, CDCl₃): δ = 8.44 (d, J = 8.4 Hz, 1 H, ArH), 8.24

(s, 1 H, ArH), 8.19–8.14 (m, 1 H, ArH), 8.09 (d, J = 8.1 Hz, 1 H,

ArH), 7.79–7.76 (m, 2 H, ArH), 7.59–7.50 (m, 1 H, ArH), 7.48–

7.45 (m, 2 H, ArH), 7.42–7.33 (m, 2 H, ArH), 7.29–7.23 (m, 1 H,

ArH), 7.13 (dd, J = 2.7, 8.3 Hz, 1 H, ArH), 3.59 (s, 3 H, OMe),

2.77 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 168.7,

165.6, 162.2, 145.1, 139.1, 138.8 (d, J = 9.6 Hz), 138.5, 137.1, 134.4,

134.2, 132.0, 129.3, 128.9, 127.7, 127.1 (d, J = 9.9 Hz), 126.5, 125.4,

124.5, 123.1, 119.2 (d, J = 24 Hz), 115.9 (d, J = 23 Hz), 52.1,

18.3 ppm. C₂₇H₁₉FN₂O₆S (518.51): calcd. C 62.54, H 3.69, N 5.40;

found C 62.81, H 3.91, N 5.72.

General Procedure for Electrocyclization Reaction of 1-(Phenylsulf-

onyl)-2,3-divinylindoles: To solution of divinyl compound 21a–21n

(1 g) in dry xylene (10 mL), 10% Pd/C (0.1 g) was added. The reac-

tion mixture was heated to reflux for 24 h. Then, the reaction mix-

ture was filtered through a Celite pad and washed with hot xylenes

(3ϫ 10 mL). The combined filtrate was concentrated under re-

duced pressure and the resulting crude product was triturated with

MeOH (5 mL) to afford carbazoles 24a–24n as pale yellow solids.

Methyl 4-Methyl-2-(2Ј-nitrophenyl)-9-(phenylsulfonyl)carbazole-3- Methyl 2-(5-Chloro-2-nitrophenyl)-4-methyl-9-(phenylsulfonyl)-9H-

carboxylate (24a): 0.85 g (85%). M.p. 206–208 °C. IR (KBr): ν =

carbazole-3-carboxylate (24f): 0.83 g (83%). M.p. 211–213 °C. ¹H

NMR (300 MHz, CDCl₃): δ = 8.43 (d, J = 8.4 Hz, 1 H, ArH), 8.23

˜

1709, 1598, 1372, 1174 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ =

8.37 (d, J = 8.4 Hz, 1 H, ArH), 8.04–8.00 (m, 2 H, ArH), 8.18 (s, (s, 1 H, ArH), 8.09–8.04 (m, 2 H, ArH), 7.77 (d, J = 7.8 Hz, 2 H,

1 H, ArH), 7.72 (d, J = 7.8 Hz, 2 H, ArH), 7.62–7.57 (m, 1 H, ArH), 7.58–7.37 (m, 7 H, ArH), 3.59 (s, 3 H, OMe), 2.76 (s, 3 H,

ArH), 7.54–7.46 (m, 2 H, ArH), 7.43–7.26 (m, 5 H, ArH), 3.53 (s,

Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 168.6, 147.2, 139.1,

3 H, OMe), 2.76 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): 138.8, 138.4, 137.3, 137.1, 134.2, 134.1, 132.0, 132.0, 129.2, 129.0,

δ = 169.0, 149.0, 139.1, 138.5, 137.1, 135.5, 135.3, 134.2, 132.5,

132.1, 131.6, 129.3, 129.2, 128.9, 127.5, 126.7, 126.5, 125.1, 124.5,

128.9, 127.7, 126.5, 125.7, 125.4, 124.5, 123.1, 115.3, 113.4, 52.1,

18.2 ppm.

Eur. J. Org. Chem. 2015, 7131–7145

www.eurjoc.org

7137

P. Raju, G. Gobi Rajeshwaran, A. K. Mohanakrishnan

FULL PAPER

Methyl 2-(5-Bromo-2-nitrophenyl)-4-methyl-9-(phenylsulfonyl)-9H- Methyl 2-(2-Chloro-6-nitrophenyl)-4-methyl-9-(phenylsulfonyl)-9H-

1

carbazole-3-carboxylate (24g): 0.85 g (85%). M.p. 216–218 °C. ¹H

NMR (300 MHz, CDCl₃): δ = 8.44 (d, J = 8.4 Hz, 1 H, ArH), 8.23 NMR (300 MHz, CDCl₃): δ = 8.37 (d, J = 8.4 Hz, 1 H, ArH), 8.17

(s, 1 H, ArH), 8.09 (d, J = 7.8 Hz, 1 H, ArH), 7.97 (d, J = 8.7 Hz, (s, 1 H, ArH), 8.01 (d, J = 8.1 Hz, 1 H, ArH), 7.91 (d, J = 8.1 Hz,

1 H, ArH), 7.78–7.69 (m, 3 H, ArH), 7.59–7.36 (m, 6 H, ArH), 1 H, ArH), 7.72–7.68 (m, 3 H, ArH), 7.48–7.34 (m, 4 H, ArH),

carbazole-3-carboxylate (24m): 0.81 g (81%). M.p. 226–228 °C. H

3.60 (s, 3 H, OMe), 2.77 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 168.6, 147.7, 139.1, 138.4, 137.3, 137.1, 134.9, 134.2,

134.0, 132.0, 129.2, 128.9, 127.7, 127.1, 126.5, 125.6, 125.4, 124.5,

123.1, 115.3, 113.5, 52.1, 18.2 ppm. C₂₇H₁₉BrN₂O₆S (579.42):

calcd. C 55.97, H 3.31, N 4.83; found C 55.69, H 3.12, N 4.55.

7.27–7.18 (m, 2 H, ArH), 3.49 (s, 3 H, OMe), 2.71 (s, 3 H,

Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 168.2, 150.3, 139.1,

138.7, 137.0, 136.4, 134.3, 134.1, 133.7, 132.5, 132.4, 129.3, 129.1,

128.8, 127.6, 126.7, 126.5, 125.8, 124.5, 123.5, 123.1, 122.4, 115.3,

114.3, 51.9, 18.4 ppm.

Methyl 2-(4,5-Dichloro-2-nitrophenyl)-4-methyl-9-(phenylsulfonyl)-

Methyl 4-Methyl-2-(5-nitrobenzo[d][1,3]dioxol-6-yl)-9-(phenylsulf-

9H-carbazole-3-carboxylate (24h): 0.84 g (84%). M.p. 242–244 °C.

onyl)carbazole-3-carboxylate (24n): 0.89 g (89%). M.p. 203–204 °C.

1

¹H NMR (300 MHz, CDCl₃): δ = 8.35 (d, J = 8.4 Hz, 1 H, ArH), IR (KBr): ν = 1721, 1482, 1374, 1174 cm^–1. H NMR (300 MHz,

˜

8.14 (S, 2 H, ArH), 8.01 (d, J = 7.8 Hz, 1 H, ArH), 7.68 (d, J =

CDCl₃): δ = 8.43 (d, J = 8.4 Hz, 1 H, ArH), 8.22 (s, 1 H, ArH),

8.06 (d, J = 7.8 Hz, 1 H, ArH), 7.76 (d, J = 7.5 Hz, 2 H, ArH),

7.5 Hz, 2 H, ArH), 7.51–7.29 (m, 7 H, ArH), 3.56 (s, 3 H, OMe),

2.69 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 168.4, 7.60 (s, 1 H, ArH), 7.54 (t, J = 8.1 Hz, 1 H, ArH), 7.48–7.26 (m,

147.1, 139.0, 138.4, 137.3, 137.0, 135.2, 134.2, 133.4, 133.1, 132.1,

129.2, 128.7, 127.7, 126.4, 126.3, 126.1, 125.5, 124.5, 123.1, 115.2,

113.4, 52.2, 18.3 ppm.

4 H, ArH), 6.79 (s, 1 H, ArH), 6.18 (s, 2 H, ArH), 3.63 (s, 3 H,

OMe), 2.73 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ =

169.1, 151.0, 147.2, 142.9, 139.0, 138.5, 137.1, 135.7, 134.2, 131.8,

131.4, 129.3, 129.2, 127.5, 126.7, 126.5, 125.0, 124.5, 123.0, 115.3,

113.6, 111.1, 105.3, 103.2, 52.2, 18.3 ppm. C₂₈H₂₀N₂O₈S (544.53):

calcd. C 61.76, H 3.70, N 5.14; found C 62.00, H 3.91, N 5.44.

Methyl 2-(5-Chloro-4-fluoro-2-nitrophenyl)-4-methyl-9-(phenylsulf-

onyl)-9H-carbazole-3-carboxylate (24i): 0.81 g (81%). M.p. 218–

220 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.35 (d, J = 8.4 Hz, 1

H, ArH), 8.14 (s, 1 H, ArH), 8.01 (d, J = 8.1 Hz, 1 H, ArH), 7.86

(d, J = 8.4 Hz, 1 H, ArH), 7.68 (d, J = 7.8 Hz, 2 H, ArH), 7.54–

7.18 (m, 6 H, ArH), 3.55 (s, 3 H, OMe), 2.68 (s, 3 H, Me) ppm.

General Procedure for Allylic Bromination of 2-(2Ј-Nitroaryl)-4-

methylcarbazoles:

A

mixture of 4-methylcarbazole 24a–24l

(1 mmol) and NBS (1.5 mmol) in dry CCl₄(100 mL) that contained

¹³C NMR (75.4 MHz, CDCl₃): δ = 168.5, 158.7, 155.3, 147.3, a catalytic amount of AIBN (0.1 mmol) was heated to reflux for

147.2, 139.0, 138.4, 137.0, 134.2, 133.8, 133.2, 132.6, 132.0, 129.2,

128.9, 127.7, 126.4, 126.3, 126.1, 125.4, 124.5, 123.1, 115.2, 113.6,

113.2, 112.9, 52.2, 18.3 ppm.

2 h. Then, the reaction mixture was cooled to room temperature

and an additional portion of NBS (1.5 mmol) and AIBN

(0.1 mmol) was added and heated to reflux for a further 2 h. Then,

the reaction mixture was cooled to room temperature and the insol-

uble succinimide was filtered off through a Na₂SO₄pad under hot

conditions. Removal of solvent under reduced pressure followed by

trituration of the crude product from methanol (10 mL) furnished

4-bromomethyl carbazoles 25a–25l as pale yellow solids.

