ISOLATION, BIOLOGICAL ACTIVITIES AND SYNTHESIS OF ...
Transcript of 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.
2
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].
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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.
4
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
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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).
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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).
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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).
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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).
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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)
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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).
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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.
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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.
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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.
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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-
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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.
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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-
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
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.
[2] Cimanga, K.; De Bruyne, T.; Pieters, L.; Vlietinck, A. J.; Turger, C. A. In Vitro and in Vivo
Antiplasmodial Activity of Cryptolepine and Related Alkaloids from Cryptolepis sanguinolenta.
J. Nat. Prod., 1997, 60, 688.
[3] Paulo, A.; Gomes, E. T.; Steele, J.; Warhurst, D. C.; Houghton, P. J. Antiplasmodial Activity of
Cryptolepis sanguinolenta Alkaloids from Leaves and Roots. Planta Med., 2000, 66, 30.
[4] Miert, S. V.; Hostyn, S.; Maes, B. U. M.; Cimanga, K.; Brun, R.; Kaiser, M.; Matyus, P.;
Dommisse, R.; Lemiere, G.; Vlietinck, A.; Pieters, L. Isoneocryptolepine, a Synthetic
Indoloquinoline Alkaloid, as an Antiplasmodial Lead Compound. J. Nat. Prod., 2005, 68, 674.
[5] Website of the World Health Organization : http://www.who.int/en/ (Accessed Jan. 05, 2010).
[6] Gellert, E.; Hamet, R.; Schlitter, E. Die Konstitution des Alkaloids Cryptolepin. Helv. Chim. Acta,
1951, 34, 642.
[7] Dwuma-Badu, D.; Ayim, J. S. K.; Fiagbe, N. Y. Y.; Knapp, J. E.; Schiff, P. L. Jr.; Slatkin, D. J.
Constituents of West African medicinal plants XX: Quindoline from Cryptolepis sanguinolenta. J.
Pharm. Sci., 1978, 67, 433.
32
[8] Ablordeppey, S. D.; Hufford, C. D.; Bourne, R. F.; Dwama-Badu, D. 1H-NMR and 13C-NMR
Assignments of Cryptolepine, A 3:4-Benz-δ-carboline Derivative Isolated from Cryptolepis
sanguinolenta. Planta Med., 1990, 56, 416.
[9] Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlietinck, A. New alkaloids from Cryptolepis
sanguinolenta. Tetrahedron Lett., 1996, 37, 1703.
[10] Pousset, J.-L.; Martin, M.-T.; Jossang, A.; Bodo, B. Isocryptolepine from Cryptolepis
sanguinolenta. Phytochemistry, 1995, 39, 735.
[11] Tackie, A. N.; Sharaf, M. H. M.; Schiff, P. L. Jr.; Boye, G. L.; Crouch, R. C.; Martin, G. E.
Assignment of the Proton and Carbon NMR Spectra of the Indoloquinoline Alkaloid
Cryptolepine. J. Heterocycl. Chem., 1991, 28, 1429.
[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 Indirectly Establish Protonated Carbon-Protonated
Carbon Connectivities. J. Heterocycl. Chem., 1991, 28, 2065.
[13] Tackie, A. N.; Boye, G. L.; Sharaf, M. H. M.; Schiff, P. L. Jr.; Crouch, R. C.;
Spitzer, T. D.; Johnson, R. L.; Dunn, J.; Minick, D.; Martin, G. E. Cryptospirolepine, a Unique
Spiro-nonacyclic Alkaloid Isolated from Cryptolepis sanguinolenta. J. Nat. Prod., 1993, 56, 653.
[14] Crouch, R. C.; Davis, A. O.; Spitzer, T. D.; Martin, G. E.; Sharaf, M. H. M.; Schiff, P. L. Jr.;
Phoebe, C. H. Jr.; Tackie, A. N. Elucidation of the Structure of Quindolinone, a Minor Alkaloid
of Cryptolepis sanguinolenta: Submiligram 1H-13C and 1H-15N Heteronuclear Shift Correlation
Experiments Using Micro Inverse-Detection. J. Heterocycl. Chem., 1995, 32, 1077.
