review síntese

1036 Current Organic Chemistry, 2011, 15, 1036-1057

1385-2728/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.

Isolation, Biological Activities and Synthesis of Indoloquinoline Alkaloids: Cryptole-pine, Isocryptolepine and Neocryptolepine

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

aNational Institute of Oceanography, Dona Paula, Goa 403 004, IndiabDepartment of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India cNational Institute of Oceanography, Regional Centre, Kochi 682 018, India

Abstract: The tetracyclic heteroaromatic compounds cryptolepine, isocryptolepine and neocryptolepine are all naturally occurring in-doloquinoline 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, isoc-ryptolepine 2 and neocryptolepine 3.

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

1. INTRODUCTION

1.1. General

In recent years, indoloquinoline alkaloids have received consid-erable attention due to their promising DNA intercalating [1] and antimalarial properties [2-4]. According to World Health Organiza-tion (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 clas-sification as a dreaded infectious disease along with tuberculosis and AIDS [5].

The roots of the West African plant Cryptolepis sanguinolenta[6-19] have 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 rheu-matism, 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 2and neocryptolepine 3 have been reported from the roots of the West African plant C. sanguinolenta (Fig. 1).

N

NCH3

N NCH3

N

NCH3

21 3Fig. (1).

Among these, cryptolepine 1 is a rare example of natural prod-uct whose synthesis was reported prior to its isolation from nature. It was synthesized in 1906 by Fichter and Boehringer [24] for pos-sible use as a dye while its isolation from C. triangularis was

*Address correspondence to these authors at the Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India; Tel: 91-(0)-484-2390814 / 832-6519317; Fax: 91-(0)-484-2390618 / 832-2452868; E-mails: [email protected]; [email protected]

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. Isocryp-tolepine 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].

Other alkaloids reported from the plant C. sanguinolenta in-clude quindoline 4 [7], cryptospirolepine 5 [13], cryptolepicarboline 6 [27], cryptomisrine 7 [28], 11-isopropylcryptolepine 8 [17], cryp-tolepinone 9 [13-15], and bis-cryptolepine 10 [9] (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 an-tiplasmodial 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 alka-loids also intercalate with DNA double helix, causing dramatic changes in DNA conformation leading to inhibition of DNA repli-cation 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, antihypergly-cemic and cytotoxic properties in vitro and antitumor activity in vivo [19, 23, 35-38].

Recent Development in Indoloquinoline Alkaloids Current Organic Chemistry, 2011, Vol. 15, No. 7 1037

These alkaloids, due to their wide spectrum of biological activi-ties, have been targets of synthetic chemists in recent years.

2. SYNTHESIS

The synthetic methods used for the preparation of indoloquino-line alkaloids may be classified under the following six major cate-gories based on the method of formation of the ring system – palla-dium-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 power-ful tool for the synthetic chemists particularly for the synthesis of biologically active natural products and for the preparation of versa-

tile 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 (Schemes 1 & 2).

The reaction of 3-bromoquinoline 11 with N-pivaloylamino- phenyl 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 16.Regioselective methylation on quinoline nitrogen using dimethyl sulfate yielded the target molecule isocryptolepine 2 (Schemes 1).

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

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).

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.

1038 Current Organic Chemistry, 2011, Vol. 15, No. 7 Parvatkar et al.

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 22with triphenylbismuth diacetate using metallic copper, followed by oxidative cyclization of the resultant anilinoquinoline 23 using palladium acetate (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).

Pd-catalyzed cross-coupling reaction between boronic acid 12and 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 quin-

doline 4 in 83% yield. The intramolecular nucleophilic displace-ment 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.

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] 30with 12 taking into consideration the fact that the �-heteroaryl halo-gen atom is more reactive than the �-halogen atom [56] to give N-pivaloyl-2-(2'-anilino)-3-bromoquinoline 31. Hydrolysis of 31 af-

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.

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.

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.


forded the free amine 32 which underwent cyclization when heated at 200-220°C in presence of pyridinium hydrochloride to give quin-doline 4 (Scheme 6).

