Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles

Accepted Manuscript

Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-

oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen

heterocycles

Shashikant U. Dighe, Surya K. Samanta, Shivalinga Kolle, Sanjay Batra

PII:

S0040-4020(17)30265-X

10.1016/j.tet.2017.03.031

TET 28537

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 16 February 2017

Revised Date: 2 March 2017

Accepted Date: 10 March 2017

Please cite this article as: Dighe SU, Samanta SK, Kolle S, Batra S, Iodine-mediated oxidative Pictet-

Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-

carbolines and fused-nitrogen heterocycles, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.031.

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Iodine-mediated oxidative Pictet-Spengler

reaction using terminal alkyne as the 2-

oxoaldehyde surrogate for the synthesis of 1-

aroyl-β-carbolines and fused-nitrogen

heterocycles

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Shashikant U. Dighe, Surya Kanta Samanta, Shivalinga Kolle, Sanjay Batra*

1

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Tetrahedron

journal homepage: www.elsevier.com

Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the

2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-

nitrogen heterocycles^§

Shashikant U. Dighe^a, Surya K. Samanta^a, Shivalinga Kolle^a, Sanjay Batra^{a, b,}

^aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road, PO Box 173,

Lucknow 226 021, India

^bAcademy of Scientific and Innovative Research, New Delhi, India

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

An efficient iodine-mediated oxidative Pictet-Spengler reaction in dimethyl sulphoxide (DMSO)

using terminal alkynes as the 2-oxoaldehyde surrogate for the synthesis of aryl (9H-pyrido[3,4-

b]indol-1-yl)methanones is described. The scope of the protocol includes the total synthesis of

Fascaplysin, Eudistomins Y₁and Y₂. The methodology is extended for preparing pyrrolo[1,2-a]-

quinoxaline and indolo[1,5-a]quinoxaline derivatives. The utility of 1-aroyl-β-carbolines was

demonstrated by performing palladium-catalyzed β-carboline directed ortho-C(sp2)-H

functionalization of the phenyl ring with thiomethyl (SMe) group using DMSO as source and for

accessing 4-aryl-canthin-6-ones.

Available online

Keywords:

Pictet-Spengler reaction

Iodine

Domino reaction

Nitrogen Heterocycle

Thiomethylation

.

1. Introduction

Previous work

O

I₂, with or

without external

oxidant

R¹

[O]

β-Carboline represents a privileged structural motif that is

found in many natural products with important biological

activities.^1-2Amongst them, several β-carboline derivatives with

aroyl substitution at the C-1 position were reported to display

potent antiinflammatory, anti-malarial, anti-cancer, anti-

phospholipase A2, P-glycoprotein-inducer and anti-microbial

activities.³Traditionally, the Pictet–Spengler reaction of

tryptamine or tryptophan methyl ester derivatives with 2-

oxoaldehydes is performed under strong acidic condition to

obtain 1-acyl (or aroyl)-β-carbolines.^3a,b,4Nonetheless, with

continuous development in applications of oxidative coupling

reaction, Wu et al. pioneered to disclose iodine-mediated

oxidative domino reaction between acetophenones and

tryptamine in the presence of an external oxidant under DMSO as

medium for the synthesis of 1-aroyl-β-carbolines (Scheme 1).⁵

The reaction was suggested to proceed via oxidation of

acetophenone to 2-oxoaldehyde in situ, under the influence of

iodine (0.8 equiv) and an external oxidant (1.5 equiv). Later,

Ahmed et al. too demonstrated synthesis of analogous

compounds via iodine-mediated two-step one-pot reaction

between tryptamine and acetophenones.⁶Notably they performed

R

+

NH₂

R¹

N

DMSO, 90 ^oC

or 110 ^oC, 3 h

or 2-6 h

N

H

O

N

H

R¹

O

This work

R¹

R

I₂(0.5 equiv)

NH₂

+

N

R²DMSO,

100 ^oC, 4-5 h

N

H

R²

O

Scheme 1. Oxidative Pictet-Spengler reaction for the synthesis of 1-aroyl-

β-carbolines.

the reaction employing 1.0 equiv of iodine but did not use any

external oxidant. They extended the scope of the protocol to

terminal alkenes which in the presence of iodine (1.0 equiv) and

IBX (1.0 equiv) in DMSO as medium furnished 1-aroyl-β-

carbolines albeit in moderate yields. We have been interested in

accessing 1-aroyl-β-carbolines for probing the β-carboline-

directed C(sp2)-H functionalization of the aromatic ring as

———

Corresponding author. Tel.: +91-522-2772450/2772550 xtn 4705/4706/4732; e-mail: batra_san@yahoo.co.uk, s_batra@cdri.res.in

^§CDRI Communication No. 201/2016/SB

2

Tetrahedron

ACCEPTED MANUSCRIPT

prelude to preparing more complex structures.⁷Like

(TBAI) were screened (entries 4-7), but with no success.

acetophenones, terminal alkynes undergo iodine-mediated

transformation to 2-oxoaldehydes under oxidative conditions.⁸As

there is lack of report for use of terminal alkynes in the oxidative

Pictet-Spengler reaction, we sought to explore their utility

towards synthesizing 1-aroyl-β-carbolines and extending it to

pyrrole and indole-based fused heterocycles. The envisaged

approach is expected to offer a complementary route to these

heterocycles. Herein we present the details of our study in this

direction. The developed protocol was extended to preparing a

few simple β-carboline-based natural compounds. In context of

our interest in palladium-catalyzed β-carboline-directed ortho-

C(sp2)-H functionalization of the phenyl ring, the title

compounds were successfully thiomethylated in the presence of

DMSO. Additionally, treating them with acetic anhydride

resulted into easy access to 4-aryl-canthin-6-ones.

Subsequently titrating the loading of iodine, it was pleasing to

discover that with 50 mol % of iodine the reaction was completed

in 4 h to give 3aa in 84% yield (Table 1, entry 8). Performing the

reaction under inert atmosphere or adding an external oxidant

(H₂O₂), however had detrimental effect on the reaction. Finally,

screening of the solvents revealed that reaction failed in DMA,

H₂O or DMF as medium (entries 13-15). Thus the optimized

reaction conditions that produced best yield of 3aa was heating

tryptamine 1a (1.0 mmol), phenylacetylene 2a (1.2 mmol), and

iodine (50 mol %) at 100 ^oC in DMSO for 4 h.

With optimized conditions for the protocol in hand, we

investigated the scope with respect to both reactants. In first set

of reactions tryptamine (1a) was treated with different terminal

alkynes under the optimized conditions (Scheme 2). It was

observed that all alkynes (2b-s) reacted with 1a to give the

respective 1-benzoyl-β-carbolines (3aa-as) in 74-95% yields.

Notably the reactions of alkynes with phenyl ring bearing

electron withdrawing groups were completed in 5 h as compared

to 4 h for the ones with electron donating groups. The terminal

alkynes 2t-v bearing the heteroaryl group were also compatible to

the protocol to produce substituted 1-aroyl-β-carbolines (3at-

3av) in good yields. However, the reaction of aliphatic alkyne i.e.

1-hexyne was unsuccessful. Next the tryptamine was replaced by

tryptophan alkyl esters (1b and 1c) and it was found they reacted

smoothly with all terminal alkynes to afford the corresponding β-

carboline derivatives. Likewise, 5-chlorotryptamine 1d was

compatible with the protocol resulting in formation of the

expected product 3da in 75% yield.

2. Results and Discussion

We commenced our investigations by reacting tryptamine (1a)

with phenylacetylene (2a) (1.2 equiv) in the presence of iodine

(30 mol %) in DMSO as the medium under air atmosphere at

room temperature. Unfortunately, the reaction failed and

therefore it was repeated under heating at 80 ^oC. Gratifyingly, the

reaction was completed in 8 h resulting in a mixture of products

from which the major compound was only in 46% isolated yield

and was identified to be the expected phenyl(9H-pyrido[3,4-

b]indol-1-yl)methanone (3aa) (Table 1 entry 2). The yield of 3aa

(65%) improved when the same reaction was performed at 100

^oC for 6 h (Table 1, entry 3). Towards obtaining superior yield of

3aa other reagents including N-iodosuccinimide (NIS), N-

bromosuccinimide (NBS), KI, and tetrabutylammonium iodide

A plausible mechanism for the reaction is outlined in Scheme

3. Initially the primary alkyne 2a in the presence of iodine-

DMSO is transformed to 2-iodo-1-phenylethan-1-one (A) which

is oxidized in situ to afford the 2-oxoaldehyde (B) followed by its

usual Pictet-Spengler reaction with tryptamine (1a) to afford the

product 3aa. In order to provide support for the mechanism, we

treated 2-iodo-1-phenylethan-1-one (4) with 1a independently

that resulted in formation of 3aa (Scheme 4). Further to ascertain

that the 2-oxocarbaldehyde (5) was the species involved for the

Pictet-Spengler reaction, it was treated with tryptamine in DMSO

at 100 ^oC to produce 3aa in 92% yield in 1 h.

Table 1. Optimization of the Reaction Conditions for

oxidative Pictet-Spengler reaction using terminal alkyne^a

entry

reagent

(equiv)

solvent

temp

time yield

(h)

12.0

8.0

6.0

4.0

(%)^b

-

1

I₂(0.3)

DMSO

DMA

25

In order to assess the usefulness of the methodology for

synthesizing natural products, 3ah was used for preparing

Eudistomin Y₁(6) and Y₂(7) whereas 3am was transformed into

fascaplysin (8) (Scheme 5). Based on the results of the study, we

reasoned that reaction of diethynylbenzene would offer a dimeric

β-carboline. Accordingly, 1,3-diethynylbenzene (2x) was

prepared and reacted with 2.0 equiv of 1a but we found that only

one alkyne group participated in the reaction to afford 3ax

(Scheme 6). Increasing the amount of iodine or varying reaction

conditions did not influence the outcome and 3ax was obtained

exclusively. Assuming that the steric constraint could be a

contributing factor towards this observation, next we reacted 1,4-

diethynylbenzene (2y) with 1a following the optimized

procedure. It was pleasing to discover that the reaction was

successful to furnish 9 in 75% yield.

2

I₂(0.3)

80

46

3

I₂(0.3)

100

65

4

NIS (0.3)

NBS (0.3)

KI (0.3)

TBAI (0.3)

I₂(0.5)

22

5

18

6

ND

84

7

8

9^c

10^d

11

12

13

14

15

43

I₂(0.5)

68

I₂(0.8)

80

I₂(1.0)

77

Aiming to examine scope of the protocol for the synthesis of

I₂(0.5)

ND

isoquinolines, in

phenylethylamine

a

representative reaction 3,4-dimethoxy-

(10) was treated with 3,5-

I₂(0.5)

H₂O

dimethoxyphenylacetylene (2z) under the optimized condition.

The reaction offered (E)-1,4-bis(3,4-dimethoxyphenyl)but-2-ene-

1,4-dione (11) in 78% yield instead of the expected isoquinoline,

suggesting self-condensation of the two alkyne units (Scheme 7).

This was ascertained by treating 2z exclusively with I₂in DMSO

as medium to obtain 11. Though it is reported that terminal as

I₂(0.5)

DMF

^aReaction conditions: All reactions were carried out using 1a

(0.2 g, 1.25 mmol), 2a (165 µL, 1.49 mmol), DMSO (5 mL).

^bIsolated yields ^cReactions were performed under inert

atmosphere. ^dOxidant H₂O₂(2.0 equiv).

3

ACCEPTED MANUSCRIPT

Scheme 2. Scope of the protocol for the synthesis of 1-aroyl-β-carbolines

Scheme 5. Synthesis of Eudistomin Y1 and Y2 and

Fascaplysin.

Scheme 3. Plausible mechanism for the reaction

Scheme 6. Scope of the protocol with diethynylbenzenes.

Scheme 4. Control experiments.

well as internal alkynes undergo iron(III) perchlorate-

mediated oxidative dimerization to produce such conjugated

diketones,⁹there is lack of report of similar transformation in the

presence of iodine. Conversely, acetophenones and terminal

alkynes are known to afford 2-thio-1,4-enediones via CuI/

DMSO or I₂/Lewis acid/DMSO, respectively under heating.¹⁰

This prompted us to probe the outcome of the self- condensation

reaction of alkyne 2z beyond 5 h, and we found that in 12 h

Scheme 7. Self-condensation of alkynes under different

conditions.

4

Tetrahedron

ACCEPTED MANUSCRIPT

the expected 2-thio-1,4-enedione (12z) was isolated in 90%

probed the reaction of 3aa with Cu(OAc)₂under different

yield. Alternatively, treating acetophenones (13e,13j) with I₂in

DMSO as a medium for 12 h under heating afforded the

corresponding 2-thio-1,4-enediones (12e,12j) in good yields.

This result suggests that contrary to the previous reports, such

transformation can be accomplished under metal-free condition.

conditions, but failed. Subsequently we performed the reaction of

3aa with Pd(OAc)₂(10 mol%) in the presence of Cu(OAc)₂(1.0

equiv) in DMSO as medium under heating. Fortunately, at 120

^oC, the reaction was successful to afford the required (2-

(methylthio)phenyl)(9H-pyrido[3,4-b]indol-1-

yl)methanone

(18aa) in 64% yield (Scheme 9). The success of this reaction

prompted us to study the generality of β-carboline-directed

In the next stage, pyrrole- and indole-based substrates 14a and

14b,c were evaluated for their compatibility to the protocol.

Treating 14a with different alkynes 2a, 2b, 2e and 2h smoothly

afforded corresponding products 15aa, 15ab, 15ae and 15ah in

82-91% yields (Scheme 8). Very recently, Wu et al. disclosed the

para-selective coupling of phenols with aryl methyl ketones by

overcoming the challenge of self-condensation of arylmethyl

ketones.¹¹Based on this report we hypothesized that use of

higher amount of terminal alkyne would offer more glyoxal

which may induce concomitant oxidative Pictet-Spengler

reaction and electrophilic substitution of the 2-position (electron-

rich) of the pyrrole subunit. Accordingly, we probed the reaction

of 14a with 2.5 equiv of 2a and 2e in the presence of I₂in DMSO

as medium for 12 h. We were delighted to note the formation of

16aa and 16ae, respectively in excellent yields (Scheme 8).

thiomethylation of the phenyl ring. As

a

result,

3ab,3ae,3ah,3aj,3bw were subjected to the Pd-catalyzed

oxidative reaction under the optimized conditions. Although all

substrates

afforded

the

thiomethylated

products

18ab,18ae,18ah,18aj, it was noticed that 3bw invariably

underwent decarboxylative removal of the ester moiety to furnish

18aw exclusively. Mechanistically, the reaction is suggested to

proceed via Pd(II)-intermediate as shown in Scheme 10.