[15] Paulo, A.; Gomes, E. T.; Hougton, P. J. New Alkaloids from Cryptolepis sanguinolenta. J. Nat
Prod., 1995, 58, 1485.
[16] Fort, D. M.; Litvak, J.; Chen, J. L.; Lu, Q.; Phuan, P. W.; Cooper, R.; Bierer, D. E. Isolation and
Unambiguous Synthesis of Cryptolepinone: An Oxidation Artifact of Cryptolepine. J. Nat. Prod.,
1998, 61, 1528.
[17] Hadden, C. E.; Sharaf, M. H. M.; Guido, J. E.; Robins, R. H.; Tackie, A. N.; Phoebe, C. H. Jr.;
Schiff, P. L. Jr. Martin, G. E. 11-Isopropylcryptolepine: A Novel Alkaloid Isolated from
Cryptolepis sanguinolenta Characterized Using Submicro NMR Techniques. J. Nat. Prod., 1999,
62, 238.
[18] Blinov, K.; Elyashberg, M.; Martirosian, E. R.; Molodtsov, S. G.; Williams, A. J. A. J.; Tackie, A.
N.; Sharaf, M. H. M.; Schiff, P. L. Jr.; Crouch, R. C.; Martin, G. E.; Hadden, C. E.; Guido, J. E.;
Mills, K. A. Quindolinocryptotackieine: the elucidation of a novel indoloquinoline alkaloid
structure through the use of computer-assisted structure elucidation and 2D NMR. Magn. Reson.
Chem., 2003, 41, 577.
[19] Cimanga, K.; DeBruyne, T.; Lasure, A.; Poel, B. V.; Pieters, L.; Claeys, M.; Berghe, D. V.;
Vlietinck, A. J. In Vitro Biological Activities of Alkaloids from Cryptolepis sanguinolenta.
Planta Med., 1996, 62, 22.
[20] Oliver-Bever, B. Medicinal Plants in Tropical West Africa, Cambridge University Press:
Cambridge, UK, 1986, 41.
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
33
[21] Boakye-Yiadom, K. Antimicrobial Properties of Some West African Plants. Quart. J. Crude Drug
Res. 1979, 17, 78.
[22] Boye, G. L.; Ampofo, O. Proceedings of the First International Symposium on Cryptolepine,
Ghana, University of Science and Technology: Kumasi, Ghana, 1983, 37.
[23] Bierer, D. E.; Fort, D. M.; Mendez, C. D.; Luo, J.; Imbach, P. A.; Dubenko, L. G.; Jolad, S. D.;
Gerber, R. E.; Litvak, J.; Lu, Q.; Zhang, P.; Reed, M. J.; Waldeck, N.; Bruening, R. C.; Noamesi,
B. K.; Hector, R. F.; Carlson, T. J.; King, S. R. Ethnobotanical-Directed Discovery of the
Antihyperglycemic Properties of Cryptolepine: Its Isolation from Cryptolepis sanguinolenta,
Synthesis, and in Vitro and in Vivo Activities. J. Med. Chem., 1998, 41, 894.
[24] Fichter, F.; Boehringer, R. Ueber Chindolin. (Over Quindoline). Chem. Ber., 1906, 39, 3932.
[25] Clinquart, E. Sur la composition chimique de Cryptolepis triangularies. Plante congolaise. (On the
Chemical Composition of Cryptolepis triangularies. Plants from the (Belgian) Congo).
Bull Acad. R. Med. Belg., 1929, 9, 627.
[26] Sharaf, M. H. M.; Schiff, P. L. Jr.; Tackie, A. N.; Phoebe, C. H. Jr.; Martin, G. E. Two New
Indoloquinoline Alkaloids from Cryptolepis sanguinolenta: Cryptosanguinolentine and
Cryptotackieine. J. Heterocycl. Chem., 1996, 33, 239.
[27] Sharaf, M. H. M.; Schiff, P. L. Jr.; Tackie, A. N.; Phoebe, C. H. Jr.; Howard, L.;
Meyers, C.; Hadden, C. E.; Wrenn, S. K.; Davis, A. O.; Andrews, C. W.; Minick,
D.; Johnson, R. L.; Shockcor, J. P.; Crouch, R. C.; Martin, G. E. Submicromole structure
elucidation: Cryptolepicarboline—a novel dimeric alkaloid from Cryptolepis sanguinolenta.