Jonckers et al. [57] described the Pd-catalyzed 'amination-arylation' approach for the synthesis of isocryptolepine (Scheme 7).

This approach consists of two consecutive Pd-catalyzed reac-tions – a selective Buchwald-Hartwig [58-63] reaction of 2-chloroaniline 34 with 4-chloroquinoline 33 followed by an in-tramolecular 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 cryptole-pine, neocryptolepine and isocryptolepine via two routes – 1. Su-zuki 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).

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).

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 io-dide in refluxing toluene afforded the isoneocryptolepine 43(Scheme 9).

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.

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.

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.


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).

Miki and co-workers [72] have developed a simple approach to-wards isocryptolepine by applying Myers method [73-75] (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 decar-boxylated product 54 in 12% yield. The compound 53 was con-verted to 2 by treatment with LiAlH4 in hot dioxane.

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.

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 43Scheme 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.


Mori and Ichikawa [76] reported the synthesis of 11-alkylated cryptolepines via radical cyclization and Stille coupling reaction (Scheme 12).

o-Isocyano-substituted �,�-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 fol-lowed by methylation furnished the 11-n-butyl and 11-isopropyl cryptolepines 1b-c.

2.2. Aza-Wittig Reaction

Aza-Wittig reaction [77-78] has become one of the important reactions in organic synthetic strategies directed towards the con-struction of acyclic and cyclic compounds as the reaction is mostly

carried out in neutral conditions, in the absence of catalyst, gener-ally at mild temperature and usually proceeds in high yield.

Alajarin and co-workers [79] described the synthesis of neoc-ryptolepine using aza-Wittig reaction of the iminophosphorane 59with phenyl isocyanate 60 to yield carbodiimide 61 and triphenyl-phosphine oxide which, without purification, was subjected to thermal treatment to give 48 and 2-anilinoquinoline 62 in 19% and 40% yield, respectively (Scheme 13).

Shi et al. [80] prepared various derivatives of 6H-indolo[2,3-b]quinoline 48 using the above methodology [79] (Scheme 14).

The introduction of trimethylsilyl group at the acetylenic termi-nus 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

N

O

O

OSO2Ph

NHCH3

N

NO

CH3

COOH

SO2Ph

N 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

5354

2

Scheme 11.

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.

N PPh3NH

N N NH

Ph

Ph-NCO

toluene

toluene

sealed tubeNN

+

r.t., 15min.

1600C

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

62

60

Scheme 13.


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, an-tiplasmodial and antitrypanosomal activities.

Molina and co-workers [81] reported the synthesis of neocryp-tolepine via Staudinger, aza-Wittig and electrocyclization reactions (Scheme 15).

The iminophosphorane 69 was prepared by condensing 2-(nitrobenzyl)triphenylphosphonium bromide 63 with 2-bromo- benzaldehyde 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 car-bodiimide 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 mole-cule 3.

Fresneda and co-workers [82] devised a divergent synthetic ap-proach 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).

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. Reac-tion 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 isocy-anate 79. Electrocyclic ring closure of 79 was achieved via micro-wave 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

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.

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

3Scheme 15.


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.

2.3. Trasition-metal Mediated Reductive Cyclization

Reductive cyclization [83] using transition metals is an effec-tive protocol for the synthesis of compounds containing quinoline ring and thus is being used by several research groups for the syn-thesis 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).

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 fol-lowed 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 re-action (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 �-hydroxy lactams 92a-e which, on treatment with iron underwent reduction-cyclization and dehy-dration 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).

Condensation of 2-nitrobenzaldehyde 94 with 2-nitrophenyl acetic acid 85 in refluxing acetic anhydride in presence of Et3Ngave the �,�-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 cy-clization reactions in one-pot.

Sharma and Kundu [89] achieved the synthesis of neocryptole-pine using indole 96 and 2- nitrobenzyl bromide 97 as the starting materials (Scheme 20).

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.

MW

nitrobenzene

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.