Finally, we sought to study the utility of the 1-aroyl-β-

carbolines for generating substituted canthin-6-ones. It may be

noted that though several substituted canthin-6-ones are known,

there is lack of report describing the synthesis of 4-aryl

substituted canthin-6-one. In one of the approaches with limited

scope, 1-formyl-β-carboline was treated with acetyl chloride or

acetic anhydride in the presence of a base to offer canthin-6-

one.¹⁵Therefore, we considered probing the reported protocol for

preparing substituted canthin-6-ones and after a short screening

discovered that reaction of substituted 1-aroyl-β-carbolines (3aa-

ac, 3ae, 3ah, 3aj, 3am, 3av) with acetic anhydride in the

presence of sodium hydride as the base in THF as medium under

heating afforded the corresponding 4-aryl substituted canthin-6-

ones (19aa-ac, 19ae, 19ah, 19aj, 19am, 19av) in good yields

(Scheme 11).

Scheme 8. Reaction of 1,2-dihydroisoquinoline-fused

quinazolinone with iodine.

Interestingly however, treating the N-substituted indole 14b

with alkyne 2a gave the 3-thiomethylated indolo[1,2-

a]quinoxaline 17ba in 84% yield. The formation of 17ba is

attributed to initial oxidative Pictet Spengler reaction of alkyne

with 14b followed by nucleophilic attack of thiomethyl group

onto the unsubstituted 3-position of the indole. The thiomethyl

group in turn originates from the dimethylsulphide which is

liberated from DMSO in the presence of HI during the reaction.

Similar thiomethylation was not observed when acetophenone

was employed as the source of glyoxal for oxidative Pictet-

Spengler reaction of indoles in the presence of iodine and

DMSO.¹²We discovered that the developed protocol was general

in nature as reactions of 14b with other alkynes 2d, 2h and 2v

gave the respective products 17bd, 17bh, 17bv in 82-92% yields.

Perhaps higher loading of iodine and longer reaction time as

compared to previous report may be attributed to such difference

in results. Conversely, when the 3-position of the indole was

blocked by placing a methyl group as in 14c, its reaction with 2d

resulted in the formation of the expected product 15ch in 91%

yields.

Scheme 9. β-Carboline-directed thiomethylation under

oxidative conditions

Encouraged by the above results and in our interest to study

the β-carboline-directed C(sp2)-H functionalization of the

aromatic ring of the benzoyl moiety, we probed installing the

thiomethyl group using DMSO at he ortho-position.¹³Most often

copper salts have been used in stoichiometric amount in reports

describing DMSO-mediated thiomethylation of phenyl ring via

oxidative C(sp2)-H activation.¹⁴As a consequence, initially we

Scheme 10. Plausible mechanism for oxidative

thiomethylation.

5

4.2. General Procedure for transformation of 1 to 3 as

exemplified for 3aa .

ACCEPTED MANUSCRIPT

To a stirred solution of phenylacetylene 2a (165 µL, 1.49

mmol) in DMSO (5 mL) were added molecular iodine (0.157 g,

0.62 mmol) and 1a (0.2 g, 1.25 mmol) at room temperature and

the reaction was allowed to continue for 4 h at 100 ^oC.

Thereafter, the reaction was quenched by adding aqueous

Na₂S₂O₃(10% w/v, 10 mL) and the resulting mixture was

extracted with EtOAc (3 x 20 mL). The organic fractions were

pooled, dried over anhydrous Na₂SO₄and evaporated under

vacuum. The crude product thus obtained was purified by

chromatography over a column of silica gel using hexanes/

EtOAc (8.0:2.0, v/v) as eluent to afford the desired product 3aa

(0.285 g, 84%) as a yellow solid.

Scheme 11. Synthesis of 4-aryl substituted canthin-6-ones.

3. Conclusion

4.2.1. Phenyl(9H-pyrido[3,4-b]indol-1-

yl)methanone (3aa).⁵Mp 132-134 ^oC [Lit 130-131

^oC]; R_f= 0.42 (hexane: EtOAc, 6:4, v/v); IR (KBr)

In summary, we have developed an alternative route to the

synthesis of 1-aroyl-β-carbolines via iodine-mediated oxidative

Pictet-Spengler reaction using terminal alkynes as the 2-

oxoaldehyde surrogate. Lower loading of iodine and better yields

of products as compared to the reported methodologies where

acetophenones have been used as the 2-oxoaldehyde source are

attractive attributes of this protocol. The protocol is amenable to

aryl terminal alkynes whereas alkyl-based terminal alkynes failed

to react. The generality of the methodology is further

demonstrated via oxidative Pictet-Spengler reaction of pyrrole

and indole-based substrates. Moreover, it was shown that based

on the amount of alkyne used, divergent products can be accessed

for the pyrrole-based substrates. However, the protocol is not

suited to produce isoquinolines since terminal alkyne during the

reaction underwent oxidative dimerization to produce enedione

derivative. Interestingly longer duration of the reaction afforded

2-methylthio-1,4-ene-diones in good yields. Further, the

methodology accommodates acetophenones to afford the 2-

methylthio-1,4-ene-diones under metal-free conditions. This

work also revealed palladium-catalyzed β-carboline-directed

oxidative thiomethylation of the phenyl ring in 1-aroyl-β-

carbolines which are also versatile precursor to 4-aryl-canthin-6-

ones.

ν_{ma x}: 669, 759, 1115, 1705, 2401 cm^{- 1 1}H NMR

.

(400 MHz, CDCl₃): δ (ppm) 7.26-7.29 (m, 1H,

ArH), 7.44-7.48 (m, 2H, ArH), 7.52-7.56 (m, 3H,

ArH), 8.08-8.11 (m, 2H, ArH), 8.24-8.26 (m, 2H,

ArH), 8.54 (d, J = 4.9Hz, 1H, ArH), 7.67 (s, 1H,

ArH) 10.38 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 112.0, 118.5, 120.8, 120.9,

121.8, 128.0, 129.3, 131.2, 131.7, 132.4, 137.4,

137.6, 138.1, 141.1, 195.5. MS (ESI+): m/z =

273.1. ESI-HR-MS calculated for C_{1 8}H_{1 2}N₂O

(M⁺+H): 273.1028, found: 273.1025.

4.2.2. (4-Bromophenyl)(9H-pyrido[3,4-b]indol-1-

yl)methanone (3ab).⁵. Yield: 90% (0.394 g from

0.2 g); a yellow solid, mp 176-178 oC [Lit 180-181

oC]; R_f= 0.70 (hexane: EtOAc, 8:2, v/v); IR (KBr)

νmax: 778, 1089, 1248, 1702, 2348 cm-1. 1H NMR

(400 MHz, CDCl3): δ (ppm) 6.34 (bs, 1H, ArH),

7.42 (d, J = 8.3 Hz, 1H, ArH), 7.65-7.71 (m, 3H,

ArH), 7.89 (dd, J₁= 1.6 Hz, J₂= 8.5 Hz, 1H, ArH),

8.13 (d, J = 4.9 Hz, 1H, ArH), 8.27 (d, J = 8.5 Hz,

2H, ArH), 8.51-8.52 (m, 1H, ArH), 8.63 (d, J = 4.9

Hz, 1H, ArH), 10.46 (m, 1H, NH); 13C NMR (100

MHz, CDCl3): δ (ppm) = 113.9, 118.8, 123.3,

127.8, 130.4, 130.8, 131.4, 132.8, 136.0, 136.2,

137.1, 137.7, 138.0, 138.5, 140.0, 194.0. MS

(ESI+): m/z = 351.0. ESI-HR-MS calculated for

C18H11BrN2O (M++H): 351.0133, found:

4. Experimental

4.1. General

Unless otherwise stated all reactions were performed in non-

dry glassware under an air atmosphere and were monitored by

analytical thin layer chromatography (TLC). TLC was performed

on pre-coated silica gel plates. After elution, plate was visualized

under UV illumination at 254 nm for UV active materials.

Further visualization was achieved by staining with KMnO₄and

charring on a hot plate. The melting points were recorded on a

351.0138.

4.2.3. (4-Chlorophenyl)(9H-pyrido[3,4-b]indol-1-

yl)methanone (3ac).⁵. Yield: 91% (0.345 g from

0.2 g); a yellow solid, mp 160-162 ^oC [Lit 162-163

^oC]; R_f= 0.71 (hexane: EtOAc, 8:2, v/v); IR (KBr)

ν_{ma x}: 689, 989, 1145, 1568, 1698, 3256 cm^{- 1 1}H

.

1

hot stage apparatus and are uncorrected. H NMR and ¹³C NMR

NMR (400 MHz, CDCl₃): δ (ppm) 7.26-7.31 (m,

1H, ArH), 7.44 (d, J = 8.6 Hz, 2H, ArH), 7.53-7.57

(m, 2H, ArH), 8.09-8.12 (m, 2H, ArH), 8.26 (d, J =

8.4 Hz, 2H, ArH), 8.52 (d, J = 4.8 Hz, 1H, ArH),

10.36 (s, 1H, NH); ^{1 3}C NMR (100 MHz, CDCl₃): δ

(ppm) = 112.3, 119.0, 121.1, 121.2, 122.2, 128.6,

129.8, 132.1, 133.1, 136.1, 136.4, 137.7, 138.4,

139.3, 141.4, 194.3. MS (ESI+): m/z = 307.1. ESI-

HR-MS calculated for C_{1 8}H_{1 1}ClN₂O (M⁺+H):

307.0638, found: 307.0642.

spectra were recorded on 400 and 500 MHz spectrometers and

1

are reported in ppm using solvent residue (CDCl₃: H; δ = 7.26

1

ppm, ¹³C δ = 77.16 ppm; DMSO-d₆: H; δ = 2.50 ppm; ¹³C δ =

39.5 ppm; CD₃OD: ¹³C δ = 49.2 ppm) as an internal reference

1

relative to TMS (chemical shifts in δ). Peak multiplicities of H-

NMR signals were designated as s (singlet), bs (broad singlet), d

(doublet), dd (doublet of doublet), t (triplet), m (multiplet) etc.

Coupling constants (J) are in Hz. The LC-ESI-MS were recorded

on

triple

quadrupole

Mass

spectrometer.

Column

4.2.4. (4-Nitrophenyl)(9H-pyrido[3,4-b]indol-1-

yl)methanone (3ad).⁵Yield: 78% (0.308 g from 0.2

g); a yellow solid, mp 240-242 ^oC [Lit 243-244

^oC]; R_f= 0.62 (hexane: EtOAc, 8:2, v/v); IR (KBr)

chromatography was performed using silica gel (particle size

100-200 mesh). Analytical grade solvents for the column

chromatography were used as received. Commercial grade

reagents and solvents were purchased from different commercial

sources and used without further purification.

ν_{ma x}: 689, 1256, 1708, 2356, 3006 cm^{- 1 1}H NMR

.

(400 MHz, DMSO-d₆): δ (ppm) 7.35 (dt, J₁= 0.6

Hz, J₂= 7.8 Hz, 1H, ArH), 7.64 (dt, J₁= 1.1 Hz, J₂

6

Tetrahedron

= 8.2 Hz, 1H, ArH), 7.85 (d, J = 8.2 Hz, 1H,

137.4, 137.5, 142.0, 163.3, 192.1. MS (ESI+): m/z

ACCEPTED MANUSCRIPT

ArH), 8.34-8.36 (m, 3H, ArH), 8.39-8.42 (m, 2H,

= 303.1. ESI-HR-MS calculated for C_{1 9}H_{1 4}N₂O₂

ArH), 8.49-8.54 (m, 2H, ArH), 12.18 (s, 1H, NH);

^{1 3}C NMR (100 MHz, DMSO-d₆): δ (ppm) = 113.6,

120.0, 120.5, 120.9, 122.4, 123.4, 129.6, 131.8,

132.3, 135.8, 136.4, 137.9, 142.3, 143.7, 149.6,

193.5. MS (ESI+): m/z = 318.1. ESI-HR-MS

calculated for C_{1 8}H_{1 1}N₃O₃(M⁺+H): 318.0879,

found: 318.0883.

(M⁺+H): 303.1134, found: 303.1138.

4.2.9. Biphenyl-4-yl(9H-pyrido[3,4-b]indol-1-

yl)methanone (3ai).⁵. Yield: 82% (0.356 g from

0.2 g); a yellow solid, mp 182-184 ^oC [Lit 182-183

^oC]; R_f= 0.65 (hexane: EtOAc, 8:2, v/v); IR (KBr)

ν_{ma x}: 1652, 1708, 3456 cm^{- 1 1}H NMR (400 MHz,

.

CDCl₃): δ (ppm) 7.24-7.27 (m, 1H, ArH), 7.31 (t, J

= 7.4 Hz, 1H, ArH), 7.39 (t, J = 7.1 Hz, 2H, ArH),

7.51-7.52 (m, 2H, ArH), 7.57-7.59 (m, 2H, ArH),

7.66 (d, J = 8.5 Hz, 2H, ArH), 8.06-8.09 (m, 2H,

ArH), 8.34 (d, J = 8.6 Hz, 2H, ArH), 8.54 (d, J =

4.9 Hz, 1H, ArH), 10.40 (s, 1H, NH); ^{1 3}C NMR

(100 MHz, CDCl₃): δ (ppm) = 112.0, 118.5, 120.8,

120.9, 121.8, 126.8, 127.4, 128.0, 128.9, 129.3,

131.7, 131.8, 136.3, 136.5, 137.3, 138.0, 140.4,

141.0, 145.1, 194.9. MS (ESI+): m/z = 349.1. ESI-

HR-MS calculated for C_{2 4}H_{1 6}N₂O (M⁺+H):

4.2.5. (9H-Pyrido[3,4-b]indol-1-yl)(p-

tolyl)methanone (3ae).⁵. Yield: 86% (0.307 g from

0.2 g); a yellow solid, mp 153-155 ^oC [Lit 155-156

^oC]; R_f= 0.72 (hexane: EtOAc, 8:2, v/v); IR (KBr)

ν_{ma x}: 789, 1025, 1489, 1701, 2896 cm^{- 1 1}H NMR

.