Magn. Reson. Chem., 1995, 33, 767.
[28] Sharaf, M. H. M.; Schiff, P. L. Jr.; Tackie, A. N.; Phoebe, C. H. Jr.; Johson, R.
L.; Minick, D.; Andrews, C. W.; Crouch, R. C.; Martin, G. E. The Isolation and Structure
Determination of Cryptomisrine, A Novel Indolo[3,2-b]quinoline Dimeric Alkaloid from
Cryptolepis sanguinolenta. J. Heterocycl. Chem., 1996, 33, 789.
[29] Grellier, P.; Ramiaramanana, L.; Millerioux, V.; Deharo, E.; Schrevel, J.; Frappier, F.; Trigalo, F.;
Bodo, B.; Pousset, J.-L. Antimalarial activity of Cryptolepine and Isocryptolepine, Alkaloids
Isolated from Cryptolepis sanguinolenta. Phytother. Res., 1996, 10, 317.
[30] Wright, C. W.; Addae-Kyereme, J.; Breen, A. G.; Brown, J. E.; Cox, M. F.; Croft, S. L.; Gokcek,
Y.; Kendrick, H.; Phillips, R. M.; Pollet, P. L. Synthesis and Evaluation of Cryptolepine
Analogues for Their Potential as New Antimalarial Agents. J. Med. Chem., 2001, 44, 3187.
[31] Arzel, E.; Rocca, P.; Grellier, P.; Labaeid, M.; Frappier, F.; Gueritte, F.; Gaspard, C.; Marsais, F.;
Godard, A.; Queguiner, G. New Synthesis of Benzo-δ-carbolines, Cryptolepines, and Their Salts:
In Vitro Cytotoxic, Antiplasmodial, and Antitrypanosomal Activities of δ-Carbolines, Benzo-δ-
carbolines, and Cryptolepines. J. Med. Chem., 2001, 44, 949.
[32] Jonckers, T. H. M.; van Miert, S.; Cimanga, K.; Bailly, C.; Colson, P.; De Pauw-Gillet, M.-C.;
Van den Heuvel, H.; Claeys, M.; Dommisse, R.; Lemiere, G. L. F.; Vlietinck, A.; Pieters, L.
Synthesis, Cytotoxicity, and Antiplasmodial and Antitrypanosomal Activity of New
Neocryptolepine Derivatives. J. Med. Chem., 2002, 45, 3497.
[33] Dassoneville, L.; Bonjean, K.; De Pauw-Gillet, M. C.; Colson, P.; Houssier, C.; Quetin-Leclercq,
34
J.; Angenot, L.; Bailly, C. Stimulation of Topoisomerase II-Mediated DNA Cleavage by Three
DNA-Intercalating Plant Alkaloids: Cryptolepine, Matadine, and Serpentine. Biochemistry, 1999,
38, 7719.
[34] Lisgarten, J. N.; Pous, J.; Coll, M.; Wright, C. W.; Aymami, J. Crystallization and preliminary X-
ray analysis of the antimalarial and cytotoxic alkaloid cryptolepine complexed with the DNA
fragment d(CCTAGG)2. Acta Crystallogr. D Biol. Crystallogr., 2002, 58, 312.
[35] Kirby, G. C.; Paine, A.; Warhurst, D. C.; Noamese, B. K.; Phillipson, J. D. In vitro and in vivo
antimalarial activity of cryptolepine, a plant-derived Indoloquinoline. Phytother. Res., 1995, 9,
359.
[36] Peczynska-Czoch, W.; Pognan, F.; Kaczmarek, L.; Boratynski, J. Synthesis and Structure-Activity
Relationship of Methyl-Substituted Indolo[2,3-b]quinolines: Novel Cytotoxic, DNA
Topoisomerase II Inhibitors. J. Med. Chem., 1994, 37, 3503.
