ISOLATION, BIOLOGICAL ACTIVITIES AND SYNTHESIS OF

Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057

1

ISOLATION, BIOLOGICAL ACTIVITIES AND SYNTHESIS OF INDOLOQUINOLINE

ALKALOIDS: CRYPTOLEPINE, ISOCRYPTOLEPINE AND NEOCRYPTOLEPINE

Prakash T. Parvatkar,a,b Perunninakulath S. Parameswaran,*,c and Santosh G. Tilve*,b

aNational Institute of Oceanography, Dona Paula, Goa 403 004, India

bDepartment of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India

cNational Institute of Oceanography, Regional Centre, Kochi 682 018, India

Tel.: 91-(0)-484-2390814 / 832-6519317

Fax: 91-(0)-484-2390618 / 832-2452886

E-mail: [email protected]; [email protected]

Running Title:

Recent Development in Indoloquinoline Alkaloids

Abstract: The tetracyclic heteroaromatic compounds cryptolepine, isocryptolepine and neocryptolepine are all

naturally occurring indoloquinoline alkaloids isolated from the shrub Cryptolepis sanguinolenta and are

important due to their wide spectrum of biological properties. This review describes the isolation, brief

biological activities and various synthetic methodologies developed during recent years for the preparation of

this important class of alkaloids, with special emphasis on preparation and properties of cryptolepine 1,

isocryptolepine 2 and neocryptolepine 3.

Keywords: Alkaloid, cryptolepine, heteroaromatic, indoloquinoline, isocryptolepine, and neocryptolepine.

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1. INTRODUCTION

1.1. General

In recent years, indoloquinoline alkaloids have received considerable attention due to their promising DNA

intercalating [1] and antimalarial properties [2 - 4]. According to World Health Organization (WHO), about 3.3

billion people are at risk of malaria. Every year, this leads to about 250 million malaria cases, causing nearly a

million deaths, mostly of children under 5 years, justifying its classification as a dreaded infectious disease

along with tuberculosis and AIDS [5].

The roots of the West African plant Cryptolepis sanguinolenta [6 - 19] has long been used in folk medicine

for the treatment of infectious diseases, amoebiasis, fever and malaria. Since 1974, a decoction of this plant is

being used in the clinical therapy of rheumatism, urinary tract infections, malaria and other diseases [20 - 23].

Chemical examination indicated this plant to be a rich source of several indoloquinoline alkaloids [6 - 19].

1.2. Isolation

So far 13 alkaloids including cryptolepine 1, isocryptolepine 2 and neocryptolepine 3 have been reported

from the roots of the West African plant C. sanguinolenta (Figure 1).

N

NCH3

N NCH3

N

NCH3

21 3

Fig. (1).

Among these, cryptolepine 1 is a rare example of natural product whose synthesis was reported prior to its

isolation from nature. It was synthesized in 1906 by Fichter and Boehringer [24] for possible use as a dye while

its isolation from C. triangularis was reported only in 1929 [25]. Subsequently, in 1951, Gellert et al. [6]

reported this compound from the roots of C. sanguinolenta.

In 1995, two research groups, i.e., Pousset et al. [10] and Sharaf et al. [26] independently reported a related

alkaloid 2 and named it as isocryptolepine and cryptosanguinolentine, respectively. Isocryptolepine 2 is an

angularly-fused alkaloid with indolo[3,2-c]quinoline ring system whereas cryptolepine 1 is a linearly-fused

alkaloid with indolo[3,2-b]quinoline ring system.

Subsequently in 1996, a new linearly-fused indolo[2,3-b]quinoline alkaloid 3 was reported by two

independent research groups and named it as neocryptolepine by Pieter's group [9] and cryptotackieine by

Schiff's group [26].


3

Other alkaloids reported from the plant C. sanguinolenta include quindoline 4 [7], cryptospirolepine 5 [13],

cryptolepicarboline 6 [27], cryptomisrine 7 [28], 11-isopropylcryptolepine 8 [17], cryptolepinone 9 [13 - 15],

and bis-cryptolepine 10 [9] (Figure 2).

NH

N

NNO

NH

N

CH3

CH3

NN

N

CH3

NH

N

NH

N

O

N

N

CH3

CH3CH3

NH

N

O

CH3

N

N

CH3

N

N

CH3

4 5 6

7 8 9 10 Fig. (2).

1.3. Brief Biological activities

The tetracyclic heteroaromatic compounds 1 and 3 are linearly fused indoloquinolines, while compound 2

has angularly-fused ring system. All the three compounds exhibit promising antiplasmodial activity [2 - 4, 29]

against chloroquine-resistant P. falciparum and cryptolepine has been used as a lead compound for synthetic

antiplasmodial agents [30 – 31]. Initially, neocryptolepine was reported to show an activity comparable to

cryptolepine [2 - 3], more recent studies have shown that, it was 7 times less active against the chloroquine-

resistant P. falciparum Ghana-strain [32]. These alkaloids also intercalate with DNA double helix, causing

dramatic changes in DNA conformation leading to inhibition of DNA replication and transcription [1]. The

strength and mode of binding of these alkaloids to DNA have been investigated by spectroscopy and X-ray

analysis [33 - 34]. Cryptolepine binds 10-fold more tightly to DNA than other alkaloids and proves to be much

more cytotoxic toward B16 melanoma cells [33]. In addition, these compounds as well as some of their methyl

derivatives have also shown promising antimuscarinic, antibacterial, antiviral, antimicotic, antihyperglycemic

and cytotoxic properties in vitro and antitumor activity in vivo [19, 23, 35 - 38].

These alkaloids, due to their wide spectrum of biological activities, have been targets of synthetic chemists in

recent years.

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2. SYNTHESIS

The synthetic methods used for the preparation of indoloquinoline alkaloids may be classified under the

following six major categories based on the method of formation of the ring system – palladium-catalyzed

coupling reaction, aza-Wittig reaction, transition-metal mediated reductive cyclization, photochemical reactions,

Graebe-Ullmann reaction and other miscellaneous methods.

2.1. Palladium-catalyzed coupling reaction

Pd-catalyzed coupling reactions [39 - 43] have become a powerful tool for the synthetic chemists particularly

for the synthesis of biologically active natural products and for the preparation of versatile organic building

blocks. Palladium catalysts possess a higher activity than other metal alternatives (Cu, Ni or Fe) enabling the

conversion of less reactive substrates and performance at relatively low temperature.

Timari et al. [44] reported the synthesis of isocryptolepine and neocryptolepine using Suzuki procedure

(Scheme 1 & 2).