(400 MHz, CDCl₃): δ (ppm) 2.48 (s, 3H, CH₃),

7.34-7.38 (m, 3H, ArH), 7.62-7.64 (m, 2H, ArH),

8.16-8.21 (m, 2H, ArH), 8.28 (d, J = 8.4 Hz, 2H,

ArH), 8.63 (d, J = 4.9 Hz, 1H, ArH), 10.49 (s, 1H,

NH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 21.7,

112.0, 118.3, 120.7, 120.9, 121.8, 128.8, 129.2,

131.4, 131.6, 134.9, 136.6, 137.3, 137.9, 141.0,

143.2, 195.1. MS (ESI+): m/z = 287.1. ESI-HR-MS

calculated for C_{1 9}H_{1 4}N₂O (M⁺+H): 287.1184,

found: 287.1185.

349.1341, found: 349.1345.

4.2.10. (3-Chlorophenyl)(9H-pyrido[3,4-b]indol-1-

yl)methanone (3aj). Yield: 85% (0.324 g from 0.2

g); a yellow solid, mp 206-208^oC; R_f= 0.69

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 648,

4.2.6. (4-Butylphenyl)(9H-pyrido[3,4-b]indol-1-

yl)methanone (3af). Yield: 90% (0.368 g from 0.2

g); a yellow solid, mp 189-191 ^oC; R_f= 0.70

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 789,

985, 1145, 1623, 1702, 2689 cm^{- 1 1}H NMR (400

.

MHz, CDCl₃): δ (ppm) 7.35-7.39 (m, 1H, ArH),

7.48 (t, J = 7.8 Hz, 1H, ArH), 7.57-7.66 (m, 3H,

ArH), 8.17-8.19 (m, 2H, ArH), 8.24-8.27 (m, 1H,

ArH), 8.36 (t, J = 1.7 Hz, 1H, ArH), 8.62 (d, J =

4.9 Hz, 1H, ArH), 10.45 (s, 1H, NH); ^{1 3}C NMR

(100 MHz, CDCl₃): δ (ppm) = 112.0, 118.8, 120.8,

120.9, 121.8, 129.3, 129.4, 131.2, 131.8, 132.2,

134.1, 135.8, 137.4, 138.1, 139.0, 141.1, 193.8.

MS (ESI+): m/z = 307.1. ESI-HR-MS calculated

for C_{1 8}H_{1 1}ClN₂O (M⁺+H): 307.0638, found:

307.0643.

1256, 1700, 3256 cm^{- 1 1}H NMR (400 MHz,

.

CDCl₃): δ (ppm) 0.99 (t, J = 7.4 Hz, 3H, CH₃),

1.43 (q, J = 7.4 Hz, 2H, CH₂), 1.65-1.76 (m, 2H,

CH₂), 2.74 (t, J = 7.6 Hz, 2H, ArH), 7.33-7.38 (m,

3H, ArH), 7.57-7.63 (m, 2H, ArH), 8.14-8.18 (m,

2H, ArH), 8.32 (d, J = 8.1 Hz, 2H, ArH), 8.63 (d, J

= 4.8 Hz, 1H, ArH), 10.52 (s, 1H, NH); ^{1 3}C NMR

(100 MHz, CDCl₃): δ (ppm) = 13.9, 22.4, 33.3,

35.8, 112.0, 118.3, 120.7, 120.8, 121.8, 128.2,

129.2, 131.5, 131.6, 135.1, 136.6, 137.3, 137.9,

141.0, 148.1, 195.0. MS (ESI+): m/z = 329.1. ESI-

HR-MS calculated for C_{2 2}H_{2 0}N₂O (M⁺+H):

329.1654, found: 329.1656.

4.2.11. (3-Methoxyphenyl)(9H-pyrido[3,4-b]indol-

1-yl)methanone (3ak). Yield: 88% (0.331 g from

0.2 g); a yellow solid, mp 184-186 ^oC; R_f= 0.66

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 1614,

1699, 3214 cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ

.

4.2.7. (4-tert-Butylphenyl)(9H-pyrido[3,4-b]indol-

1-yl)methanone (3ag). Yield: 95% (0.389 g from

0.2 g); a yellow solid, mp 193-195 ^oC; R_f= 0.71

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 1710,

(ppm) 3.79 (s, 3H, OCH₃), 7.05-7.07 (m, 1H, ArH),

7.22-7.26 (m, 1H, ArH), 7.35 (t, J = 8.1 Hz, 1H,

ArH), 7.46-7.51 (m, 2H, ArH), 7.78 (s, 1H, ArH),

7.78 (d, J = 7.7 Hz, 1H, ArH), 8.03-8.07 (m, 2H,

ArH), 8.51 (d, J = 4.8 Hz, 1H, ArH), 10.36 (s, 1H,

NH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 55.5,

112.0, 115.8, 118.5, 118.7, 120.7, 120.8, 121.8,

124.0, 129.0, 129.3, 131.7, 136.3, 137.3, 138.0,

138.8, 141.0, 159.3, 195.2. MS (ESI+): m/z =

303.1. ESI-HR-MS calculated for C_{1 9}H_{1 4}N₂O₂

(M⁺+H): 303.1134, found: 303.1132.

2356 cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ (ppm)

.

1.38 (s, 9H, CH₃), 7.32-7.38 (m, 1H, ArH), 7.55-

7.64 (m, 4H, ArH), 8.07-8.18 (m, 2H, ArH), 8.29

(d, J = 8.4 Hz, 2H, ArH), 8.61-8.63 (m, 1H, ArH),

10.47 (s, 1H, NH); ^{1 3}C NMR (100 MHz, CDCl₃): δ

(ppm) = 31.2, 35.1, 112.0, 118.4, 120.7, 121.8,

125.1, 129.2, 131.2, 134.8, 137.5, 138.0, 138.4,

141.0, 156.0, 195.1. MS (ESI+): m/z = 329.2. ESI-

HR-MS calculated for C_{2 2}H_{2 0}N₂O (M⁺+H):

329.1654, found: 329.1656.

4.2.12. (3-Nitrophenyl)(9H-pyrido[3,4-b]indol-1-

yl)methanone (3al). Yield: 74% (0.292 g from 0.2

g); a yellow solid, mp 212-214 ^oC; R_f= 0.63

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 1256,

4.2.8. (4-Methoxyphenyl)(9H-pyrido[3,4-b]indol-

1-yl)methanone (3ah).⁵. Yield: 87% (0.339 g from

0.2 g); a yellow solid, mp 168-170 ^oC [Lit 169-170

^oC]; R_f= 0.66 (hexane: EtOAc, 8:2, v/v); IR (KBr)

1625, 1696, 2986 cm^{- 1}¹H NMR (400 MHz,

.

CDCl₃): δ (ppm) 7.27-7.31 (m, 1H, ArH), 7.52-

7.64 (m, 3H, ArH), 8.08-8.12 (m, 2H, ArH), 8.35

(dd, J₁= 1.1 Hz, J₂= 8.2 Hz, 1H, ArH), 8.52 (d, J

= 4.8 Hz, 1H, ArH), 8.61 (d, J = 7.7 Hz, 1H, ArH),

9.17 (s, 1H, ArH), 10.34 (s, 1H, NH); ^{1 3}C NMR

(100 MHz, CDCl₃): δ (ppm) = 112.1, 119.2, 120.8,

121.1, 121.9, 126.5, 129.0, 129.6, 132.0, 135.3,

136.9, 137.5, 138.3, 138.8, 141.0, 147.9, 192.6.

MS (ESI+): m/z = 318.0. ESI-HR-MS calculated

for C_{1 8}H_{1 1}N₃O₃(M⁺+H): 318.0879, found:

318.0881.

ν_{ma x}: 1547, 1623, 1697, 2389 cm^{- 1 1}H NMR (400

.

MHz, DMSO-d₆): δ (ppm) 3.88 (s, 3H, OMe), 7.12

(dd, J₁= 1.9 Hz, J₂= 6.8 Hz, 2H, ArH), 7.29-7.33

(m, 1H, ArH), 7.58-7.62 (m, 1H, ArH), 7.79 (d, J =

8.3 Hz, 1H, ArH), 8.30-8.34 (m, 3H, ArH), 8.42 (d,

J = 4.9 Hz, 1H, ArH), 8.53 (d, J = 4.9 Hz, 1H,

ArH), 11.98 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

DMSO-d₆): δ (ppm) = 56.0, 113.4, 113.9, 118.9,

120.6, 122.3, 129.3, 130.2, 131.3, 133.8, 136.2,

7

4.2.13. (2-Chlorophenyl)(9H-pyrido[3,4-b]indol-1-

CDCl₃): δ (ppm) 4.01 (s, 3H, OCH₃), 4.02 (s, 3H,

OCH₃), 7.03 (d, J = 8.6 Hz, 1H, ArH), 7.34-7.38

ACCEPTED MANUSCRIPT

yl)methanone (3am).^{3 a}Yield: 83% (0.317 g from

0.2 g); a yellow solid, mp 202-204 ^oC [Lit 203-205

^oC]; R_f= 0.70 (hexane: EtOAc, 8:2, v/v); IR (KBr)

(m, 1H, ArH), 7.60-7.65 (m, 2H, ArH), 8.01 (d, J =

1.4 Hz, 1H, ArH), 8.17-8.21 (m, 2H, ArH), 8.29 (d,

J₁= 1.4 Hz, J₂= 8.3 Hz, 1H, ArH), 8.62 (d, J = 4.9

Hz, 1H, ArH), 10.47 (bs, 1H, NH); ^{1 3}C NMR (100

MHz, CDCl₃): δ (ppm) = 56.0, 56.1, 110.0, 111.9,

113.6, 118.2, 120.6, 120.9, 121.7, 126.9, 129.2,

130.2, 131.6, 136.9, 137.3, 137.8, 140.9, 148.6,

153.0, 193.1. MS (ESI+): m/z = 333.1. ESI-HR-MS

calculated for C_{2 0}H_{1 6}N₂O₃(M⁺+H): 333.1239,

found: 333.1240.

ν_{ma x}: 789, 1148, 1620, 1701, 3025 cm^{- 1 1}H NMR

.

(400 MHz, CDCl₃): δ (ppm) 7.33-7.51 (m, 4H,

ArH), 7.58-7.62 (m, 3H, ArH), 8.14-8.17 (m, 2H,

ArH), 8.54 (d, J = 4.8 Hz, 1H, ArH), 10.48 (s, 1H,

NH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

112.1, 119.2, 120.7, 121.0, 121.9, 126.3, 129.5,

129.9, 130.0, 131.2, 131.8, 135.5, 136.8, 138.4,

138.8, 141.3, 197.6. MS (ESI+): m/z = 307.0. ESI-

HR-MS calculated for C_{1 8}H_{1 1}ClN₂O (M⁺+H):

307.0638, found: 307.0635.

4.2.18. (9H-Pyrido[3,4-b]indol-1-yl)(2,4,5-

trimethylphenyl)methanone (3ar). Yield: 80%

(0.313 g from 0.2 g); a yellow solid, mp 191-193

^oC; R_f= 0.70 (hexane: EtOAc, 8:2, v/v); IR (KBr)

4.2.14. (2-Methoxyphenyl)(9H-pyrido[3,4-b]indol-

1-yl)methanone (3an).⁵.Yield: 90% (0.339 g from

0.2 g); a yellow solid, mp 220-222 ^oC [Lit 219-220

^oC]; R_f= 0.68 (hexane: EtOAc, 8:2, v/v); IR (KBr)

ν_{ma x}: 1624, 1702, 2356, 3025 cm^{- 1 1}H NMR (400

.

MHz, CDCl₃): δ (ppm) 2.07 (s, 6H, CH₃), 2.32 (s,

3H, CH₃), 6.80 (s, 1H, ArH), 6.86 (s, 2H, ArH),

7.54-7.55 (m, 2H, ArH), 8.06 (d, J = 4.9 Hz, ¹H,

ArH), 8.11 (d, J = 7.8 Hz, 1H, ArH), 8.47 (d, J =

4.9 Hz, 1H, ArH), 10.53 (s, 1H, NH); ^{1 3}C NMR

(100 MHz, CDCl₃): δ (ppm) = 19.8, 20.3, 21.4,

112.2, 119.2, 121.0, 122.0, 128.5, 128.8, 129.5,

131.9, 134.5, 135.9, 136.3, 136.5, 137.2, 138.9,

139.2, 139.8, 141.4, 204.6. MS (ESI+): m/z =

315.2. ESI-HR-MS calculated for C_{2 1}H_{1 8}N₂O

(M⁺+H): 315.1497, found: 315.1494.

ν_{ma x}: 1608, 1703, 2789, 3123 cm^{- 1 1}H NMR (400

.

MHz, CDCl₃): δ (ppm) 3.69 (s, 3H, OCH₃), 6.97-

7.04 (m, 2H, ArH), 7.25-7.29 (m, 1H, ArH), 7.41-

7.45 (m, 1H, ArH), 7.49 (dd, J₁= 1.6 Hz, J₂= 7.5

Hz, 1H, ArH), 7.53-7.55 (m, 2H, ArH), 8.05 (d, J =

4.8 Hz, 1H, ArH), 8.09 (d, J = 7.6 Hz, 1H, ArH),

8.46 (d, J = 4.9 Hz, 1H, ArH), 10.36 (s, 1H, NH);

^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 55.9,

111.9, 112.1, 118.7, 120.3, 120.8, 121.9, 128.7,

129.3, 130.2, 131.6, 132.1, 136.6, 138.6, 141.3,

157.9, 198.8. MS (ESI+): m/z = 303.1. ESI-HR-MS

calculated for C_{1 9}H_{1 4}N₂O₂(M⁺+H): 303.1134,

found: 303.1138.