[37] Cimanga, K.; De Bruyne, T.; Pieters, L.; Totte, J.; Tona, L.; Kambu, K.; Berghe, D.-V.; Vlietinck,
A. J. Antibacterial and antifungal activities of neocryptolepine, biscryptolepine and
cryptoquindoline, alkaloids isolated from Cryptolepis sanguinolenta. Phytomedicine, 1998, 5, 209.
[38] Abblordeppey, S. Y.; Fan, P.; Clark, A. M.; Nimrod, A. Probing the N-5 region of the
indoloquinoline alkaloid, cryptolepine for anticryptococcal activity. Bioorg. Med. Chem., 1999, 7,
343.
[39] Torborg, C.; Beller, M. Recent Applications of Palladium-Catalyzed Coupling Reactions in the
Pharmaceutical, Agrochemical, and Fine Chemical Industries. Adv. Synth. Catal., 2009, 351,
3027.
[40] Yin, L.; Liebscher, J. Carbon−Carbon Coupling Reactions Catalyzed by Heterogeneous Palladium
Catalysts. Chem. Rev., 2007, 107, 133.
[41] Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. On the Nature of the Active Species in Palladium
Catalyzed Mizoroki–Heck and Suzuki–Miyaura Couplings – Homogeneous or Heterogeneous
Catalysis, A Critical Review. Adv. Synth. Catal., 2006, 348, 609.
[42] Nicolau, K. C.; Bulger, P. G.; Sarlah, D. Palladium-Catalyzed Cross-Coupling Reactions in Total
Synthesis. Angew. Chem. Int. Ed., 2005, 44, 4442.
[43] Farina, V. High-Turnover Palladium Catalysts in Cross-Coupling and Heck Chemistry: A Critical
Overview. Adv. Synth. Catal., 2004, 346, 1553.
[44] Timari, G.; Soos, T.; Hajos, G. A Convenient Synthesis of Two New Indoloquinoline Alkaloids.
Synlett, 1997, 1067.
[45] Fan, P.; Ablordeppey, S. Y. An Alternative Synthesis of 10H-Indolo[3,2-b]quinoline and its
Selective N-Alkylation. J. Heterocycl. Chem., 1997, 34, 1789.
[46] Arzel, E.; Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. First halogen-dance reaction in
quinoline series: application to a new synthesis of quindoline. Tetrahedron Lett., 1998, 39, 6465.
[47] Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.; Mallet, M.; Godard, A.;
Queguiner, G. First metalation of aryl iodides: directed ortho-lithiation of iodopyridines, halogen-
dance, and application to synthesis. J. Org. Chem., 1993, 58, 7832.
[48] Miyaura, N.; Yanagi, T.; Suzuki, A. The Palladium-Catalyzed Cross-Coupling Reaction of
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
35
Phenylboronic Acid with Haloarenes in the Presence of Bases. Synth. Commun., 1981, 513.
[49] Godard, A.; Rocca, P.; Pomel, V.; Thomas-dit-Dumont, L.; Rovera, J. C.;
Thaburet, J. F.; Marsais, F.; Queguiner, G. Metalation in Connection with Cross-coupling
Reactions. Coupling of Hindered Aryls for the Synthesis of 4-Phenylpyridines as Part of
Streptonigrin and Lavendamycin Analogues. J. Organomet. Chem., 1996, 517, 25.
[50] Alonso, F.; Beletskaya, I. P.; Yus, M. Non-conventional methodologies for transition-metal
catalysed carbon–carbon coupling: a critical overview. Part 2: The Suzuki reaction. Tetrahedron,
2008, 64, 3047.
[51] Bellina, F.; Carpita, A.; Rossi, R. Palladium Catalysts for the Suzuki Cross-Coupling Reaction: An
Overview of Recent Advances. Synthesis, 2004, 2419.
[52] Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Connection between metalation and cross-
coupling strategies. A new convergent route to azacarbazoles. Tetrahedron, 1993, 1, 49.
[53] Murray, P. E.; Mills, K.; Joule, J. A. A Synthesis of Isocryptolepine.
J. Chem. Res. (S), 1998, 377.
[54] Csanyi, D.; Timari, G.; Hajos, G. An alternative synthesis of quindoline and one of its closely
related derivatives. Synth. Commun., 1999, 29, 3959.
