Synthesis of some fused β-carbolines including the first example of the pyrrolo[3,2-c]-β-carboline system

Article abstract of DOI:10.1002/jhet.5570410409

Condensation of 1-methyl-β-carboline-3-carbaldehyde with ethyl azidoacetate and subsequent thermolysis of the resulting azidopropenoate was used to [c] annulate a pyrrole ring onto the β-carboline moiety, thus producing the first example of the pyrrolo[3,

Full text of DOI:10.1002/jhet.5570410409

Jul-Aug 2004
Synthesis of some Fused β-Carbolines Including the First Example of
the Pyrrolo[3,2-c]-β-carboline System
531
Glenn C. Condie and Jan Bergman*
Unit for Organic Chemistry, CNT, Department of Biosciences at Novum, Karolinska Institute, Novum
Research Park, SE-141 57 Huddinge, Sweden.
Received January 16, 2004
Condensation of 1-methyl-β-carboline-3-carbaldehyde with ethyl azidoacetate and subsequent thermoly-
sis of the resulting azidopropenoate was used to [c] annulate a pyrrole ring onto the β-carboline moiety, thus
producing the first example of the pyrrolo[3,2-c]-β-carboline ring system. The latter ring system results
from cyclization at the C-4 carbon, whereas cyclization at the N-2 nitrogen atom also occurs to form a pyra-
zolo[3,2-c]-β-carboline ring system. Condensation of β-carboline-1-carbaldehyde with ethyl azidoacetate
produced a non-isolable intermediate, which immediately underwent cyclization, however in this case
cyclization occurred via attack at the ester and the azide remained intact. The resulting 5-azidocanthin-6-one
was transformed to the first examples of 5-aminocanthin-6-ones. β-Carboline-1,3-dicarbaldehyde failed to
give an acceptable reaction with ethyl azidoacetate, but did undergo selective condensation with dimethyl
acetylene dicarboxylate at the C-1 carbaldehyde with concomitant cyclization to form a highly functional-
ized 2-formyl-canthine derivative.
J. Heterocyclic Chem., 41, 531 (2004).
Introduction.
(6) [7], particularly with respect to the position of the new
pyrrolo nitrogen. We envisioned the synthesis of 5 from a
β-carboline-3-carbaldehyde, via Hemetsberger methodol-
ogy [8]. Here we report a brief study of the condensation
of β-carboline-carbaldehydes with ethyl azidoacetate
towards the formation of new ring systems.
The potential DNA-intercalating ability of polycyclic N-
heteroaromatic compounds has spurred much interest in
this area in recent years [1], exemplified by ellipticine (1)
[2] and syntheses directed towards the preparation of ellip-
ticine analogues [1c]. We are interested in annulated β-
carbolines, particularly those bearing extended [a], [b] and
[
c] annulated heteroarene rings (Figures 1 and 2) since
they have potential as DNA intercalators.
Figure 1
The preparations of new tetrahydro-β-carboline-contain-
ing ring systems bearing further rings fused at either the
[
a], or [b] position, or at both of these positions, have
recently been disclosed by Nefzi and co-workers [3].
However, as planarity seems to be an important require-
ment towards DNA intercalation, our interests lies primar-
ily in fully aromatic annulated β-carbolines and we note
the recent first syntheses of such compounds as indazolo-
Figure 2
[
3,2-a]-β-carbolines and benzo[4',5'][1,2,3]triazino[6,1-
a]-β-carbolines [1d], imidazo[4,5-c]-β-carbolines (2) [4],
and pyrazolo[4,3-c]-β-carbolines (3) [5]. A whole series
of compounds based on 7,12-dihydropyrido[3,2-:5,4-
Results and Discussion.
1. Reactions of β-Carboline-3-carbaldehydes with Ethyl

']diindole (4) have been synthesized and employed as
azidoacetate.
probes, "molecular yardsticks" to define the spatial dimen-
sions of the lipophilic regions of the benzodiazepine recep-
tor binding cleft [6], whilst the parent pyrrolo[3,2-c] -β-
carboline (5) itself remained unknown. We note the struc-
tural similarity between 5 and the staurosporine aglycone
Our previous report concerning the synthesis of canthine
and canthinone derivatives utilized 1-dichloromethyl-β-
carboline-3-carboxylate (7), which is readily available
from L-tryptophan in two steps via a convenient and high

532
G. C. Condie and J. Bergman
Vol. 41
yielding synthesis that requires no purification [9]. In that
work, 1-dichloromethyl-β-carboline-3-carboxylate (7)
was converted to the corresponding ester 8 in quantitative
yield using ethereal diazomethane. Reduction of the ester
using lithium aluminium hydride proceeded cleanly and
gave the known alcohol, 3-hydroxymethylharmane [10]
with pyridines substituted with an aldehyde at either C-2
[13-15], C-3 [15-17], or C-4 [15-16] have been described,
generally occurring in low to moderate yields. The subse-
quent thermal decomposition of the resulting vinyl azides
has received little attention, a 4-substituted 3-pyridyl vinyl
azide (12) gave a good yield of the expected 7-azaindole
13 (Scheme 2) [17], however thermolysis of ethyl 2-azido-
3-(2-pyridyl)propenoate (14) gave a very high yield of a
pyrazolopyridine 15 resulting from cyclization of the
vinylnitrene intermediate onto the pyridine nitrogen
(Scheme 2) [14], and not a pyrrolopyridine which would
result from cyclization onto the pyridine C-3 position.
Condensation of aldehyde 10 with a ten times excess of
ethyl azidoacetate proceeded very slowly at –15 ºC, while
(9) in 86% yield. Alternatively, reduction of the free acid
7
with lithium aluminium hydride proceeded in essentially
quantitative yield. Shorter reaction times during the latter
reduction led to an incomplete conversion as evident by
the isolation, in up to 8% yield, of aldehyde 10. Oxidation
of alcohol 9 proceeded in a very sluggish manner using
"
1
very active manganese dioxide", [11] however aldehyde
0 was consistently prepared in 87% yield (Scheme 1).
Heating 3-hydroxymethyl-β-carboline (9) in glacial
Scheme 2
acetic acid simply resulted in the formation of acetoxy
derivative 11, which clearly shows the behavioural differ-
ences between the less reactive pyridine ring and that of
indole, since in the case of a hydroxymethylindole, a diin-
dolylmethane will often form via intramolecular substitu-
tion by the nucleophilic indole [12].