Methyl 2-(4-Chloro-5-fluoro-2-nitrophenyl)-4-methyl-9-(phenylsulf-

onyl)-9H-carbazole-3-carboxylate (24j): 0.81 g (81%). M.p. 244–

246 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.44 (d, J = 8.4 Hz, 1

H, ArH), 8.24–8.21 (m, 2 H, ArH), 8.07 (d, J = 8.1 Hz, 1 H, ArH),

7.75 (d, J = 7.5 Hz, 2 H, ArH), 7.58–7.21 (m, 6 H, ArH), 3.63 (s,

3 H, OMe), 2.76 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): Methyl 4-(Bromomethyl)-2-(2Ј-nitrophenyl)-9-(phenylsulfonyl)carb-

δ = 168.5, 161.3, 157.8, 144.9, 139.0, 138.4, 137.1, 136.8, 136.7,

134.2, 133.4, 132.2, 129.2, 128.7, 127.8, 127.3, 126.4, 126.4, 125.5,

azole-3-carboxylate (25a): 0.51 g (89%). M.p. 194–196 °C. ¹H

NMR (300 MHz, CDCl₃): δ = 8.46 (d, J = 8.4 Hz, 1 H, ArH), 8.40

124.5, 123.1, 121.9, 121.6, 120.1, 119.8, 115.2, 113.3, 52.2, (s, 1 H, ArH), 8.21 (d, J = 7.8 Hz, 1 H, ArH), 8.13 (dd, J = 1.4,

18.3 ppm.

8.0 Hz, 1 H, ArH), 7.82–7.79 (m, 2 H, ArH), 7.71–7.58 (m, 3 H,

ArH), 7.57–7.36 (m, 5 H, ArH), 5.06 (d, J = 10.8 Hz, 1 H, CH₂Br),

4.89 (d, J = 10.8 Hz, 1 H, CH₂Br), 3.56 (s, 3 H, OMe) ppm. ¹³C

NMR (75.4 MHz, CDCl₃): δ = 167.8, 148.9, 139.3, 139.1, 137.0,

136.3, 135.1, 134.4, 132.6, 132.0, 130.6, 129.4, 129.2, 128.6, 128.3,

126.6, 125.0, 124.8, 124.6, 124.4, 124.0, 116.4, 115.3, 52.3,

27.7 ppm. HRMS (ESI): calcd. for C₂₇H₁₉BrKN₂O₆S [M + K]⁺

616.9784; found 616.5785.

Methyl 2-(5-Bromo-4-fluoro-2-nitrophenyl)-4-methyl-9-(phenylsulf-

onyl)-9H-carbazole-3-carboxylate (24k): 0.89 g (89%). M.p. 228–

230 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.44 (d, J = 8.8 Hz, 1

H, ArH), 8.22 (s, 1 H, ArH), 8.09 (d, J = 8.1 Hz, 1 H, ArH), 7.89

(d, J = 7.8 Hz, 1 H, ArH), 7.76 (d, J = 8.1 Hz, 2 H, ArH), 7.67 (d,

J = 6.9 Hz, 1 H, ArH), 7.59–7.38 (m, 5 H, ArH), 3.62 (s, 3 H,

OMe), 2.76 (s, 3 H, Me) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ =

168.7, 159.9, 156.6, 148.1, 139.1, 138.5, 137.1, 136.7, 134.2, 133.2,

132.7, 132.7, 132.7, 132.0, 129.2, 129.0, 127.7, 126.5, 126.4, 125.5,

124.5, 123.1, 115.3, 114.7, 114.4, 113.7, 112.9, 112.5, 52.2,

18.3 ppm.

Methyl

2-(4Ј,5Ј-Dimethoxy-2Ј-nitrophenyl)-4-(bromomethyl)-9-

(phenylsulfonyl)carbazole-3-carboxylate (25b): 0.59 g (92%). M.p.

1

216–218 °C. H NMR (300 MHz, CDCl₃): δ = 8.45 (d, J = 8.4 Hz,

1 H, ArH), 8.38 (s, 1 H, ArH), 8.20 (d, J = 7.8 Hz, 1 H, ArH),

7.79 (d, J = 7.8 Hz, 2 H, ArH), 7.74 (s, 1 H, ArH), 7.62 (t, J =

8.0 Hz, 1 H, ArH), 7.50 (t, J = 7.7 Hz, 2 H, ArH), 7.37 (t, J =

7.7 Hz, 2 H, ArH), 6.82 (s, 1 H, ArH), 5.04 (d, J = 10.8 Hz, 1 H,

CH₂Br), 4.86 (d, J = 11.0 Hz, 1 H, CH₂Br), 4.05 (s, 3 H, OMe),

3.96 (s, 3 H, OMe), 3.62 (s, 3 H, OMe) ppm. ¹³C NMR (75.4 MHz,

CDCl₃): δ = 168.0, 152.4, 148.6, 141.1, 139.3, 139.1, 137.0, 136.5,

134.4, 130.2, 129.3, 128.9, 128.3, 126.6, 125.0, 124.7, 124.6, 124.0,

116.5, 115.3, 113.4, 107.6, 56.7, 56.5, 52.5, 27.8 ppm.

Methyl 2-(2,3-Dichloro-6-nitrophenyl)-4-methyl-9-(phenylsulfonyl)-

9H-carbazole-3-carboxylate (24l): 0.90 g (90%). M.p. 226–228 °C.

¹H NMR (300 MHz, CDCl₃): δ = 8.47 (d, J = 8.4 Hz, 1 H, ArH),

8.13 (s, 1 H, ArH), 8.02 (d, J = 7.8 Hz, 1 H, ArH), 7.88 (d, J =

8.7 Hz, 1 H, ArH), 7.69 (d, J = 7.8 Hz, 2 H, ArH), 7.62 (d, J =

8.7 Hz, 1 H, ArH), 7.49 (t, J = 7.6 Hz, 1 H, ArH), 7.41–7.18 (m,

4 H, ArH), 3.53 (s, 3 H, OMe), 2.73 (s, 3 H, Me) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 168.1, 148.3, 139.1, 138.8, 138.4, 137.0,

136.5, 135.1, 134.2, 132.5, 130.1, 129.1, 128.4, 127.8, 126.6, 126.5,

126.0, 124.5, 123.2, 122.9, 115.3, 114.0, 52.0, 18.6 ppm.

C₂₇H₁₈Cl₂N₂O₆S (569.41): calcd. C 56.95, H 3.19, N 4.92; found C

57.24, H 3.48, N 4.65.

Methyl 4-(Bromomethyl)-2-(4Ј-chloro-2Ј-nitrophenyl)-9-(phenylsulf-

onyl)carbazole-3-carboxylate (25c): 0.55 g (91%). M.p. 192–193 °C.

¹H NMR (300 MHz, CDCl₃): δ = 8.46 (d, J = 8.4 Hz, 1 H, ArH),

8.35 (s, 1 H, ArH), 8.21 (d, J = 7.8 Hz, 1 H, ArH), 8.13 (d, J =

7138

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Eur. J. Org. Chem. 2015, 7131–7145

Facile Synthesis of Staurosporinone Analogues

1.8 Hz, 1 H, ArH), 7.79 (d, J = 7.5 Hz, 2 H, ArH), 7.67–7.60 (m,

Methyl

4-(Bromomethyl)-2-(5-chloro-4-fluoro-2-nitrophenyl)-9-

2 H, ArH), 7.50 (t, J = 7.4 Hz, 2 H, ArH), 7.41–7.26 (m, 3 H, (phenylsulfonyl)-9H-carbazole-3-carboxylate (25i): 0.55 g (87%).

ArH), 5.05 (d, J = 11 Hz, 1 H, CH₂Br), 4.88 (d, J = 11 Hz, 1 H, M.p. 198–200 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.37 (d, J =

CH₂Br), 3.62 (s, 3 H, OMe) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 167.6, 149.1, 139.3, 139.1, 137.0, 135.1, 134.9, 134.4, 133.6,

133.1, 132.7, 130.8, 129.4, 128.5, 126.5, 125.0, 124.6, 124.5, 124.1,

116.3, 115.3, 52.4, 27.6 ppm.

8.7 Hz, 1 H, ArH), 8.28 (s, 1 H, ArH), 8.13 (d, J = 7.8 Hz, 1 H,

ArH), 7.90 (d, J = 8.1 Hz, 1 H, ArH), 7.70 (d, J = 7.5 Hz, 2 H,

ArH), 7.57–7.27 (m, 6 H, ArH), 4.97 (d, J = 10.5 Hz, 1 H, CH₂Br),

4.81 (d, J = 10.8 Hz, 1 H, CH₂Br), 3.59 (s, 3 H, OMe) ppm. ¹³C

NMR (75.4 MHz, CDCl₃): δ = 167.3, 158.8, 155.4, 147.2, 147.1,

139.3, 139.0, 136.9, 134.0, 133.6, 132.2, 132.1, 130.9, 129.3, 128.5,

128.2, 126.5, 126.5, 126.3, 125.1, 125.0, 124.3, 124.0, 116.3, 115.2,

113.3, 113.0, 52.5, 27.5 ppm.

Methyl 2-(4Ј-Fluoro-2Ј-nitrophenyl)-4-(bromomethyl)-9-(phenylsulf-

onyl)carbazole-3-carboxylate (25d): 0.52 g (88%). M.p. 163–165 °C.

¹H NMR (300 MHz, CDCl₃): δ = 8.46 (d, J = 8.4 Hz, 1 H, ArH),

8.37 (s, 1 H, ArH), 8.21 (d, J = 8.1 Hz, 1 H, ArH), 7.87 (dd, J =

2.1, 8.4 Hz, 1 H, ArH), 7.81–7.78 (m, 2 H, ArH), 7.65–7.60 (m, 1

H, ArH), 7.53–7.48 (m, 2 H, ArH), 7.44–7.36 (m, 4 H, ArH), 5.05

(d, J = 11.0 Hz, 1 H, CH₂Br), 4.88 (d, J = 11.0 Hz, 1 H, CH₂Br),

Methyl

4-(Bromomethyl)-2-(4-chloro-5-fluoro-2-nitrophenyl)-9-

(phenylsulfonyl)-9H-carbazole-3-carboxylate (25j): 0.56 g (89%).

M.p. 197–199 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.45 (d, J =

3.61 (s, 3 H, OMe) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 167.7, 8.4 Hz, 1 H, ArH), 8.34 (s, 1 H, ArH), 8.27 (d, J = 6.3 Hz, 1 H,

139.3, 139.1, 137.0, 135.0, 134.4, 133.6 (d, J = 31.2 Hz), 131.2 (d, ArH), 8.22 (d, J = 8.1 Hz, 1 H, ArH), 7.77 (d, J = 7.8 Hz, 2 H,

J = 4.9 Hz), 130.7, 129.4, 128.8, 128.5, 126.6, 125.0, 125.0, 124.5,

124.1, 119.9 (d, J = 20.96 Hz), 116.5, 115.3, 112.2 (d, J = 26.5 Hz),

52.4, 27.6 ppm.