4.2.15. (2,4-Dimethylphenyl)(9H-pyrido[3,4-

b]indol-1-yl)methanone (3ao). Yield: 86% (0.322 g

from 0.2 g); a yellow solid, mp 228-230 ^oC; Rf =

0.73 (hexane: EtOAc, 8:2, v/v); IR (KBr) νmax:

778, 1125, 1614, 2896 cm-1. ¹H NMR (400 MHz,

CDCl3): δ (ppm) 2.31 (s, 6H, CH₃), 7.03-7.06 (m,

2H, ArH), 7.24-7.28 (m, 1H, ArH), 7.47-7.53 (m,

3H, ArH), 8.04 (d, J = 4.9 Hz, 1H, ArH), 8.08 (d, J

= 7.6 Hz, 1H, ArH), 8.48 (d, J = 4.9 Hz, 1H, ArH),

10.43 (, 1H, NH); ^{1 3}C NMR (100 MHz, CDCl₃): δ

(ppm) = 20.3, 21.5, 112.0, 118.6, 120.8, 121.8,

125.8, 129.3, 130.3, 131.7, 131.8, 135.3, 136.6,

136.9, 137.8, 138.5, 140.8, 141.1, 200.1. MS

(ESI+): m/z = 301.1. ESI-HR-MS calculated for

C_{2 0}H_{1 6}N₂O (M⁺+H): 301.1341, found: 301.1344.

4.2.16. (2,4-Dimethoxyphenyl)(9H-pyrido[3,4-

b]indol-1-yl)methanone (3ap). Yield: 90% (0.373 g

from 0.2 g); a yellow solid, mp 185-187 ^oC; Rf =

0.61 (hexane: EtOAc, 8:2, v/v); IR (KBr) νmax:

778, 1204, 1706, 2456, 2963 cm-1. ¹H NMR (400

MHz, CDCl₃): δ (ppm) 3.70 (s, 3H, OCH₃), 3.81 (s,

3H, OCH₃), 6.51-6.55 (m, 2H, ArH), 7.24-7.28 (m,

1H, ArH), 7.52-7.53 (m, 2H, ArH), 7.61 (d, J = 8.4

Hz, 1H, ArH), 8.04 (d, J = 4.9 Hz, 1H, ArH), 8.09

(d, J = 7.8 Hz, 1H, ArH), 8.47 (d, J = 4.9 Hz, 1H,

ArH), 10.35 (bs, 1H, NH); ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 55.6, 55.9, 99.3, 104.5, 112.1,

118.4, 120.7, 120.9, 121.1, 121.9, 129.3, 131.6,

133.1, 136.8, 137.1, 138.3, 141.3, 160.4, 163.5,

196.9. MS (ESI+): m/z = 333.1. ESI-HR-MS

calculated for C_{2 0}H_{1 6}N₂O₃(M⁺+H): 333.1239,

found: 333.1243.

4.2.19. Naphthalen-1-yl(9H-pyrido[3,4-b]indol-1-

yl)methanone (3as).⁵. Yield: 92% (0.369 g from

0.2 g); a yellow solid, mp 122-124 ^oC [Lit 123-124

^oC]; R_f= 0.62(hexane: EtOAc, 8:2, v/v); IR (KBr)

ν_{ma x}: 1625, 1710, 1752, 2356 cm^{- 1 1}H NMR (400

.

MHz, CDCl₃): δ (ppm) 7.35-7.39 (m, 1H, ArH),

7.48-7.52 (m, 2H, ArH), 7.58-7.64 (m, 3H, ArH),

7.92-7.94 (m, 2H, ArH), 8.03 (d, J = 8.2 Hz, 1H,

ArH), 8.15-8.21 (m, 3H, ArH), 8.53 (d, J = 4.9 Hz,

1H, ArH), 10.61 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 112.1, 118.8, 120.8, 120.9,

121.9, 124.4, 125.6, 126.1, 127.0, 128.5, 129.4,

129.5, 131.3, 131.4, 131.8, 133.9, 135.5, 136.7,

137.3, 138.6, 141.2, 199.4. MS (ESI+): m/z =

323.2. ESI-HR-MS calculated for C_{2 2}H_{1 4}N₂O

(M⁺+H): 323.1184, found: 323.1188.

4.2.20. Pyridin-2-yl(9H-pyrido[3,4-b]indol-1-

yl)methanone (3at). Yield: 68% (0.231 g from 0.2

g); a brown solid, mp 237-239 ^oC; R_f= 0.58

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 669,

789, 1254, 1620, 1697, 2378 cm^{- 1 1}H NMR (400

.

MHz, CDCl₃): δ (ppm) 7.23-7.27 (m, 1H, ArH),

7.39 (dd, J₁= 5.1 Hz, J₂= 7.3 Hz, 1H, ArH), 7.50-

7.53 (m, 2H, ArH), 7.78-7.82 (m, 1H, ArH), 8.05-

8.07 (m, 2H, ArH), 8.14 (d, J = 7.7 Hz, 1H, ArH),

8.51 (d, J = 4.9 Hz, 1H, ArH), 8.77 (d, J = 4.5 Hz,

1H, ArH), 10.40 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 112.3, 119.0, 120.8, 120.9,

121.9, 125.8, 126.4, 129.5, 131.8, 135.6, 136.3,

137.5, 138.6, 141.2, 149.8, 155.1, 194.5. MS

(ESI+): m/z = 274.1. ESI-HR-MS calculated for

C_{1 7}H_{1 1}N₃O (M⁺+H): 274.0980, found: 274.0984.

4.2.21. Pyridin-4-yl(9H-pyrido[3,4-b]indol-1-

yl)methanone (3au). Yield: 71% (0.241 g from 0.2

g); a yellow solid, mp 213-215 ^oC; R_f= 0.60

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 745,

4.2.17. (3,4-Dimethoxyphenyl)(9H-pyrido[3,4-

b]indol-1-yl)methanone (3aq).^{3 a}Yield: 91% (0.377

g from 0.2 g); a yellow solid, mp 233-235 ^oC; IR

(KBr) νmax: 668, 778, 1699, 2896 cm-1. Rf = 0.63

(hexane: EtOAc, 8:2, v/v); ¹H NMR (400 MHz,

1123, 1658, 1711, 1752, 2569, 3254 cm^{- 1 1}H NMR

.

(400 MHz, CDCl₃): δ (ppm) 7.29-7.32 (m, 1H,

ArH), 7.56-7.57 (m, 2H, ArH), 8.04 (dd, J₁= 1.4

Hz, J₂= 4.5 Hz, 2H, ArH), 8.11-8.15 (m, 2H,

8

Tetrahedron

ArH), 8.53 (d, J = 4.9 Hz, 1H, ArH), 8.78 (d, J =

136.0, 136.5, 138.4, 141.4, 148.9, 166.4, 193.3.

ACCEPTED MANUSCRIPT

5.7 Hz, 2H, ArH), 10.36 (s, 1H, NH); ^{1 3}C NMR

MS (ESI+): m/z = 387.0. ESI-HR-MS calculated

for C_{2 4}H_{2 2}N₂O₃(M⁺+H): 387.1709, found:

387.1711.

(100 MHz, CDCl₃): δ (ppm) = 112.2, 119.5, 120.9,

121.3, 122.0, 124.4, 129.8, 132.2, 135.4, 137.5,

138.5, 141.2, 144.2, 150.2, 194.5. MS (ESI+): m/z

= 274.1. ESI-HR-MS calculated for C_{1 7}H_{1 1}N₃O

(M⁺+H): 274.0980, found: 274.0983.

4.2.26. Methyl 1-(4-tert-butylbenzoyl)-9H-

pyrido[3,4-b]indole-3-carboxylate (3bg). Yield:

95% (0.336 g from 0.2 g); a yellow solid, mp 230-

232 ^oC; R_f= 0.67 (hexane: EtOAc, 8:2, v/v); IR

4.2.22. (9H-Pyrido[3,4-b]indol-1-yl)(thiophen-2-

yl)methanone (3av).⁵. Yield: 87% (0.301 g from

0.2 g); a yellow solid, mp 211-212 ^oC [Lit 208-210

^oC]; R_f= 0.65 (hexane: EtOAc, 8:2, v/v); IR (KBr)

(KBr) ν_{ma x}: 778, 1254, 1645, 1710, 1752, 3457 cm^-

1

.

¹H NMR (400 MHz, CDCl₃): δ (ppm) 1.33 (s,

9H, CH₃), 4.01 (s, 3H, CO₂CH₃), 7.31-7.35 (m, 1H,

ArH), 7.51-7.61 (m, 4H, ArH), 8.16 (d, J = 7.9 Hz,

1H, ArH), 8.54 (d, J = 8.4 Hz, 2H, ArH), 8.97 (s,

1H, ArH), 10.65 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 31.1, 35.2, 52.8, 112.4, 120.5,

121.2, 121.6, 122.0, 125.2, 129.7, 131.9, 134.1,

135.9, 136.3, 138.3, 141.3, 156.7, 166.2, 193.2.

MS (ESI+): m/z = 387.1. ESI-HR-MS calculated

for C_{2 4}H_{2 2}N₂O₃(M⁺+H): 387.1709, found:

387.1712.

ν_{ma x}: 668, 1145, 1623, 1702, 2354, 3012 cm^{- 1 1}H

.

NMR (400 MHz, CDCl₃): δ (ppm) 7.16-71.18 (m,

1H, ArH), 7.25-7.29 (m, 1H, ArH), 7.51-7.57 (m,

2H, ArH), 7.73 (dd, J₁= 4.8 Hz, J₂= 0.97 Hz, 1H,

ArH), 8.09-8.12 (m, 2H, ArH), 8.53-8.56 (m, 2H,

ArH), 10.42 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 112.0, 118.8, 120.8, 121.8,

127.4, 129.3, 131.7, 135.7, 136.4, 136.8, 137.7,

139.8, 141.1, 185.3. MS (ESI+): m/z = 279.0. ESI-

HR-MS calculated for C_{1 6}H_{1 0}N₂OS (M⁺+H):

279.0592, found: 279.0595.

4.2.23. Methyl 1-benzoyl-9H-pyrido[3,4-b]indole-

3-carboxylate (3ba).⁶. Yield: 79% (0.239 g from

0.2 g); a grey solid, mp 234-236 ^oC [Lit 237-238

^oC]; R_f= 0.68 (hexane: EtOAc, 8:2, v/v); IR (KBr)

4.2.27. Methyl 1-(4-fluorobenzoyl)-9H-pyrido[3,4-

b]indole-3-carboxylate (3bw). Yield: 87% (0.277 g

from 0.2 g); a yellow solid, mp 185-187 ^oC; R_f=

0.65 (hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}

:

1708, 1740, 2945 cm^{- 1 1}H NMR (400 MHz,

.

CDCl₃): δ (ppm) 3.99 (s, 3H, CH₃), 7.12-7.17 (m,

2H, ArH), 7.31-7.35 (m, 1H, ArH), 7.55-7.60 (m,

2H, ArH), 8.15 (d, J = 7.9 Hz, 1H, ArH), 8.64-8.67

(m, ArH), 8.95 (s, 1H, ArH), 10.58 (s, 1H, NH);

^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 52.8,

112.4, 115.3 (d, J = 21.9 Hz), 120.6, 121.8, (d, J =

32.6 Hz), 129.8, 132.1, 133.0, 134.7(d, J = 8.9

Hz), 135.5, 136.3, 138.2, 141.3, 165.8 (d, J =

255.4 Hz), 166.1, 191.7. MS (ESI+): m/z = 349.1.

ESI-HR-MS calculated for C_{2 0}H_{1 3}FN₂O₃(M⁺+H):

349.0988, found: 349.0991.

ν

_{ma x}: 1623, 1708, 1746, 2354, 3247 cm^{- 1 1}H NMR

.

(400 MHz CDCl₃): δ (ppm) 3.99 (s, 3H, CO₂CH₃),

7.32-7.36 (m, 1H, ArH), 7.47-7.58 (m, 5H, ArH),

8.17 (d, J = 7.9 Hz, 1H, ArH), 8.55 (d, J = 7.9 Hz,

2H, ArH), 8.98 (s, 1H, ArH), 10.62 (s, 1H, NH);

^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 52.9,

112.5, 120.8, 121.4, 121.8, 122.2, 128.3, 129.9,

132.1, 133.1, 136.6, 136.9, 138.4, 141.4, 166.3,

193.9. MS (ESI+): m/z = 331.1. ESI-HR-MS

calculated for C_{2 0}H_{1 4}N₂O₃(M⁺+H): 331.1083,

found: 331.1080.

4.2.28. Ethyl 1-benzoyl-9H-pyrido[3,4-b]indole-3-

carboxylate (3ca). Yield: 76% (0.225 g from 0.2

g); a yellow solid, mp 202-204 ^oC; R_f= 0.68

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 1245,

1547, 1623, 1697, 1735, 3256 cm^{- 1 1}H NMR (400

MHz, DMSO-d₆): δ (ppm) 1.41 (t, J = 7.2 Hz, 3H,

CH₃), 4.41 (q, J = 6.9 Hz, 2H, CH₂), 7.38 (t, J =

7.8 Hz, 1H, ArH), 7.60 (t, J = 7.8 Hz, 2H, ArH),

7.66-7.72 (m, 2H, ArH), 8.86 (d, J = 8.2 Hz, 1H,

ArH), 8.49 (t, J = 8.0 Hz, 3H, ArH), 9.17 (s, 1H,

ArH), 12.47 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

DMSO-d₆): δ (ppm) = 14.1, 60.6, 113.2, 120.0,

120.7, 121.7, 127.7, 129.0, 131.3, 132.4, 132.5,

135.2, 135.5, 136.6, 136.7, 142.0, 164.7, 191.8.

MS (ESI+): m/z = 345.1. ESI-HR-MS calculated

for C_{2 1}H_{1 6}N₂O₃(M⁺+H): 345.1239, found:

345.1242.

4.2.24. Methyl 1-(4-methylbenzoyl)-9H-

pyrido[3,4-b]indole-3-carboxylate (3be).⁶Yield:

84% (0.265 g from 0.2 g); a yellow solid, mp 211-

213 ^oC [Lit 214-215 ^oC]; R_f= 0.68 (hexane:

EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 667, 1247, 1548,

1634, 1706, 1738, 2896, 3254 cm^{- 1 1}H NMR (400

.