N

Br B(OH)2

N

N

NH2

N

N3

N

NH

N

N

CH3

Pd(PPh3)4

+DME, H2O

NaHCO3, reflux, 4 h

20% H2SO4

reflux, 1d

Conc. HCl, NaNO2 00C, 1h

NaN3, 00C, 1h

1,2-dichlorobenzene

1800C, 5 h

Me2SO4, CH3CN reflux, 5 h

90% 93%

80% 75%

93%

11 12 13

14 15 16

2

i)

ii)

tBuCOHN

NHCOtBu

Scheme 1.

The reaction of 3-bromoquinoline 11 with N-pivaloylaminophenyl boronic acid 12 in presence of Pd(0)

catalyst afforded the desired biaryl compound 13 which, on hydrolysis with sulfuric acid gave amine 14. The

compound 14 was converted to azide 15 which, on nitrene insertion, gave exclusively the indolo[3,2-c]quinoline


5

16. Regioselective methylation on quinoline nitrogen using dimethyl sulfate yielded the target molecule

isocryptolepine 2 (Scheme 1).

N

Br

N

Br

O

NH

Br

O

NCH3

ONHCOtBu

NCH3

ONH2 N N

CH3

N

Br

OCH3

B(OH)2

CHCl3, r.t.

TsCl

CHCl3, K2CO3

MeI

NaHCO3,

H2SO4, EtOH

POCl3, benzene

reflux,

Pd(PPh3)4, DME, H2O

1d, 98% r.t., 6h, 55%DMF, 600C

3h, 85%

reflux, 2d

3h

3h, 81%

~100%

65%

1117 18

19

12

20

21 3

m-CPBA

NHCOtBu

Scheme

2.

3-Bromo-1H-2-quinoline 18 was prepared from 3-bromo-quinoline 11 via its N-oxide 17 which, on treatment

with methyl iodide, gave N-methyl compound 19. Coupling reaction of 19 with 12 in the presence of Pd(0)

catalyst afforded the biaryl compound 20. Hydrolysis of 20 with sulfuric acid followed by cyclization using

POCl3 furnished neocryptolepine 3 (Scheme 2).

Fan and Ablordeppy [45] described the synthesis of 10H-indolo[3,2-b]quinoline 4 via N-arylation of 3-

bromoquinoline 22 with triphenylbismuth diacetate using metallic copper, followed by oxidative cyclization of

the resultant anilinoquinoline 23 using palladium acetate (Scheme 3).

N

NH2Ph3Bi(OAc)2

Cu, CH2Cl2 N

NH

N

NH

Pd(OAc)2

CF3COOH

r.t., 10h, 94%900C, 40min.

23%2322 4

Scheme 3.

Arzel et al. [46] described the first halogen-dance reaction [47] in quinoline series and its application to a

synthesis of quindoline (Scheme 4).

6

N

F

I

B(OH)2

NHCOtBu

Pd(PPh3)4, EtOH, toluene

reflux N

FNHCOtBu

Pyridinium hydrochloride

NH4OH N

NH

+94%

2150C

83%

24 12 25

4

Scheme 4.

Pd-catalyzed cross-coupling reaction between boronic acid 12 and 3-fluoro-2-iodoquinoline 24 using Suzuki

procedure [48 - 51] afforded the biaryl compound 25 which, underwent cyclization on treatment with boiling

pyridinium hydrochloride [52] to give quindoline 4 in 83% yield. The intramolecular nucleophilic displacement

of fluorine with amino group is facilitated by the formation of quinoline hydrochloride.

Murray et al. [53] achieved the synthesis of isocryptolepine as depicted in scheme 5.

NSnBu3

R

NR

O2N

NR

NCH3

OHC

N

NCH3

I

O2N

THF, reflux

R = CH2O(CH2)2SiMe3

CH3COOCHO (AFA)

Pd(PPh3)4

+

i) H2, Pd/C, EtOH r.t. and pressure, 98%

iii) NaH, THF, r.t. then MeI, 96%

EtOH

H2SO4 (10%)reflux, 50%

98%26 27 28

292

ii) THF, -200C, 95%

Scheme 5.

Pd(0)-catalyzed Stille coupling reaction of 2-tributylstannyl-N-protected indole 26 with 2-iodonitrobenzene

27 gave 2-(o-nitrophenyl)indole 28 which on reduction, N-formylation and N-methylation afforded the desired

formamide 29. Final ring closure was achieved by refluxing compound 29 in ethanol in presence of sulfuric acid

to give isocryptolepine 2.

Csanyi et al. [54] accomplished the synthesis of quindoline 4 by a regioselective coupling reaction of 2,3-

dibromoquinoline [55] 30 with 12 taking into consideration the fact that the α-heteroaryl halogen atom is more

reactive than the β-halogen atom [56] to give N-pivaloyl-2-(2'-anilino)-3-bromoquinoline 31. Hydrolysis of 31


7

afforded the free amine 32 which underwent cyclization when heated at 200-2200C in presence of pyridinium

hydrochloride to give quindoline 4 (Scheme 6).

N

Br

Br

B(OH)2

NHpiv N

BrNHpiv

Pyridinium hydrochloride

N

NH

N

BrNH2

Pd(PPh3)4

aq. NH3

+

54%

200-2200C, 4h

66%

stir, r.t., 6h

25% aq. H2SO4

1200C, 5.5h85%30 12 31

32 4

Scheme 6.

Jonckers et al. [57] described the Pd-catalyzed 'amination-arylation' approach for the synthesis of

isocryptolepine (Scheme 7).

N

ClCl

NH2

N

NHCl

N

NH

N

N

CH3

+

Pd2(dba)3 (1 mol%),XANTPHOS (2.2 mol%)

Cs2CO3, dioxanereflux, overnight, 81%

Pd2(dba)3 (2.5 mol%),P(tBu)3 (10 mol%)

K3PO4, dioxanepressure tube1200C, 3h, 95%

CH3I, DMF, 800C, 1 h

r.t., overnight 75%

33 3435

162

Scheme 7.

This approach consists of two consecutive Pd-catalyzed reactions – a selective Buchwald-Hartwig [58 – 63]

reaction of 2-chloroaniline 34 with 4-chloroquinoline 33 followed by an intramolecular arylation [64 – 66] of

the resulting compound 35 to afford the 11H-indolo[3,2-c]quinoline 16.

Hostyn et al. [67] reported the synthesis of isoneocryptolepine, a missing indoloquinoline isomer in the

alkaloid series cryptolepine, neocryptolepine and isocryptolepine via two routes – 1. Suzuki arylation with an

intramolecular nitrene insertion (Scheme 8) and 2. With a combination of a selective Buchwald-Hartwig-

amination with an intramolecular Heck-type reaction (Scheme 9).