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.

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.

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.


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.

2.4. 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 activa-tion 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 us-ing photo-cyclization as the main step (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 viainitial photo-isomerization of the Schiff's base 103 from E- to Z-isomer followed by conrotatory ring closure and subsequent oxida-tion by iodine.

Dhanabal et al. [92] reported the synthesis of cryptolepine 1,isocryptolepine 2 and neocryptolepine 3 via heteroatom directed photoannulation technique (Schemes 22 - 24).

Nucleophilic substitution of 3-bromoquinoline 11 with aniline 102 was achieved by heating at 2000C and the resultant anilinoqui-noline 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 isoneoc-ryptolepine 43 respectively (Scheme 22).

Synthesis of isocryptolepine 2 and neocryptolepine 3 were ob-tained by photocyclization of the respective anilinoquinolines 105a

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 2Scheme 21.


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.

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 h83%

72%

104a 102105a

162

X = Cl, H, OH or OMe

Scheme 23.

N Cl

NH2

X

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.


and 105b and subsequent methylation at the quinoline nitrogen. Anilinoquinolines 105a-b were obtained from the corresponding chloroquinolines 104a-b (Schemes 23 and 24).

Pitchai et al. [93] reported a simple photo-induced method for the synthesis of the methyl derivative of isocryptolepine (Scheme 25).

4-Hydroxy-2-methyl quinoline 107 was prepared by microwave irradiation of �-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 chlorin-ated compound 109. The amination reaction of 109 with aniline afforded the compound 110 which on photo irradiation and subse-quent N-methylation yielded the methyl derivative of isocryptole-pine.

2.5. 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 pyroly-sis (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 mate-rials.

Peczynska-Czoch and co-workers [36] reported the synthesis of various derivatives of neocryptolepines via Graebe-Ullmann reac-tion (Scheme 26) and these were evaluated for their in vitro antimi-crobial and cytotoxic activities.

Triazoles 114a-d were prepared by heating the corresponding chloroquinolines 104a-d with benzotriazoles 113 at 110-120°C. Decomposition of the triazoles 114a-d by heating at 130-180°C 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]

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.

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.


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 neoc-ryptolepine 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.

Sayed et al. [98] described the synthesis of neocryptolepines with A or D-ring substitutions using the methodology of Peczyn-ska-Czoch and co-workers [36] and the side chain was introduced on the 2-, 3-, 8- and 9-positions using Pd-catalyzed amination reac-tion (Scheme 28). All these compounds were screened for in vitro

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

N

(CH2)nNR2NaC10H17, THF

N N

CH3

CH3

NH

(CH2)nNR2

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%

Scheme 27.

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.


antiplasmodial activity against a chloroquine-sensitive P. falcipa-rum strain and for cytotoxicity on a human cell (MRC5) line.

Vera-Luque et al. [99] achieved the synthesis of 6H-indolo[2,3-b]quinolines via modified Graebe-Ullmann reaction under micro-wave irradiation (Scheme 29).

Microwave irradiation of benzotriazoles 113 and 2-chloroquinoline 104 afforded the respective triazoles 114a-d. The subsequent microwave irradiation of the resultant triazoles 114a-din the presence of acid gave the respective 6H-indolo[2,3-b]quinolines 48a-d.

2.6. Other Miscellaneous Methods

Cooper et al. [100] described the synthesis of quindoline utiliz-ing the intramolecular �-nucleophilic substitution as the main step (Scheme 30).

Amido ketone 127 was prepared by directed lithiation of 126followed by addition of 94, subsequent oxidation of the resultant alcohol with MnO2, reduction of nitro group using catalytic hydro-genation 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 sul-fonate. N-deprotection of 128 using NaOH in MeOH and subse-quent 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 cryp-tolepine and its analogues by utilizing the procedures of Holt and Petrow [102] and Degutis and Ezerskaite [103] (Scheme 31).

Reaction of substituted indolyl acetates 131 with isatin deriva-tives 132 gave the respective quindoline carboxylic acids 133 which were decarboxylated by heating at 2550C in Ph2O and the subse-quent 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

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.

