Synthesis of 8-substituted tetrahydro-γ-carbolines

Article abstract of DOI:10.1002/jhet.5570430308

The Fischer reaction is applied to the synthesis of 8-substituted tetrahydro-γ-carbolines with electron-donating or electron-withdrawing groups, using catalytic or thermal methods. The reaction conditions must be varied according to the nature of the N 1 substituent of the piperidone. The best results are observed when a releasing group is present on the arylhydrazine and a benzyl substituent on the nitrogen of piperidone. Formation of carbolines with a withdrawing substituent is observed in soft acidic conditions; in others, reaction ended at the hydrazone level or did not evolve.

Full text of DOI:10.1002/jhet.5570430308

May-Jun 2006
571
Synthesis of 8-Substituted Tetrahydro-ꢀ-Carbolines
Alexandre Bridoux, Laurence Goossens, Raymond Houssin and Jean-Pierre Hénichart*
Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, Université de Lille 2,
3, rue du Professeur Laguesse, B.P. 83, 59006 Lille, France
Fax: 33 3 20 96 49 06; E-mail: jean-pierre.henichart@univ-lille2.fr
Received July 8, 2005
R2
N
R2
R2
N
R1
R1
Methods A-E
Methods A-C
N
R1
+
NH2
N
O
N
H
N
H
N
H
.HCl
Methods C, F (according to R1 and R2)
Method A: ethanol, reflux
Method D: N-methylpyrrolidone, reflux
Method B: ethanol/hydrochloric acid, reflux Method E: diphenyl ether, reflux
Method C: acetic acid/hydrochloric acid
Method F: 7% sulfuric acid, 1,4-dioxane, reflux
The Fischer reaction is applied to the synthesis of 8-substituted tetrahydro-ꢀ-carbolines with electron-
donating or electron-withdrawing groups, using catalytic or thermal methods. The reaction conditions must
be varied according to the nature of the N 1 substituent of the piperidone. The best results are observed
when a releasing group is present on the arylhydrazine and a benzyl substituent on the nitrogen of
piperidone. Formation of carbolines with a withdrawing substituent is observed in soft acidic conditions; in
others, reaction ended at the hydrazone level or did not evolve.
J. Heterocyclic Chem., 43, 571 (2006).
Introduction.
possessing electron withdrawing substituents on C 8
and a free reactive site on piperidine nitrogen. The
influence of the N-protective group of 4-piperidone on
the course of cyclization was also studied as well as the
conditions required for its feasibility.
Over the years, a number of reports have shown that
ꢀ-carbolines ꢀ or pyrido[4,3-b]indoles ꢀ have various
biological activities in antipsychotic [1], antibiotic [2]
and antitumor [3] fields, although studies of their
chemical activities are limited compared to those of ꢁ-
carbolines ꢀ or pyrido[3,4-b]indoles ꢀ structurally
related to tryptophan and serotonin. ꢀ-Carbolines can be
synthesized using various methods like the Graebe-
Ullmann procedure [4], Pictet-Spengler cyclization,
Fischer annulation [5], ring closure of aldimine [6],
Suzuki-type reaction [7], intramolecular Diels-Alder
reaction [8] or Pd-catalyzed annulation of alkynes [5].
In the course of our project directed towards the
development of new antitumor compounds, we have
envisaged the synthesis of new tetrahydro-ꢀ-carbolines
via the most widely used method, the Fischer reaction
[9]. They constitute a scaffold possessing three potential
sites of reactivity and of modulation, the carbon atoms
of the homocycle and the nitrogen atoms of the pyrrole
and of the piperidine. As for indole, the synthesis of
Chemistry.