MHz, DMSO-d₆): δ (ppm) 2.49 (s, 3H, CH₃), 4.09

(s, 3H, CO₂CH₃), 7.37-7.44 (m, 3H, ArH), 7.66-

7.69 (m, 2H, ArH), 8.25 (d, J = 7.8 Hz, 1H, ArH),

8.57 (d, J = 7.9 Hz, 2H, ArH), 9.06 (s, 1H, ArH),

10.72 (s, 1H, NH); ^{1 3}C NMR (100 MHz, DMSO-

d₆): δ (ppm) = 21.9, 52.8, 112.5, 120.6, 121.3,

121.7, 122.1, 129.0, 129.8, 132.1, 132.2, 134.3,

136.0, 136.4, 138.3, 141.4, 143.9, 166.4, 193.3.

MS (ESI+): m/z = 345.1. ESI-HR-MS calculated

for C_{2 1}H_{1 6}N₂O₃(M⁺+H): 345.1239, found:

345.1243.

4.2.29. 6-Chloro-9H-pyrido[3,4-b]indol-1-

4.2.25. Methyl 1-(4-butylbenzoyl)-9H-pyrido[3,4-

b]indole-3-carboxylate (3bf). Yield: 93% (0.329 g

from 0.2 g); a yellow solid, mp 178-180 ^oC; R_f=

yl)(phenyl)methanone (3da). Yield: 75% (0.236 g

from 0.2 g); a yellow solid, mp 196-198 ^oC; R_f=

0.68 (hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}

:

0.69 (hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}

:

1625, 1706, 1723, 2319 cm^{- 1 1}H NMR (400 MHz,

.

1708, 1745, 3263 cm^{- 1}¹H NMR (400 MHz,

.

CDCl₃): δ (ppm) 7.58-7.65 (m, 5H, ArH), 8.17 (bs,

2H, ArH), 8.35 (d, J = 6.9 Hz, 2H, ArH), 8.65 (s,

1H, ArH), 10.52 (bs, 1H, NH); ^{1 3}C NMR (100

MHz, CDCl₃): δ (ppm) 113.1, 118.6, 121.5, 122.0,

126.4, 128.1, 129.5, 130.7, 132.6, 137.4, 137.6,

138.3, 139.3, 142.1, 196.8. MS (ESI+): m/z =

307.1. ESI-HR-MS calculated for C_{1 8}H_{1 1}ClN₂O

(M⁺+H): 307.0638, found: 307.0641.

CDCl₃): δ (ppm) 0.88 (t, J = 7.4 Hz, 3H, CH₃),

1.33 (q, J = 7.6 Hz, 2H, CH₂), 1.56-1.62 (m, 2H,

CH₂), 2.65 (t, J = 7.6 Hz, 2H, CH₂), 4.01 (s, 3H,

CO₂CH₃), 7.28-7.35 (m, 3H, ArH), 7.54-7.58 (m,

2H, ArH), 8.15 (d, J = 7.8 Hz, 1H, ArH), 8.51 (d, J

= 8.3 Hz, 2H, ArH), 8.96 (s, 1H, ArH), 10.64 (s,

1H, NH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

14.1, 22.5, 33.4, 35.9, 52.9, 112.5, 120.6, 121.3,

121.7, 122.1, 128.4, 129.8, 132.1, 132.3, 134.5,

4.2.30. (3-Ethynylphenyl)(9H-pyrido[3,4-b]indol-

1-yl)methanone (3ax). Yield: 88% (0.325 g from

9

0.2 g); a yellow solid, mp 168-170 ^oC; R_f= 0.62

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 978,

110.9, 112.8, 114.8, 118.2, 119.0, 120.0, 121.7,

128.3, 128.8, 130.7, 133.7, 135.4, 135.6, 136.8,

137.4, 141.5, 161.8, 191.3. MS (ESI+): m/z =

367.2. ESI-HR-MS calculated for C_{1 8}H_{1 1}BrN₂O₂

(M⁺+H): 367.0082, found: 367.0085.

ACCEPTED MANUSCRIPT

1025, 1235, 1456, 1589, 1604, 1699, 1735, 3258

cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ (ppm) 3.05 (s,

.

1H, H-C≡C), 7.25-7.28 (m, 1H, ArH), 7.42 (t, J =

7.7 Hz, 1H, ArH), 7.52-7.55 (m, 2H, ArH), 7.63 (d,

J = 7.7 Hz, 1H, ArH), 8.07-8.09 (m, 2H, ArH),

8.23 (d, J = 7.5 Hz, 1H, ArH), 8.38 (s, 1H, ArH),

8.53 (d, J = 4.8 Hz, 1H, ArH), 10.35 (s, 1H, NH);

^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 77.9, 83.4,

112.2, 111.8, 120.9, 121.0, 121.9, 122.3, 128.2,

129.5, 131.6, 131.8, 135.0, 135.7, 136.1, 137.5,

137.8, 138.3, 141.2, 194.5. MS (ESI+): m/z =

297.1. ESI-HR-MS calculated for C_{2 0}H_{1 2}N₂O

(M⁺+H): 297.1028, found: 297.1031.

4.5. Experimental procedure for Fascaplysin 8.

A round bottom flask charged with 3am (0.1 g) was heated at

220 C for 20 minutes. The content was cooled and the residue

was recrystallized from CH₂Cl₂/diethyl ether producing

corresponding quaternary fascaplysin analogs 8 (0.084 g, 84%)

as dark red solid.

o

4.5.1. Fascaplysin (8)⁶. Mp 233-235 ^oC [Lit 230-

232 ^oC]; R_f= 0.11 (hexane: EtOAc, 6:4, v/v); IR

(KBr) ν_{ma x}: 769, 896, 1269, 1523, 1647, 1711,

4.3. Experimental procedure for the formation of Eudistomin Y1

(6).

2389, 3214 cm^{- 1 1}H NMR (400 MHz, DMSO-d₆): δ

.

(ppm) 7.32 (t, J = 7.4 Hz, 1H, ArH), 7.46-7.62 (m,

5H, ArH), 7.88 (d, J = 8.3 Hz, 1H, ArH), 8.31 (d, J

= 8.1 Hz, 1H, ArH), 8.41-8.45 (m, 2H, ArH), 12.25

(s, 1H, NH); ^{1 3}C NMR (100 MHz, DMSO-d₆): δ

(ppm) = 113.6, 120.1, 120.4, 120.9, 122.3, 127.2,

129.6, 129.8, 130.0, 130.7, 131.5, 131.8, 135.7,

135.8, 138.3, 139.8, 142.4, 196.6. MS (ESI+): m/z

= 271.1. ESI-HR-MS calculated for C_{1 8}H_{1 1}N₂O

(M)⁺: 271.0866, found: 271.0869.

To a stirred solution of 3ah (0.15 g, 0.49 mmol) in MeCN (10

mL) was added AlCl₃(0.198 g, 1.49 mmol) and the resulting

reaction mixture was reflux for 18 h. After completion of the

reaction (as monitored by TLC), the reaction mixture was

quenched by adding H₂O (5 mL) extracted with EtOAc (3 × 20

mL). The combined organic extracts were washed with brine (15

mL), dried over anhydrous Na₂SO₄and concentrated under

reduced pressure. The crude residue was purified by

chromatography over a column of silica gel using hexanes/

EtOAc (6.0:4.0, v/v) as eluent to afford the desired product 6

(0.124 g, 79%) as a yellow solid

4.5.2. 1,4-Phenylenebis((9H-pyrido[3,4-b]indol-1-

yl)methanone) (9). Yield: 75% (0.277 g from 0.2

g); a yellow solid, mp <250 ^oC; R_f= 0.48 (hexane:

EtOAc, 6:4, v/v); IR (KBr) ν_{ma x}: 698, 768, 965,

1253, 1524, 1635, 1706, 2354, 2589 cm^{- 1 1}H NMR

.

4.3.1. (4-Hydroxyphenyl)(9H-pyrido[3,4-b]indol-

1-yl)methanone (6).⁵. Mp 215-217 ^oC [Lit 217-218

^oC]; R_f= 0.56 (hexane: EtOAc, 8:2, v/v); IR (KBr)

ν_{ma x}: 659, 758, 1056, 1458, 1589, 1710, 2569, 3296

(400 MHz, DMSO-d₆): δ (ppm) 7.35 (bs, 2H, ArH),

7.63 (bs, 2H, ArH), 7.84 (d, J = 7.1 Hz, 2H, ArH),

8.13 (d, J = 7.7 Hz, 2H, ArH), 8.24-8.36 (m, 5H,

ArH), 8.50-8.58 (m, 3H, ArH), 12.13 (bs, 1H, NH),

12.17 (bs, 1H, NH); ^{1 3}C NMR (100 MHz, DMSO-

d₆): δ (ppm) = 113.5, 119.7, 120.5, 120.8, 122.3,

129.2, 129.5, 130.5, 131.2, 131.7, 134.0, 136.3,

136.4, 137.8, 141.7, 142.2, 167.4, 194.2. MS

(ESI+): m/z = 467.1. ESI-HR-MS calculated for

C_{3 0}H_{1 8}N₄O₂(M⁺+H): 467.1508, found: 467.1511.

cm^{- 1 1}H NMR (400 MHz, DMSO-d₆): δ (ppm) 6.94

.

(d, J = 8.7 Hz, 2H, ArH), 7.31 (t, J = 7.8 Hz, 1H,

ArH) 7.60 (t, J = 7.4 Hz, 1H, ArH), 7.79 (d, J =

8.1 Hz, 1H, ArH), 8.27 (d, J = 8.4 Hz, 2H, ArH),

8.32 (d, J = 7.8 Hz, 1H, ArH), 8.41 (d, J = 4.9 Hz,

1H, ArH), 8.52 (d, J = 4.9 Hz, 1H, ArH), 10.39 (s,

1H, NH), 11.94 (s, 1H, OH); ^{1 3}C NMR (100 MHz,

DMSO-d⁶): δ (ppm) = 112.8, 114.8, 118.2, 119.9,

120.0, 121.7, 128.3, 128.8, 130.7, 133.7, 135.6,

136.8, 137.4, 141.5, 161.8, 191.4. MS (ESI+): m/z

= 289.1. ESI-HR-MS calculated for C_{1 8}H_{1 2}N₂O₂

(M⁺+H): 289.0977, found: 289.0980.

4.5.3. (E)-1,4-bis(3,4-dimethoxyphenyl)but-2-ene-

1,4-dione (11). Yield: 90% (0.351 g from 0.2 g); a

yellow solid, mp 198-200 ^oC; R_f= 0.54 (hexane:

EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 675, 778, 925,

1026, 1536, 1645, 1713, 2458 cm^{- 1 1}H NMR (400

.

4.4. Experimental procedure for formation of Eudistomin Y2 (7).

MHz, CDCl₃): δ (ppm) 3.91 (s, 12H, OCH₃), 6.87

(d, J = 8.2 Hz, 2H, ArH), 7.55 (s, 2H, H-C=C-H),

7.67 (d, J = 7.9 Hz, 1H, ArH), 7.96 (s, 1H, ArH);

^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 56.2, 56.3,

110.3, 110.7, 124.2, 130.4, 134.5, 149.6, 154.3,

188.1. MS (ESI+): m/z = 357.1. ESI-HR-MS

calculated for C_{2 0}H_{2 0}O₆(M⁺+H): 357.1338, found:

357.1341. Three bond HMBC correlations of 2, 6-

H and 8’-H to C-7 and 2’, 6’-H and H-8 to C-7’

confirmed the formation of the compound.

Although compound is symmetrical in nature even

then it showed an important three bond HMBC

correlations of 8’-H to C-7 and H-8 to C-7’, which

strengthened the formation of a symmetrical dimer

To a stirred solution of 6 (0.1 g, 0.34 mmol) in AcOH (5 mL)

was added NBS (0.062 g, 0.34 mmol) at room temperature and

the reaction was allowed to continue for 8 h. After completion (as

monitored by TLC), the reaction mixture was neutralised with

aqueous NaHCO₃solution. The mixture was extracted with

EtOAc (3 × 15 mL) and water (25 mL). The organic layers were

pooled, dried over anhydrous Na₂SO₄and concentrated under

reduced pressure to furnish a residue that was purified by silica

gel column chromatography using hexanes/ EtOAc (6.0:4.0, v/v)

as eluent to afford 7 (0.072 g, 91%) as a yellow solid.

4.4.1. 6-Bromo-9H-pyrido[3,4-b]indol-1-yl)(4-

hydroxyphenyl)methanone (7)⁵. Mp 270-272 ^oC

[Lit 273-274^oC]; R_f= 0.55 (hexane: EtOAc, 8:2,

v/v); IR (KBr) ν_{ma x}: 633, 869, 1204, 1563, 1608,

1712, 2354, 3025, 3248 cm^{- 1 1}H NMR (400 MHz,

.

DMSO-d₆): δ (ppm) 7.60 (d, J = 7.4 Hz, 2H, ArH),

8.32 (t, J = 6.9 Hz, 1H, ArH) 8.40 (d, J = 4.6 Hz,

1H, ArH), 8.47 (d, J = 4.4 Hz, 1H, ArH), 8.51-8.57

(m, 4H, ArH), 10.38 (s, 1H, NH), 11.93 (s, 1H,

OH); ^{1 3}C NMR (100 MHz DMSO- d₆): δ (ppm) =

10

Tetrahedron

ACCEPTED MANUSCRIPT

4.5.4. 1,4-Bis(3,4-dimethoxyphenyl)-2-

1H, ArH), 7.20 (dd, J₁= 4.2 Hz, J₂= 0.8 Hz, 1H,

(methylthio)but-2-ene-1,4-dione (12z). Yield: 78%

ArH), 7.40-7.44 (m, 1H, ArH), 7.44-7.61 (m, 3H,

ArH), 7.86 (d, J = 8.1 Hz, 1H, ArH), 7.93-8.09 (m,

1H, ArH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

109.1, 113.9, 114.8, 115.0, 124.3, 125.5, 128.8,

129.7, 131.2, 131.6, 132.6, 134.6, 134.8, 149.2,

191.3. MS (ESI+): m/z = 351.2. ESI-HR-MS

calculated for C_{1 8}H_{1 1}BrN₂O (M⁺+H): 351.0133,

found: 351.0138.