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

4Scheme 30.


[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 (Schemes 32 and 33)and evaluated for their antimalarial and antihyperglycemic activities.

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 102provided the anthranilic acid derivatives 143. Acid-promoted cycli-zation 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

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.

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

+4A 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.

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.


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

Nucleophilic denitrocyclization [107] of 149 with NaH gave the required tetracyclic compound 129 which on treatment with PCl5afforded 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 neocryp-tolepine by simply heating the chloroindole derivative 150 with excess of N-methylaniline at reflux temperature (Scheme 35).

Sundaram et al. [109] reported the synthesis of 6H-indolo[2,3-b]quinoline 48 using conjugate addition-elimination and the hetero-cyclization as the main steps (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-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).

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.

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.

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

4A 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.


Fischer indole reaction of 157 with 158 gave indoloquinoline 84 which exist predominantly in the hydroxy form 159 as con-firmed 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).

2-Nitroacetophenone 161 underwent Vilsmeier-Haack reaction when treated with POCl3 in DMF to give the �-chlorocinna- maldehyde 162 which, on treatment with excess arylamines 102a-d

in presence of 2N ethanolic HCl afforded the corresponding enami-noimine hydrochlorides 163a-d. Thermal cyclization of 163a-d at 200-250°C provided the respective 2-(2-nitrophenyl)quinoline de-rivatives 164a-d. The quindolines 4a-d was prepared by heating 164a-d with triethyl phosphite at 160°C.

Portela-Cubillo et al. [112] described the microwave-mediated formal synthesis of neocryptolepine via radical intermediate (Scheme 39).

The indolo-ketone 165 was treated with O-phenylhydroxy- lamine hydrochloride and the resultant O-phenyl oxime ether 166was subjected to microwave irridiation in ionic liquid emimPF6 to give tetrahydroindolo[2,3-b]quinoline 155 in 69% yield.

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 2

Scheme 37.

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, IScheme 38.


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 an-tiplasmodial activity against a chloroquine-sensitive P. falciparumstrain and for cytotoxicity on a human cell line (MRC5).

The key intermediate 169 was obtained via chlorination of 168with NCS in presence of 1,4-dimethylpiperazine followed by addi-tion of aniline which underwent cyclization when refluxed in Ph2Oto 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 de-rivatives.

Recently, we reported [114] the synthesis of series of novel 6H-indolo[2,3-b]quinolines using iodine as a catalyst in one-pot viaSchiff's base intermediate (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 an-nulation.

Kraus and Guo [115] achieved a formal synthesis of neocryp-tolepine 3 and isocryptolepine 2 from a common intermediate 83using an intramolecular Wittig reaction and regioselective methyla-tion as the key steps (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-(amino- benzyl)triphenylphosphonium bromide with 174, followed by in-tramolecular 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

NH O

PhONH2.HCl

pyridine, stir, r.t.NH N

OPh

NH .N N

HN N N

CH3

70%1600C, 30min.

69%

Ref. 109

165 166

167155 3

t-BuPh, IL, MW

Scheme 39.

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.


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 impor-tant fields of research in medicinal chemistry. This review presents a collection of highly interesting and useful methods for the synthe-sis of different types of indoloquinoline alkaloids which includes cryptolepine, isocryptolepine and neocryptolepine. Several syn-thetic 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.

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[12] Spitzer, T. D.; Crouch, R. C.; Martin, G. E.; Sharaf, M. H. M.; Schiff, P. L. Jr.; Tackie, A. N.; Boye, G. L. Total Assignment of the Proton and Carbon NMR Spectra of the Alkaloid Quindoline-Utilization of HMQC-TOCSY to

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.

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.


Indirectly Establish Protonated Carbon-Protonated Carbon Connectivities. J. Heterocycl. Chem., 1991, 28, 2065.

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Received: 04 May, 2010 Revised: 28 September, 2010 Accepted: 30 September, 2010

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