A search through the literature revealed no reference to
either a β-carboline-3-carbaldehyde or 1-carbaldehyde
having been condensed with an alkyl azidoacetate, and
hence further ring formation from such an intermediate
has not been described. The corresponding condensation

Jul-Aug 2004
Synthesis of some Fused β-Carbolines
533
allowing the temperature to rise above 0 ºC incurred visi-
ble decomposition of the azide. Non-dehydrated alcoholic
intermediates were sometimes observed by H NMR
Initially we looked favourably upon the methyl sub-
stituent at C-1 of aldehyde 10 , since the compounds
formed from 10 would be derivatives of harmane (1-
methyl-β-carboline) [19], but furthermore, the position of
the methyl group bears some resemblance to the corre-
sponding substituent in ellipticine (1). However, its pres-
ence might have caused some steric hindrance about the
pyridine nitrogen, hindering attack at this position during
the thermolysis of 18. Furthermore, the acidic nature of
this group may have interfered with the condensation of 10
with ethyl azidoacetate and therefore the parent aldehyde
[20] (16) was employed, but condensation of 16 with ethyl
azidoacetate failed to provide the corresponding 2-azido-
propenoate. The N-protected aldehyde (17), which con-
tains a less activated β-carboline ring system and therefore
more reactive aldehyde group, similarly failed. In both of
these cases little reaction was observed, whilst any product
formed could not be separated from the starting material.
1
analysis during the reaction and it was deemed necessary
to allow the reaction to warm to room temperature to effect
complete dehydration to form the unsaturated azide (18).
Perhaps consequently, full conversion of the aldehyde was
not achieved, 44% of the starting material was recovered,
and with consideration of the 56% conversion of the start-
ing material, the crude 2-azidopropenoate 18 was recov-
ered in a modest 55% yield after deduction of the recov-
ered starting material (31% yield without this deduction).
Thermolysis of 2-azidopropenoate 18 produced two prod-
ucts which were easily separated by chromatography and
thus the pyrrolo[4',5':5,6]pyrido[3,4-b]indole derivative
(
[
1 9) and its structural isomer pyrazolo[1',5':1,6]pyrido-
3,4-b]indole derivative (20) were each recovered in 41%
1
yield (Scheme 3). The H NMR spectrum of the pyrrolo-
[
3,2-c]-β-carboline (19) exhibited two NH resonances,
2
. Reaction of 1-Formyl-β-carboline with Ethyl azido-
both of which underwent exchange with D O, while the
2
acetate.
absence of a signal assignable to a β-carboline H4 proton,
indicates that substitution has occurred at C-4. A singlet
appearing at 7.47 ppm was assigned to H3. Conversely,
the H NMR spectrum of the pyrazolo[3,2-c]-β-carboline
(
assigned to the H4 proton coincides with that expected for
the β-carboline H4 proton. A singlet appearing at 7.26 was
assigned to H3.
We have previously reported the preparation of aldehyde
21 from the 1-dichloromethyl-β-carboline [9] (7), indeed
the aldehyde 21 was prepared in four steps from readily
available tryptophan in 54% overall yield. Condensation
of aldehyde 21 with ethyl azidoacetate gave the 5-azido-
canthin-6-one derivative (2 4) directly and in good yield
(Scheme 4).
1
20) exhibited a single NH resonance, while a singlet
Scheme 3
The pyrazolo[1',5':1,6]pyrido[3,4-b]indole ring system
is rare; there are only a few reports dealing with the
reduced 9,10-dihydro system, which have been reported to
exhibit pepsin-inhibiting and anti-ulcerogenic properties
Presumably, the cis-isomer 23 (cis with respect to the
ester) is formed preferentially and undergoes spontaneous
cyclization. 1H NMR analysis revealed that the reaction
proceeds in a very clean manner and only signals attrib-
uted to the starting material (2 1) and product 24 were
observed.
[18], whilst the fully unsaturated pyrazolo[1',5':1,6]pyrido-
[
3,4-b]indole is hitherto unknown. The presumed pla-
narity, as well as the potential bridgehead quarternary
nitrogen, ought to make product 20 a possible candidate
for DNA intercalating studies.
The alternative product 25 shown in Scheme 4, resulting
from decomposition of azide 23 and the subsequent
cyclization of the presumed nitrene intermediate onto the

534
G. C. Condie and J. Bergman
Vol. 41
pyridine nitrogen, i.e. at N-2, analogous to the formation of
5 from 14 (Scheme 2), was not expected to form under
Scheme 5
1
the mild conditions employed for the condensation of alde-
hyde 21 and ethyl azidoacetate. However, whilst we were
unable to isolate the presumed non-cyclized intermediate
2
3 (or the corresponding trans isomer), we were interested
in examining the thermal decomposition of such a com-
pound as the resulting pyrazolo[1,5-a]-β-carboline struc-
ture (25) is unknown. The [a] benzo-annulated ring sys-
tem of 25 has only recently been synthesized for the first
time [1d] and its intercalation ability has been examined
[
1c]. Our strategy was to block the indole nitrogen N-9
with a methyl substituent, however the resulting aldehyde
2 failed to condense with ethyl azidoacetate. This failure
2
could in part be due to steric hindrance in the proximity of
the aldehyde caused by the N-substituent, conversely, we
feel that the ready condensation of aldehyde 21 with ethyl
azidoacetate was facilitated by the subsequent intramolec-
ular cyclization, which would reduce the steric hindrance
of the azidopropenoate substituent at C-1 of the presumed
intermediate 23.
The reduction of azide 24 to the corresponding amino
derivative 27 was achieved in high yield using palladium-
catalyzed hydrogenation. An alternate two-step reduction
gave the expected phosphine imine 26, contaminated with
triphenylphosphine oxide, in low yield after chromatogra-
phy on silica gel, whilst the major product isolated was the
amine 27. Presumably, hydrolysis of 26 occurs in the pres-
ence of silica gel and unfortunately the resulting amine 27
has an undesirable affinity for silica gel. Fortunately, par-
tial precipitation of phosphine imine 26 usually occurs
[
21] involving an initial reaction with triphenylphosphine,
Scheme 6

Jul-Aug 2004
Synthesis of some Fused β-Carbolines
535
during the reaction and 26 was collected in an analytically
pure state and fully characterized. Amine 27 was found to
be relatively insoluble and consequently the more soluble
acetyl derivative 28 was prepared and fully characterized.
It is worth noting that the 5-aminocanthin-6-ones (24-
bolines 35 [24], which, not surprisingly, underwent
cyclization to the hexahydroindolizino[8,7-b]indole deriv-
atives (36) (Scheme 7).
3
. Reaction of 1,3-β-Carbolinedicarbaldehyde with Ethyl
Azidoacetate and other Activated Methylene Compounds.
2
8) are the first examples of canthin-6-ones or indeed can-
thine derivatives possessing a nitrogen substituent at the
C-5 position. The only other heteroatom substituent
observed at the C-5 position of canthin-6-one or canthine
derivatives described previously have been hydroxy or
alkoxy substituents [22] and we anticipate the future isola-
tion of canthine derived natural products containing a C-5
nitrogen substituent. It is also interesting to note the
potential biosynthetic pathway to the formation of 5-
aminocanthin-6-ones (Scheme 6).
Thus 5-aminocanthin-6-one 27 could result from the
oxidation of the product formed from the favoured
intramolecular cyclization of β-(β-carboline)alanine (29).