[55] Hertog, H. J.; Buurman, D. J. Reactivity of 2,3-, 2,4-, and 3,4-Dibromoquinoline Towards
Potassium Amide in Liquid Ammonia. Recl. Trav. Chim. Pays-Bas, 1973, 304, 305.
[56] Ford, A.; Sinn, E.; Woodward, S. Exploitation of differential reactivity of the carbon–chlorine
bonds in 1,3-dichloroisoquinoline. Routes to new N,N-chelate ligands and 1,3-disubstituted
isoquinolines. J. Chem. Soc., Perkin Trans. 1, 1997, 927.
[57] Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Rombouts, G.; Pieters,
L.; Haemers, A.; Dommisse, R. A. Synthesis of Isocryptolepine via a Pd-Catalyzed ‘Amination-
Arylation’ Approach. Synlett, 2003, 615.
[58] Frost, C. G.; Mendonca, P. Recent developments in aromatic heteroatom coupling reactions.
J. Chem. Soc., Perkin Trans. 1, 1998, 2615.
[59] Muci, A. R.; Buchwald, S. L. Practical Palladium Catalysts for C-N and C-O Bond Formation.
Top. Curr. Chem., 2002, 219, 131.
[60] Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Industrial-Scale Palladium-Catalyzed
Coupling of Aryl Halides and Amines –A Personal Account. Adv. Synth. Catal., 2006, 348, 23.
[61] Hartwig, J. F. Discovery and Understanding of Transition-Metal-Catalyzed Aromatic Substitution
Reactions. Synlett, 2006, 1283.
[62] Joucla, L.; Djakovitch, L. Transition Metal-Catalysed, Direct and Site-Selective N1-, C2- or C3-
Arylation of the Indole Nucleus: 20 Years of Improvements. Adv. Synth. Catal., 2009, 351, 673.
[63] Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel, P. Modern Amination Reactions.
Eur. J. Org. Chem., 2007, 4166.
[64] Ames, D. E.; Bull, D. Some reactions of 3-halogenocinnolines catalysed by palladium
compounds. Tetrahedron, 1982, 38, 383.
[65] Iwaki, T.; Yasuhara, A.; Sakamoto, T. Novel synthetic strategy of carbolines via palladium-
catalyzed amination and arylation reaction. J. Chem. Soc., Perkin Trans. 1, 1999, 1505.
36
[66] Bedford, R. B.; Cazin, C. S. J. A novel catalytic one-pot synthesis of carbazoles via consecutive
amination and C–H activation. Chem. Commun., 2002, 2310.
[67] Hostyn, S.; Maes, B. U. W.; Pieters, L.; Lemiere, G. L. F.; Matyus, P.; Hajos, G.; Dommisse, R.
A. Synthesis of the benzo-β-carboline isoneocryptolepine: the missing indoloquinoline isomer in
the alkaloid series cryptolepine, neocryptolepine and isocryptolepine. Tetrahedron, 2005, 61,
1571.
[68] Gronowitz, S.; Bobosik, V.; Lawitz, K. Palladium Catalyzed Synthesis of Unsymmetrical
Bithienyls from Thiopheneboronic acids and Halothiophenes. Chem. Scr., 1984, 23, 120.
[69] Martin, A. R.; Yang, Y. H. Palladium-Catalyzed Cross-Coupling Reactions of Organoboronic
Acids with Organic Electrophiles. Acta Chem. Scand., 1993, 47, 221.
[70] Kermack, W. O.; Slater, R. H. CVII.—Syntheses in the indole series. Part III. The theory of
anhydronium base formation and the constitution of methosulphates, with some observations on
the fluorescence of 5 : 6-benz-4-carboline and its derivatives. J. Chem. Soc., 1928, 789.
[71] Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Junjappa, H. Palladium-Catalyzed Intramolecular N-
Arylation of Heteroarenes: A Novel and Efficient Route to Benzimidazo[1,2-a]quinolines. J. Org.
Chem., 2006, 71, 1280.