(0.193 g from 0.2 g); a yellow solid, mp 140-142

^oC; R_f= 0.56 (hexane: EtOAc, 8:2, v/v); IR (KBr)

ν_{ma x}: 1602, 1694, 2348, 3214 cm^{- 1 1}H NMR (400

.

MHz, CDCl₃): δ (ppm) 2.16 (s, 3H, SCH₃), 3.93 (s,

3H, OCH₃), 3.94 (s. 3H, OCH₃), 3.96 (s, 3H,

OCH₃), 3.98 (s, 3H, OCH₃), 6.86 (d, J = 8.3 Hz,

1H, ArH), 6.92 (d, J = 8.4 Hz, 1H, ArH), 7.07 (s,

1H, ArH), 7.52 (dd, J₁= 8.4 Hz, J₂= 1.6 Hz, 1H,

ArH), 7.61 (d, J = 1.9 Hz, 2H, ArH), 7.67 (dd, J₁

8.4 Hz, J₂= 1.7 Hz, 1H, ArH); ^{1 3}C NMR (100

MHz, CDCl₃): δ (ppm) = 15.5, 55.9, 56.0, 56.1,

56.3, 110.0, 110.3, 110.4, 110.5, 115.7, 122.3,

126.3, 128.1, 131.1, 149.2, 149.5, 153.0, 154.8,

4.5.9. Pyrrolo[1,2-a]quinoxalin-4-yl(p-

=

tolyl)methanone (15ae). Yield: 91% (0.329 g from

0.2 g); a yellow solid, mp 164-166 ^oC; R_f= 0.66

(hexane: EtOAc, 9:1, v/v); IR (KBr) ν_{ma x}: 758,

936, 1298, 1536, 1637, 1714, 2389, 3014 cm^{- 1 1}H

.

NMR (400 MHz, CDCl₃): δ (ppm) 2.44 (s, 3H,

159.9, 186.8, 190.6. MS (ESI+): m/z = 403.1. ESI-

HR-MS calculated for C_{2 1}H_{2 2}O₆S (M⁺+H):

403.1215, found: 403.1213.

CH₃), 6.94 (dd, J₁= 3.9 Hz, J₂= 2.7 Hz, 1H, ArH),

7.16 (dd, J₁= 4.0 Hz, J₂= 1.1 Hz, 1H, ArH), 7.29

(d, J = 8.2 Hz, 2H, ArH), 7.45-7.48 (m, 1H, ArH),

7.57-7.62 (m, 1H, ArH), 7.91 (d, J = 8.2 Hz, 1H,

ArH), 8.01-8.03 (m, 2H, ArH), 8.06 (d, J = 8.2 Hz,

2H, ArH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

21.8, 108.8, 113.9, 114.7, 114.8, 124.4, 125.4,

127.9, 129.1, 129.3, 131.0, 131.2, 133.3, 134.8,

144.7, 150.4, 192.0. MS (ESI+): m/z = 287.1. ESI-

HR-MS calculated for C_{1 9}H_{1 4}N₂O (M⁺+H):

4.5.5. 2-(Methylthio)-1,4-dip-tolylbut-2-ene-1,4-

dione (12e). Yield: 68% (0.181 g from 0.2 g); a

yellow solid, mp 95-97 ^oC; R_f= 0.62 (hexane:

EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 789, 1258, 1635,

1702, 2789 cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ

.

(ppm) 2.14 (s, 3H, SCH₃), 2.39 (s, 3H, CH₃), 2.45

(s. 3H, CH₃), 7.06 (s, 1H, H-C=C), 7.23 (d, J = 8.1

Hz, 2H, ArH), 7.32 (d, J = 8.1 Hz, 2H, ArH), 7.84

(d, J = 8.2 Hz, 2H, ArH), 7.95 (dd, J = 8.2 Hz, 2H,

ArH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

15.4, 21.6, 21.8, 115.9, 128.2, 129.3, 129.8, 130.2,

143.5, 146.0, 160.3, 187.9, 191.6. MS (ESI+): m/z

= 311.1. ESI-HR-MS calculated for C_{1 9}H_{1 8}O₂S

(M⁺+H): 311.1106, found: 311.1109.

287.1184, found: 287.1184.

4.5.10. (4-Methoxyphenyl)(pyrrolo[1,2-

a]quinoxalin-4-yl)methanone (15ah). Yield: 82%

(0.313 g from 0.2 g); a yellow solid, mp 184-186

^oC; R_f= 0.63 (hexane: EtOAc, 9:1, v/v); IR (KBr)

ν_{ma x}: 889, 1298, 1547, 1612, 1704, 2596 cm^{- 1 1}H

.

NMR (400 MHz, CDCl₃): δ (ppm) 3.89 (s, 3H,

4.5.6. 1,4-Bis(3-chlorophenyl)-2-(methylthio)but-

2-ene-1,4-dione (12j). Yield: 74% (0.190 g from

0.2 g); a yellow solid, mp 178-180 ^oC; R_f= 0.60

(hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}: 1298,

OCH₃), 6.93-6.98 (m, 3H, ArH), 7.15 (dd, J₁= 4.1

Hz, J₂= 1.1 Hz, 1H, ArH), 7.46-7.50 (m, 1H,

ArH), 7.59-7.63 (m, 1H, ArH), 7.91-7.93 (m, 1H,

ArH), 8.02-8.05 (m, 2H, ArH), 8.18 (d, J = 8.9 Hz,

2H, ArH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

55.6, 108.8, 113.7, 113.9, 114.7, 114.8, 124.5,

125.4, 127.9, 128.6, 129.2, 130.9, 133.4, 134.8,

150.7, 164.2, 190.8. MS (ESI+): m/z = 303.1. ESI-

HR-MS calculated for C_{1 9}H_{1 4}N₂O₂(M⁺+H):

303.1134, found: 303.1138.

1547, 1658, 1714, 2589 cm^{- 1 1}H NMR (400 MHz,

.

CDCl₃): δ (ppm) 2.17 (s, 3H, SCH₃), 7.01 (s, 1H,

H-C=C), 7.39 (t, J = 7.8 Hz, 1H, ArH), 7.46-7.53

(m, 2H, ArH), 7.63-7.66 (m, 1H, ArH), 7.79-7.81

(m, 1H, ArH), 7.90-7.94 (m, 2H, ArH), 8.03 (t, J =

1.7 Hz, 1H, ArH); ^{1 3}C NMR (100 MHz, CDCl₃): δ

(ppm) = 15.5, 115.7, 126.1, 128.1, 128.2, 129.6,

130.0, 130.5, 132.7, 134.8, 135.0, 135.6, 136.4,

139.4, 160.9, 186.7, 190.4. MS (ESI+): m/z =

351.1. ESI-HR-MS calculated for C_{1 7}H_{1 2}Cl₂O₂S

(M⁺+H): 351.0013, found: 351.0019.

4.5.11. 1-(4-Benzoylpyrrolo[1,2-a]quinoxalin-1-

yl)-2-phenylethane-1,2-dione (16aa). Yield: 90%

(0.460 g from 0.2 g); a yellow solid, mp 202-204

^oC; R_f= 0.55 (hexane: EtOAc, 8:2, v/v); IR (KBr)

ν_{ma x}: 1589, 1612, 1657, 1714, 2689, 3145 cm^{- 1 1}H

.

4.5.7. Phenyl(pyrrolo[1,2-a]quinoxalin-4-

NMR (400 MHz, CDCl₃): δ (ppm) 7.33 (d, J = 4.7

Hz, 1H, ArH), 7.54-7.58 (m, 5H, ArH), 7.67-7.12

(m, 3H, ArH), 7.81-7.83 (m, 1H, ArH), 8.05-8.07

(m, 2H, ArH), 8.17-8.19 (m, 3H, ArH), 9.26 (dd, J₁

= 8.6 Hz, J₂= 0.9 Hz, 1H, ArH); ^{1 3}C NMR (100

MHz, CDCl₃): δ (ppm) = 109.8, 120.3, 127.5,

127.8, 128.5, 128.7, 129.0, 130.2, 130.3, 130.4,

131.2, 131.9, 133.0, 133.9, 134.8, 135.4, 136.6,

149.1, 182.7, 191.4, 193.1. MS (ESI+): m/z =

405.2. ESI-HR-MS calculated for C_{2 6}H_{1 6}N₂O₃

(M⁺+H): 405.1239, found: 405.1243.

yl)methanone (15aa).^{1 2}. Yield: 84% (0.289 g from

0.2 g); a yellow solid, mp 148-150 ^oC; R_f= 0.68

(hexane: EtOAc, 9:1, v/v); IR (KBr) ν_{ma x}: 668,

963, 1249, 1624, 1704, 2349 cm^{- 1 1}H NMR (400

.

MHz, CDCl₃): δ (ppm) 6.96-6.97 (m, 1H, ArH),

7.21-7.25 (m, 1H, ArH), 7.46-7.52 (m, 3H, ArH),

7.62-7.65 (m, 2H, ArH), 7.92-7.93 (m, 1H, ArH),

8.02-8.03 (m, 2H, ArH), 8.16-8.18 (m, 2H, ArH);

^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 108.9,

113.9, 114.8, 114.9, 124.4, 125.5, 127.9, 128.4,

129.4, 131.0, 131.1, 133.6, 134.8, 135.9, 149.9,

192.4. MS (ESI+): m/z = 273.0. ESI-HR-MS

calculated for C_{1 8}H_{1 2}N₂O (M⁺+H): 273.1028,

found: 273.1033.

4.5.12. 1-(4-(4-Methylbenzoyl)pyrrolo[1,2-

a]quinoxalin-1-yl)-2-p-tolylethane-1,2-dione

(16ae). Yield: 92% (0.524 g from 0.2 g); a yellow

solid, mp 210-212 ^oC; R_f= 0.53 (hexane: EtOAc,

8:2, v/v); IR (KBr) ν_{ma x}: 1247, 1607, 1669, 1712,

4.5.8. (4-Bromophenyl)(pyrrolo[1,2-a]quinoxalin-

4-yl)methanone (15ab). Yield: 85% (0.376 g from

0.2 g); a yellow solid, mp 161-163 ^oC; R_f= 0.65

(hexane: EtOAc, 9:1, v/v); IR (KBr) ν_{ma x}: 1247,

3289 cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ (ppm)

.

2.45 (s, 3H, CH₃), 2.46 (s, 3H, CH₃), 7.29 (d, J =

4.7 Hz, 1H, ArH), 7.31 (d, J = 3.5 Hz, 2H, ArH),

7.33 (d, J = 3.5 Hz, 2H, ArH), 7.49 (d, J = 4.6 Hz,

1H, ArH), 7.64-7.68 (m, 1H, ArH), 7.75-7.79 (m,

1647, 1689, 1712, 3289 cm^{- 1 1}H NMR (400 MHz,

.

CDCl₃): δ (ppm) 6.91 (dd, J₁= 3.9 Hz, J₂= 2.8 Hz,

11

1H, ArH), 7.93 (d, J = 8.3 Hz, 2H, ArH), 8.05 (d, J

= 8.3 Hz, 2H, ArH), 8.14 (dd, J₁= 8.1 Hz, J₂= 1.5

Hz, 1H, ArH), 9.23 (dd, J₁= 8.6 Hz, J₂= 0.9 Hz,

1H, ArH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

21.8, 21.9, 109.7, 120.3, 127.4, 127.9, 128.7,

129.3, 129.8, 130.0, 130.2, 130.4, 130.5, 131.2,

131.9, 132.8, 136.6, 145.2, 146.2, 149.5, 182.9,

191.1, 192.9. MS (ESI+): m/z = 433.2. ESI-HR-MS

calculated for C_{2 8}H_{2 0}N₂O₃(M⁺+H): 433.1552,

found: 433.1555.

(d, J = 4.0 Hz, 1H, ArH), 8.04 (d, J = 7.8 Hz,

ACCEPTED MANUSCRIPT

1H, ArH), 8.13 (d, J = 7.8 Hz, 1H, ArH), 8.47 (d, J

= 8.6 Hz, 1H, ArH), 8.51 (d, J = 8.4 Hz, 1H, ArH);

^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 20.2,

106.5, 114.8, 114.9, 121.4, 123.6, 124.8, 125.6,

128.3, 128.6, 129.9, 130.5, 130.9, 131.4, 132.9,

135.2, 135.6, 143.3, 153.7, 184.8. MS (ESI+): m/z

= 375.1. ESI-HR-MS calculated for C_{2 1}H_{1 4}N₂OS₂

(M⁺+H): 375.0626, found: 375.0628.

4.5.17. (4-Methoxyphenyl)(7-methylindolo[1,2-

a]quinoxalin-6-yl)methanone (15ch). Yield: 91%

(0.3 g from 0.2 g); a yellow solid, mp 156-158 ^oC

[Lit 162-163 ^oC]; R_f= 0.66 (hexane: EtOAc, 9:1,

v/v); IR (KBr) ν_{ma x}: 689, 1249, 1628, 1696, 2378

4.5.13. (7-(Methylthio)indolo[1,2-a]quinoxalin-6-

yl)(phenyl)methanone (17ba). Yield: 88% (0.311 g

from 0.2 g); a yellow solid, mp 222-224 ^oC; R_f=

0.60 (hexane: EtOAc, 9:1, v/v); IR (KBr) ν_{ma x}

:

774, 1247, 1685, 1702, 2496, 3247 cm^{- 1 1}H NMR

.

cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ (ppm) 2.32 (s,

.