ArH), 7.63 (t, J = 7.9 Hz, 1 H, ArH), 7.51 (t, J = 7.3 Hz, 2 H,

ArH), 7.38 (t, J = 7.6 Hz, 2 H, ArH), 7.26–7.23 (m, 1 H, ArH),

5.05 (d, J = 10.8 Hz, 1 H, CH₂Br), 4.90 (d, J = 10.8 Hz, 1 H,

CH₂Br), 3.68 (s, 3 H, OMe) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 161.4, 157.9, 144.7, 139.3, 139.0, 137.0, 136.3, 136.2, 134.2,

134.4, 134.1, 131.0, 129.3, 128.6, 127.9127.4, 126.5, 125.2, 125.0,

124.3124.1, 122.0 (d, J = 19.1 Hz), 119.8 (d, J = 23.2 Hz), 113.9,

115.2, 52.5, 27.4 ppm.

Methyl 2-(5Ј-Fluoro-2Ј-nitrophenyl)-4-(bromomethyl)-9-(phenylsulf-

onyl)carbazole-3-carboxylate (25e): 0.55 g (93%). M.p. 180–182 °C.

¹H NMR (300 MHz, CDCl₃): δ = 8.46 (d, J = 8.4 Hz, 1 H, ArH),

8.38 (s, 1 H, ArH), 8.23–8.19 (m, 2 H, ArH), 7.80–7.78 (m, 2 H,

ArH), 7.67–7.60 (m, 1 H, ArH), 7.54–7.49 (m, 2 H, ArH), 7.42–

7.36 (m, 2 H, ArH), 7.32–7.28 (m, 1 H, ArH), 7.15 (dd, J = 2.7,

Methyl2-(5-bromo-4-fluoro-2-nitrophenyl)-4-(bromomethyl)-9-(phen-

8.1 Hz, 1 H, ArH), 5.06 (d, J = 11.1 Hz, 1 H, CH₂Br), 4.91 (d, J ylsulfonyl)-9H-carbazole-3-carboxylate (25k): 0.56 g (84%). M.p.

1

= 11.1 Hz, 1 H, CH₂Br), 3.63 (s, 3 H, OMe) ppm. ¹³C NMR 198–200 °C. H NMR (300 MHz, CDCl₃): δ = 8.44 (d, J = 8.4 Hz,

(75.4 MHz, CDCl₃): δ = 167.5, 139.4, 139.1, 138.4 (d, J = 13.3 Hz), 1 H, ArH), 8.36 (s, 1 H, ArH), 8.20 (d, J = 7.8 Hz, 1 H, ArH),

137.1, 135.1, 134.4, 130.9, 129.4, 128.5, 128.2, 127.2 (d, J = 7.93–7.90 (m, 1 H, ArH), 7.78–7.47 (m, 6 H, ArH), 7.36 (t, J =

12.1 Hz), 126.6, 125.1, 125.0, 124.5, 124.1, 119.4, 119.0, 116.3,

116.0, 115.9, 115.3, 52.4, 27.5 ppm.

7.3 Hz, 2 H, ArH), 5.04 (d, J = 10.8 Hz, 1 H, CH₂Br), 4.88 (d, J

= 10.5 Hz, 1 H, CH₂Br), 3.66 (s, 3 H, OMe) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 168.5, 160.0, 156.7, 148.0, 147.9, 139.2 (d,

J = 19.6 Hz), 137.0, 136.6, 134.4, 133.9, 132.3, 132.3, 131.0, 129.3,

128.5, 128.3, 126.5, 125.2, 125.0, 124.3, 124.1, 116.4, 115.3, 114.7

(d, J = 21.2 Hz), 112.8 (d, J = 27.2 Hz), 52.5, 27.5 ppm.

Methyl 4-(Bromomethyl)-2-(5-chloro-2-nitrophenyl)-9-(phenylsulf-

onyl)-9H-carbazole-3-carboxylate (25f): 0.54 g (89%). M.p. 198–

200 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.37 (d, J = 8.1 Hz, 1

H, ArH), 8.29 (s, 1 H, ArH), 8.13 (d, J = 7.8 Hz, 1 H, ArH), 8.01

(d, J = 8.7 Hz, 1 H, ArH), 7.71 (d, J = 7.8 Hz, 2 H, ArH), 7.56–

7.32 (m, 7 H, ArH), 4.98 (d, J = 10.8 Hz, 1 H, CH₂Br), 4.82 (d, J

Methyl 4-(Bromomethyl)-2-(2,3-dichloro-6-nitrophenyl)-9-(phenyl-

sulfonyl)-9H-carbazole-3-carboxylate (25l): 0.56 g (87%). M.p. 195–

= 10.8 Hz, 1 H, CH₂Br), 3.55 (s, 3 H, OMe) ppm. ¹³C NMR 197 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.37 (d, J = 8.1 Hz, 1

(75.4 MHz, CDCl₃): δ = 167.4, 147.0, 139.3, 139.1, 139.0, 136.9,

139.0, 136.9 (d, J = 5.9 Hz), 134.9, 134.4, 131.9, 130.9, 129.3, 129.2,

128.5, 128.2, 126.5, 125.8, 125.1, 125.0, 124.4, 124.1, 116.1, 115.3,

52.4, 27.5 ppm.

H, ArH), 8.28 (s, 1 H, ArH), 8.13 (d, J = 7.8 Hz, 1 H, ArH), 7.90

(d, J = 8.4 Hz, 1 H, ArH), 7.70 (d, J = 7.5 Hz, 2 H, ArH), 7.55 (t,

J = 7.65 Hz, 1 H, ArH), 7.26–7.23 (m, 5 H, ArH), 4.96 (d, J =

10.8 Hz, 1 H, CH₂Br), 4.80 (d, J = 10.8 Hz, 1 H, CH₂Br), 3.59 (s,

3 H, OMe) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 167.4, 158.8,

155.4, 147.2, 147.1, 139.1 (d, J = 17.3 Hz), 136.9, 134.4, 134.0,

133.6, 132.1 (d, J = 4.6 Hz), 130.9, 129.3, 128.5, 128.2, 126.5, 125.1,

125.0, 124.3, 124.0, 116.3, 115.2, 113.2 (d, J = 26.0 Hz), 52.5,

27.5 ppm.

Methyl 2-(5-Bromo-2-nitrophenyl)-4-(bromomethyl)-9-(phenylsulf-

onyl)-9H-carbazole-3-carboxylate (25g): 0.53 g (80%). M.p. 198–

200 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.45 (d, J = 8.4 Hz, 1

H, ArH), 8.37 (s, 1 H, ArH), 8.21 (d, J = 7.8 Hz, 1 H, ArH), 8.01

(d, J = 8.4 Hz, 1 H, ArH), 7.80–7.35 (m, 9 H, ArH), 5.05 (d, J =

11.1 Hz, 1 H, CH₂Br), 4.90 (d, J = 10.8 Hz, 1 H, CH₂Br), 3.63 (s, General Procedure for Amidation Reaction of 4-(Bromomethyl)carb-

3 H, OMe) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 167.4, 147.5,

139.3, 139.0, 137.0, 136.9, 134.8, 134.4, 132.3, 130.9, 129.4, 128.5,

128.2, 127.4, 126.5, 125.8, 125.1, 125.0, 124.4, 124.1, 116.2, 115.3,

52.4, 27.6 ppm.

azoles (25a–25l): Aqueous NH₃(10 mL, 25%) was added to a solu-

tion of bromo compound 25a–25l (1 mmol) in THF (20 mL) and

heated to reflux for 2 h. After consumption of the bromo com-

pound (monitored by TLC), the solvent was concentrated under

reduced pressure and the resulting residue was poured onto iced

water (100 g). The solid obtained was filtered and dried (Na₂SO₄).

The crude product was washed with CHCl₃(1 mL) to afford

amides 26a–26l as brown solids.

Methyl 4-(Bromomethyl)-2-(4,5-dichloro-2-nitrophenyl)-9-(phenyl-

sulfonyl)-9H-carbazole-3-carboxylate (25h): 0.56 g (86%). M.p.

1

195–197 °C. H NMR (300 MHz, CDCl₃): δ = 8.45 (d, J = 8.4 Hz,

1 H, ArH), 8.34 (s, 1 H, ArH), 8.25–8.20 (m, 2 H, ArH), 7.77 (d,

J = 7.8 Hz, 2 H, ArH), 7.66–7.38 (m, 6 H, ArH), 5.05 (d, J =

4-(2-Nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydropyrrolo[3,4-c]carb-

11.1 Hz, 1 H, CH₂Br), 4.92 (d, J = 10.8 Hz, 1 H, CH₂Br), 3.68 (s, azol-3(6H)-one (26a): 0.44 g (92%). M.p. 304–308 °C. IR (KBr): ν

˜

3 H, OMe) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 166.0, 145.9,

138.0, 137.7, 136.2, 135.7, 133.6, 133.5, 132.9, 132.7, 132.1, 129.9,

128.4, 127.6, 127.3, 127.2, 125.3, 125.2, 124.0, 123.8, 123.1, 123.0,

114.8, 114.1, 113.9, 51.4, 26.6 ppm.

= 3300, 1651, 1540, 1364, 1172 cm^–1. ¹H NMR (300 MHz, [D₆]-

DMSO): δ = 8.68 (s, 1 H, NH), 8.37 (d, J = 8.4 Hz, 1 H, ArH),

8.23 (s, 1 H, ArH), 8.19 (dd, J = 1.2, 8.1 Hz, 1 H, ArH), 7.98 (d,

J = 7.5 Hz, 1 H, ArH), 7.91–7.85 (m, 3 H, ArH), 7.76–7.49 (m, 4

Eur. J. Org. Chem. 2015, 7131–7145

www.eurjoc.org

7139

P. Raju, G. Gobi Rajeshwaran, A. K. Mohanakrishnan

FULL PAPER

H, ArH), 4.88 (d, J = 18.6 Hz, 1 H, CH₂), 4.77 (d, J = 18.6 Hz, 1 (d, J = 5.05 Hz), 123.9, 122.6, 120.7, 114.6 (d, J = 21.4 Hz),

H, CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 168.8, 148.6, 43.9 ppm.