The latter product could result from oxidation of the prod-
uct formed from the biosynthetic Pictet Spengler-type [23]
condensation of tryptophan (3 0) with 2-amino-4-oxobu-
tanoic acid (31) or aspartic acid (32). However, the reac-
tion of tryptophan methyl and benzyl esters (33) with alde-
hyde 34 has been conducted under Pictet-Spengler condi-
tions by De la Figuera et. al. to provide tetrahydro-β-car-
We have previously described the high yielding conver-
sion of 1-dichloromethyl-β-carboline (7) to 1-formyl-β-
carboline [9] (3 7), conducted under acidic conditions.
Reduction of 37 with lithium aluminium hydride gave the
diol 38 in moderate yield, whilst the subsequent oxidation
with "very active manganese dioxide" consistently gave
39, but in only 58% yield.
The double condensation of dialdehyde 39 with ethyl
azidoacetate did not give any reasonable product, however
regioselective condensation of dialdehyde 3 9 w i t h
dimethyl acetylene dicarboxylate (DMAD) in the presence
of triphenylphosphine gave a high yield of the canthine
derivative (41). The mechanism is assumed to be analo-
gous to that proposed by Yavari and co-workers for similar
condensations of DMAD in the presence of triphenyl
phosphine with aldehydes and leading to the preparation of
various heterocycles [25]. Hence, a 1:1 adduct is formed
between triphenylphosphine and DMAD, which deproto-
nates the β-carboline and the latter species subsequently

536
G. C. Condie and J. Bergman
Vol. 41
attacks the 1:1 adduct to form phosphorane 40, and
cyclization is accomplished via an intramolecular Wittig
reaction to give the functionalized unsaturated canthine
derivative (41) (Scheme 9). The formation of the phos-
phorane via substitution onto the β-carboline N9 conse-
quently allows for the regioselective Wittig reaction to
occur exclusively at the aldehyde substituent at C1.
Mass spectra (ESI) were obtained using a Perkin-Elmer API 150
EX spectrometer. Elemental analyses were performed by H. Kolbe
Mikroanalytisches Laboratorium, Mulheim an der Ruhr, Germany.
Melting points were measured on a Buchi B-545 apparatus and are
uncorrected. Chromatography was performed using Merck Silica
Gel 60. All solvents were purified by distillation or otherwise were
analytical grade and used as received. Tetrahydrofuran was dis-
tilled from sodium and benzophenone.
We have previously described the reaction of the less
reactive aldehyde 21 under similar conditions [9], which
gave a high yield of the corresponding canthine derivative
containing an ester at C-2, but took 20 hours.
3-Hydroxymethyl-1-methylpyrido[3,4-b]indole (9).
Method A.
A suspension of LiAlH (0.16 g, 4.2 mmol) in anhydrous THF
4
(
10 mL) was stirred and cooled in a salt-ice slurry, under nitro-
Having regioselectively reacted the C-1 aldehyde of
dialdehyde 39 we next looked at the reactivity of the
remaining aldehyde of product 41, however attempted
condensation with ethyl azidoacetate gave a complex mix-
ture, which is not entirely surprising given that the highly
functionalized canthine (4 1) ought to be susceptible to
Michael addition at C-4.
gen. A solution of methyl 1-dichloromethyl-β-carboline-3-car-
boxylate [9] (8) (0.250 g, 0.809 mmol) in anhydrous THF (20
mL) was added dropwise, over 14 minutes, and stirring was con-
tinued for 70 minutes with cooling and under argon. Water (0.23
mL) was cautiously added dropwise, followed by 2 M NaOH (1.7
mL), and finally further water (1.7 mL). The resulting precipitate
was filtered and washed with ethyl acetate. The combined filtrate
was washed with brine twice, dried (MgSO ), and evaporated in
4
vacuo and the remaining residue was purified via column chro-
EXPERIMENTAL
matography (alumina-5% MeOH/CH Cl ) to give the title com-
2
2
pound (0.148 g, 86%) as a colourless powder, mp 192–194 ºC
(lit. [10] 196–197 ºC).
NMR spectra were recorded on a Bruker DPX 300 spectrometer,
at 300 MHz for H and 75.4 MHz for 13C. Chemical shifts were
recorded as δ values in parts per million (ppm). Protons attached to
1
Method B.
heteroatoms were confirmed using D O exchange experiments.
Infrared spectra were recorded on a Thermo Nicolet® Avatar® 330
Fourier Transform Infrared Spectrophotometer as neat samples.
Following Method A, but with β-carboline 7 (0.250 g, 0.847
mmol) and a duration of 4 hours, gave the title compound (0.178
g, 99%) as a white powder.
2

Jul-Aug 2004
Synthesis of some Fused β-Carbolines
537
1-Methylpyrido[3,4-b]indole-3-carbaldehyde (10).
Anal. Calcd. for C18H18N O : C, 69.66; H, 5.85; N, 9.03.
2 3
Found: C, 69.58; H, 5.74; N, 8.86.
3
-Hydroxymethyl-β-carboline (9) (0.100 g, 0.446 mmol) and
manganese dioxide [11] (0.388 g, 4.46 mmol) were heated at
reflux together in dry dichloromethane (35 mL) for two days.
The resulting mixture was passed through a short column of sil-
ica, topped with a thin layer of celite, initially using
dichloromethane, and then 5% MeOH/CH Cl to give the title
Methyl 2-Azido-3-(1-methylpyrido[3,4-b] i n d o l - 3 - y l ) - 2 -
propenoic Acid (18).
Sodium (0.10 g, 4.4 mmol) was dissolved in methanol (4.0 ml)
and the stirred solution was cooled in a salt-ice slurry, under
a rgon. A solution containing β-carboline-3-carbaldehyde (1 0)
2
2
compound (86 mg, 87%) as an off-white powder, mp 208–209
ºC; R (5% MeOH/CH Cl ) 0.33; ir: 3279, 2825, 1681, 1591,
(
0.100 g, 0.476 mmol) and ethyl azidoacetate (0.625 g, 4.8
f
2
2
mmol) in methanol (8.0 mL) was added dropwise, over 28 min-
utes, to the methoxide solution and the resulting bright yellow
solution was stirred further with cooling for 4 hours. The cooling
bath was then removed and the solution was stirred at ambient
temperature for 22 hours before it was poured onto ice and
allowed to sit overnight. The resulting precipitate was collected
by filtration, washed with water, and dried to give the title com-
pound (45 mg, 31%). The mother liquor was extracted with ethyl
acetate and the organic extract was washed with brine, dried
–
1 1
1
571, 1503, 1370, 1343, 1249, 844, 740 cm ; H nmr (dimethyl
sulfoxide-d ): δ 12.12 (s, 1H, NH), 10.06 (s, 1H, CHO), 8.65 (s,
6
1
1
H, H4), 8.36 (d, J = 7.9 Hz, 1H, aryl CH), 7.67 (d, J = 8.1 Hz,
H, aryl CH), 7.60 (t, J = 8.1 Hz, 1H, aryl CH), 7.32 (t, J = 7.9
1
3
Hz, 1H, aryl CH), 2.85 (s, 3H, CH3); C nmr (dimethyl sulfox-
ide-d ): δ 192.83 (CHO), 142.75 (2 C, aryl C), 140.82, 136.94
6
(
1
aryl C), 128.52 (aryl CH), 126.81 (aryl C), 122.18 (aryl CH),
21.53 (aryl C), 120.33, 113.36, 112.41 (aryl CH), 20.27 (CH );
3
+
+
ms: m/z = 211 [M+H] , 209 [M-H] .