8

N

ClB(OH)2

NHpivN

NHpiv

N

NH

Pd(PPh3)4

Na2CO3, DME

aq. H2SO4

EtOH

N

NH2

aq. HCl, aq. NaNO2

N

N3

N

NH

+reflux, 20h, 96%

+

reflux, 24h, 89%

00C, 1.5h

i)

ii) aq. NaN3, NaOAc.3H2O

00C, 1h

1800C, 3h

88% (trace amount)

33 1236 37

3839 40

o-dichlorobenzene

Scheme 8.

Suzuki reaction of 33 with 12 under Gronowitz conditions [68 – 69] yielded compound 36 which on

hydrolysis provided amine 37. Diazotization of the resulting amine 37 followed by introduction of azido group

and then thermal decomposition of azide 38 in boiling o-dichlorobenzene yielded the target molecule 39 as the

major product and 40 in trace amount (Scheme 8).

N

Br Br

NH2

Pd2(dba)3

XANTPHOS

Cs2CO3, dioxane N

NHBr PdCl2(PPh3)2

N

NH

N

NH MeI, toluene

N

N

CH3

+

reflux, 30h, 83%

NaOAc.3H2O

DMA, 1300C, 5h

+

(45%)(4%)

reflux, 2h

88%

11 41 42

4 39 43

Scheme 9.

Regioselective amination of 11 with 41 in presence of Pd(0) catalyst gave compound 42 which on Heck-type

cyclization yielded predominantly 7H-indolo[2,3-c]quinoline 39 and small amount of quindoline 4. Selective N-

methylation [70] of 39 using methyl iodide in refluxing toluene afforded the isoneocryptolepine 43 (Scheme 9).

Venkatesh et al. [71] reported the synthesis of benzimidazo[1,2-a]quinoline 47 via Pd-catalyzed

intramolecular heterocyclization of 2-(2-bromoanilino)quinoline 46 in which 6H-indolo[2,3-b]quinoline 48

(precursor to neocryptolepine) was formed as a minor product (Scheme 10).


9

N SMe N SO2Me

Br

NH2

NH

NBr

N

N

NH

N

CH2Cl2, r.t. sealed tube

Pd(OAc)2, PPh3

NaHCO3, DMF

+

6h, 80% 160-1700C 6h, 75%

1300C, 12h (55%) (25%)

44 45

41

46

4748

m-CPBA

Scheme 10.

Miki and co-workers [72] have developed a simple approach towards isocryptolepine by applying Myers

method [73 - 75] (Scheme 11).

N

O

O

OSO2Ph

NHCH3

N

NO

CH3

COOH

SO2PhN O

NCOOH

SO2Ph

CH3

Pd(OCOCF3)2Ag2CO3

N

N

SO2Ph

O CH3

N

N

SO2Ph

O CH3

LiAlH4

dioxane,N

NCH3

CH3CN, r.t.+

5% DMSO in DMF500C, 48 h

+

1 h

+0.5h

(73%) (22%)

(71%)(12%)

98%

49 50 51 52

53 542

Scheme 11.

Reaction of 49 with N-methyl aniline 50 in acetonitrile afforded a mixture of acids 51 and 52 respectively.

The decarboxylative Heck-type cyclization of 51 was achieved using Pd(OCOCF3)2 and Ag2CO3 to give the

required compound 53 in 71% yield and decarboxylated product 54 in 12% yield. The compound 53 was

converted to 2 by treatment with LiAlH4 in hot dioxane.

Mori and Ichikawa [76] reported the synthesis of 11-alkylated cryptolepines via radical cyclization and Stille

coupling reaction (Scheme 12).

10

CF2

R

NC

cat. AIBN

toluene

Pd(PPh3)4, CuI

N

RFBocHN

NH

N

R

N

N

R

CH3

800C, 1hDMF, 800C, 4h

i)

ii) DBU, 800C, 1h

Pyridinium hydrochloride 1800C, 12-15h

aq. NH3

MeI, THF reflux, 20h

R = n-Bu, i-Pr

55

56

57

581b-c

n-Bu3SnH o-BocNHC6H4I

57-61%

61-74%66-75%

Scheme 12.

o-Isocyano-substituted β,β-difluorostyrenes 55 on treatment with tributyltin hydride in presence of catalytic

amount of AIBN and subsequent Pd-catalyzed coupling reaction with 56 afforded the 2,4-disustituted-3-

fluoroquinolines 57 which, on cyclization followed by methylation furnished the 11-n-butyl and 11-isopropyl

cryptolepines 1b-c.

1.2. Aza-Wittig reaction

Aza-Wittig reaction [77 - 78] has become one of the important reactions in organic synthetic strategies

directed towards the construction of acyclic and cyclic compounds as the reaction is mostly carried out in

neutral conditions, in the absence of catalyst, generally at mild temperature and usually proceeds in high yield.

Alajarin and co-workers [79] described the synthesis of neocryptolepine using aza-Wittig reaction of the

iminophosphorane 59 with phenyl isocyanate 60 to yield carbodiimide 61 and triphenylphosphine oxide which,

without purification, was subjected to thermal treatment to give 48 and 2-anilinoquinoline 62 in 19% and 40%

yield, respectively (Scheme 13).

N PPh3NH

N N NH

Ph

Ph-NCO

toluene

toluene

sealed tubeNN

+

r.t., 15min.

1600C

10h(19%) (40%)59 61 48 62

60

C

Scheme 13.

Shi et al. [80] prepared various derivatives of 6H-indolo[2,3-b]quinoline 48 using the above methodology

[79] (Scheme 14).


11

N PPh3

R

NH

N

R

OCN+

59a-e 60 48a-e(76-91%)

R = H, 16%

R = Me3Si, 86%6N NaOH

(92%)R = H, Me3Si, Me, n-Pr, t-Bu, Ph

Scheme 14.

The introduction of trimethylsilyl group at the acetylenic terminus provided an efficient route to 48 by

suppressing the competing pathway toward the 2-anilinoquinoline 62 as the trimethylsilyl group serve as a

surrogate for the hydrogen atom in directing the reaction toward the indoloquinoline. A subsequent

protodesilylation using NaOH furnished 48 in good yield. Similarly, the derivatives of 48 with substitutents at

C-11 position are prepared by treating the corresponding iminophosphoranes with phenyl isocyanate.

Using the methodology of Alajarin et al. [79], Jonckers and co-workers [32] also prepared various

cryptolepines with substituents on A-ring or D-ring and were evaluated for their cytotoxicity, antiplasmodial and

antitrypanosomal activities.

Molina and co-workers [81] reported the synthesis of neocryptolepine via Staudinger, aza-Wittig and

electrocyclization reactions (Scheme 15).