139.1, 138.8, 138.1, 136.3, 134.7, 133.3, 133.0, 132.7, 129.7, 129.1,

4-(5-Bromo-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydropyrrolo-

128.2, 126.2, 125.0, 124.9, 124.1, 123.8, 122.5, 120.5, 114.7, 114.5,

[3,4-c]carbazol-3(6H)-one (26g): 0.47 g (83%). M.p. 297–299 °C. ¹H

43.9 ppm. HRMS (FAB⁺): calcd. for C₂₆H₁₇N₃O₅S [M]⁺483.0889,

NMR (300 MHz, [D₆]DMSO): δ = 8.75 (s, 1 H, NH), 8.35 (d, J =

found 483.0892.

8.4 Hz, 1 H, ArH), 8.25 (s, 1 H, ArH), 8.14 (d, J = 9.0 Hz, 1 H,

4-(4,5-Dimethoxy-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydro-

ArH), 8.01–7.84 (m, 4 H, ArH), 7.84 (s, 1 H, ArH), 7.72–7.64 (m,

2 H, ArH), 7.57–7.48 (m, 3 H, ArH), 4.85 (q, J = 32.2 Hz, 2 H,

CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 167.2, 146.2,

137.4 (d, J = 7.0 Hz), 136.5, 134.6, 133.6, 133.4 (d, J = 4.0 Hz),

131.5, 130.6, 128.3, 127.0, 125.2, 124.8, 124.3, 123.5, 122.4, 121.1,

119.2, 113.0 (d, J = 20.1 Hz), 42.4 ppm. C₂₆H₁₆BrN₃O₅S (562.39):

calcd. C 55.53, H 2.87, N 7.47; found C 55.71, H 2.63, N 7.29.

pyrrolo[3,4-c]carbazol-3(6H)-one (26b): 0.49 g (90%). M.p. 312–

314 °C. IR (KBr): ν = 3290, 1645, 1537, 1371, 1175 cm^–1. ¹H NMR

˜

(300 MHz, [D₆]DMSO): δ = 8.67 (s, 1 H, NH), 8.39 (d, J = 8.4 Hz,

1 H, ArH), 8.19 (s, 1 H, ArH), 8.0 (d, J = 7.8 Hz, 1 H, ArH), 7.93

(d, J = 7.8 Hz, 2 H, ArH), 7.78 (s, 1 H, ArH), 7.72–7.65 (m, 2 H,

ArH), 7.58–7.49 (m, 3 H, ArH), 6.99 (s, 1 H, ArH), 4.89 (d, J =

18.6 Hz, 1 H, CH₂), 4.76 (d, J = 18.6 Hz, 1 H, CH₂), 3.96 (s, 3 H,

OMe), 3.94 (s, 3 H, OMe) ppm. ¹³C NMR (75.4 MHz, [D₆]-

DMSO): δ = 168.9, 152.3, 148.0, 140.9, 139.0, 138.9, 138.139,

136.2, 135.4, 135.1, 129.8, 128.3, 127.4, 126.3, 125.3, 125.0, 124.1,

122.6, 120.1, 114.7, 114.5, 114.4, 107.4, 56.3, 56.1, 43.8 ppm.

4-(4,5-Dichloro-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydropyrr-

olo[3,4-c]carbazol-3(6H)-one (26h): 0.48 g (88%). M.p. 303–305 °C.

¹H NMR (300 MHz, [D₆]DMSO): δ = 8.76 (s, 1 H, NH), 8.48 (s,

1 H, ArH), 8.33 (d, J = 8.4 Hz, 1 H, ArH), 8.27 (s, 1 H, ArH),

8.00–7.91 (m, 4 H, ArH), 7.66 (q, J = 15.7 Hz, 2 H, ArH), 7.55–

7.51 (m, 3 H, ArH), 4.83 (q, J = 32.5 Hz, 2 H, CH₂) ppm. ¹³C

NMR (75.4 MHz, [D₆]DMSO): δ = 168.7, 147.4, 139.0 (d, J =

4.5 Hz), 138.1, 136.1 (d, J = 10.4 Hz), 135.1, 133.9, 133.0, 132.0,

131.5, 129.8, 128.6, 126.4, 125.7, 125.0, 123.8, 122.7, 120.9, 114.6

(d, J = 13.5 Hz), 44.0 ppm.

4-(4-Chloro-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydropyrrolo-

[3,4-c]carbazol-3(6H)-one (26c): 0.47 g (91%). M.p. 314–320 °C. IR

(KBr): ν = 3345, 1655, 1560, 1378, 1180 cm^–1. ¹H NMR (300 MHz,

˜

[D₆]DMSO): δ = 8.76 (s, 1 H, NH), 8.37 (d, J = 8.4 Hz, 1 H, ArH),

8.28–8.24 (m, 2 H, ArH), 8.02–7.91 (m, 4 H, ArH), 7.73–7.65 (m,

3 H, ArH), 7.58–7.50 (m, 3 H, ArH), 4.90 (d, J = 19 Hz, 1 H,

CH₂), 4.79 (d, J = 19 Hz, 1 H, CH₂) ppm. ¹³C NMR (75.4 MHz,

[D₆]DMSO): δ = 168.8, 149.1, 139.1, 139.0, 138.1, 136.2, 135.2,

134.3, 133.4, 133.4, 133.2, 131.65, 129.9, 128.6, 126.3, 125.1, 124.0,

123.8, 122.7, 120.7, 114.7, 114.5, 44.0 ppm.

4-(5-Chloro-4-fluoro-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydro-

pyrrolo[3,4-c]carbazol-3(6H)-one (26i): 0.48 g (90%). M.p. 306–

1

308 °C. H NMR (300 MHz, [D₆]DMSO): δ = 8.77 (s, 1 H, NH),

8.37 (d, J = 9.3 Hz, 1 H, ArH), 8.29 (s, 1 H, ArH), 8.01–7.92 (m,

4 H, ArH), 7.68 (q, J = 7.5 Hz, 2 H, ArH), 7.54–7.51 (m, 3 H,

ArH), 4.85 (q, J = 33.0 Hz, 2 H, CH₂) ppm. ¹³C NMR (75.4 MHz,

[D₆]DMSO): δ = 168.5, 158.0, 154.6, 147.5, 147.4, 139.0 (d, J =

6.1 Hz), 138.0, 136.1, 135.1, 134.0, 132.2, 130.3 (d, J = 4.2 Hz),

128.0, 124.9, 124.6, 123.9, 122.7, 120.8, 114.6 (d, J = 5.3 Hz), 113.1

(d, J = 26.4 Hz), 43.9 ppm.

4-(4-Fluoro-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydropyrrolo-

[3,4-c]carbazol-3(6H)-one (26d): 0.44 g (89%). M.p. 296–298 °C. IR

(KBr): ν = 3340, 1654, 1562, 1375, 1177 cm^–1. ¹H NMR (300 MHz,

˜

[D₆]DMSO): δ = 8.74 (s, 1 H, NH), 8.37 (d, J = 8.4 Hz, 1 H, ArH),

8.24 (s, 1 H, ArH), 8.13 (d, J = 7.8 Hz, 1 H, ArH), 8.00 (d, J =

7.5 Hz, 1 H, ArH), 7.93 (d, J = 7.5 Hz, 2 H, ArH), 7.82–7.77 (m,

1 H, ArH), 7.72–7.65 (m, 3 H, ArH), 7.57–7.50 (m, 3 H, ArH),

4.90 (d, J = 19.2 Hz, 1 H, CH₂), 4.79 (d, J = 18.3 Hz, 1 H,

CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 168.8, 149.1 (d,

J = 9.0 Hz), 139.1 (d, J = 5.4 Hz), 138.1, 136.2, 135.2, 134.6 (d, J

= 8.1 Hz), 133.7, 129.9, 129.2, 128.5, 126.3, 125.1, 124.0, 122.7,

120.6, 120.3, 114.7 (d, J = 11.3 Hz), 111.6 (d, J = 27.4 Hz),

43.9 ppm.

4-(4-Chloro-5-fluoro-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydro-

pyrrolo[3,4-c]carbazol-3(6H)-one (26j): 0.45 g (85%). M.p. 302–

1

304 °C. H NMR (300 MHz, [D₆]DMSO): δ = 8.80 (s, 1 H, NH),

8.53 (d, J = 6.9 Hz, 1 H, ArH), 8.36 (d, J = 8.4 Hz, 1 H, ArH),

8.30 (s, 1 H, ArH), 8.01 (d, J = 7.8 Hz, 1 H, ArH), 7.95 (d, J =

7.8 Hz, 2 H, ArH), 7.84 (d, J = 9.3 Hz, 1 H, ArH), 7.69 (q, J =

7.6 Hz, 2 H, ArH), 7.58–7.49 (m, 3 H, ArH), 4.84 (q, J = 19.0 Hz,

2 H, CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 160.8,

157.4, 145.1, 139.0 (d, J = 2.2 Hz), 138.0, 136.1, 135.2, 134.5 (d, J

= 9.0 Hz), 132.3, 128.6, 126.7, 126.4, 125.0 (d, J = 6.0 Hz), 123.8,

122.7, 120.9, 120.1, 119.9, 114.6, 114.4, 44.0 ppm.

4-(5-Fluoro-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydropyrrolo-

[3,4-c]carbazol-3(6H)-one (26e): 0.43 g (88%). M.p. 297–299 °C. IR

(KBr): ν = 3340, 1654, 1562, 1375, 1177 cm^–1. ¹H NMR (300 MHz,

˜

[D₆]DMSO): δ = 8.73 (s, 1 H, NH), 8.35 (d, J = 8.4 Hz, 1 H, ArH),

8.30 (dd, J₁= 5.1, J₂= 9 Hz, 1 H, ArH), 8.26 (s, 1 H, ArH), 8.00

(d, J = 7.5 Hz, 1 H, ArH), 7.93 (d, J = 7.5 Hz, 2 H, ArH), 7.72–

7.64 (m, 2 H, ArH), 7.62–7.51 (m, 5 H, ArH), 4.90 (d, J = 18.6 Hz,

1 H, CH₂), 4.79 (d, J = 18.6 Hz, 1 H, CH₂) ppm. ¹³C NMR

(75.4 MHz, [D₆]DMSO): δ = 168.7, 145.1, 139.1, 138.9, 138.0,

136.2, 136.1, 133.4, 129.8, 128.6, 127.1 (d, J = 10.3 Hz), 126.4,

125.1, 125.0, 123.9, 122.7, 120.7, 119.6 (d, J = 24.5 Hz), 116.0 (d,

J = 23.2 Hz), 114.7, 114.4, 44.0 ppm.