(
MgSO ), and evaporated in vacuo to give starting material (44
4
A n a l. Calcd. for C13H10N O: C, 74.27; H, 4.79; N, 13.33.
2
mg). The yield of the title compound was 55%, taking into
account the recovered starting material, obtained as a pale orange
powder, mp 164 ºC (decomp.); R (2.5% MeOH/CH Cl ) 0.18;
Found: C, 74.16; H, 4.73; N, 13.24.
3-Acetoxymethyl-1-methylpyrido[3,4-b]indole (11).
f
2
2
ir: 2119, 1719, 1693, 1624, 1500, 1342, 1297, 1233, 1209, 1080,
3
-Hydroxymethyl-β-carboline (9) (0.183 g, 0.862 mmol) was
9
1
7
7
04, 825, 742 cm–1; 1H nmr (dimethyl sulfoxide-d ): δ 11.85 (s,
stirred in glacial acetic acid at room temperature for 5 days, fol-
lowed by heating at reflux for 14 hours. The resulting dark solu-
tion was evaporated in vacuo and the remaining residue purified
via column chromatography (silica gel-ethyl acetate) to give the
title compound (0.133 g, 61%) as a pale yellow powder, mp
6
H, NH), 8.87 (s, 1H, H4'), 8.31 (d, J = 7.8 Hz, 1H, aryl CH),
.63-7.53 (m, 2H, aryl CH), 7.27 (t, J = 7.0 Hz, 1H, aryl CH),
.18 (s, 1H, H3), 3.87 (s, 3H, OCH ), 2.76 (s, 3H, CH ); 13C nmr
3
3
(
dimethyl sulfoxide-d ): δ 164.56 (CO CH ), 143.18, 141.64,
6 2 3
1
1
41.06, 134.92 (aryl C), 129.02, 128.20 (aryl CH), 127.89,
24.30 (aryl C), 122.81 (aryl CH), 122.18 (aryl C), 120.68,
1
1
25–127 ºC; R (10% MeOH/CH Cl ) 0.39; ir: 3340, 1705, 1626,
f 2 2
564, 1501, 1455, 1360, 1263, 1249, 1234, 1026, 954, 879, 745
cm ; 1H nmr (deuteriochloroform): δ 10.17 (bs, 1H, NH), 8.07
d, J = 7.9 Hz, 1H, aryl CH), 7.91 (s, 1H, H4), 7.52–7.43 (m, 2H,
aryl CH), 7.26 (t, J = 8.0 Hz, 1H, aryl CH), 5.41 (s, 2H, CH ),
–
1
116.28, 11 3 . 11 (aryl CH and C-3), 53.89 (CO CH ), 21.30
2 3
+
(
CH ); ms: m/z = 306 [M-H] .
(
3
A n a l. Calcd. for C16H13N O : C, 62.53; H, 4.26; N, 22.79.
5
2
2
1
3
Found: C, 62.44; H, 4.33; N, 22.68.
2
.75 (s, 3H, CH ), 2.06 (s, 3H, COCH ); C NMR (deuteri-
3 3
ochloroform): δ 170.78 (COCH ), 142.92, 141.44, 140.38,
3
Thermolysis of Methyl 2-Azido-3-(1-methylpyrido[3,4-b]indol-
1
33.92, 128.36 (aryl C), 127.83, 121.29 (aryl CH), 121.21 (aryl
3
-yl)-2-propenoic Acid (10).
C), 119.53, 112.21, 111.27 (aryl CH), 67.49 (CH ), 20.58, 19.51
2
+
A solution of the azidopropenoate 10 (32 mg, 0.10 mmol) in
5% dichloromethane/xylene (40 mL) was added dropwise, over
3 minutes, to a vigorously stirred and rapidly refluxing solution
(
COCH and CH ); ms: m/z = 253 [M-H] .
3 3
2
1
A n a l. Calcd. for C15H14N O : C, 70.85; H, 5.55; N, 11.02.
2
2
Found: C, 70.69; H, 5.48; N, 10.92.
of xylene (10 mL), at such a rate as to allow the dichloromethane
to be rapidly distilled off. A reflux condenser was then installed
and heating at reflux was continued for one hour. The solution
was then allowed to cool, evaporated in vacuo, and the remaining
residue was purified via column chromatography (silica gel-ethyl
acetate) to give two products;
9
- tert-Butyloxycarbonyl-1-methylpyrido[3, 4- b]indole-3-car-
baldehyde (17).
A suspension of β-carboline 10 (0.116 g, 0.55 mmol) and di-
t e rt-butyldicarbonate (0.249 g, 1.14 mmol) in anhydrous acetoni-
trile (25 mL), containing a catalytic quantity of N,N- d i m e t h y-
laminopyridine, was stirred at room temperature, under nitrogen,
for 50 minutes. The solvent was then evaporated in vacuo and the
remaining residue purified v i a column chromatography (silica gel-
chloroform) to give the title compound (0.117 g, 68%) as a white
Methyl 1,6-Dihydro-5-methylpyrrolo[4',5':5,6]pyrido[3,4-
b]indole-2-carboxylate (19).
The title compound (12 mg, 41%) was recovered as a pale yel-
powder, mp 144–145 ºC (decomp.); R (10% MeOH/CH Cl )
low powder, mp 265 ºC (decomp.); R (2.5% MeOH/CH Cl )
f
2
2
f 2 2
0
1
.52; ir: 2856, 1738, 1689, 1569, 1440, 1369, 1343, 1284, 1228,
0.06; ir: 3314, 1676, 1529, 1353, 1289, 1272, 1207, 1168, 1101,
–1
1
–1 1
150, 1110, 916, 836, 766, 742 cm
;
H nmr (deuteriochloro-
1006, 827, 760, 736 cm ; H nmr (deuteriochloroform): δ 9.44
and 8.83 (each bs, 1H, NH), 8.19 (d, J = 7.8 Hz, 1H, aryl CH),
7.61-7.52 (m, 2H, aryl CH), 7.47 (s, 1H, H3), 7.37 (t, J = 7.2 Hz,
form): δ 10.15 (s, 1H, CHO), 8.37 (s, 1H, H4), 8.05 (d, J = 8.5 Hz,
1
1
1
1
1
1
H, aryl CH), 8.01 (d, J = 7.7 Hz, 1H, aryl CH), 7.59 (t, J = 8.4 Hz,
H, aryl CH), 7.40 (t, J = 7.5 Hz, 1H, aryl CH), 2.85 (s, 3H, CH ),
1
3
1H, aryl CH), 3.99 (s, 3H, OCH ), 2.87 (s, 3H, CH ); C NMR
3
3
3
1
3
.73 (s, 9H, C(CH ) ); C NMR (dimethyl sulfoxide-d ): δ
(deuteriochloroform): δ 162.59 (CO CH ), 139.74, 138.83,
3
3
6
2 3
93.01 (CHO), 149.55 (CO), 146.87 (aryl C), 146.71 (2 C, aryl C),
40.45, 136.50, 133.23 (aryl C), 129.92, 123.68, 121.26, 115.22,
136.82, 132.61 (aryl C), 127.15 (aryl CH), 125.77, 124.34 (aryl
C), 122.15, 120.68 (aryl CH), 120.26, 112.61 (aryl C), 111.89
10.95 (aryl CH), 85.44 (C(CH ) ), 28.04 (C(CH ) ), 24.83
(aryl CH), 109.50 (C-3), 52.05 (CO CH ), 20.39 (CH ); ms: m/z
3
3
3 3
2 3 3
+
+
+
(CH ); ms: m/z = 311 [M+H] .