[72] Miki, Y.; Kuromatsu, M.; Miyatake, H.; Hamamoto, H. Synthesis of benzo-γ-carboline alkaloid
cryptosanginolentine by reaction of indole-2,3-dicarboxylic anhydrides with anilines.
Tetrahedron Lett., 2007, 48, 9093.
[73] Tanaka, D.; Romeril, S. P.; Myers, A. G. On the Mechanism of the Palladium(II)-Catalyzed
Decarboxylative Olefination of Arene Carboxylic Acids. Crystallographic Characterization of
Non-Phosphine Palladium(II) Intermediates and Observation of Their Stepwise Transformation in
Heck-like Processes. J. Am. Chem. Soc., 2005, 127, 10323.
[74] Tanaka, D.; Myers, A. G. Heck-Type Arylation of 2-Cycloalken-1-ones with Arylpalladium
Intermediates Formed by Decarboxylative Palladation and by Aryl Iodide Insertion.
Org. Lett., 2004, 6, 433.
[75] Myers, A. G.; Tanaka, D.; Mannion, M. R. Development of a Decarboxylative Palladation
Reaction and Its Use in a Heck-type Olefination of Arene Carboxylates. J. Am. Chem. Soc., 2002,
124, 11250.
[76] Mori, T.; Ichikawa, J. Radical 6-endo-trig Cyclization of β,β-Difluoro-o-isocyanostyrenes: A
Facile Synthesis of 3-Fluoroquinolines and Their Application to the Synthesis of 11-Alkylated
Cryptolepines. Synlett, 2007, 1169.
[77] Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de los Santos, J. M. The aza-Wittig reaction:
an efficient tool for the construction of carbon–nitrogen double bonds. Tetrahedron 2007, 63, 523.
[78] Fresneda, P. M.; Molina, P. Application of Iminophosphorane-Based Methodologies for the
Synthesis of Natural Products. Synlett, 2004, 1.
[79] Alajarin, M.; Molina, P.; Vidal, A. Formal Total Synthesis of the Alkaloid Cryptotackieine
(Neocryptolepine). J. Nat. Prod., 1997, 60, 747.
[80] Shi, C.; Zhang, Q.; Wang, K. K. Biradicals from Thermolysis of N-[2-(1-Alkynyl)phenyl]-N-
phenylcarbodiimides and Their Subsequent Transformations to 6H-Indolo[2,3-b]quinolines.
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
37
J. Org. Chem., 1999, 64, 925.
[81] Molina, P.; Fresneda, P. M.; Delgado, S. Iminophosphorane-Mediated Synthesis of the Alkaloid
Cryptotackieine. Synthesis, 1999, 326.
[82] Fresneda, P. M.; Molina, P.; Delgado, S. A novel approach to the indoloquinoline alkaloids
cryptotackieine and cryptosanguinolentine by application of cyclization of o-vinylsubstituted
arylheterocumulenes. Tetrahedron, 2001, 57, 6197.
[83] Agarwal, P. K.; Sharma, S. K.; Sawant, D.; Kundu, B. Application of the Pictet–Spengler reaction
to aryl amine-based substrates having pyrimidine as a π-nucleophile: synthesis of
pyrimidoquinolines with structural analogy to benzonaphthyridines present in alkaloids.
Tetrahedron, 2009, 65, 1153.
[84] Ho, T.-L.; Jou, D.-G. Synthesis of Cryptolepine and Cryptoteckieine from a Common
Intermediate. Helv. Chim. Acta, 2002, 85, 3823.
[85] Amiri-Attou, Q.; Terme, T.; Vanelle, P. Original and Rapid Access to New Alkaloid Analogues of
Neocryptolepine: Synthesis of Substituted 6-Methyl-6H-indolo[2,3-b]quinolines via TDAE
Strategy. Synlett, 2005, 3047.
[86] Ait-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier, W. R. Jr. Nucleophilic
Trifluoromethylation Using Trifluoromethyl Iodide. A New and Simple Alternative for the
Trifluoromethylation of Aldehydes and Ketones. Org. Lett., 2001, 3, 4271.