4-(5-Bromo-4-fluoro-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydro-

pyrrolo[3,4-c]carbazol-3(6H)-one (26k): 0.50 g (88%). M.p. 305–

1

307 °C. H NMR (300 MHz, [D₆]DMSO): δ = 8.77 (s, 1 H, NH),

8.36–8.28 (m, 3 H, ArH), 8.06–7.92 (m, 4 H, ArH), 7.72–7.65 (m,

2 H, ArH), 7.57–7.48 (m, 3 H, ArH), 4.85 (q, J = 32.7 Hz, 2 H,

CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 168.7, 159.2,

155.9, 148.2, 148.1, 139.0 (d, J = 7.0 Hz), 138.0, 136.8, 136.1, 135.1,

132.2, 130.4 (d, J = 4.1 Hz), 129.8, 128.5, 126.3, 125.0 (d, J =

4.0 Hz), 123.9, 122.7, 120.8, 114.7, 114.6, 113.8 (d, J = 21.0 Hz),

112.6 (d, J = 28.0 Hz), 43.9 ppm.

4-(5-Chloro-2-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydropyrrolo-

1

[3,4-c]carbazol-3(6H)-one (26f): 0.46 g (90%). M.p. 304–308 °C. H

NMR (300 MHz, [D₆]DMSO): δ = 8.71 (s, 1 H, NH), 8.35 (d, J = 4-(2,3-Dichloro-6-nitrophenyl)-6-(phenylsulfonyl)-1,2-dihydropyrr-

8.4 Hz, 1 H, ArH), 8.25–8.21 (m, 2 H, ArH), 7.99 (d, J = 7.5 Hz,

1 H, ArH), 7.92 (d, J = 7.5 Hz, 2 H, ArH), 7.81 (d, J = 8.7 Hz, 1

H, ArH), 7.71–7.64 (m, 3 H, ArH), 7.56–7.48 (m, 3 H, ArH), 4.84

olo[3,4-c]carbazol-3(6H)-one (26l): 0.48 g (88%). M.p. 301–303 °C.

¹H NMR (300 MHz, [D₆]DMSO): δ = 8.76 (s, 1 H, NH), 8.41 (d,

J = 8.4 Hz, 1 H, ArH), 8.27 (s, 1 H, ArH), 8.21 (d, J = 9.0 Hz, 1

(q, J = 31.5 Hz, 2 H, CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]- H, ArH), 8.08–8.00 (m, 2 H, ArH), 7.88 (d, J = 7.8 Hz, 2 H, ArH),

DMSO): δ = 168.7, 147.3, 139.0 (d, J = 7.1 Hz), 138.1, 137.7, 136.2,

7.72–7.49 (m, 5 H, ArH), 4.89 (s, 2 H, CH₂) ppm. ¹³C NMR

135.1, 134.9, 133.1, 132.1, 129.8, 129.1, 128.5, 126.3, 125.8, 125.0

(75.4 MHz, [D₆]DMSO): δ = 168.3, 148.2, 138.9 (d, J = 21.6 Hz),

7140

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Eur. J. Org. Chem. 2015, 7131–7145

Facile Synthesis of Staurosporinone Analogues

138.2, 136.8, 135.9, 135.1, 133.8, 133.3, 130.6, 130.1, 129.7, 128.7,

3-Fluoro-12-(phenylsulfonyl)-6,7,12,13-tetrahydro-5H-indolo[2,3-a]-

126.2, 126.0, 125.1, 123.8 (d, J = 14.1 Hz), 122.8, 121.4, 114.7 (d, pyrrolo[3,4-c]carbazol-5-one (27e): Brown solid. 0.04 g (92%). M.p.

J = 11.3 Hz), 44.1 ppm. C₂₆H₁₅Cl₂N₃O₅S (552.38): calcd. C 56.53,

Ͼ 310 °C. IR (KBr): ν = 3412, 3340, 1673, 1381, 1182 cm^–1. ¹H

˜

H 2.74, N 7.61; found C 56.78, H 2.48, N 7.84.

NMR (300 MHz, [D₆]DMSO): δ = 11.39 (br. s, 1 H, NH), 9.15–

9.11 (m, 1 H, ArH), 8.95 (s, 1 H, NH), 8.40 (d, J = 8.4 Hz, 1 H,

ArH), 8.01 (dd, J₁= 4.8, J₂= 8.7 Hz, 1 H, ArH), 7.93 (d, J =

7.8 Hz, 1 H, ArH), 7.65 (t, J = 8.1 Hz, 1 H, ArH), 7.56–7.40 (m,

6 H, ArH), 4.92 (s, 2 H, CH₂) ppm. C₂₆H₁₆FN₃O₃S (469.49): calcd.

C 66.51, H 3.44, N 8.95; found C 66.62, H 3.51, N 9.12.

General Procedure for Triethyl Phosphite-Mediated Nitrene Inser-

tion of 2Ј-Nitroaryl Carbazolamides 26a–26k: A mixture of 2Ј-nitro-

arylcarbazole (26a–26k; 0.1 mmol) and triethyl phosphite (2 mL)

in o-DCB (5 mL) was heated to reflux under N₂for 12 h. After

consumption of the nitro compound (monitored by TLC), the sol-

vent was removed under reduced pressure and the solid obtained

was washed with hexane (5 mL) to afford N-protected indolo carb-

azoles 27a–27e. The crude product 27f–27k was used in the next

step (hydrolysis) without further characterization.

General Procedure for Hydrolysis Reaction of Indolocarbazoles 27a–

27k: To a suspension of N-protected indolo carbazoles 27a–27k

(0.5 mmol) in MeOH (5 mL) and THF (5 mL), K₂CO₃(1.5 mmol)

was added and the reaction mixture was heat to reflux for 10 h.

After completion of the reaction (monitored by TLC), the solvent

was removed under reduced pressure and the resulting residue was

poured over crushed ice (25 g) that contained dilute HCl (5 mL).

The solid formed was filtered and washed with water and dried to

afford indolocarbazoles 28a–28k as brown solids.

12-(Phenylsulfonyl)-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo-

[3,4-c]carbazol-5-one (27a): Brown solid. 0.04 g (89%). M.p. 300–

302 °C. IR (KBr): ν = 3410, 3345, 1652, 1365, 1172 cm^–1. ¹H NMR

˜

(300 MHz, [D₆]DMSO): δ = 11.28 (br. s, 1 H, NH), 9.38 (d, J =

8.1 Hz, 1 H, ArH), 8.85 (s, 1 H, NH), 8.39 (d, J = 8.4 Hz, 1 H,

ArH), 7.97 (d, J = 8.1 Hz, 1 H, ArH), 7.90 (d, J = 7.8 Hz, 1 H,

ArH), 7.63 (t, J = 7.2 Hz, 1 H, ArH), 7.55–7.50 (m, 5 H, ArH),

7.35–7.26 (m, 3 H, ArH), 4.90 (s, 2 H, CH₂) ppm. ¹³C NMR

(75.4 MHz, [D₆]DMSO): δ = 170.8, 139.8, 138.5, 134.9, 134.8,

130.8, 129.5, 127.7, 127.4, 126.9, 126.4, 126.3, 125.8, 125.5, 125.0,

124.9, 121.8, 121.4, 120.1, 119.5, 116.5, 112.3, 45.0 ppm. HRMS

(ESI): calcd. for C₂₆H₁₇N₃NaO₃S [M + Na]⁺474.0888; found

474.5312.

6,7,12,13-Tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one

(28a): 0.14 g (91%). M.p. Ͼ 310 °C. ¹H NMR (300 MHz, [D₆]-

DMSO): δ = 11.52 (br. s, 1 H, NH), 11.35 (br. s, 1 H, NH), 9.24

(d, J = 7.5 Hz, 1 H, ArH), 8.51 (s, 1 H, NH), 8.06 (d, J = 7.8 Hz,

1 H, ArH), 7.80 (d, J = 8.7 Hz, 1 H, ArH), 7.74 (d, J = 7.8 Hz, 1

H, ArH), 7.52–7.41 (m, 2 H, ArH), 7.32 (t, J = 7.4 Hz, 1 H, ArH),

7.24 (t, J = 7.5 Hz, 1 H, ArH), 4.96 (s, 2 H, CH₂) ppm. ¹³C NMR

(75.4 MHz, [D₆]DMSO): δ = 172.4, 139.2, 139.1, 132.9, 127.8,

125.3, 125.2, 124.99 (2 C), 127.8, 122.5, 121.1, 119.9, 118.929,

118.8, 115.6, 114.1, 111.9, 111.3, 45.3 ppm. HRMS (FAB⁺): calcd.

for C₂₀H₁₃N₃O [M]⁺311.1059; found 311.1063.

2,3-Dimethoxy-12-(phenylsulfonyl)-6,7,12,13-tetrahydro-5H-

indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one (27b): Brown solid. 0.04 g

(85%). M.p. 294–296 °C. IR (KBr): ν = 3409, 3340, 1648, 1371,

˜

1182 cm^–1. ¹H NMR (300 MHz, [D₆]DMSO): δ = 11.04 (br. s, 1 H,

NH), 8.93 (s, 1 H, ArH), 8.74 (s, 1 H, NH), 8.36 (d, J = 8.1 Hz, 1

H, ArH), 7.84 (d, J = 7.5 Hz, 1 H, ArH), 7.60–7.49 (m, 6 H, ArH),

7.33 (m, 2 H, ArH), 4.85 (s, 2 H, CH₂), 3.92 (s, 3 H, OMe), 3.87

(s, 3 H, OMe) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 171.1,

150.1, 144.1, 138.1, 135.4, 135.0, 134.8, 130.4, 129.5, 127.0, 126.9,

126.3, 125.7, 124.8, 123.5, 121.5, 120.1, 118.3, 116.3, 113.7, 107.5,

95.3, 56.0, 55.5, 45.1 ppm. C₂₈H₂₁N₃O₅S (511.54): calcd. C 65.74,

H 4.14, N 8.21; found C 65.47, H 4.39, N 8.48.