The aim of this work was access to ꢀ-carbolines using,
if possible, a limited number of one-pot procedures as
well as easily reproducible acidic conditions. The Fischer
synthesis of indole [11] is by far the most widely used
method to synthesize this condensed heterocycle [1,10-
15]. We applied this principle to prepare tetrahydro-
carbolines 7-11 (Scheme 1) by reacting equimolar
quantities of substituted arylhydrazines 1-5 with N-
protected-4-piperidones 6a,b,d or 4-piperidone hydro-
chloride 6c, in a nitrogen atmosphere, according to
different cyclization conditions (methods A, B or C),
thereby bypassing isolation of the arylhydrazone
intermediate. Carbolines 7b, 8b, 8c, 9b, 9c, 11b, 11c were
obtained thermally according to an unlikely free-radical
mechanism (method A: ethanol reflux, 2 hours) in 55-
95% yields (Table 1). Cyclization into compounds 7c, 8a,
9a, 10a, 10b was best obtained and gave good yields (61-
92%) in a saturated hydrochloric acid-ethanol refluxing
solution (method B: 3 hours), compared to other Lewis
acid catalysts already described such as boron trifluoride,
polyphosphoric acid, cuprous or zinc chloride [16]. This
acid-catalyzed Fischer reaction is initiated by the
tetrahydro-ꢀ-carbolines proceeds through
a
[3,3]
sigmatropic rearrangement followed by cyclization and
elimination of ammonia. Regioselectivity is only
observed when the intermediate arylhydrazone comes
from a symmetrical substituted ꢀ-piperidone. Electron
donor groups have previously been investigated as
substituents of the benzo cycle [10], but our interest
focused on the design of tetrahydro-ꢀ-carbolines

572
A. Bridoux, L. Goossens, R. Houssin and J.-P. Hénichart
Vol 43
Scheme 1
R2
N
R1
R2
R1
Method A, B or C
N
+
NH2
[hydrazone]
N
H
O
N
H
•HCl
1-5
6a-d
a R2 = Bn
b R2 = COOEt
c R2 = H
d R2 = Boc
7a-c, 8a-c, 9a-c, 10a,b, 11a-c
1,7 R1 = OMe
2,8 R1 = F
3,9 R1 = Br
4,10 R1 = SMe
5,11 R1 = H
Method A: ethanol, reflux
Method B: ethanol/hydrochloric acid, reflux
Method C: acetic acid/hydrochloric acid
Table 1
Tetrahydropyrido[4,3-b]indoles 7-11, 18-20
conventional mechanism involving the rupture of the N-N
bond of low energy and a Cope rearrangement.
Whatever the method used (A or B) for preparing
tetrahydrocarbolines 7b-9c, yields ranged from good to
high whereas 7a resulted from cyclization in hydrochloric
medium only (88% yield) [15] at room temperature
(method C), following formation in situ of the corre-
sponding phenylhydrazone in glacial acetic acid. More
difficulties were encountered for the synthesis of
carbolines 10 possessing a SMe substituent. It should be
noted that 10a,b and 10c were synthesized following
methods B and C, whereas none of these compounds were
obtained according to method A (thermal conditions) and
synthesis of 10d was unsuccessful using any of the three
methods. This may be explained by the fact that starting
materials 4 and 6d were insoluble in the reaction medium,
even under reflux conditions. Whereas compound 11a
was synthesized by method C (71% yield), 11b and 11c
were synthesized according to method A in 95 and 80%
yields, respectively. The best yields as regards cyclization
(Table 1) combine a p-releasing group (R1) and a benzyl
group (R2) which increase the basicity of the piperidone
nitrogen; these contradict previous conclusions where
an N-carbethoxy group was found to favor Fischer
cyclization [10].
R1
R2
N
N
H
Compd
R1
R2
Method
Yield (%)
*7a
*7b
OMe
OMe
OMe
F
F
F
Br
Bn
C
A
B
88
60
75
82
55
88
92
55
70
88
61
20
-
71
95
80
20
3
65
65
70
COOEt
H
Bn
COOEt
H
Bn
COOEt
H
Bn
COOEt
H
Boc
Bn
COOEt
H
Bn
**7c
**8a
B
*8b
A
A
B
A
A
B
**8c
**9a
*9b
Br
Br
**9c
*10a
*10b
*10c
10d
SMe
SMe
SMe
SMe
H
B
C
none
C
A
A
C
C
F
F
F
*11a
*11b
**11c
**18a
*18b
***19a
***19c
***20a
H
H
NO2
NO2
SO2Me
SO2Me
SO2NH2
COOEt
Bn
H
Bn
* : base; ** : hydrochloride; *** : sulfate; Methods A-C: see Scheme 1;
Method F: 7% sulfuric acid, 1,4-dioxane, 80°.