[87] Medebielle, M.; Keirouz, R.; Okada, E.; Ashida, T. Tetrakis(dimethylamino)ethylene (TDAE)
Mediated Addition of Heterocyclic Difluoromethyl Anions to Heteroaryl Aldehydes. A Facile
Synthetic Method for New gem-Difluorinated Alcohols Derived from 4-Bromo-1-naphthylamine
and 8-Quinolylamine. Synlett, 2001, 821.
[88] Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Double reductive cyclization: a facile synthesis
of the indoloquinoline alkaloid cryptotackieine. Tetrahedron Lett., 2007, 48, 7870.
[89] Sharma, S.; Kundu, B. Unprecedented SnCl2·2H2O-mediated intramolecular cyclization of
nitroarenes via C–N bond formation: a new entry to the synthesis of cryptotackieine and related
skeletons. Tetrahedron Lett., 2008, 49, 7062.
[90] Hoffmann, N. Photochemical Reactions as Key Steps in Organic Synthesis.
Chem. Rev., 2008, 108, 1052.
[91] Kumar, R. N.; Suresh, T.; Mohan, P. S. A photochemical route to synthesize
cryptosanguinolentine. Tetrahedron Lett., 2002, 43, 3327.
[92] Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Heteroatom directed photoannulation: synthesis of
indoloquinoline alkaloids: cryptolepine, cryptotackieine, cryptosanguinolentine, and their methyl
derivatives. Tetrahedron, 2006, 62, 6258.
[93] Pitchai, P.; Mohan, P. S.; Gengan, R. M. Photo induced synthesis of methyl derivative of
cryptosanguinolentine. Indian J. Chem., 2009, 48B, 692.
[94] Renault, J.; Mlliet, P.; Reanault, S.; Berlot, J. A Convenient Synthesis of 3-Halo-4-oxo-1,4-
dihydroquinolines (3-Halo-4-hydroxyquinolines). Synthesis, 1977, 865.
[95] Horning, E. C.; Horning, M. G.; Walker, G. N. Aromatization Studies. VII. Alkylcarbazoles. J.
Am. Chem. Soc., 1948, 70, 3935.
38
[96] Graebe, C.; Ullmann, F. Graebe-Ullmann Synthesis. Justus Liebigs Ann. Chem., 1896, 291, 16.
[97] Godlewska, J.; Luniewski, W.; Zagrodzki, B.; Kaczmarek, L.; Bielawska-Pohl, A.; Dus, D.;
Wietrzyk, J.; Opolski, A.; Siwko, M.; Jaromin, A.; Jakubiak, A.; Kozubek, A.; Peczynska-Czoch,
W. Biological Evaluation of ω-(Dialkylamino)alkyl Derivatives of 6H-indolo[2,3-b]quinoline –
Novel Cytotoxic DNA Topoisomerase II Inhibitors. Anticancer Res., 2005, 25, 2857.
[98] Sayed, I. E.; Van der Veken, P.; Steert, K.; Dhooghe, L.; Hostyn, S.; Van Baelen, G.; Lemiere, G.;
Maes, B. U. W.; Cos, P.; Maes, L.; Joossens, J.; Haemers, A.; Pieters, L.; Augustyns, K. Synthesis
and Antiplasmodial Activity of Aminoalkylamino-Substituted Neocryptolepine Derivatives. J.
Med. Chem., 2009, 52, 2979.
[99] Vera-Luque, P.; Alajarin, R.; Alvarez-Builla, J.; Vaquero, J. J. An Improved Synthesis of α-
Carbolines under Microwave Irradiation. Org. Lett., 2006, 8, 415.
[100] Cooper, M. M.; Lovell, J. M.; Joule, J. A. Indole-β-nucleophilic substitution. Part 9 nitrogen
nucleophiles. Syntheses of hydroxycryptolepine, cryptolepine, and quindoline. Tetrahedron
Lett., 1996, 37, 4283.
[101] Bierer, D. E.; Dubenko, L. G.; Zhang, P.; Lu, Q.; Imbach, P. A.; Garofalo, A. W.; Phuan, P.-W.;
Fort, D. M.; Litvak, J.; Gerber, R. E.; Sloan, B.; Luo, J.; Cooper, R.; Reaven, G. M.