2,3-Dimethoxy-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]-

carbazol-5-one (28b): 0.16 g (86 %). M.p. Ͼ 310 °C. ¹H NMR

(300 MHz, [D₆]DMSO): δ = 11.07 (br. s, 1 H, NH), 10.63 (s, 1 H,

NH), 8.90 (s, 1 H, NH), 7.90 (d, J = 7.5 Hz, 1 H, ArH), 7.66 (s, 1

H, ArH), 7.63–7.60 (m, 2 H, ArH), 7.43 (t, J = 7.5 Hz, 1 H, ArH),

7.28 (m, 1 H, ArH), 7.09 (s, 1 H, ArH), 4.93 (s, 2 H, CH₂), 4.03

(s, 3 H, OMe), 4.00 (s, 3 H, OMe) ppm. ¹³C NMR (75.4 MHz, [D₆]-

DMSO): δ = 172.6, 149.0, 143.6, 139.1, 134.3, 132.4, 128.1, 124.9,

124.5, 122.7, 120.8, 119.6, 117.9, 116.2, 115.1, 112.9, 111.6, 107.9,

94.7, 56.1, 55.6. 45.3 ppm. HRMS (FAB⁺): calcd. for C₂₂H₁₇N₃O₃

[M]⁺371.1270; found 371.1260.

2-Chloro-12-(phenylsulfonyl)-6,7,12,13-tetrahydro-5H-indolo[2,3-a]-

pyrrolo[3,4-c]carbazol-5-one (27c): Brown solid. 0.04 g (90%). M.p.

Ͼ 310 °C. IR (KBr): ν = 3405, 3322, 1682, 1376, 1182 cm^–1. ¹H

˜

2-Chloro-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]-

carbazol-5-one (28c): 0.15 g (88 %). M.p. Ͼ 310 °C. ¹H NMR

(300 MHz, [D₆]DMSO): δ = 11.70 (s, 1 H, NH), 11.55 (s, 1 H,

NH), 9.20 (d, J = 8.7 Hz, 1 H, ArH), 8.55 (s, 1 H, NH), 8.31 (s, 1

H, ArH), 8.05 (d, J = 7.8 Hz, 1 H, ArH), 7.84 (s, 1 H, ArH), 7.78

(d, J = 8.1 Hz, 1 H, ArH), 7.48 (t, J = 7.5 Hz, 1 H, ArH), 7.34–

7.24 (m, 2 H, ArH), 4.96 (s, 2 H, CH₂) ppm. ¹³C NMR (75.4 MHz,

[D₆]DMSO): δ = 173.0, 139.5, 139.2, 133.5, 129.8, 127.5, 125.7,

125.4, 125.4, 122.0, 121.0, 120.8, 120.3, 119.3, 117.5, 114.7, 114.2,

111.7, 110.8, 45.4 ppm. HRMS (FAB⁺): calcd. for C₂₀H₁₂ClN₃O

[M]⁺345.0669; found 345.0660.

NMR (300 MHz, [D₆]DMSO): δ = 11.39 (br. s, 1 H, NH), 9.34 (d,

J = 8.1 Hz, 1 H, ArH), 8.91 (s, 1 H, NH), 8.37 (d, J = 7.5 Hz, 1

H, ArH), 8.06 (s, 1 H, ArH), 7.89 (d, J = 6.6 Hz, 1 H, ArH),

7.63–7.50 (m, 6 H, ArH), 7.35–7.32 (m, 2 H, ArH) ppm. ¹³C NMR

(75.4 MHz, [D₆]DMSO): δ = 170.7, 140.3, 138.4, 134.9, 134.8,

131.3, 130.9, 129.6, 128.0, 127.6, 126.7, 126.6, 126.4, 125.8, 124.9,

124.7, 121.8, 120.4, 120.2, 119.8, 118.9, 116.5, 112.0, 45.1 ppm.

2-Fluoro-12-(phenylsulfonyl)-6,7,12,13-tetrahydro-5H-indolo[2,3-a]-

pyrrolo[3,4-c]carbazol-5-one (27d): Brown solid. 0.04 g (89%). M.p.

Ͼ 310 °C. IR (KBr): ν = 3411, 3320, 1683, 1312, 1172 cm^–1. ¹H

˜

NMR (300 MHz, [D₆]DMSO): δ = 11.41 (br. s, 1 H, NH), 9.39–

9.34 (m, 1 H, ArH), 8.89 (s, 1 H, NH), 8.38 (d, J = 7.5 Hz, 1 H, 2-Fluoro-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carb-

ArH), 7.90 (d, J = 7.5 Hz, 1 H, ArH), 7.78 (d, J = 9.9 Hz, 1 H,

ArH), 7.63 (t, J = 7.8 Hz, 1 H, ArH), 7.53–7.51 (m, 3 H, ArH),

7.36–7.31 (m, 3 H, ArH), 7.17–7.11 (m, 1 H, ArH), 4.89 (s, 2 H,

azol-5-one (28d): 0.15 g (91 %). M.p. Ͼ 310 °C. ¹H NMR

(300 MHz, [D₆]DMSO): δ = 11.55 (br. s, 1 H, NH), 11.45 (br. s, 1

H, NH), 9.25–9.20 (m, 1 H, ArH), 8.53 (s, 1 H, NH), 8.03 (d, J =

CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 170.8, 140.6 (d, 7.8 Hz, 1 H, ArH), 7.78 (d, J = 8.1 Hz, 1 H, ArH), 7.57 (d, J =

J = 13.6 Hz), 138.4, 134.8, 131.2, 130.7, 129.6, 128.8, 128.2, 127.4,

127.0 (d, J = 9.8 Hz), 126.8, 126.4, 125.8, 124.9, 124.5, 121.8, 119.9,

119.2, 118.3, 116.5, 107.1 (d, J = 24.13 Hz), 98.7, 98.4 (d, J =

26.4 Hz) ppm. C₂₆H₁₆FN₃O₃S (469.49): calcd. C 66.51, H 3.44, N

8.95; found C 66.78, H 3.71, N 7.67.

10.2 Hz, 1 H, ArH), 7.47 (t, J = 7.5 Hz, 1 H, ArH), 7.30 (t, J =

7.5 Hz, 1 H, ArH), 7.09 (t, J = 9.2 Hz, 1 H, ArH), 4.96 (s, 2 H,

CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 172.4, 139.6 (d,

J = 12.8 Hz), 139.2, 133.1, 127.7, 126.5, 126.3, 125.9, 125.0, 122.5,

121.1, 119.9, 119.6, 118.5, 115.3, 114.1, 111.9, 107.1 (d, J =

Eur. J. Org. Chem. 2015, 7131–7145

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7141

P. Raju, G. Gobi Rajeshwaran, A. K. Mohanakrishnan

FULL PAPER

23.6 Hz), 97.7 (d, J = 26.2 Hz), 45.3 ppm. HRMS (FAB⁺): calcd. [D₆]DMSO): δ = 172.2, 152.5, 149.4, 139.2, 135.5, 133.4, 127.6,

for C₂₀H₁₂FN₃O [M]⁺329.0964; found 329.0973.

126.8, 125.2, 122.3, 121.7 (d, J = 9.8 Hz), 121.2, 120.0, 118.6, 116.6

(d, J = 21.1 Hz), 114.8, 114.7, 112.5, 111.9, 110.8 (d, J = 24.8 Hz),

45.37 ppm. C₂₀H₁₁ClFN₃O (363.77): calcd. C 66.03, H 3.05, N

11.55; found C 65.71, H 3.31, N 11.79.

3-Fluoro-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carb-

azol-5-one (28e): 0.15 g (91 %). M.p. Ͼ 310 °C. ¹H NMR

(300 MHz, [D₆]DMSO): δ = 11.71 (br. s, 1 H, NH), 11.53 (br. s, 1

H, NH), 8.96 (d, J = 10.2 Hz, 1 H, ArH), 8.55 (br. s, 1 H, NH), 3-Bromo-2-fluoro-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo-

1

8.05 (d, J = 7.5 Hz, 1 H, ArH), 7.80–7.71 (m, 2 H, ArH), 7.48 (t, [3,4-c]carbazol-5-one (28k): 0.17 (85%). M.p. Ͼ 310 °C. H NMR

J = 7.2 Hz, 1 H, ArH), 7.34–7.29 (m, 2 H, ArH), 4.97 (s, 2 H,

CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 172.3, 139.2,

135.7, 135.0, 133.0, 127.8, 126.7, 125.1, 122.5, 121.1, 120.0, 119.6,

(300 MHz, [D₆]DMSO): δ = 11.63 (s, 2 H, NH), 9.48 (d, J = 7.2 Hz,

1 H, ArH), 8.59 (s, 1 H, NH), 8.04 (d, J = 7.5 Hz, 1 H, ArH), 7.79

(d, J = 9.0 Hz, 2 H, ArH), 7.49 (t, J = 7.3 Hz, 1 H, ArH), 7.32 (d,

118.8, 114.4, 112.8 (d, J = 26 Hz), 112.3 (d, J = 9.6 Hz), 112.0, J = 7.3 Hz, 1 H, ArH), 4.96 (s, 2 H, CH₂) ppm. ¹³C NMR

109.7 (d, J = 24.8 Hz), 45.4 ppm. HRMS (FAB⁺): calcd. for

(75.4 MHz, [D₆]DMSO): δ = 172.2, 157.5, 154.3, 139.2, 138.5 (d, J

= 11.7 Hz), 133.5, 128.3, 127.5, 126.3, 125.2, 122.3, 121.2, 120.7,

120.0, 118.4, 114.5, 114.2, 111.9, 99.3 (d, J = 27.1 Hz), 98.2 (d, J

= 22.6 Hz), 45.4 ppm. HRMS (EI): calcd. for C₂₀H₁₁BrFN₃O

[M]⁺407.0070; found 407.0070.

C₂₀H₁₂FN₃O [M]⁺329.0964; found 329.0965.

3-Chloro-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carb-

azol-5-one (28f): 0.14 g (83%). M.p. Ͼ 310 °C. ¹H NMR (300 MHz,

[D₆]DMSO): δ = 11.57 (s, 1 H, NH), 11.50 (s, 1 H, NH), 9.27 (s, 1

H, ArH), 8.55 (s, 1 H, NH), 8.05 (d, J = 7.8 Hz, 1 H, ArH), 7.79

(t, J = 8.8 Hz, 2 H, ArH), 7.52–7.42 (m, 2 H, ArH), 7.32 (t, J =

7.3 Hz, 1 H, ArH), 4.98 (s, 2 H, CH₂) ppm. ¹³C NMR (75.4 MHz,

[D₆]DMSO): δ = 172.2, 139.2, 137.5, 133.3, 127.7, 126.2, 125.1,

124.7, 124.0, 123.8, 123.0, 122.4, 121.1, 120.0, 118.8, 114.6 (d, J =

3.3 Hz), 112.9, 112.0, 45.3 ppm. HRMS (EI): calcd. for

C₂₀H₁₂ClN₃O [M]⁺345.0669; found 345.0650.