Scheme 2
Method C
when 12 and 6a,b
R2
R2
N
N
R2
R1
R1
R1
Methods A-E
N
Methods A-C
+
NH2
•HCl
N
N
H
O
N
H
N
H
6a-c
15c, 16a-c, 17a-c
18a,b, 19a,c, 20a
12-14
Method F
when 13 or 14 and 6a,c
12, 15, 18 R1 = NO2
a R2 = Bn
Methods A-C: see Scheme 1
13, 16, 19 R1 = SO2Me b R2 = COOEt
14, 17, 20 R1 = SO2NH2 c R2 = H
Method D: N-methylpyrrolidone, reflux
Method E: diphenyl ether, reflux
Method F: see Table 1

May-Jun 2006
Synthesis of 8-Substituted Tetrahydro-ꢀ-Carbolines
573
When R2 = H, cyclization into 7c, 8c, 9c, 11c also gave
fairly good yields (70-88%) while they have been
obtained in a two-step procedure involving hydrolysis of
the carbethoxy N-protective group [10].
Finally, milder acidic conditions [20] (Method F: 7%
sulfuric acid, 1,4-dioxane, 80°) led to sulfones 19a, 19c,
20a with similar yields as did methods A-C, without the
formation of tetrahydrocarboline 18a,b. A structural proof
for 19a was given (Scheme 4) by a coupling reaction of
Lastly, we undertook the preparation of tetrahydro-
carbolines possessing an electron withdrawing group R1,
such as NO2, SO2Me or SO2NH2. With the exception of
the 8-nitro tetrahydrocarbolines 18a, 18b from method C,
and whatever the conditions used (methods A-C, method
D: refluxing in N-methylpyrrolidone or method E:
refluxing in diphenyl ether [17], sulfuric acid-hydro-
chloric acid or polyphosphoric acid) or the nature of
substituent R2, reaction stopped at the hydrazone step to
give compounds 15c, 16, 17 (Scheme 2, Table 2).
Scheme 4
Bn
Bn
N
N
MeSO2
Br
MeSO2Na, CuI, L-Pro
80°
N
H
N
H
9a
19a (base)
This method has until now been the only way to obtain
8-nitro-1,2,3,4-tetrahydro-ꢀ-carbolines. It offers the best
access to 18b, since nitration (sodium nitrite/ trifluoro-
acetic acid) [18] failed on tetrahydrocarboline 11b, while
corresponding carbolines were synthesized by electro-
philic aromatic nitration [4], and reduction of the pyridine
system remain versatile.
Low yields observed for preparation of tetrahydro-
carbolines 18a,b or formation of hydrazones 15c, 16, 17
can be attributed to the strong withdrawing and
deactivating effect of the substituent on carbon 8
conjugated with hydrazine: the tautomeric hydrazone-
enehydrazine equilibrium is displaced toward the former
in strong acidic medium via a N 4 ꢀ C 3 proton transfer
[19] (Scheme 3) or even in thermal conditions and
competes with Cope cyclization.
8-bromotetrahydrocarboline 9a with sodium methane-
sulfonate catalyzed by a mixture of cuprous iodide/L-Pro
[21]. Several attempts at direct sulfide oxidation of the 8-
SMe moiety of carboline 10a using Oxone™ [22], m-
chloroperbenzoic acid [23], magnesium monoperoxy-
phtalate [24], potassium permanganate [25], periodic
oxide [26] or hydrogen peroxide [27] failed, presumably
due to the instability of the electron rich indole part [28].
Previous protection (and deactivation) of the nitrogen
indole [29] of 10c as carbamate (21) made it difficult to
obtain Oxone™ oxidation of the thioether into the
corresponding sulfone 22 (Scheme 5).
Even if the Fischer reaction has been shown to be
versatile toward indole or other heterocycles synthesis, its
use in ꢀ-carboline formation has given either low yields
without forced thermal conditions or activated pyridine
use [4], or none. This study has proved, that unlike what
has been stated, the formation of tetrahydro-ꢀ-carbolines
bearing a strong electron-withdrawing substituent on C 8
is possible, depending on the nature of the piperidone N-
protective group. These results indicate the scope and the
generality of the Fischer reaction in ꢀ-carboline synthesis
which greatly depends on the concentration of the acidic
catalyst used.