Antihyperglycemic Activities of Cryptolepine Analogues: An Ethnobotanical Lead Structure
Isolated from Cryptolepis sanguinolenta. J. Med. Chem., 1998, 41, 2754.
[102] Holt, J. S.; Petrow, V. Carbazoles, carbolines, and related compounds. I Quindoline derivatives.
J. Chem. Soc., 1947, 607.
[103] Degutis, J.; Ezerskaite, A. Alkylation of quindoline and 11-quindolinecarboxylic acid.
Khim. Geterotsikl. Soedin., 1986, 1375 (Chem. Abstr. no. 107 : 39658y).
[104] Yang, S.-W.; Abdel-Kader, M.; Malone, S.; Werkhoven, M. C. M.; Wisse, J. H.; Bursuker, I.;
Neddermann, K.; Fairchild, C.; Raventos-Suarez, C.; Menendez, A. T.; Lane, K.; Kingston, D.
G. I. Synthesis and Biological Evaluation of Analogues of Cryptolepine, an Alkaloid Isolated
from the Suriname Rainforest. J. Nat. Prod., 1999, 62, 976.
[105] Onyeibor, O.; Croft, S. L.; Dodson, H. I.; Feiz-Haddad, M.; Kendrick, H.;
Millington, N. J.; Parapini, S.; Phillips, R. M.; Seville, S.; Shnyder, S. D.; Taramelli, D.; Wright,
C. W. Synthesis of Some Cryptolepine Analogues, Assessment of Their Antimalarial and
Cytotoxic Activities, and Consideration of Their Antimalarial Mode of Action. J. Med. Chem.,
2005, 48, 2701.
[106] Radl, S.; Konvicka, P.; Vachal, P. A New Approach to the Synthesis of Benzofuro[3,2-
b]quinolines, Benzothieno[3,2-b]quinolines and Indolo[3,2-b]quinolines. J. Heterocycl. Chem.,
2000, 37, 855.
[107] Radl, S. Some Examples of Aromatic Nucleophilic Denitrocyclization Reactions. Janssen
Chimica Acta., 1993, 11, 12.
[108] Engqvist, R.; Bergman, J. An improved synthesis of neocryptolepine. Org. Prep. Proced. Int.,
2004, 36, 386.
[109] Sundaram, G. S. M.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. A Concise Formal
Synthesis of Alkaloid Cryptotackiene and Substituted 6H-Indolo[2,3-b]quinolines.J. Org. Chem.,
Author version: Curr. Org. Chem., vol.15(7); 2011; 1036-1057
39
2004, 69, 5760.
[110] Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Fischer indole synthesis of the indoloquinoline
alkaloid: cryptosanguinolentine. Tetrahedron Lett., 2005, 46, 4509.
[111] Dutta, B.; Some, S.; Ray, J. K. Thermal cyclization of 3-arylamino-3-(2-nitrophenyl)-propenal
Schiff base hydrochlorides followed by triethyl phosphite mediated deoxygenation: a facile
synthesis of quindolines. Tetrahedron Lett., 2006, 47, 377.
[112] Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. Microwave-Assisted Syntheses of N-Heterocycles
Using Alkenone-, Alkynone- and Aryl-carbonyl O-Phenyl Oximes: Formal Synthesis of
Neocryptolepine. J. Org. Chem., 2008, 73, 5558.
[113] Bergman, J.; Engqvist, R.; Stalhandske, C.; Wallberg, H. Studies of the reactions between indole-
2,3-diones (isatins) and 2-aminobenzylamine. Tetrahedron, 2003, 59, 1033.
[114] Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. An Expeditious I2-Catalyzed Entry into 6H-
Indolo[2,3-b]quinoline System of Cryptotackieine. J. Org. Chem., 2009, 74, 8369.
[115] Kraus, G. A.; Guo, H. A direct synthesis of neocryptolepine and isocryptolepine. Tetrahedron
Lett., 2010, 51, 4137.
[116] Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Biomimetic Approach to Perophoramidine and
Communesin via an Intramolecular Cyclopropanation Reaction. Org. Lett., 2006, 8, 2187.