Ethyl (E)-3-[3-(2-Nitrostyryl)-1-(phenylsulfonyl)-1H-indol-2-yl]-

acrylate (30a): To a solution of phosphonate ester 29^[27](1.0 g,

1.97 mmol) in dry DMF, K₂CO₃(0.54 g, 3.95 mmol) and 2-

nitrobenzaldehyde (0.32 g, 2.17 mmol) were added and the reaction

mixture was stirred at room temperature for 14 h. After completion

of the reaction (monitored by TLC), it was poured over crushed

ice (30 g) that contained conc. HCl (8 mL). The crude product was

then extracted with EtOAc (2ϫ 20 mL) and dried (Na₂SO₄). The

solvent was removed under reduced pressure and the crude product

was purified by column chromatography (1% EtOAc/hexane) gave

compound 30a as a yellow solid. 0.75 g (75%). M.p. 158–160 °C.

¹H NMR (300 MHz, CDCl₃): δ = 8.26 (s, 1 H, ArH), 8.22–8.20

(m, 1 H, ArH), 7.93 (d, J = 8.1 Hz, 1 H, ArH), 7.87 (d, J = 7.8 Hz,

1 H, ArH), 7.68–7.63 (m, 4 H, ArH), 7.56 (t, J = 7.5 Hz, 1 H,

ArH), 7.47–7.29 (m, 6 H, ArH), 6.96 (d, J = 16.5 Hz, 1 H, ArH),

6.06 (d, J = 15.9 Hz, 1 H, ArH), 4.27 (q, J = 7.2 Hz, 2 H, OCH₂),

1.32 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 165.8, 147.6, 137.6, 137.4, 134.2, 134.0, 133.8, 133.5, 133.0,

129.2, 128.4, 128.2, 128.0, 127.9, 126.8, 126.7, 125.6, 125.0, 124.7,

123.2, 121.3, 115.3, 61.0, 14.3 ppm.

3-Bromo-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carb-

azol-5-one (28g): 0.17 g (88 %). M.p. Ͼ 310 °C. ¹H NMR

(300 MHz, [D₆]DMSO): δ = 11.60 (s, 1 H, NH), 11.54 (s, 1 H,

NH), 9.41 (s, 1 H, ArH), 8.58 (s, 1 H, NH), 8.06 (d, J = 6.0 Hz, 1

H, ArH), 7.81 (d, J = 7.2 Hz, 1 H, ArH), 7.73 (d, J = 7.8 Hz, 1 H,

ArH), 7.56–7.50 (m, 2 H, ArH), 7.32–7.30 (m, 1 H, ArH), 4.98 (s,

2 H, CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ = 172.2,

139.2, 137.7, 133.3, 127.6, 127.2, 127.0, 126.0, 125.1, 124.5, 122.4,

121.1, 120.0, 118.8, 114.6, 114.5, 113.4, 112.0, 110.9, 45.3 ppm.

HRMS (EI): calcd. for C₂₀H₁₂BrN₃O [M]⁺389.0164; found

389.0160.

2,3-Dichloro-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo[3,4-c]-

carbazol-5-one (28h): 0.17 g (89 %). M.p. Ͼ 310 °C. ¹H NMR

(300 MHz, [D₆]DMSO): δ = 11.68 (s, 1 H, NH), 11.56 (s, 1 H,

NH), 9.41 (s, 1 H, ArH), 8.62 (s, 1 H, NH), 8.07–7.80 (m, 3 H,

ArH), 7.51–7.33 (m, 2 H, ArH), 4.98 (s, 2 H, CH₂) ppm. ¹³C NMR

(75.4 MHz, [D₆]DMSO): δ = 172.1, 139.2, 137.9, 133.6, 127.5,

126.9, 126.5, 125.5, 125.3, 122.7, 122.3, 121.2, 120.9, 120.0, 118.7,

114.9, 114.1, 113.1, 112.0, 45.4 ppm. HRMS (EI): calcd. for

C₂₀H₁₁Cl₂N₃O [M]⁺379.0279; found 379.0270.

Ethyl (E)-3-[3-(5-Fluoro-2-nitrostyryl)-1-(phenylsulfonyl)-1H-indol-

2-yl]acrylate (30b): The Wittig–Horner reaction of phosphonate es-

ter 29^[27](1.0 g, 1.97 mmol) with 5-fluoro-2-nitrobenzaldehyde

(0.36 g, 2.17 mmol) by means of a procedure similar to that for the

production of 30a afforded 30b as a yellow solid. 0.80 g (78%).

M.p. 156–158 °C. ¹H NMR (300 MHz, CDCl₃): δ = 8.33 (d, J =

6.6 Hz, 1 H, ArH), 8.30 (s, 1 H, ArH), 8.12 (q, J = 5.1 Hz, 1 H,

ArH), 7.95 (d, J = 7.8 Hz, 1 H, ArH), 7.81–7.76 (m, 3 H, ArH),

7.58–7.40 (m, 6 H, ArH), 7.16–7.13 (m, 1 H, ArH), 7.04 (d, J =

16.5 Hz, 1 H, ArH), 6.13 (d, J = 15.9 Hz, 1 H, ArH), 4.37 (q, J =

7.2 Hz, 2 H, OCH₂), 1.42 (t, J = 7.0 Hz, 3 H, CH₃) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 165.7, 164.5 (d, J = 190.0 Hz), 143.7,

137.7, 137.3, 136.4 (d, J = 9.0 Hz), 134.5, 134.3, 133.7, 129.3, 128.1,

128.0, 126.9 (d, J = 3.0 Hz), 126.7, 126.0 (d, J = 6.7 Hz), 125.0,

122.6, 121.1, 115.5, 115.3, 115.2, 114.5 (d, J = 24.1 Hz), 61.1,

14.3 ppm. C₂₇H₂₁FN₂O₆S (520.52): calcd. C 62.30, H 4.07, N 5.38;

found C 62.56, H 3.88, N 5.21.

3-Chloro-2-fluoro-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo-

1

[3,4-c]carbazol-5-one (28i): 0.16 g (88%). M.p. Ͼ 310 °C. H NMR

(300 MHz, [D₆]DMSO): δ = 11.59 (s, 2 H, NH), 9.35 (d, J = 8.1 Hz,

1 H, NH), 8.56 (s, 1 H, NH), 8.03 (d, J = 7.5 Hz, 1 H, ArH), 7.78

(m, 2 H, ArH), 7.49 (t, J = 7.3 Hz, 1 H, ArH), 7.31 (m, 1 H, ArH),

4.95 (s, 2 H, CH₂) ppm. ¹³C NMR (75.4 MHz, [D₆]DMSO): δ =

172.2, 156.7, 153.5, 139.24, 137.3 (d, J = 11.6 Hz), 133.4, 127.5,

126.3, 125.5, 125.2, 122.3, 121.2, 120.0, 119.9, 118.4, 114.4 (d, J =

8.6 Hz), 111.9, 110.5 (d, J = 19.4 Hz), 99.4 (d, J = 25.6 Hz) ppm.

HRMS (EI): calcd. for C₂₀H₁₁ClFN₃O [M]⁺363.0575; found

363.0570.

Ethyl 3-(2-Nitrophenyl)-9-(phenylsulfonyl)-9H-carbazole-2-carb-

oxylate (31a): To a solution of divinyl compound 30a (0.5 g) in dry

2-Chloro-3-fluoro-6,7,12,13-tetrahydro-5H-indolo[2,3-a]pyrrolo- xylenes (10 mL), 10% Pd/C (0.2 g) was added. The reaction mix-

1

[3,4-c]carbazol-5-one (28j): 0.16 g (88%). M.p. Ͼ 310 °C. H NMR ture was heated to reflux for 24 h. Then, the reaction mixture was

(300 MHz, [D₆]DMSO): δ = 11.75 (s, 1 H, NH), 11.56 (s, 1 H, filtered through a Celite pad and washed with hot xylenes (10 mL).

NH), 9.10 (d, J = 10.2 Hz, 1 H, ArH), 8.59 (s, 1 H, NH), 8.03 (d, The combined filtrate was concentrated under reduced pressure

J = 7.5 Hz, 1 H, ArH), 7.9 (d, J = 6.0 Hz, 1 H, ArH), 7.78 (d, J = and the resulting crude product was triturated with MeOH (3 mL)

7.8 Hz, 1 H, ArH), 7.49 (t, J = 7.2 Hz, 1 H, ArH), 7.31 (t, J =

to afford carbazole 31a as a pale yellow solid. 0.45 g (92%). M.p.

1

6.9 Hz, 1 H, ArH), 4.95 (s, 2 H, CH₂) ppm. ¹³C NMR (75.4 MHz, 178–180 °C. H NMR (300 MHz, CDCl₃): δ = 9.00 (s, 1 H, ArH),

7142

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Eur. J. Org. Chem. 2015, 7131–7145

Facile Synthesis of Staurosporinone Analogues

8.29 (d, J = 8.4 Hz, 1 H, ArH), 8.06 (d, J = 8.1 Hz, 1 H, ArH),

oxylate (31b): The reaction of 5-fluoro-2Ј-nitroarylcarbazole (31b;

7.83–7.81 (m, 3 H, ArH), 7.67 (s, 1 H, ArH), 7.61–7.42 (m, 4 H,

0.2 g) with triethyl phosphite (2 mL) by using the procedure de-

ArH), 7.35–7.29 (m, 4 H, ArH), 4.11 (q, J = 6.9 Hz, 2 H, OCH₂), scribed above, followed by workup and column chromatographic

1.09 (t, J = 7.0 Hz, 3 H, CH₃) ppm. ¹³C NMR (75.4 MHz, CDCl₃):

δ = 166.2, 148.3, 139.7, 137.6, 137.5, 137.4, 135.5, 134.1, 132.6,

131.7, 129.2, 129.1, 128.8, 128.2, 128.0, 126.5, 125.1, 124.3, 124.0,

121.2, 120.8, 117.3, 115.2, 61.2, 13.8 ppm. C₂₇H₂₀N₂O₆S (500.52):

calcd. C 64.79, H 4.03, N 5.60; found C 64.92, H 4.25, N 5.58.

separation, led to isolation of indolocarbazole 32b and quinocarb-

azole 33b in a 3:1 ratio.

Data for indolocarbazole 32b: Colorless solid. 0.13 g (68%). M.p.