Table 2
Arylhydrazones 15c, 16, 17
N
N
R2
R1
NH
Compd
R1
R2
Method
Yield (%)
*15c
**16a
**16b
*16c
**17a
*17b
**17c
NO2
H
Bn
COOEt
H
Bn
A
C
A
A
C
A
B
85
90
90
95
90
72
95
SO2Me
SO2Me
SO2Me
SO2NH2
SO2NH2
SO2NH2
EXPERIMENTAL
COOEt
H
Moisture-sensitive reactions were performed in dry nitrogen.
Analytical tlc was performed on precoated Kieselgel 60F254
plates (Merck). Compounds were visualized by uv and/or with
iodine. Flash chromatography was performed with silica gel
Kieselgel Si 60, 0.040-0.063 mm (Merck). Melting points were
determined with a Büchi 535 capillary melting point apparatus
and remain uncorrected. The structure of all compounds are
supported by ir spectra on a Brucker Vector 22 instrument and
1H nmr spectrum at 300 MHz on a Brucker DPX-300
spectrometer. Chemical shifts are reported in ppm downfield
from tetramethylsilane, J values are in Hertz, and the splitting
* : hydrochloride; ** : base; Methods A, C: see Scheme 1.
Scheme 3
H
R2
H
R2
+
+
N
N
H
H
R1
R1
Products
N
N
N
H
H
N
H

574
A. Bridoux, L. Goossens, R. Houssin and J.-P. Hénichart
Vol 43
Scheme 5
Bn
Bn
Bn
N
N
N
MeS
MeS
MeSO2
(Boc)2O
20°
Oxone™
N
H
N
N
Boc
Boc
10a
21
22
patterns are designed as follows: s, singlet; d, doublet; t, triplet;
q, quartet; m, multiplet; b, broad. APCI+ (atmospheric pressure
chemical ionization) mass spectra were obtained on an lc-ms
system Thermo Electron Surveyor MSQ. 4-Substituted
phenylhydrazines were purchased from commercial suppliers
with the exception of the methylthio derivative 4 which was
prepared as reported [30].
hours. Monitoring by tlc indicated a degradation of the starting
product or traces of ꢀ-carboline.
Method F.
1-Benzyl-4-piperidone (0.2 mL, 1 mmol) was added dropwise
a stirred suspension of 4-substituted phenylhydrazine
to
hydrochloride (1 mmol) in a solution of 7% concentrated
sulfuric acid (20 mL) in 1,4-dioxane (20 mL). The mixture was
heated at reflux for 18 hours then cooled to room temperature.
The solvent was evaporated and the organic product was filtered
and recrystallized.
General Procedures for the Preparation of Tetrahydropyrido[4,3-b]-
indoles and Arylhydrazones.
Method A.
Ethyl 1,3,4,5-Tetrahydro-8-methoxy-2H-pyrido[4,3-b]indole-
2-carboxylate (7b).
A mixture of 4-substituted phenylhydrazine hydrochloride (1
mmol) and appropriate 4-piperidone derivative (1 mmol) in
ethanol (30 mL) was heated at reflux for 2 hours. The precipitate
that formed was collected by filtration and recrystallized.
This compound was obtained at 60% yield according to
method A; mp 160° (ethanol 95%) lit [10] 159-160°; Rf = 0.49
(methylene dichloride:methanol+ammonia, 9:1, v/v); orange
solid; ir (neat): 3305 (NH), 1670 (C=O) cm-1; uv: ꢁ max 250 nm;
1H nmr (DMSO-d6): ꢂ 1.22 (t, J = 7.3 Hz, 3H, CH3), 2.77 (m,
2H, CH2), 3.72 (s, 2H, CH2), 3.75 (s, 3H, CH3), 4.10 (q, J = 7.3
Hz, 2H, CH2), 4.55 (s, 2H, CH2), 6.67 (dd, J = 2.3, 8.5 Hz, 1H,
CH), 6.93 (s, 1H, CH), 7.17 (d, J = 8.5 Hz, 1H, CH), 10.73 (b,
1H, NH); ms: m/z 275 (M+H)+.
Method B.