= 280 [M+H] , 278 [M-H] .
3

538
G. C. Condie and J. Bergman
Vol. 41
A n a l. Calcd. for C16H13N O : C, 68.81; H, 4.69; N, 15.05.
192.27 (CHO), 164.89 (CO CH ), 142.88, 136.92, 135.89,
2 3
3
2
Found: C, 68.68; H, 4.74; N, 15.15.
135.72, 131.74 (aryl C), 129.70, 121.95, 121.38, 120.32 (aryl
CH), 120.17 (aryl C), 110.97 (aryl CH), 52.23 (CO CH ), 34.13
2
3
Methyl 10-Methylpyrazolo[1',5':1,6]pyrido[3,4-b]indole (20).
The title compound (12 mg, 41%) was recovered as a pale yel-
+
(
CH ); ms: m/z = 269 [M+H] .
3
A n a l. Calcd. for C15H12N O : C, 67.16; H, 4.51; N, 10.44.
2
3
low powder, mp 260 ºC (decomp.); R (2% MeOH/CH Cl ) 0.35;
f
2
2
Found: C, 67.04; H, 4.60; N, 10.33.
ir: 3325, 1712, 1616, 1538, 1495, 1482, 1466, 1390, 1311, 1216,
–
1
1
5-(Triphenylphosphoranylidene)amino-6-oxoindolo[3,2,1-de]-
1
183, 1007, 841, 765, 745, 689 cm ; H nmr (dimethyl sulfox-
[1,5]naphthyridine-2-carboxylate (26).
ide-d ): δ 11.04 (bs, 1H, NH), 8.39 (s, 1H, H4), 8.17 (d, J = 6.7
6
Hz, 1H, aryl CH), 7.49-7.40 (m, 2H, aryl CH), 7.26 (s, 1H, H3),
A suspension of azide 24 (101 mg, 0.32 mmol) and triph-
7
.15 (t, J = 6.7 Hz, 1H, aryl CH), 3.89 (s, 3H, OCH ), 2.95 (s, 3H,
3
enylphosphine (83 mg, 0.32 mmol) in dichloromethane (5 mL)
was stirred at room temperature for 2 hours. The resulting pre-
cipitate was collected by filtration and washed with a little
dichloromethane and dried to give the title compound (63 mg,
36%) as a bright yellow powder, mp 276 ºC (decomp.); Rf
13
CH3); C (dimethyl sulfoxide-d ): δ 163.91 (CO CH ), 145.08,
6
2
3
1
43.03, 138.19, 131.96 (aryl C), 129.74 (aryl CH), 126.71 (aryl
C), 122.76 (aryl CH), 122.01 (aryl C), 119.82 (aryl CH), 119.47
(
1
aryl C), 111.62, 105.84, 100.02 (aryl CH), 52.53 (CO CH ),
2 3
+
+
3.86 (CH ); ms: m/z = 280 [M+H] , 278 [M-H] .
3
(2.5% MeOH/CH Cl ) 0.48; ir: 1658, 1533, 1486, 1453, 1431,
2 2
A n a l. Calcd. for C16H13N O : C, 68.81; H, 4.69; N, 15.05.
3
2
1308, 1292, 1280, 1246, 1223, 1102, 983, 856, 791, 744, 712,
90 cm–1; 1H nmr (deuteriochloroform): δ 8.70 (d, J = 8.2 Hz,
H, aryl CH), 8.54 (s, 1H, H1), 8.09 (d, J = 7.7 Hz, 1H, aryl
CH), 7.94-7.87 (m, 6H, aryl CH), 7.64 (t, J = 7.3 Hz, 1H, aryl
Found: C, 69.00; H, 4.61; N, 15.11.
6
1
Methyl 5-Azido-6-oxoindolo[3,2,1-d e][1,5]naphthyridine-2-car-
boxylate (24).
CH), 7.59-7.47 (m, 10H, aryl CH), 7.06 (s, 1H, H4), 4.05 (s,
A solution of aldehyde [9] 2 1 (0.273 g, 1.07 mmol) and ethyl
azidoacetate (1.385 g, 10.7 mmol) in methanol (40 mL) was
added dropwise over 38 minutes, under argon, to a stirred solu-
tion of sodium ethoxide (0.657 g, 9.66 mmol) in methanol (10
mL), cooled via an ice-salt slurry. Stirring was continued with
cooling via an iced water bath for 24 hours before the mixture
was poured onto crushed ice. The resulting precipitate was
collected and washed with water, then with 1:1 methanol/water
13
3
(
H, OCH ); C nmr (deuteriochloroform) [26]: δ 166. 61
3
3
CO CH ), 159.91 ( J = 23.5 Hz, C-6), 149.45, 143.26 (aryl
2
3
p-c
2
2
C), 140.02 ( J = 8.8 Hz, C-5), 132.68 ( J = 10.0 Hz, C ),
p-c
p-c
o
4
1
1
1
(
32.07 ( J = 2.8 Hz, C ), 130.01 (aryl CH), 129.68 (q, J
02.0 Hz, C ), 129.21 ( J = 12.3 Hz, C ), 128.19, 125.37
aryl C), 125.25, 122.35, 117.34 (aryl CH), 114.79 ( J = 14.4
=
p-c
p
3
p-c
i
p-c
m
3
p-c
Hz, C-4), 113.54 (aryl CH), 52.96 (CO CH ); ms: m/z = 554
2
3
+
[
M+H] .
Anal. Calcd. for C34H24N O P.2(H O): C, 69.26; H, 4.79; N,
(
2 mL), and dried to give the title compound (0.262 g, 76%) as
a pale orange powder, mp 200 ºC (darkens), 209 ºC (decomp.);
R (2.5% MeOH/CH Cl ) 0.73; ir: 2139, 1710, 1673, 1451,
3
3
2
7
.13. Found: C, 69.51; H, 4.68; N, 7.13.
f
2
2
1
7
1
1
438, 1375, 1328, 1301, 1285, 1263, 1225, 1143, 1119, 879,
Methyl 5-Amino-6-oxoindolo[3,2,1-de ][1,5]naphthyridine-2-
carboxylate (27).