(400 MHz, CDCl₃): δ (ppm) 2.09 (s, 3H, SCH₃),

7.48-7.75 (m, 7H, ArH), 8.05 (d, J = 7.5 Hz, 2H,

ArH), 8.09 (d, J = 7.9 Hz, 1H, ArH), 8.16 (d, J =

7.9 Hz, 1H, ArH), 8.55 (d, J = 8.6 Hz, 1H, ArH),

8.59 (d, J = 8.4 Hz, 1H, ArH); ^{1 3}C NMR (100

MHz, CDCl₃): δ (ppm) = 20.1, 106.2, 114.8, 114.9,

121.4, 123.6, 124.8, 125.6, 128.7, 129.1, 129.7,

130.0, 130.4, 130.9, 121.3, 133.0, 133.8, 135.4,

136.1, 154.8, 192.5. MS (ESI+): m/z = 369.0. ESI-

HR-MS calculated for C_{2 3}H_{1 6}N₂OS (M⁺+H):

369.1062, found: 369.1059.

3H, CH₃), 4.06 (s, 3H, OCH₃), 7.15 (d, J = 8.9 Hz,

2H, ArH), 7.66 (t, J = 7.4 Hz, 1H, ArH), 7.72 (t, J

= 7.6 Hz, 1H, ArH), 7.79-7.89 (m, 2H, ArH), 8.19

(d, J = 8.7 Hz, 2H, ArH), 8.24 (dd, J₁= 7.9 Hz, J₂

= 1.1 Hz, 1H, ArH), 8.32 (d, J = 7.9 Hz, 1H, ArH),

8.68 (d, J = 8.8 Hz, 1H, ArH), 8.71 (d, J = 8.2 Hz,

1H, ArH); ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

10.7, 55.6, 110.9, 114.2, 114.9, 121.5, 123.7,

134.9, 125.6, 129.7, 130.5, 130.9, 131.5, 132.5,

133.1, 135.5, 155.1, 164.3, 191.3. MS (ESI+): m/z

= 367.1. ESI-HR-MS calculated for C_{2 4}H_{1 8}N₂O₂

(M⁺+H): 367.1447, found: 367.1449.

4.5.14. (7-(Methylthio)indolo[1,2-a]quinoxalin-6-

yl)(4-nitrophenyl)methanone (17bd). Yield: 82%

(0.325 g from 0.2 g); a yellow solid, mp 188-190

^oC; R_f= 0.58 (hexane: EtOAc, 9:1, v/v); IR (KBr)

ν_{ma x}: 875, 967, 1238, 1526, 1645, 1702, 2549, 3145

4.6. General Procedure for thiomethylation as exemplified for

18aa.

To a solution of 3aa (0.1 g, 0.36 mmol) in DMSO (5 mL)

were added Pd(OAc)₂(0.082 g, 0.036 mmol) and Cu(OAc)₂

(0.065 g, 0.36 mmol) and the mixture was stirred under heating at

cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ (ppm) 2.05 (s,

.

3H, SCH₃), 7.44-7.51 (m, 2H, ArH), 7.59-7.67 (m,

2H, ArH), 7.97 (d, J = 7.9 Hz, 1H, ArH), 8.04-8.13

(m, 3H, ArH), 8.24-8.26 (m, 3H, ArH), 8.45-8.51

(m, 1H, ArH); ^{1 3}C NMR (100 MHz, CDCl₃): δ

(ppm) = 20.3, 105.9, 114.9, 115.0, 121.4, 123.9,

125.0, 125.9, 130.2, 130.5, 130.8, 131.0, 131.1,

131.4, 132.0, 133.2, 134.6, 135.3, 140.6, 150.6,

153.5, 190.5. MS (ESI+): m/z = 414.1. ESI-HR-MS

calculated for C_{2 3}H_{1 5}N₃O₃S (M⁺+H): 414.0912,

found: 414.0915.

o

120 C for 30 h. On completion as monitored by the TLC, the

mixture was quenched with water and extracted with EtOAc (3 x

20 mL). The organic layers were pooled, dried over anhydrous

Na₂SO₄and concentrated under reduced pressure to furnsih a

residue. This residue was purified by silica gel column

chromatography using hexanes/ EtOAc (8.0:2.0, v/v) as eluent to

afford 18aa (0.074 g, 64%) as a yellow solid.

4.6.1. (2-(Methylthio)phenyl)(9H-pyrido[3,4-

b]indol-1-yl)methanone (18aa). Mp 168-170 ^oC; R_f

4.5.15. (4-Methoxyphenyl)(7-

= 0.69 (hexane: EtOAc, 8:2, v/v); IR (KBr) ν_{ma x}

665, 856, 1246, 1623, 1702, 2563, 3266 cm^{- 1 1}H

NMR (400 MHz, CDCl₃): δ (ppm) 2.43 (s, 3H,

:

(methylthio)indolo[1,2-a]quinoxalin-6-

yl)methanone (17bh). Yield: 92% (0.352 g from

0.2 g); a yellow solid, mp 152-154 ^oC; R_f= 0.62

(hexane: EtOAc, 9:1, v/v); IR (KBr) ν_{ma x}: 1247,

.

SCH₃), 6.97-7.04 (m, 2H, ArH), 7.25-7.29 (m, 1H,

ArH), 7.41-7.45 (m, 1H, ArH), 7.48-7.49 (m, 1H,

ArH), 7.52-7.55 (m, 2H, ArH), 8.05 (d, J = 4.9 Hz,

1H, ArH), 8.10 (d, J = 7.6 Hz, 1H, ArH), 8.46 (d, J

= 4.9 Hz, 1H, ArH), 10.36 (s, 1H, NH); ^{1 3}C NMR

(100 MHz, CDCl₃): δ (ppm) = 16.4, 111.9, 112.1,

118.7, 120.4, 120.8, 121.8, 128.7, 129.3, 130.2,

131.6, 132.1, 136.6, 138.6, 140.1, 141.3, 198.8.

MS (ESI+): m/z = 319.1. ESI-HR-MS calculated

for C_{1 9}H_{1 4}N₂OS (M⁺+H): 319.0905, found:

319.0911.

1675, 1712, 3289 cm^{- 1 1}H NMR (400 MHz,

.

CDCl₃): δ (ppm) 2.03 (s, 3H, SCH₃), 3.78 (s, 3H,

OCH₃), 6.87 (d, J = 8.8 Hz, 2H, ArH), 7.38-7.48

(m, 2H, ArH), 7.54-7.63 (m, 2H, ArH), 7.91 (d, J =

8.7 Hz, 2H, ArH), 7.98 (d, J = 7.8 Hz, 1H, ArH),

8.06 (d, J = 8.0 Hz, 1H, ArH), 8.43 (d, J = 8.6 Hz,

1H, ArH), 8.47 (d, J = 8.4 Hz, 1H, ArH); ^{1 3}C NMR

(100 MHz, CDCl₃): δ (ppm) = 20.3, 55.6, 106.3,

114.1, 114.8, 114.9, 121.4, 123.6, 124.8, 125.5,

129.3, 129.6, 130.4, 130.8, 132.4, 135.4, 155.0,

164.2, 191.2. MS (ESI+): m/z = 399.2. ESI-HR-MS

calculated for C_{2 4}H_{1 8}N₂O₂S (M⁺+H): 399.1167,

found: 399.1164.

4.6.2. (4-Bromo-2-(methylthio)phenyl)(9H-

pyrido[3,4-b]indol-1-yl)methanone (18ab). Yield:

66% (0.074 g from 0.1 g); a yellow solid, mp 202-

204 ^oC; R_f= 0.67 (hexane: EtOAc, 8:2, v/v); IR

4.5.16. (7-(Methylthio)indolo[1,2-a]quinoxalin-6-

yl)(thiophen-2-yl)methanone (17bv). Yield: 89%

(0.320 g from 0.2 g); a yellow solid, mp 214-216

^oC; R_f= 0.59 (hexane: EtOAc, 9:1, v/v); IR (KBr)

(KBr) ν_{ma x}: 887, 1145, 1656, 1697, 2459, 3045 cm^-

1

.

¹H NMR (400 MHz, CDCl₃): δ (ppm) 2.58 (m,

3H SCH₃), 7.15 (dd, J₁= 2.5 Hz, J₂= 8.5 Hz, 1H,

ArH), 7.32-7.39 (m, 3H, ArH), 7.55-7.58 (m, 1H,

ArH), 7.63-7.64 (m, 1H, ArH), 8.21 (d, J = 7.5 Hz,

1H, ArH), 8.37 (d, J = 8.4 Hz, 1H, ArH), 8.63 (s,

1H, ArH), 10.48 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 16.2, 112.0, 119.1, 120.7,

ν_{ma x}: 1478, 1621, 1697, 2746 cm^{- 1 1}H NMR (400

.

MHz, CDCl₃): δ (ppm) 2.16 (s, 3H, CH₃), 7.10 (s,

1H, ArH), 7.46 (t, J = 7.3 Hz, 1H, ArH), 7.52 (t, J

= 7.4 Hz, 1H, ArH), 7.59-7.69 (m, 3H, ArH), 7.79

12

Tetrahedron

ACCEPTED MANUSCRIPT

120.9, 121.8, 123.9, 124.5, 124.7, 128.0, 129.3,

NMR (100 MHz, CDCl₃): δ (ppm) = 16.7, 112.5,

131.8, 133.7, 138.5, 138.6, 141.0, 145.2, 147.1,

115.4 (d, J = 21.9 Hz), 120.7, 121.3, 121.9 (d, J =

32.1 Hz), 129.4, 132.2, 134.8 (d, J = 9.2 Hz),

136.4, 138.4, 139.8, 141.4, 143.0, 165.9 (d, J =

255.2 Hz), 191.8. MS (ESI+): m/z = 337.1. ESI-

HR-MS calculated for C_{1 9}H_{1 3}FN₂OS (M⁺+H):

337.0811, found: 337.0809.

194.2. MS (ESI+): m/z = 397.0. ESI-HR-MS

calculated for C_{1 9}H_{1 3}BrN₂OS (M⁺+H): 397.0010,

found: 397.0009.

4.6.3. (4-Methyl-2-(methylthio)phenyl)(9H-

pyrido[3,4-b]indol-1-yl)methanone (18ae). Yield:

61% (0.071 g from 0.2 g); a yellow solid, mp 177-

178 ^oC; R_f= 0.70 (hexane: EtOAc, 8:2, v/v); IR

(KBr) ν_{ma x}: 986, 1292, 1546, 1647, 1703, 2569,

4.7. General Procedure for the synthesis of Canthin-6-ones 19 as

exemplified for 19aa.

2756 cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ (ppm)

.

To a stirred solution of 3aa (0.1 g, 0.36 mmol) in THF (5 mL)

was added NaH (60% dispersion in mineral oil) (2.0 equiv) at 0

^oC. After 15 min. acetic anhydride (0.052 µL, 0.54 mmol) was

added to the above solution. After 15 min the reaction mixture

was transferred to oil bath and heated at 70 ^oC. After completion

of reaction (as monitored by TLC), the reaction mixture was

quenched with water (50 mL) and extracted with ethyl acetate (2

x 50 mL). The organic layers were collected, dried over

anhydrous Na₂SO₄and evaporated to get the crude product. The

crude product was purified by column chromatography over a

column of silica gel using hexanes/EtOAc (8.0:2.0, v/v) as eluent

to get 19aa (0.089 g, 83%) as a pale yellow solid.

2.36 (s, 3H SCH₃), 2.47 (s, 3H, ArH), 6.79 (s, 1H,

ArH), 6.83 (d, J = 7.8 Hz, 1H, ArH), 7.25-7.28 (m,

1H, ArH), 7.43 (d, J = 7.8 Hz, 1H, ArH), 7.52-7.54

(m, 2H, ArH), 8.04 (d, J = 5.1 Hz, 1H, ArH), 8.09

(d, J = 7.9 Hz, 1H, ArH), 8.46 (d, J = 4.9 Hz, 1H,

ArH), 10.45 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 16.4, 22.0, 112.1, 112.6, 118.5,

120.6, 120.8, 121.0, 121.8, 125.7, 129.1, 130.5,

131.5, 136.6, 136.8, 138.5, 139.7, 141.2, 142.9,

198.4. MS (ESI+): m/z = 333.1. ESI-HR-MS

calculated for C_{2 0}H_{1 6}N₂OS (M⁺+H): 333.1062,

found: 333.1066.

4.7.1. 4-Phenyl-6H-indolo[3,2,1-

4.6.4. (4-Methoxy-2-(methylthio)phenyl)(9H-

pyrido[3,4-b]indol-1-yl)methanone (18ah). Yield:

70% (0.08 g from 0.1 g); a yellow solid, mp 145-

147 ^oC; R_f= 0.64 (hexane: EtOAc, 8:2, v/v); IR

(KBr) ν_{ma x}: 668, 956, 1146, 1536, 1643, 1710,

de][1,5]naphthyridin-6-one (19aa). Yield: 83%

(0.089 g from 0.1 g); a pale yellow solid, mp 146-

148 ^oC; R_f= 0.62 (Hexanes: EtOAc, 8:2, v/v). IR

(KBr) ν_{ma x}: 669, 759, 1215, 1668, 2401, 3020 cm^{- 1}

.

¹H NMR (400 MHz, CDCl₃): δ (ppm) = 6.94 (s, 1H,

H-C=C), 7.41-7.49 (m, 4H, ArH), 7.59-7.63 (m,

1H, ArH), 7.79-7.82 (m, 2H, ArH), 7.87 (d, J = 4.9

Hz, 1H, ArH), 8.00 (d, J = 7.7 Hz, 1H, ArH), 8.59

(d, J = 8.2 Hz, 1H, ArH), 8.78 (d, J = 4.9 Hz, 1H,

ArH). ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

116.4, 117.4, 122.7, 124.7, 125.7, 126.5, 128.7,

129.9, 130.1, 130.8, 130.9, 132.6, 134.5, 135.9,

139.2, 145.6, 151.3, 159.7. MS (ESI+) m/z =

297.1. ESI-HRMS calculated for C_{2 0}H_{1 2}N₂O

[MH]⁺: 297.1028, found: 297.1032.

2563, 3056 cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ

.