1

260–262 °C. H NMR (300 MHz, CDCl₃): δ = 11.64 (s, 1 H, NH),

8.79 (s, 1 H, ArH), 8.60 (d, J = 7.5 Hz, 1 H, ArH), 8.50 (d, J =

10.8 Hz, 1 H, ArH), 8.35 (d, J = 8.4 Hz, 1 H, ArH), 7.76 (d, J =

7.5 Hz, 2 H, ArH), 7.58–7.27 (m, 6 H, ArH), 7.14 (t, J = 7.8 Hz,

1 H, ArH), 4.55 (q, J = 6.9 Hz, 2 H, OCH₂), 1.52 (t, J = 7.0 Hz,

3 H, CH₃) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 172.2, 160.3

(d, J = 190.0 Hz), 143.4, 142.5, 142.1, 140.6, 139.7, 139.0, 134.0,

132.3, 131.1, 129.4, 129.2 (d, J = 2.2 Hz), 127.2, 126.7 (d, J =

11.3 Hz), 122.7 (d, J = 4.5 Hz), 119.7, 118.7, 118.4 (d, J = 8.3 Hz),

116.7 (d, J = 9.8 Hz), 115.0 (d, J = 26.4 Hz), 114.3, 66.1, 19.3 ppm.

DEPT 135 (75.4 MHz, CDCl₃): δ = 139.1, 134.0, 132.3, 131.1,

129.3, 127.2, 119.7, 118.6 (d, J = 26.6 Hz), 116.7 (d, J = 9.8 Hz),

115.0 (d, J = 25.6 Hz), 114.3, 66.1, 19.3 ppm. HRMS (EI): calcd.

for C₂₇H₁₉N₂O₄S [M]⁺486.1050; found 486.1050.

Ethyl 3-(5-Fluoro-2-nitrophenyl)-9-(phenylsulfonyl)-9H-carbazole-2-

carboxylate (31b): The procedure was similar to that for the pro-

duction of 31a. 0.46 g (93 %). M.p. 180–182 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 8.99 (s, 1 H, ArH), 8.24 (d, J = 8.4 Hz, 1

H, ArH), 8.09 (dd, J₁= 5.1, J₂= 5.1 Hz, 1 H, ArH), 7.82–7.74 (m,

3 H, ArH), 7.64 (s, 1 H, ArH), 7.49–7.40 (m, 3 H, ArH), 7.37–7.25

(m, 2 H, ArH), 7.16–7.08 (m, 1 H, ArH), 6.96 (dd, J₁= 2.7, J₂=

2.7 Hz, 1 H, ArH), 4.12 (q, J = 6.6 Hz, 2 H, OCH₂), 1.11 (t, J =

7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 165.8,

162.5, 144.4, 140.7 (d, J = 9.8 Hz), 139.6, 137.5, 134.6, 134.1, 129.2,

129.1, 128.9, 127.6, 126.8 (d, J = 9.8 Hz), 126.5, 124.9, 124.3, 120.8

(d, J = 4.5 Hz), 118.9, 118.6, 117.4, 115.2, 114.8, 61.3, 13.8 ppm.

C₂₇H₁₉FN₂O₆S (518.51): calcd. C 62.54, H 3.69, N 5.40; found C

62.73, H 3.52, N 5.61.

6-Ethoxy-2-fluoro-8-(phenylsulfonyl)-8H-indolo[2,3-j]phen-

anthridine (33b): Colorless solid. 0.05 g (25%). M.p. 250–252 °C.

¹H NMR (300 MHz, CDCl₃): δ = 9.26 (s, 1 H, NH), 8.31–8.27 (m,

3 H, ArH), 7.91 (d, J = 7.5 Hz, 1 H, ArH), 7.78 (d, J = 8.1 Hz, 2

H, ArH), 7.60 (dd, J₁= 2.1, J₂= 2.1 Hz, 1 H, ArH), 7.46–7.09 (m,

6 H, ArH), 4.63 (q, J = 7.2 Hz, 2 H, OCH₂), 1.63 (t, J = 7.0 Hz,

3 H, CH₃) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 159.5 (d, J =

241.2 Hz), 152.1, 139.2, 138.5 (d, J = 3.7 Hz), 137.8, 135.3, 133.8,

129.0, 127.2, 126.6, 126.1, 124.2, 123.0, 122.5 (d, J = 3.0 Hz), 119.8,

117.4 (d, J = 8.3 Hz), 115.3, 114.5, 114.1, 110.4, 105.7, 105.3, 103.4,

63.6, 14.4 ppm. DEPT 135 (75.4 MHz, CDCl₃): δ = 133.8, 129.0,

127.4, 126.4, 124.2, 119.8, 117.4 (d, J = 8.3 Hz), 115.3, 114.3 (d, J

= 24.8 Hz), 110.5, 105.5 (d, J = 24.1 Hz), 103.4, 63.6, 14.4 ppm.

HRMS (EI): calcd. for C₂₇H₁₉N₂O₃S [M]⁺470.1100; found

470.1100.

Triethyl Phosphite-Mediated Nitrene Insertion Reaction of 3-(2-

Nitrophenyl)-9-(phenylsulfonyl)-9H-carbazole-2-carboxylate (31a):

A mixture of 2Ј-nitroarylcarbazoles 31a (0.2 g) and triethyl phos-

phite (2 mL) was heated to reflux under N₂for 6 h. After consump-

tion of 31a (monitored by TLC), the reaction mixture poured over

crushed ice (20 g) that contained conc. HCl (5 mL). It was then

extracted with EtOAc (20 mL) and dried (Na₂SO₄). The solvent

was removed under reduced pressure to afford a mixture of

indolocarbazole 32a and quinocarbazole 33a in a 3:1 ratio. Careful

separation by silica-gel column chromatography (5% EtOAc/hex-

ane) gave quinocarbazole 33a. Further elution gave indolocarb-

azole 32a.

Data for indolocarbazole 32a: Colorless solid. 0.11 g (60%). M.p.

1

Experimental Procedure for CDK5/p25 Assay: The CDK5/p25 en-

zymatic reactions for indolocarbazoles were performed in duplicate

in a 10 μL reaction volume by using an assay buffer of Tris

(50 mm), pH 7.5, MgCl₂(5 mm), Brij-35 (0.01%) in Proxiplate 384

Plus white plates (Perkin–Elmer). Appropriate concentrations (100,

33.33, 11.11, ... 0.000063 μm) of indolocarbazoles were pre-incu-

bated for 30 min with CDK5-p25 enzyme (5 nm) and the enzymatic

reactions were initiated by the addition of Lance Ultra ULight-

MBP peptide (50 nm, Perkin–Elmer, TRF0109-M). Reactions were

terminated after 30 min by addition of reaction termination and

detection reagents (10 μL) that are composed of EDTA (10 mm) in

1X LANCE detection buffer and LANCE Ultra Eu-anti-phospho-

MBP (2 nm, Perkin–Elmer, TRF0201-M), respectively. After incu-

bation for 1 h at room temperature, the samples were read by using

a multi-label plate reader (Envision, Perkin–Elmer).

225–227 °C. H NMR (300 MHz, CDCl₃): δ = 12.14 (s, 1 H, NH),

8.78 (d, J = 7.8 Hz, 1 H, ArH), 8.77 (s, 1 H, ArH), 8.71 (d, J =

8.4 Hz, 1 H, ArH), 8.39 (d, J = 8.1 Hz, 1 H, ArH), 7.85 (d, J =

7.8 Hz, 2 H, ArH), 7.75–7.45 (m, 7 H, ArH), 7.27 (t, J = 7.6 Hz,

1 H, ArH), 4.58 (q, J = 7.0 Hz, 2 H, OCH₂), 1.49 (t, J = 7.0 Hz,

3 H, CH₃) ppm. ¹³C NMR (75.4 MHz, CDCl₃): δ = 167.1, 140.9,

137.9, 136.4, 135.1, 134.8, 133.3, 129.7, 127.8, 126.0, 124.7, 124.3,

124.1, 124.0, 122.4, 120.8, 119.6, 117.4, 114.7, 112.9, 111.5, 108.5,

61.2, 14.2 ppm. DEPT 135 (75.4 MHz, CDCl₃): δ = 134.8, 129.7,

127.8, 126.1, 126.0, 124.7, 124.1, 122.4, 119.6, 114.7, 111.5, 108.5,

61.2, 14.2 ppm. HRMS (EI): calcd. for C₂₇H₂₀N₂O₄S [M]⁺

468.1144; found 468.1144.

6-Ethoxy-8-(phenylsulfonyl)-8H-indolo[2,3-j]phenanthridine (33a):

Colorless solid. 0.03 g (20 %). M.p. 190–192 °C. ¹H NMR

(300 MHz, CDCl₃): δ = 9.30 (s, 1 H, NH), 8.34–8.29 (m, 3 H,

ArH), 7.95 (dd, J₁= 7.5, J₂= 7.8 Hz, 2 H, ArH), 7.78 (d, J =

7.5 Hz, 2 H, ArH), 7.46–7.20 (m, 7 H, ArH), 4.64 (q, J = 7.0 Hz,

2 H, OCH₂), 1.63 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR

(75.4 MHz, CDCl₃): δ = 152.3, 139.2, 138.2, 138.0, 137.7, 133.8,

129.0, 127.2, 127.0, 126.5, 125.5, 124.1, 123.5, 123.4, 123.0, 119.7,

119.4, 116.4, 115.4, 110.2, 103.4, 96.1, 63.5, 14.5 ppm. DEPT 135

(75.4 MHz, CDCl₃): δ = 132.7, 128.0, 126.2, 126.0, 125.4, 123.1,

122.4, 118.7, 118.4, 115.3, 114.3, 109.2, 102.4, 62.4, 13.4 ppm.

HRMS (EI): calcd. for C₂₇H₂₀N₂O₃S [M]⁺452.1195; found

452.1194.

Supporting Information (see footnote on the first page of this arti-

cle): Copies of ¹H NMR, ¹³C NMR, and DEPT 135 spectra of

prepared compounds are provided.

Acknowledgments

The authors thank the Council of Scientific and Industrial Re-

search (CSIR), New Delhi [02(0214)/14/EMR-II dt. 17/11/2014] for

financial support. DST-FIST is thanked for the NMR facility. P. R.

thanks the University Grants Commission (UGC) for his fellow-

ship. Dr. Neelamegam Ramesh is thanked for CDK5/p25 kinase

Triethyl Phosphite-Mediated Nitrene Insertion Reaction of Ethyl 3-

(5-Fluoro-2-nitrophenyl)-9-(phenylsulfonyl)-9H-carbazole-2-carb- assay data.

Eur. J. Org. Chem. 2015, 7131–7145

www.eurjoc.org

7143

P. Raju, G. Gobi Rajeshwaran, A. K. Mohanakrishnan

FULL PAPER

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Received: July 16, 2015

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Published Online: October 1, 2015

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7145

Article Doi

Synthetic studies on indolocarbazoles: A facile synthesis of staurosporinone analogues

DOI: 10.1002/ejoc.201500939

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