12

NO2

PPh3

Br

Br

CHO

BrNO2

BrNO2 NH2

BrN

BrPPh3

NNBr

BrN NH

N N N NH N N

CH3

K2CO3

CH2Cl2, r.t.

PhSH, AIBN

benzenereflux

Fe

reflux

benzene

TsNCO

toluene

toluene

reflux

NaH, CuI

diglyme, r.t.

TBAF

THF, r.t.

Me2SO4, DMF

MW

AcOH, EtOH

+

+

Ts

Ts

Dibenzo-18-crown-6

00C to r.t.

00C to r.t.

1400C, 5 min

16h, 95% 2h, 89%

2h, 85% 1h, 87%

72% 85%

90%75%

Ts

63 6465

66 67

PPh3.Br2 68

69

70

7172

7348

3

C

Scheme

15.

The iminophosphorane 69 was prepared by condensing 2-(nitrobenzyl)triphenylphosphonium bromide 63

with 2-bromobenzaldehyde 64 in the presence of K2CO3 followed by reduction of nitro group with iron and then

treatment of the resultant amino-stilbene derivative 67 with triphenylphosphine dibromide 68. An aza-Wittig

reaction of 69 with tosyl isocyanate 70 afforded the carbodiimide 71 which on heating underwent electrocyclic

ring closure to give compound 72. Treatment of 72 with NaH in presence of CuI and subsequent detosylation

using TBAF yielded 48. Microwave-promoted methylation with DMS in DMF provided the target molecule 3.

Fresneda and co-workers [82] devised a divergent synthetic approach to the alkaloids isocryptolepine and

neocryptolepine which was based on the formation of key common intermediate 1-methyl-(o-

azidophenyl)quinoline-2-one 83 (Scheme 16).


13

NO2

PPh3

Br

N3

CHOO2N

N3

N

O2N

PBu3

O2N

NH2

O2N

NCO

NH

O

O2N

N O

O2N

CH3

N O

NH2

CH3

N OCH3

N3

NCH3

O

NH

NCH3

N

DMF

Me3P, nitrobenzene

NCH3

N

K2CO3, CH3I

Red-Al, toluene

CH2Cl2, r.t.

+-

+K2CO3, 18-crown-6

CH2Cl2, r.t., 16h, 85%

ii) PhSH, AIBNbenzene, reflux

i) THF, H2O, r.t., 1h 84%

Triphosgene

CH2Cl2, 1h 00C to r.t.

MWnitrobenzene

600C, 2h 82%

H2, Pd-C

EtOH, r.t.

i) NaNO2, H2SO4,

ii) aq. NaN3

o-xylene

1500C

2h, 92%

1500C, 12min.80% 5h, 91%

00C, 30min.

r.t., 5h, 85%

MW, 1800C, 30min., 40%

63 74 75

7677

78

79

80 81

82 83

3

84

2

n-Bu3P

reflux, 32h

5h

Scheme 16.

The key intermediate 83 was prepared using 63 and 2-azidobenzaldehyde 74 as the starting materials which

underwent Wittig reaction in presence of K2CO3 to give compound 75. Reaction of 75 with n-Bu3P followed by

hydrolysis of the resultant iminophosphorane 76 and Z→E isomerization of the C=C bond afforded amino-

stilbene derivative 77 which, on treatment with triphosgene 78 yielded the corresponding o-vinylsubstituted

isocyanate 79. Electrocyclic ring closure of 79 was achieved via microwave irradiation to give quinoline-2-one

derivative 80 which, was converted to 83 by a four step sequence – methylation, catalytic hydrogenation and

diazotization followed by reaction with sodium azide. Selective indolization was achieved either by

intramolecular aza-Wittig reaction of the iminophosphorane derived from 83 and PPh3 under microwave

irradiation to give neocryptolepine 3 or by nitrene-insertion process followed by reduction with Red-Al to give

isocryptolepine 2.

14

1.3. Trasition-metal mediated reductive cyclization

Reductive cyclization [83] using transition metals is an effective protocol for the synthesis of compounds

containing quinoline ring and thus is being used by several research groups for the synthesis of

indoloquinolines.

Ho and co-workers [84] reported the synthesis of cryptolepine and neocryptolepine from common

intermediate 1,3-bis-(2-nitrophenyl)propan-2-one 86 (Scheme 17).

NO2

COOH DCC, DMAP, THF

O2NNO2O

Feglac. AcOH, EtOH

NH

NH2

PhI(OAc)2

THF, r.t.

NH

N

Br2, CHCl3

O2NNO2O

BrMeONa, CHCl3

NO2NO2

MeO2C

MeI, THF

Fe, glac. AcOH, EtOH

NH

N

MeI, THF

N NCH3

N

NCH3

reflux, 3h, 86% reflux, 3.5h, 95%

3h, 41%reflux, 1.5h, 98%

00C, 20minr.t., overnight 57% reflux, 18h

72%reflux, 3h, 72%

reflux, overnight 96%

85 8687

89 88

4

1348

Scheme 17.

The key intermediate 86 was readily obtained from 2-nitrophenyl acetic acid 85 by reaction with DCC in

presence of DMAP. The approach to 1 involved the reduction of nitro groups with Fe powder followed by

oxidative cyclization and subsequent N-methylation. On the other hand, 3 was obtained via bromination,

Favorskii rearrangement of the resultant bromo compound 88 followed by reduction-cyclization using Fe

powder and finally N-methylation using methyl iodide.

Amiri-Attou et al. [85] described the synthesis of analogues of neocryptolepine via one-pot reduction-

cyclization-dehydration reaction (Scheme 18).


15

Cl

NO2

N

O

CH3

OH

NO2

N NCH3

TDAEDMF

Fe, AcOH

N

O

O

CH3

R1

R2

+

R1

R2

-200C, 1h

R1

r.t., 2h36-87%

1100C, 48h33-65%

91

92a-e

93a-e

a R1 = R2 = Hb R1 = H, R2 = CH3c R1 = Cl, R2 = Hd R1 = R2 = OCH3e R1, R2 = OCH2O

R2

90a-e

Scheme 18.

Reaction of o-nitrobenzyl chlorides 90a-e with 1-methylisatin 91 in the presence of tetrakis(dimethyl-

amino)ethylene (TDAE) [86 – 87] afforded the corresponding α-hydroxy lactams 92a-e which, on treatment

with iron underwent reduction-cyclization and dehydration in one-pot to give the respective 6-methyl-6H-

indolo[2,3-b]quinolines 93a-e.

We reported [88] the synthesis of neocryptolepine using the Perkin reaction and double reduction – double

cyclization as the main steps (Scheme 19).