–
1 1
92, 757, 738 cm
; H nmr (deuteriochloroform): δ 8.76 (s,
H, H1), 8.63 (d, J = 8.2 Hz, 1H, aryl CH), 8.15 (d, J = 7.7 Hz,
H, aryl CH), 7.75 (t, J = 7.5 Hz, 1H, aryl CH), 7.67 (s, 1H,
Method A.
H4), 7.60 (t, J = 7.5 Hz, 1H, aryl CH), 4.12 (s, 3H, OCH3); 3C
1
A fine suspension of azide 24 (74 mg, 0.23 mmol) and a cat-
alytic quantity of 5% Pd/C in ethyl acetate (185 mL) was stirred
at room temperature, under 14 atmospheres of hydrogen, for 17
hours. The resulting suspension was filtered through celite and
the filtrate evaporated in vacuo to give the title compound (61
nmr (deuteriochloroform): δ 165.07 (CO C H ), 155.15,
1
CH), 130.19, 129.96 (aryl C), 126.08 (aryl CH), 124.25 (aryl
C), 122.61, 121.67, 116.90, 116.70 (aryl CH), 52.84
2
3
44.47, 139.01, 137.50, 135.00 (aryl C and C-6), 130.88 (aryl
+
mg, 90%) as a bright yellow powder, mp 259–262 ºC; R (2.5%
(
CO CH ); ms: m/z = 320 [M+H] .
f
2
3
MeOH/CH Cl ) 0.20; ir: 3459, 3307, 1745, 1679, 1602, 1578,
A n a l. Calcd. for C16H N O : C, 60.19; H, 2.84; N, 21.94.
2
2
9
5 3
1
438, 1364, 1302, 1255, 1223, 1110, 1001, 968, 827, 788, 741
Found: C, 60.25; H, 2.96; N, 21.85.
–
1 1
cm ; H nmr (deuteriochloroform): δ 8.69-8.67 (m, 2H, H1 and
Methyl 1-Formyl-9-methylpyrido[3,4-b]indole-3-carboxylate
aryl CH), 8.16 (d, J = 7.6 Hz, 1H, aryl CH), 7.74 and 7.58 (each t,
(22).
J = 7.6 Hz, 1H, H8 and H9), 7.16 (s, 1H, H4), 5.02 (bs, 2H, NH ),
2
4.11 (s, 3H, OCH3); 13C nmr (tetrahydrofuran-d8): δ 166.25
(CO2CH3), 156.60, 144.93, 144.80, 139.76, 139.54 (aryl C and
C-6), 130.16 (aryl CH), 129.76, 128.74, 126.22 (aryl C), 125.88,
123.10, 117.02, 113.34, 104.08 (aryl CH), 51.70 (CO2CH3); ms:
Sodium hydride (60% in mineral oil, 45 mg, 1.1 mmol) was
added all at once to a stirred suspension of aldehyde [9] 21 (0.250
g, 0.983 mmol) and methyl iodide (0.16 g, 1.1 mmol) in DMF
2.0 mL) and stirring was continued under argon at room temper-
ature overnight. The resulting suspension was poured onto ice
and the resulting precipitate was collected by filtration, washed
with water, and dried to give the title compound (0.238 g, 90%)
as a bright yellow powder, mp 177–179 ºC (ethanol/water); Rf
(
+
+
m/z = 294 [M+H] , 292 [M-H] .
A n a l. Calcd. for C16H N O : C, 65.53; H, 3.78; N, 14.33.
11
3 3
Found: C, 65.46; H, 3.84; N, 14.30.
Method B.
(
2.5% MeOH/CH Cl ) 0.43; ir: 2833, 1699, 1468, 1446, 1370,
2 2
1
7
318, 1261, 1192, 1133, 1123, 1056, 981, 936, 833, 785, 748,
Following the procedure for the formation of phosphine amide
26 from azide 24 (100 mg, 0.31 mmol), the whole crude reaction
mixture, including the precipitate, was chromatographed on silica
gel initiallyusing dichloromethane and then 10% MeOH/CH Cl to
–1 1
30, 717 cm ; H nmr (dimethyl sulfoxide-d ): δ 10.12 (s, 1H,
6
CHO), 8.95 (s, 1H, H4), 8.36 (d, J = 7.8 Hz, 1H, aryl CH), 7.69
(m, 2H, aryl CH), 7.36 (t, J = 7.5 Hz, 1H, aryl CH), 4.06 and 3.95
2
2
1
3
(each s, 3H, OCH and CH ); C nmr (dimethyl sulfoxide-d ): δ
give the title compound (54 mg, 59%) as a bright yellow powder.
3
3
6

Jul-Aug 2004
Synthesis of some Fused β-Carbolines
539
Methyl 5-Acetylamino-6-oxoindolo[3,2,1-de ][1, 5]naphthyri-
dine-2-carboxylate (28).
7.7 Hz, 1H, aryl CH), 7.86 (d, J = 8.2 Hz, 1H, aryl CH), 7.68 (t, J
= 7.6 Hz, 1H, aryl CH), 7.41 (t, J = 7.4 Hz, 1H, aryl CH); 13C nmr
(
1
(
2
dimethyl sulfoxide-d ): δ 193.97, 192.19 (CHO), 143.09,
42.56, 135.63, 135.52, 131.65 (aryl C), 129.80, 122.53, 121.50
aryl CH), 120.39 (aryl C), 118.25, 113.56 (aryl CH); ms: m/z =
6
A suspension of the amine 27 (0.100 g, 0.34 mmol) in acetic
anhydride (5.0 mL) was heated at reflux for 30 minutes and then
allowed to cool to room temperature. A precipitate formed and
was collected, washed with water, and dried to give the title com-
pound (82 mg, 72%) as a cream coloured powder, mp 294–295 ºC
+
+
25 [M+H] , 223 [M-H] .
A n a l. Calcd. for C13H N O : C, 69.64; H, 3.60; N, 12.49.
8
2 2
Found: C, 69.69; H, 3.54; N, 12.36.