(ppm) 2.38 (s, 3H SCH₃), 3.81 (s, 3H, OCH₃), 6.50

(d, J = 2.1 Hz, 1H, ArH), 6.52-6.55 (m, 1H, ArH),

7.24-7.28 (m, 1H, ArH), 7.51-7.53 (m, 2H, ArH),

7.60 (d, J = 8.5 Hz, 1H, ArH), 8.04 (d, J = 4.9 Hz,

1H, ArH), 8.09 (d, J = 7.8 Hz, 1H, ArH), 8.47 (d, J

= 4.9 Hz, 1H, ArH), 10.35 (s, 1H, NH); ^{1 3}C NMR

(100 MHz, CDCl₃): δ (ppm) = 15.9, 55.9, 99.3,

104.5, 112.1, 118.4, 120.7, 120.9, 121.1, 121.8,

129.3, 131.6, 133.0, 136.8, 137.1, 138.3, 139.8,

141.3, 163.6, 196.9. MS (ESI+): m/z = 349.1. ESI-

HR-MS calculated for C_{2 0}H_{1 6}N₂O₂S (M⁺+H):

349.1011, found: 349.1013.

4.7.2. 4-(4-Bromophenyl)-6H-indolo[3,2,1-

de][1,5]naphthyridin-6-one (19ab). Yield: 76%

(0.081 g from 0.1 g); a white solid, mp 196-198

^oC; R_f= 0.64 (Hexanes: EtOAc, 8:2, v/v). IR (KBr)

4.6.5. (5-Chloro-2-(methylthio)phenyl)(9H-

pyrido[3,4-b]indol-1-yl)methanone (18aj). Yield:

54% (0.062 g from 0.1 g); a grey solid, mp 180-

182 ^oC; R_f= 0.66 (hexane: EtOAc, 8:2, v/v); IR

(KBr) ν_{ma x}: 779, 936, 1238, 1543, 1659, 1702,

ν_{ma x}: 756, 1215, 1667, 2400, 3020 cm^{- 1 1}H NMR

.

(400 MHz, CDCl₃): δ (ppm) = 6.95 (s, 1H, H-

C=C), 7.47 (t, J = 7.7 Hz, 1H, ArH), 7.61-7.66 (m,

3H, ArH), 7.67-7.72 (m, 2H, ArH), 7.93 (d, J = 4.9

Hz, 1H, ArH), 8.1 (d, J = 7.8 Hz, 1H, ArH), 8.63

(d, J = 8.2 Hz, 1H, ArH), 8.79 (d, J = 4.9 Hz, 1H,

ArH). ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

116.5, 117.4, 122.7, 124.6, 124.7, 125.8, 126.4,

130.9, 131.1, 131.6, 131.9, 132.5, 133.2, 135.5,

139.2, 145.6, 149.9, 159.5. MS (ESI+) m/z =

375.0. ESI-HRMS calculated for C_{2 0}H_{1 1}BrN₂O

[M⁺+H]: 375.0133, found: 375.0130.

2614, 3214 cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ

.

(ppm) 2.47 (s, 3H SCH₃), 7.01 (d, J = 8.8 Hz, 1H,

ArH), 7.37-7.41 (m, 1H, ArH), 7.46-7.49 (m, 1H,

ArH), 7.55 (d, J = 2.3 Hz, 1H, ArH), 7.65 (bs, 2H,

ArH), 8.17-8.22 (m, 2H, ArH), 8.57 (d, J = 4.8 Hz,

1H, ArH), 10.41 (s, 1H, NH); ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 16.4, 112.2, 113.2, 119.0,

120.8, 121.0, 121.9, 125.6, 129.5, 129.8, 130.2,

121.6, 121.8, 136.1, 136.7, 138.8, 140.0, 141.3,

197.3. MS (ESI+): m/z = 353.1. ESI-HR-MS

calculated for C_{1 9}H_{1 3}ClN₂OS (M⁺+H): 353.0515,

found: 353.0518.

4.7.3. 4-(4-Chlorophenyl)-6H-indolo[3,2,1-

de][1,5]naphthyridin-6-one (19ac). Yield: 78%

(0.084 g from 0.1 g); a white solid, mp 182-184

^oC; R_f= 0.66 (Hexanes: EtOAc, 8:2, v/v). IR (KBr)

ν_{ma x}: 759, 1215, 1669, 2402, 3020 cm^{- 1 1}H NMR

.

4.6.6. (4-Fluoro-2-(methylthio)phenyl)(9H-

pyrido[3,4-b]indol-1-yl)methanone (18aw). Yield:

52% (0.050 g from 0.1 g); a yellow solid, mp 196-

198 ^oC; R_f= 0.68 (hexane: EtOAc, 8:2, v/v); IR

(KBr) ν_{ma x}: 856, 965, 1247, 1563, 1632, 1711,

(400 MHz, CDCl₃): δ (ppm) = 6.91 (s, 1H, H-C=C)

7.43 (t, J = 8.4, 3H, ArH), 7.59-7.63 (m, 1H, ArH),

7.76 (d, J = 8.5 Hz, 2H, ArH), 7.87 (d, J = 4.9 Hz,

1H, ArH), 8.00 (d, J = 7.7 Hz, 1H, ArH), 8.57 (d, J

= 8.2 Hz, 1H, ArH), 8.76 (d, J = 4.9 Hz, 1H, ArH).

^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) = 116.5,

117.4, 122.7, 124.7, 125.8, 126.4, 128.9, 130.9,

131.0, 131.4, 132.5, 132.8, 135.5, 136.3, 139.2,

145.6, 149.9, 159.5. MS (ESI+) m/z = 331.1. ESI-

2549, 2789 cm^{- 1 1}H NMR (400 MHz, CDCl₃): δ

.

(ppm)2.40 (s, 3H, SCH₃), 7.02 (d, J = 8.9 Hz, 1H,

ArH), 7.49 (d, J = 4.1 Hz, 1H, ArH), 7.73 (s, 2H,

ArH), 8.28 (d, J = 7.0 Hz, 2H, ArH), 9.11-9.15 (m,

1H, ArH), 10.75 (d, J = 10.0 Hz, 1H, ArH); ^{1 3}C

13

HRMS calculated for C_{2 0}H_{1 1}ClN₂O [M⁺+H]:

331.0638, found: 331.0637.

(ESI+) m/z = 327.1. ESI-HRMS calculated for

C_{2 1}H_{1 4}N₂O₂[M⁺+H]: 327.1134, found: 327.1132.

ACCEPTED MANUSCRIPT

4.7.4. 4-(p-Tolyl)-6H-indolo[3,2,1-

4.7.8. 4-(2-Chlorophenyl)-6H-indolo[3,2,1-

de][1,5]naphthyridin-6-one (19am). Yield: 75%

(0.081 g from 0.1 g); a brown solid, mp 172-174

de][1,5]naphthyridin-6-one (19ae). Yield: 85%

(0.093 g from 0.1 g); a pale yellow solid, mp 176-

178 ^oC; R_f= 0.64 (Hexanes: EtOAc, 8:2, v/v). IR

(KBr) ν_{ma x}: 669, 758, 1215, 1667, 2401, 3020 cm^{- 1}

¹H NMR (400 MHz, CDCl₃): δ (ppm) = .2.38 (s,

3H, CH₃), 6.94 (s, 1H, H-C=C), 7.29 (d, J = 8.0

Hz, 2H, ArH), 7.44 (t, J = 7.6 Hz, 1H, ArH), 7.63

(t, J = 7.6 Hz, 1H, ArH), 7.72 (d, J = 8.1 Hz, 2H,

ArH), 7.89 (d, J = 4.9 Hz, 1H, ArH), 8.03 (d, J =

7.8 Hz, 1H, ArH), 8.62 (d, J = 8.2 Hz, 1H, ArH),

^oC; R_f= 0.66 (Hexanes: EtOAc, 8:2, v/v). IR (KBr)

.

ν_{ma x}: 758, 1215, 1668, 2401, 3020 cm^{- 1 1}H NMR

.

(400 MHz, CDCl₃): δ (ppm) = 6.89 (s, 1H, H-

C=C), 7.35-7.51 (m, 5H, ArH), 7.61-7.65 (m, 1H,

ArH), 7.87 (d, J = 4.9 Hz, 1H, ArH), 8.03 (d, J =

7.8 Hz, 1H, ArH), 8.62 (d, J = 8.2 Hz, 1H, ArH),

8.74 (d, J = 4.9 Hz, 1H, ArH). ^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 116.6, 117.5, 122.8, 124.8,

125.8, 126.9, 128.7, 130.2, 130.6, 130.8, 131.0,

131.3, 132.2, 133.4, 133.9, 135.9, 139.4, 145.9,

150.1, 159.4. MS (ESI+) m/z = 331.1. ESI-HRMS

calculated for C_{2 0}H_{1 1}ClN₂O [M⁺+H]: 331.0638,

found: 331.0636.

8.79 (d, J = 4.9 Hz, 1H, ArH).^{1 3}C NMR (100 MHz,

CDCl₃): δ (ppm) = 21.5, 116.3, 117.4, 122.6,

124.7, 125.6, 125.9, 129.4, 130.0, 130.7, 130.9,

131.6, 132.5, 136.0, 139.2, 140.1, 145.6, 151.2,

159.8. MS (ESI+) m/z = 311.1. ESI-HRMS

calculated for C_{2 1}H_{1 4}N₂O [M⁺+H]: 311.1184,

found: 311.1186.

4.7.5. 4-(4-Methoxyphenyl)-6H-indolo[3,2,1-

de][1,5]naphthyridin-6-one (19ah). Yield: 84%

(0.091 g from 0.1 g); a pale yellow solid, mp 132-

134 ^oC; R_f= 0.58 (Hexanes: EtOAc, 8:2, v/v). IR

4.7.9. 4-(Thiophen-2-yl)-6H-indolo[3,2,1-

de][1,5]naphthyridin-6-one (19av). Yield: 72%

(0.079 g from 0.1 g); a yellow solid, mp 150-152

^oC; R_f= 0.60 (Hexanes: EtOAc, 8:2, v/v). IR (KBr)

ν_{ma x}: 667, 758, 1214, 1667, 2402, 3020 cm^{- 1 1}H

.

NMR (400 MHz, DMSO-d₆): δ (ppm) = 7.31 (t, J =

4.0 Hz, 1H, ArH), 7.38 (s, 1H, H-C=C), 7.59 (t, J

= 7.6 Hz, 1H, ArH), 7.78 (t, J = 7.6 Hz, 1H, ArH),

7.97 (d, J = 5.0 Hz, 1H, ArH), 8.35-8.41 (m, 3H,

ArH), 8.52 (d, J = 8.1 Hz, 1H, ArH), 8.92 (d, J =

4.9 Hz, 1H, ArH). ^{1 3}C NMR (100 MHz, DMSO-d₆):

δ (ppm) = 116.7, 118.1, 121.5, 124.1, 124.8, 126.0,

130.5, 131.1, 131.4, 133.6, 134.5, 138.9, 142.5,

145.3, 159.3. MS (ESI+) m/z = 303.0. ESI-HRMS

calculated for C_{1 8}H_{1 0}N₂OS [M⁺+H]: 303.0592,

found: 303.0595.

(KBr) ν_{ma x}: 670, 758, 1215, 1665, 2400, 3020 cm^{- 1}

¹H NMR (400 MHz, CDCl₃): δ (ppm) = 3.82 (s, 3H,

OCH₃), 6.90 (s, 1H, H-C=C), 6.98-7.01 (m, 2H,

ArH), 7.40-7.44 (m, 1H, ArH), 7.59-7.63 (m, 1H,

ArH), 7.80-7.87 (m, 3H, ArH), 8.00 (d, J = 7.8 Hz,

1H, ArH), 8.59 (d, J = 8.2 Hz, 1H, ArH), 8.78 (d, J

= 4.9 Hz, 1H, ArH). ^{1 3}C NMR (100 MHz, CDCl₃):

δ (ppm) = 55.5, 114.2, 116.2, 117.4, 122.6, 124.7,

125.2, 125.5, 126.8, 130.8, 130.9, 131.6, 132.6,

136.1, 139.2, 145.4, 150.6, 159.9, 161.2. MS

(ESI+) m/z = 327.1. ESI-HRMS calculated for

C_{2 1}H_{1 4}N₂O₂[M⁺+H]: 327.1134, found: 327.1134.

.

Acknowledgments

4.7.6. 4-(3-Chlorophenyl)-6H-indolo[3,2,1-

de][1,5]naphthyridin-6-one (19aj). Yield: 79%

(0.086 g from 0.1 g); a pale yellow solid, mp 168-

170 ^oC; R_f= 0.66 (Hexanes: EtOAc, 8:2, v/v). IR

The authors (SUD, SS and SK) acknowledge the financial

support from Council of Scientific and Industrial Research, New

Delhi, Ministry of Earth Science (MOES), New Delhi and

University Grant Commission, New Delhi in the form of

fellowships. The authors acknowledge the SAIF Division for the

spectroscopic data. This work was carried out with the partial

funding to SB from the projects BSC0114 and MoES/09-

DS/07/2014-PC-IV.

(KBr) ν_{ma x}: 757, 1216, 1668, 2400, 3020 cm^{- 1 1}H

.

NMR (400 MHz, CDCl₃): δ (ppm) = 7.03 (s, 1H, H-

C=C), 7.47-7.56 (m, 3H, ArH), 7.70-7.91 (m, 2H,

ArH), 7.91 (d, J = 1.4 Hz, 1H, ArH), 8.00 (d, J =

4.9 Hz, 1H, ArH), 8.13 (d, J = 7.7 Hz, 1H, ArH),

8.69 (d, J = 8.2 Hz, 1H, ArH), 8.88 (d, J = 4.9 Hz,

1H, ArH). ^{1 3}C NMR (100 MHz, CDCl₃): δ (ppm) =

116.5, 117.3, 122.6, 124.6, 125.7, 126.8, 128.1,

129.8, 129.8, 130.0, 130.8, 130.9, 132.4, 134.5,

135.3, 135.9, 139.1, 145.6, 149.6, 159.3. MS

(ESI+) m/z = 331.1. ESI-HRMS calculated for

C_{2 0}H_{1 1}ClN₂O [M⁺+H]: 331.0638, found: 331.0635.

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Iodine-mediated oxidative Pictet-Spengler reaction using terminal alkyne as the 2-oxoaldehyde surrogate for the synthesis of 1-aroyl-β-carbolines and fused-nitrogen heterocycles

DOI: 10.1016/j.tet.2017.03.031

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Full text of DOI:10.1016/j.tet.2017.03.031

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