CHO

NO2NO2

COOHCOOEt

NO2

NO2

Ac2O, Et3N

EtOH, H2SO4

Fe, HClEtOH:AcOH:H2O

NH

N N NCH3

Me2SO4, CH3CN

+

i)

ii)

71%

reflux, 5h

reflux, 24h

1200C, 24h74%

reflux, 6h

80%

94 95

48 3

85

Scheme 19.

Condensation of 2-nitrobenzaldehyde 94 with 2-nitrophenyl acetic acid 85 in refluxing acetic anhydride in

presence of Et3N gave the α,β-unsaturated acid which on esterification afforded the required ester 95 in good

yield. Reduction with Fe powder furnishes the 6H-indolo[2,3-b]quinoline 48 via double reduction-double

cyclization reactions in one-pot.

16

Sharma and Kundu [89] achieved the synthesis of neocryptolepine using indole 96 and 2- nitrobenzyl

bromide 97 as the starting materials (Scheme 20)

NH

Br

O2N

Na2CO3

CH3COCH3 : H2O

NH

NO2

N NH

NH

NH2

NN

N NCH3

SnCl2+

700C, 36h, 83% MeOH, reflux, 1h

+ +

(35%) (27%) (10%)

MeI, toluene, 1300C

sealed tube, 4h, 82%

96 97 98

48 99 100

3

2H2O.

Scheme 20.

Alkylation of indole with 2-nitrobenzyl bromide 97 yielded compound 98 which, on treatment with

SnCl2.2H2O afforded 48 in 35% yield along with other two compounds 99 and 100 in 27% and 10%

respectively.

1.4. Photochemical reactions

Photochemical reactions [90] are valuable in organic chemistry as they proceed differently than thermal

reactions and have the advantage of forming thermodynamically disfavored products by overcoming large

activation barriers and allow reactivity otherwise inaccessible by thermal methods. Photochemical substrate

activation often occurs without additional reagents which prevents the formation of any by-products and thus

become important in the context of green chemistry.

Kumar et al. [91] described the synthesis of isocryptolepine using photo-cyclization as the main step

(Scheme 21)


17

NH

CHONH2

NH

N

NH

N

N

NCH3

+glac. AcOH

reflux, 3 h

hv, 253.7 nm, r.t.

C6H6, MeOH I2, 48h, 67%

Me2SO4, CH3CN

reflux, 6 h, 83%

85%101 102103

16 2

Scheme 21.

Schiff's base 103, obtained by heating indole-3-carboxaldehyde 101 with aniline 102 in acetic acid, when

irradiated at 253.7nm underwent cyclization to give 11H-indolo[3,2-c]quinoline 16 via initial photo-

isomerization of the Schiff's base 103 from E- to Z-isomer followed by conrotatory ring closure and subsequent

oxidation by iodine.

Dhanabal et al. [92] reported the synthesis of cryptolepine 1, isocryptolepine 2 and neocryptolepine 3 via

heteroatom directed photoannulation technique (Scheme 22 - 24).

N

BrNH2

X

N

NHX

N

NH

N

NH

Me2SO4, CH3CN

Me2SO4, CH3CN

N

N

CH3

N

N

CH3

+2000C, 5 h

hvC6H6:MeOH:H2SO4

I2, r.t.

reflux, 6 h 82%

72%

+

(51%)

(16%)

reflux, 6 h 84%

11 102 23

39

4

43

1

X = Cl or H

Scheme 22.

18

N

Cl

X

NH2

N

NHX

N

NH

N

N

CH3

+2000C, 5 h hv

C6H6:MeOH:H2SO4

I2, r.t., 78%

Me2SO4CH3CN

reflux, 6 h 83%

72%

104a 102105a

162

X = Cl, H, OH or OMe

Scheme 23.

N Cl

NH2X

N NH

X

N NH

N N

CH3

C6H6:MeOH:H2SO4

Me2SO4, CH3CN

reflux,

+2000C

5 h

hv

6 h

72% I2, r.t., 70%

104b 102105b

48 3

X = Cl, H, OH or OMe

80%

Scheme 24.

Nucleophilic substitution of 3-bromoquinoline 11 with aniline 102 was achieved by heating at 2000C and the

resultant anilinoquinoline 23 was subjected to photochemical cyclization. Interestingly, both linearly-fused and

angularly-fused products 4 and 39 were obtained, which on methylation gave cryptolepine 1 and

isoneocryptolepine 43 respectively (Scheme 22).

Synthesis of isocryptolepine 2 and neocryptolepine 3 were obtained by photocyclization of the respective

anilinoquinolines 105a and 105b and subsequent methylation at the quinoline nitrogen. Anilinoquinolines 105a-

b were obtained from the corresponding chloroquinolines 104a-b (Scheme 23 and 24).


19

Pitchai et al. [93] reported a simple photo-induced method for the synthesis of the methyl derivative of

isocryptolepine (Scheme 25).

N

CO2C2H5

N CH3

OH

N CH3

OHII2, KI, NaOH

POCl3

N CH3

ClI

NH2

N CH3

NHI

C6H6:CH3OH:H2SO4

N

NH

CH3

Me2SO4, DMF

N

N

CH3

CH3

MW, 3min.

80% stir, r.t., 4h

85%

reflux, 1h 95%

EtOH, stir, r.t., 45min. 98%

I2, 48h, 78%

MW, 3min., 82%

106 107 108

109110

111 112

102

hv

Scheme 25.

4-Hydroxy-2-methyl quinoline 107 was prepared by microwave irradiation of β-anilinocrotonate 106 and

then converted to 3-iodo-4-hydroxy-2-methylquinoline 108 using a known procedure [94], which on treatment

with POCl3 afforded the corresponding chlorinated compound 109. The amination reaction of 109 with aniline

afforded the compound 110 which on photo irradiation and subsequent N-methylation yielded the methyl

derivative of isocryptolepine.

1.5. Graebe-Ullmann reaction

Graebe-Ullmann reaction [95 - 96] has been widely used for the synthesis of carbazoles as the phenyl

benzotriazoles formed in the reaction are unstable and readily undergo cyclization upon pyrolysis (catalyzed by

acid) or on photolysis. Few research groups have exploited this reaction for the synthesis of indoloquinolines

using haloquinolines instead of halopyridines as one of the starting materials.

Peczynska-Czoch and co-workers [36] reported the synthesis of various derivatives of neocryptolepines via

Graebe-Ullmann reaction (Scheme 26) and these were evaluated for their in vitro antimicrobial and cytotoxic

activities.