(
decomp.); R (ethyl acetate) 0.38; ir: 3374, 1715, 1693, 1657,
f
1
1
633, 1504, 1453, 1429, 1372, 1357, 1338, 1309, 1285, 1269,
219, 1194, 1139, 1111, 879, 796, 756, 743 cm–1; 1H nmr (deu-
Dimethyl 2-Formyl-6H-indolo[3, 2, 1-de][1,5]naphthyridine-5,6-
dicarboxylic acid (41).
teriochloroform): δ 9.22 and 8.79 (each s, 1H, H4 and H1), 8.63
d, J = 8.3 Hz, 1H, aryl CH), 8.60 (bs, 1H, NH), 8.18 (d, J = 7.8
To a stirred suspension of dialdehyde 39 (46 mg, 0.21 mmol)
and triphenylphosphine (54 mg, 0.21 mmol) in dichloromethane
(
Hz, 1H, aryl CH), 7.77 (t, J = 7.8 Hz, 1H, aryl CH), 7.61 (t, J = 7.6
Hz, 1H, aryl CH), 4.14 (s, 3H, OCH ), 2.35 (s, 3H, CH ); 13C nmr
(
8 mL), cooled via an iced brine bath (–5 ºC) and under argon,
was added a solution of dimethyl acetylene dicarboxylate (29 mg,
.21 mmol), over 4 minutes. Stirring was continued at ambient
temperature for 3.5 hours before the solvent was evaporated in
vacuo and the remaining yellow solid was purified via column
chromatography (silica gel-50% ethyl acetate/n-hexane) to give
the title compound (0.68 mg, 95%) as a bright yellow powder, mp
3
3
(
deuteriochloroform): δ 169.31, 166.26 (COCH and CO CH ),
3 2 3
0
155.97, 145.52, 139.69, 137.18, 134.70 (aryl C and C-6), 131.53
(
aryl CH), 130.80, 129.37 (aryl C), 126.97 (aryl CH), 125.34 (aryl
C), 123.46, 119.51, 117.63, 117.08 (aryl CH), 53.73 (CO CH ),
2
3
+
+
2
5.34 (COCH ); ms: m/z = 336 [M+H] , 334 [M-H] .
3
A n a l. Calcd. for C18H13N O : C, 64.47; H, 3.91; N, 12.53.
3
4
2
2
17 ºC (decomp.); R (50% ethyl acetate/n-hexane) 0.50; ir:
f
Found: C, 64.55; H, 3.85; N, 12.41.
820, 1732, 1693, 1629, 1559, 1438, 1373, 1360, 1324, 1279,
1
,3-Di(hydroxymethyl)pyrido[3,4-b]indole (38).
1237, 1204, 1176, 1140, 1086, 1057, 980, 950, 887, 778, 738,
–
1 1
7
27, 705 cm
; H nmr (deuteriochloroform): δ 10.19 (s, 1H,
A solution of 1-formyl-β-carboline-3-carboxylate [9] (37)
CHO), 8.60 (s, 1H, H1), 8.21 (d, J = 7.9 Hz, 1H, aryl CH), 8.14
(0.142 g, 0.591 mmol) in THF (30 mL) was added dropwise, over
(
s, 1H, H4), 7.75-7.67 (m, 2H, aryl CH), 7.47 (t, J = 7.9 Hz, 1H,
3
0 minutes, to a stirred suspension of LiAlH4 (0.226 g, 5.96
1
3
aryl CH), 6.43 (s, 1H, H6), 3.98 and 3.73 (each s, 3H, CH3);
C
mmol) in anhydrous THF (10 mL), with cooling via an iced water
bath and under argon. Stirring was continued at ambient temper-
ature for 5 hours under argon. Water (0.33 mL) was cautiously
added, followed by 5 M NaOH (0.98 mL), and finally further
water (0.98 mL). The resulting precipitate was filtered through
celite and washed with ethyl acetate. The combined filtrate was
washed with brine twice, dried (MgSO ), and evaporated in
vacuo to give the title compound (66 mg, 49%) as a yellow pow-
der, mp 171–174 ºC; R (20% MeOH/CHCl ) 0.13; ir: 3213,
NMR (deuteriochloroform): δ 192.98 (CHO), 167.56, 165.31
(
CO CH ), 146.40, 141.52, 136.75, 136.68 (aryl C), 135.65,
2 3
1
29.93 (aryl CH and C-4), 128.42, 126.51 (aryl C), 123.46 (aryl
CH), 123.00 (aryl C), 122.83, 117.29, 112.00 (aryl CH), 57.63
+
(
C-6), 53.73, 53.30 (CO CH ); ms: m/z = 351 [M+H] , 349 [M-
2 3
+
H] .
Anal. Calcd. for C20H16N O : C, 65.14; H, 4.03; N, 8.00.
4
2 6
Found: C, 65.19; H, 4.07; N, 7.89.
f
3
3
7
8
8
136, 1407, 1311, 1259, 1210, 1031, 1009, 961, 902, 869, 828,
36 cm–1; H nmr (dimethyl sulfoxide-d ): δ 11.26 (s, 1H, NH),
1
REFERENCES AND NOTES
6
.21 (d, J = 7.8 Hz, 1H, aryl CH), 8.04 (s, 1H, H4), 7.64 (d, J =
.2 Hz, 1H, aryl CH), 7.51 (t, J = 7.6 Hz, 1H, aryl CH), 7.20 (t, J
[*] E-mail: jabe@biosci.ki.se
=
7.5 Hz, 1H, aryl CH), 5.49 and 5.32 (each t, J = 5.7 Hz, 1H,
[1a] P. Langer, J. T. Anders, K. Weisz and J. Jähnchen, Chem. Eur.
J. , 9, 3951 (2003); [1b] A. Fontana, E. J. Benito, M. J. Martín, N.
Sánchez, R. Alajarín, J. J. Vaquero, J. Alvarez-Builla, S. Lambel-
Giraudet, S. Leonce, A. Pierré and D. Caignard, B i o o rg. Med. Chem.
Lett., 12, 2611 (2002); [1c] D. Sharples, G. Hajós, Z. Riedl, D. Csányi, J.
Molnár and D. Szabó, A rch. Pharm. Pharm. Med. Chem., 334, 269
1
3
OH), 4.94 and 4.70 (each d, J = 5.6 Hz, 2H, CH2); C nmr
dimethyl sulfoxide-d ): δ 150.07, 144.46, 141.76, 133.29,
(
6
1
1
2
29.67 (aryl C), 128.62, 122.29 (aryl CH), 121.53 (aryl C),
19.84, 113.06, 110.78 (aryl CH), 65.38, 64.30 (CH ); ms: m/z =
29 [M+H] , 227 [M-H] .
A n a l. Calcd. for C13H12N O : C, 68.41; H, 5.30; N, 12.27.
2
+
+
(
2001); [1d] D. Csányi, G. Hajós, Z. Riedl, G. Timári, Z. Bajor, F.
Cochard, J. Sapi and J.-Y. Laronze, Bioorg. Med. Chem. Lett., 10, 1767
2000); [1e] S. Mahboobi, S. Eluwa, S. Kumar KC, M. Koller and K.
2
2
Found: C, 68.34; H, 5.33; N, 12.19.
(
Störl, Arch. Pharm. Pharm. Med. Chem., 332, 249 (1999); [1f] M. Julino
and M. F. G. Stevens, J. Chem. Soc., Perkin Trans. 1, 1677 (1998); [1g] J.
Pastor, J. Siró, J. L. García-Navío, J. J. Vaquero, M. M. Rodrigo, M.
Ballesteros and J. Alvarez-Builla, Bioorg. Med. Chem. Lett., 5, 3043
(1995); [1h] V. Pierson, A. Pierre, P. De Cointet, C. H. Nguyen, E.
Bisagni and P. Gros, Biochem. Pharmacol., 38, 1395 (1989).
Pyrido[3,4-b]indole-1,3-dicarbaldehyde (39).