20

N NH N N

CH3

N Cl

NN

NH N N N

N

PPA

Me2SO4

toluene

+110-1200C

130-1800C

150-1600C12h

113114a-d

48a-d3a-d

a R1 = R2 = Hb R1 = CH3, R2 = Hc R1 = CH3, R2 = 6-CH3d R1 = CH3, R2 = 8-CH3

R1R1

R1R1

R2 R2

R2R2

104a-d65-73%

30-43%

40-67%

Scheme 26.

Triazoles 114a-d were prepared by heating the corresponding chloroquinolines 104a-d with benzotriazoles

113 at 110-1200C. Decomposition of the triazoles 114a-d by heating at 130-1800C in presence of PPA yielded

the respective indoloquinolines 48a-d, which on methylation using DMS afforded the neocryptolepines 3a-d.

Godlewska et al. [97] reported the synthesis of nitro-substituted 6H-indolo[2,3-b]quinolines 115 using the

above methodology [36] and then indole nitrogen was methylated using NaH and DMS to give the

corresponding analogue of neocryptolepines 116. The nitro group was reduced to the corresponding amine using

SnCl2, which on treatment with p-toluenesulfonyl chloride afforded sulfonamide 118. Alkylation with

(dialkylamino)alkyl chlorides and subsequent reaction with naphthylsodium yielded the 9-amino substituted

neocryptolepine 121 (Scheme 27). Similarly, the 2-amino substituted neocryptolepine was prepared using 6-

nitro-benzotriazole and 2-chloro-4-methyl-quinoline as the starting materials.


21

N NH

CH3O2N

N Cl

CH3

O2N NN

NH

NaH, toluene

Me2SO4, r.t.

N N

CH3

CH3

O2N SnCl2, HCl

N N

CH3

CH3

NH2

pyridine, r.t. N N

CH3

CH3

NH

NaOH, tolueneTBAB, reflux N N

CH3

CH3

NNaC10H17, THF

N N

CH3

CH3

NH

TsCl

+

1h, 97%

reflux, 1h30min, 77%

Cl(CH2)nNR2

3h, 57-74%

-150C, 5min

104e 113

120a-c 121a-ca n=2, R=CH3b n=3, R=CH3c n=2, R=C2H5

Ts

Ts119a-c

117118

115

116 52%

17-95%

(CH2)nNR2(CH2)nNR2

Scheme 27.

Sayed et al. [98] described the synthesis of neocryptolepines with A or D-ring substitutions using the

methodology of Peczynska-Czoch and co-workers [36] and the side chain was introduced on the 2-, 3-, 8- and 9-

positions using Pd-catalyzed amination reaction (Scheme 28). All these compounds were screened for in vitro

antiplasmodial activity against a chloroquine-sensitive P. falciparum strain and for cytotoxicity on a human cell

(MRC5) line.

22

N Cl

NN

NH

N NH

N NCH3

Pd(OAc)2

N NCH3

NHCH3

N

CH3

CH3

Pd(OAc)2

N NCH3

NH

CH3

N CH3

CH3

+

MeI, THF

reflux, 18 - 24h

toluene, reflux, 2hN',N'-diethylpentane-1,4-diamine

1,4-dioxane, reflux, 2 - 24hN',N'-diethylpentane-1,4-diamine

104 113 122

123 124

125

R1 = H, 6-Cl or 7-Cl R2 = H, 5-Cl or 6-Cl

(R1 = 8-Cl or 9-Cl, R2 = H)

(R1 = H, R2 = 2-Cl or 3-Cl)

2-(dicyclohexylphosphanyl)biphenyl (DCPB)

2-(di-t-butylphosphanyl)biphenyl (DTPB), NaOtBu

R1R1

R1

R2

R2

R2 NaOtBu

55-58%

28-67%

30-87%

Scheme 28.

Vera-Luque et al. [99] achieved the synthesis of 6H-indolo[2,3-b]quinolines via modified Graebe-Ullmann

reaction under microwave irradiation (Scheme 29).

NH

NN

N Cl

NN

N

N

NH

N

H4P2O7

MW

MW

+50 W/1800C

10 min

150 W/1700C30sec

R1 = H, Me or Cl R2 = H or Me113 104

114

48

R1

R1

R1

R1

R1

R1

R2

R2

R273-94%

19-54%

Scheme 29.


23

Microwave irradiation of benzotriazoles 113 and 2-chloroquinoline 104 afforded the respective triazoles

114a-d. The subsequent microwave irradiation of the resultant triazoles 114a-d in the presence of acid gave the

respective 6H-indolo[2,3-b]quinolines 48a-d.

1.6. Other miscellaneous methods

Cooper et al. [100] described the synthesis of quindoline utilizing the intramolecular β-nucleophilic

substitution as the main step (Scheme 30).

NSO2Ph

O2N

OHC

NSO2Ph

O

PhCOHN

NH

N

O

O Ph

NH

NH

O

POCl3

NH

N

Cl

H2, Pd/C

NH

N

BuLi, THF, -780C

40%

i) MnO2, CH2Cl2,r.t., 88%

ii) H2, Pd/C, 72%

iii) PhCOCl, PhNMe2

r.t., 87%

NaH, THF

reflux, 80%

NaOH, MeOH

heat, 85% reflux, 95%

EtOH, 95%

12694 127

128 129130

4

Scheme 30.

Amido ketone 127 was prepared by directed lithiation of 126 followed by addition of 94, subsequent

oxidation of the resultant alcohol with MnO2, reduction of nitro group using catalytic hydrogenation and N-

benzoylation using benzoylchloride. The cyclized product 128 was obtained from 127 in 80% yield by initial

1,4-addition of amido anion followed by expulsion of the phenyl sulfonate. N-deprotection of 128 using NaOH

in MeOH and subsequent reaction with POCl3 followed by catalytic hydrogenolysis of the resultant chlorinated

compound 130 afforded quindoline 4 in good yield.

Bierer and co-workers [23, 101] reported the synthesis of cryptolepine and its analogues by utilizing the

procedures of Holt and Petrow [102] and Degutis and Ezerskaite [103] (Scheme 31).

24

NH

OAcNH

O

O

KOH, H2O N

NHHOOC

Ph2O

N

NH

N

N

CH3Cl

+2550C, 6h

131 132 133

4 1

R1

R1

R1

R1

R2

R2

R2

R2

R1 = R2 = HR1 =H, R2= 2-FR1 = 7-Br, R2 =HR1 = 6-Cl, R2 =HR1 = H, R2 = 4-OMe

i) MeOTfii) Na2CO3

iii) HCl

+

25-64%

Scheme 31.

Reaction of substituted indolyl acetates 131 with isatin derivatives 132 gave the respective quindoline

carboxylic acids 133 which were decarboxylated by heating at 2550C in Ph2O and the subsequent quindolines 4

were alkylated using the method of Fichter and Boehringer [24] to give the respective cryptolepines 1. All these

compounds were evaluated for their antihyperglycemic activities in vitro and in an non-insulin-dependent

diabetes mellitus (NIDDM) mouse model.

Several other research groups [30, 104 – 105] have reported the synthesis of cryptolepine analogues using the

above methodology [23, 101] and were screened for their antimalarial and cytotoxic activities.

Bierer and co-workers [101] have reported the synthesis of 4-methoxy cryptolepine hydrochloride and a

series of 11-chlorocryptolepine analogues as shown below (Scheme 32 and 33) and evaluated for their

antimalarial and antihyperglycemic activities.

N

O

Ac

N

N

OMe

Ac

N

NH

CH3OMe

OMeO2N

OHC

piperidine (cat.)toluene, CHCl3

NAc

OMeO2NOH2, Pd/C

MeOH, r.t.overnight

KOH

stir, r.t.

N

NH

OMeCl

+4 A MS, stir, r.t. 1 week, 85%

30 minii) K2CO3

iii) HCl

+

134 135 136

137 138 139

0

41%

i) MeOTftoluene, r.t.

66%

Scheme 32.


25

N

NHCl

N

N

CH3

Cl

NH2

COOH Br

OBr

NH

OBr

HOOCNH2

NH

NHO

HOOCNH

NHO

POCl3 Cl

DMF/dioxane00C, 20 min,r.t.overnight, 50-95%

DMF, 1200C, 30h

PPA

1300C, 2h

reflux, 2h+

140142

143 144

145 146

141 102

R1

R1

R1 R1

R1

R1

R2

R2

R2 R2

R2

R1 = R2 = H R1 = 2-F, R2 = H R1 = 1-Cl, R2 = H R1 = 2-Cl, R2 = H R1 = H, R2 = 6-F R1 = H, R2 = 7-F R1 = H, R2 = 8-F R1 = H, R2 = 9-F R1 = H, R2 = 7-Ph

50-90%

10-50%(over two steps)

i) MeOTfii) Na2CO3

iii) HCl

Scheme 33.

Condensation of 134 with 135 using catalytic amount of piperidine gave compound 136 as a mixture of E/Z

isomers which on hydrogenation and subsequent deprotection using KOH followed by alkylation afforded the

methoxy cryptolepine hydrochloride 139 (Scheme 32).

Compound 142 formed by stirring anthranilic acids 140 and bromoacetyl bromide on treatment with substituted

anilines 102 provided the anthranilic acid derivatives 143. Acid-promoted cyclization of 143 with PPA gave

quindolones 144 which when refluxed in POCl3 afforded the corresponding 11-chloroquindolines 145. N-

Methylation of 145 was achieved using methyl triflate to give the respective hydrotriflate salts which, was

converted to free base and subsequently treated with HCl to provide the corresponding 11-chlorocryptolepine

hydrochloride salts 146 (Scheme 33).

Radl and co-workers [106] reported the synthesis of quindoline 4 via intermediate 149 by treating

anthranilonitrilo derivative 147 with phenacyl bromide 148 in presence of K2CO3 (Scheme 34).

NHCO2Et

CNO

Br

NO2

K2CO3, DMF

stir, r.t.

ON

NH2

NO2CO2Et

NaH, THF

stir, r.t.

NH

NHO

PCl5, reflux

N

NHCl

N

NH

+

2h, 40% 1h, 90%

3h, 70%

Ref. 100

147 148 149

129 130 4

Scheme 34.

26

Nucleophilic denitrocyclization [107] of 149 with NaH gave the required tetracyclic compound 129 which on

treatment with PCl5 afforded the corresponding chloro compound 130 in 70% yield. The compound 129 may

have formed by initial intramolecular 1,4-addition, followed by expulsion of nitro group as nitrous acid and

subsequent N-deprotection of carboethoxy group during work-up.

Engqvist and Bergman [108] achieved the synthesis of neocryptolepine by simply heating the chloroindole

derivative 150 with excess of N-methylaniline at reflux temperature (Scheme 35).

NH

Cl

RO

N NCH3

R

aq. NaHCO3

reflux, 0.25-2h

250C, 1h50-75%150 3

R = H or Me

N-methylaniline (5 eq.)

Scheme 35.

Sundaram et al. [109] reported the synthesis of 6H-indolo[2,3-b]quinoline 48 using conjugate addition-

elimination and the heterocyclization as the main steps (Scheme 36).

NH

O

SMeMeS

O

RNaH

DMF, C6H6

ONH

O

MeS

R NH4OAc, DMSO

NH

N

RMeS

NH

N

R

NH

N

NH

N

MeS

N N

R

CH3NH

N

(PPh3)2NiCl2R1MgX

Me2SO4, toluenesealed tube

+r.t., 12h

4 A MS, 120-1300C

10 - 12h

Ra - Ni

EtOH, reflux 6 - 7h

DDQ, dioxane

reflux, 6 - 8h

DDQ, dioxanereflux, 6 - 8h

80-900C

151 152153

154155

48

156 48c3

R = H or Me

48eR1 = Me (74%)R1 = Ph ( 82%)

R = H (40%)R = Me (0%)

86%

81-86% 82-53%

90-91%

150-1600C, 12h

n-BuLi, C6H6

R1

R

0

R = H (42%)R = Me (68%)

Scheme 36.

Reaction of 151 with cyclohexanones 152 in presence of NaH underwent conjugate addition-elimination to

give the corresponding adduct 153 which on heterocyclization with ammonium acetate yielded compound 154.

Dethiomethylation of 154 with Ra-Ni and subsequent dehydrogenation with DDQ afforded 48. The 11-


27

sustituted 6H-indolo[2,3-b]quinolines 48c and 48e were prepared by treating compound 154 with DDQ and

subsequent nickel-catalyzed cross-coupling reaction of resultant compound 156 with Grignard reagent.

Dhanabal et al. [110] described the synthesis of isocryptolepine using a Fischer indole cyclization as the key

step (Scheme 37).

N

OH

OCH3

NHNH2.HCl

N

NH

OCH3

N

N

CH3

OH N

N

CH3

Cl N

N

CH3

+glac. AcOH, Conc. HCl

reflux, 1350C, 5h, 65%

POCl3

reflux, 8 h

H2, Pd/C (10%)

62%70%

157 158 84

159 160 2Scheme

37.

Fischer indole reaction of 157 with 158 gave indoloquinoline 84 which exist predominantly in the hydroxy

form 159 as confirmed by IR. The enol 159 when refluxed in POCl3 afforded the corresponding chloride 160

which on catalytic hydrogenation yielded isocryptolepine 2.