A mixture of the 1,3-di(hydroxymethyl)-β-carboline (38) (100
mg, 0.438 mmol) and manganese dioxide (0.761 g, 8.75 mmol) in
anhydrous THF (25 mL) was heated at reflux for 3.5 hours. After
cooling, the mixture was filtered through celite and the celite was
washed with ethyl acetate. The combined filtrate was evaporated
in vacuo to give a motley yellow solid, which was purified via
column chromatography (silica gel-ethyl acetate) to give the title
compound (57 mg, 58%) as a bright yellow powder, mp 266–269
[
[
2] V. K. Kansal and P. Potier, Tetrahedron, 42, 2389 (1986).
3] G. Klein, J. M. Ostresh and A. Nefzi, Tetrahedron Lett., 44,
2
211 (2003).
4] S. Achab, K. Diker and P. Potier, Tetrahedron Lett., 42, 8825
2001).
[5] I. I. Fasfous, M. M. El-Abadelah and S. S. Sabri, J .
[
(
ºC; R (ethyl acetate) 0.87; ir: 3352, 2812, 1674, 1587, 1500,
f
1
cm
458, 1356, 1285, 1212, 1100, 963, 836, 760, 749, 727, 693, 676
Heterocyclic Chem., 39, 225 (2002).
[6a] M. J. Martin, M. L. Trudell, H. Diaz-Arauzo, M. S. Allen, A.
J. LaLoggia, L. Deng, C. A. Schultz, Y.-C. Tan, Y. Bi, K. Narayanan, L. J.
–
1 1
;
H nmr (dimethyl sulfoxide-d ): δ 12.57 (s, 1H, NH),
6
10.33 and 10.20 (each s, 1H, CHO), 9.09 (s, 1H, H4), 8.51 (d, J =

540
G. C. Condie and J. Bergman
Vol. 41
Dorn, K. F. Koehler, P. Skolnick and J. M. Cook, J. Med. Chem., 35,
ences therein.
4
7
105 (1992) and references therein; [6b] For a more recent discussion of
, 12-Dihydropyrido[3, 2-_:5, 4-_']diindole and various heterocyclic
[20] M. Cain, R. W. Weber, F. Guzman, J. M. Cook, S. A. Barker,
K. C. Rice, J. N. Crawley, S. M. Paul and P. Skolnick, J. Med. Chem., 25,
1081 (1982).
analogs see, Q. Huang, X. He, C. Ma, R. Liu, S. Yu, C. A. Dayer, G. R.
Wenger, R. McKernan and J. M. Cook, J. Med. Chem., 43, 71 (2000).
[21] D. L. Boger, S. R. Duff, J. S. Panek and M. Yasuda, J. Org.
Chem., 50, 5782 (1985).
[
7] R. L. Hudkins and J. L. Diebold, Tetrahedron Lett., 38, 915
1997).
8] H. Hemetsberg e r, D. Knittel and H. Weidmann, Monatsh.
(
[22] For examples of 5-hydroxy and 5-alkoxy canthin-6-ones, see:
[a] H. D. T. Mai, H. T. Van-Dufat, S. Michel, F. Tillequin, D. Bastien and
T. Sevenet, Z. Naturforsch., C: Biosci., 56, 492 (2001); [b] H. Y. Li, K.
Koike and T. Ohmoto, Chem. Pharm. Bull., 41, 1807 (1993); [c] J. Liu,
S. R. Davidson, R. Van der Heijden, R. Verpoorte and O. W. Howarth,
Liebigs Ann. Chem., 987 (1992); [d] T. Ohmoto and K. Koike, Chem.
Pharm. Bull., 33, 4901 (1985); [e] M. F. Bartlett and W. I. Taylor, J. Am.
Chem. Soc., 82, 5941 (1960).
[
Chem., 1970, 101 , 161; C. J. Moody, in Comprehensive Organic
Synthesis, Vol 7, B. M. Trost, I. Fleming and S. V. Ley, eds, Pergamon
Press, Oxford, 1991, pp 21-38.
[9] G. C. Condie and J. Bergman, Eur. J. Org. Chem., 1286
(2004).
[10] F. Leonard, U.S. Patent 19610118 (1961); Chem Abstr., 58,
1
462h (1963).
[
[23] R. B. Herbert, in Comprehensive Organic Chemistry, Vol 5, E.
Haslam, ed, Pergamon Press, Oxford, 1979, pp 1045.
11] A. J. Fatiadi, Synthesis, 65 (1976).
12] D. S. C. Black, M. C. Bowyer, N. Kumar and P. S. R. Mitchell,
J. Chem. Soc., Chem. Commun., 819 (1993).
13] P. Molina, E. Aller, A. Lorenzo, P. López-Cremades, I. Rioja,
A. Ubeda, M. C. Terencio and M. J. Alcaraz, J. Med. Chem., 44, 1011
2001).
14] D. M. B. Hickey, C. J. Moody and C. W. Rees, J. Chem. Soc.,
Perkin Trans., 1, 1119 (1986).
15] P. Molina, A. Lorenzo and E. Aller, Tetrahedron, 4 8, 4601
1992).
16] A. Arques, P. Molina, D. Auñón, M. J. Vilaplana, M. D.
Velasco, F. Martínez, D. Bautista and F. J. Lahoz, J. Organomet. Chem.,
98, 329 (2000).
17] P. M. Fresneda, P. Molina, S. Delgado and J. A. Bleda,
Tetrahedron Lett., 41, 4777 (2000).
18] H. A. Wagner, U.S. Patent 3,459,758 (1969); Chem Abstr., 71,
01853b (1969).
19] B. E. Love, Org. Prep. Proced. Int., 28, 1 (1996) and refer-
[
[24a] N. De la Figuera, I. Alkorta, M. T. Garcia-Lopez, R. Herranz
and R. Gonzalez-Muniz, Tetrahedron, 51, 7841 (1995). For more recent
applications of this synthetic route for the preparation of indolizinoin-
doles; [b] N. De la Figuera, M. Martin-Martinez, R. Herranz, M. T.
Garcia-Lopez, M. Latorre, E. Cenarruzabeitia, J. Del Rio and R.
Gonzalez-Muniz, Bioorg. Med. Chem. Lett., 9, 43 (1999); [c] M. Martin-
Martinez, N. De la Figuera, M. Latorre, R. Herranz, M. T. Garcia-Lopez,
E. Cenarruzabeitia, J. Del Rio and R. Gonzalez-Muniz, J. Med. Chem.,
43, 3770 (2000); [d] S. D'Alessio, C. Gallina, E. Gavuzzo, C. Giordano,
B. Gorini, F. Mazza, M. Paglialunga-Paradisi, G. Panini and G. Pochetti,
Eur. J. Med. Chem., 36, 43 (2001).
[25] I. Yavari, M. Adib and M. H. Sayahi, J. Chem. Soc., Perkin
Trans. 1, 1517 (2002); I. Yavari and A. Ramazani, J. Chem. Res. (S), 382
(1996).
[26] The full acquisition of the 13C nmr spectrum of structure 26
was not deemed practical after a prolonged experiment failed to resolve
two required quarternary carbons.
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