Dutta et al. [111] developed a general method for the synthesis of various 2-substituted cryptolepines which

involves regioselective thermal cyclization and reductive cyclization using triethyl phosphite as the key steps

(Scheme 38).

28

NO2

O

CH3

POCl3, DMF

Cl

H

NO2

CHO

N

H N R

R

NO2

heatN

NO2

R

P(OEt)3

reflux

N

N

R

BaO, KOHacetone

CH3I, reflux,N

N

R

CH3

NH2 R

00C, 1h

800C, 4h80%

2N ethanolic HCl

00C, 88-92%

.HCl

200-2500C

5min.

35-41%

4h68-75%

4h65-73%

161162

163a-d

164a-d

4a-d 1a-d

102a-d

R = H, CH3, Br, I

Scheme 38.

2-Nitroacetophenone 161 underwent Vilsmeier-Haack reaction when treated with POCl3 in DMF to give the

β-chlorocinnamaldehyde 162 which, on treatment with excess arylamines 102a-d in presence of 2N ethanolic

HCl afforded the corresponding enaminoimine hydrochlorides 163a-d. Thermal cyclization of 163a-d at 200-

2500C provided the respective 2-(2-nitrophenyl)quinoline derivatives 164a-d. The quindolines 4a-d was

prepared by heating 164a-d with triethyl phosphite at 1600C.

Portela-Cubillo et al. [112] described the microwave-mediated formal synthesis of neocryptolepine via

radical intermediate (Scheme 39).

NH O

PhONH2.HCl

pyridine, stir, r.t.NH N

OPh

NH .N

NH

N N NCH3

70%1600C, 30min.

69%

Ref. 109

165 166

167155 3

t-BuPh, IL, MW

Scheme 39.


29

The indolo-ketone 165 was treated with O-phenylhydroxylamine hydrochloride and the resultant O-phenyl

oxime ether 166 was subjected to microwave irridiation in ionic liquid emimPF6 to give tetrahydroindolo[2,3-

b]quinoline 155 in 69% yield.

Sayed et al. [98] reported the synthesis of aminoalkylamino-substituted neocryptolepines using the procedure

of Bergman and co-workers [113] (Scheme 40) and evaluated for their in vitro antiplasmodial activity against a

chloroquine-sensitive P. falciparum strain and for cytotoxicity on a human cell line (MRC5).

NH

OOMe

NH

OOMe

NH

RPh2O, reflux

NH

NH

O

R

POCl3, toluene

N NH

Cl

RN N

Cl

CH3R

N NH

NH

CH3N

CH3

CH3

RR

NH

CH3

N

CH3

CH3

N NCH3

NH2

R

MeI, THF,reflux

i) N-chlorosuccinimide 1,4-dimethylpiperazine

CH2Cl2, 00C, 2h

ii) trichloroacetic acid r.t., 2h

45min - 3h

reflux, 6 - 12h

N,N'-diethylpentane-1,4-diamine133 -1550C, 12h

N,N'-diethylpentane-1,4-diamine133 -1550C, 1-4h

168

102

169129

130 170

172 171

R = H, 3-Cl, 4-Cliii)

18 - 24h

47-56%

53-88%

13-79%60-75%

71-85%56-82%

Scheme 40.

The key intermediate 169 was obtained via chlorination of 168 with NCS in presence of 1,4-

dimethylpiperazine followed by addition of aniline which underwent cyclization when refluxed in Ph2O to give

compound 129 [113] and then converted to 11-chloro-6H-indolo[2,3-b]quinolines 130 using POCl3. Methylation

using methyl iodide and subsequent amination via SNAr reaction yielded the corresponding aminoalkylamino-

substituted neocryptolepine derivatives.

Recently, we reported [114] the synthesis of series of novel 6H-indolo[2,3-b]quinolines using iodine as a

catalyst in one-pot via Schiff's base intermediate (Scheme 41).

30

NH

CHO NH2

Ph2O, reflux,R N

HN

R+I2 (10 mol%)

12h29 - 53%

101 102 48R = H, 2-CH3, 3-CH3, 4-CH3, 3-Br, 2,3-benzo, 3,4-benzo

Scheme 41.

The reaction of indole-3-carboxaldehyde 101 with aryl amines 102 in presence of catalytic amount of iodine

in refluxing diphenyl ether yielded indolo[2,3-b] quinolines 48 in a one-pot experiment via sequential imination,

nucleophilic addition and subsequent annulation.

Kraus and Guo [115] achieved a formal synthesis of neocryptolepine 3 and isocryptolepine 2 from a common

intermediate 83 using an intramolecular Wittig reaction and regioselective methylation as the key steps (Scheme

42).

O

COOH

N3

SOCl2, C6H6

or(COCl)2, CH2Cl2

O

N3

COCl

NH2

PPh3

Br

NH

O O

N3Ph3PBr

NH

O

N3

MeI, K2CO3

NO

N3

CH3

NN

CH3

N

NCH3

reflux, 1h

r.t., 3h

+

CH2Cl2, r.t., 12h

+

t-BuOK, THF

r.t., 5h62% over 3 steps

DMF, 600C, 8h

98%

Ref. 82

One step

Two steps83

3

2

173 174

175

176

177

Scheme 42.

The acid 173, prepared from isatin [116] was converted to acid chloride 174 by two different methods, one

using thionyl chloride and the other using oxalyl chloride. Condensation of 2-


31

(aminobenzyl)triphenylphosphonium bromide with 174, followed by intramolecular Wittig reaction in presence

of potassium tert-butoxide at room temperature afforded lactam 177 in 62% overall yield from compound 173.

Methylation of 177 gave a known intermediate 83 which constitutes the formal synthesis of isocryptolepine 2

and neocryptolepine 3, respectively.

3. CONCLUSION

Indoloquinoline alkaloids show remarkable biological activities and constitute important scaffolds for drug

development. Due to this, synthesis of indoloquinoline alkaloids forms, one of the important fields of research in

medicinal chemistry. This review presents a collection of highly interesting and useful methods for the synthesis

of different types of indoloquinoline alkaloids which includes cryptolepine, isocryptolepine and

neocryptolepine. Several synthetic strategies are now available which provides flexibility for introducing

various substituents into the ring system.

ACKNOWLEDGMENTS

We thank CSIR, New Delhi for the financial support and one of us (P. T. P) thanks the CSIR, New Delhi for

the award of Senior Research Fellowship.

REFERENCES

[1] Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.; de Pascual-

Teresa, B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. Synthesis and DNA Binding Properties of γ-

Carbolinium Derivatives and Benzologues. J. Org. Chem., 1996, 61, 5587.

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