A solution of 4-substituted phenylhydrazine hydrochloride (1
mmol) and appropriate 4-piperidone derivative (1 mmol) was
stirred in dry hydrochloric acidꢀsaturated ethanol (30 mL). The
reaction mixture was heated at reflux for 3 hours. After standing
overnight at room temperature, the solid was collected by
filtration or the solution was made basic with 10% aqueous
potassium carbonate solution and extracted with ethyl acetate.
After concentration, the residue was either filtered or purified on
a silica gel column and recrystallized.
Ethyl 8-Fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-
carboxylate (8b).
This compound was obtained at 55% yield according to
method A; mp 169° (ethanol) lit [10] 169-170°; Rf = 0.74
(methylene dichloride:methanol+ammonia, 9:1, v/v); orange
solid; ir (neat): 3278 (NH), 1672 (C=O) cm-1; uv: ꢁ max 255 nm;
1H nmr (DMSO-d6): ꢂ 1.21 (t, J = 7.0 Hz, 3H, CH3), 2.78 (t, J =
5.2 Hz, 2H, CH2), 3.73 (t, J = 5.6 Hz, 2H, CH2), 4.09 (q, J = 7.0
Hz, 2H, CH2), 4.55 (s, 2H, CH2), 6.85 (td, J = 2.1, 9.3 Hz, 1H,
CH), 7.19 (dd, J = 2.1, 9.3 Hz, 1H, CH), 7.27 (dd, J = 4.7, 8.8
Hz, 2H, CH), 7.36 (b, 1H, NH); ms: m/z 263 (M+H)+.
Method C.
Appropriate 4-piperidone (1 mmol) was added dropwise to a
stirred suspension of 4-substituted phenylhydrazine hydro-
chloride (1 mmol) in glacial acetic acid (100 mL). The solution
was then stirred at room temperature for 2 hours before saturated
dry hydrochloric acidꢀglacial acetic acid was added. The
solution was made basic with 10% aqueous potassium carbonate
solution. The product that precipitated was filtered or the
solution was extracted with ethyl acetate. The organic phase was
dried over magnesium sulfate and the solvent was evaporated.
The residual oil was purified by chromatography on silica gel.
8-Fluoro-2,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole Monohydro-
chloride (8c).
This compound was obtained at 88% yield according to
method A; mp > 230° (ethanol) lit [1] 259-261°; Rf = 0.05
(methylene dichloride:methanol+ammonia, 9:1, v/v); bordeaux
solid; ir (neat): 3208 (NH+) cm-1; 1H nmr (DMSO-d6): ꢂ 3.03 (s,
2H, CH2), 3.44 (s, 2H, CH2), 4.25 (s, 2H, CH2), 7.11 (m, 3H,
CH), 9.47 (b, 1H, NH), 11.34 (b, 1H, NH+); ms: m/z 191
(M-HCl+H)+.
Method D.
Appropriate arylhydrazone 16a,b and 17a,b (1 mmol) was
dissolved in N-methylpyrrolidone (10 mL) and heated at reflux
for 24 hours. The solution was diluted in water, stirred for 1
hour and extracted with ethyl acetate. The organic layer was
dried over magnesium sulfate and concentrated under vacuum.
In every case, the starting product was recovered.
Ethyl 8-Bromo-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-
carboxylate (9b).
Method E.
This compound was obtained at 55% yield according to
method A; mp 193° (ethanol 95%) lit [10] 192-193°; Rf = 0.86
(methylene dichloride:methanol+ammonia, 9:1, v/v); brown
Appropriate arylhydrazone 16a,b and 17a,b (1 mmol) was
dissolved in diphenyl ether (10 mL) and heated at reflux for 24

May-Jun 2006
Synthesis of 8-Substituted Tetrahydro-ꢀ-Carbolines
575
solid; ir (neat): 3284 (NH), 1665 (C=O) cm-1; uv: ꢀ max 245 nm;
1H nmr (DMSO-d6): ꢁ 1.21 (t, J = 7.3 Hz, 3H, CH3), 2.79 (t, J =
5.5 Hz, 2H, CH2), 3.73 (t, J = 5.5 Hz, 2H, CH2), 4.41 (q, J = 7.3
Hz, 2H, CH2), 4.55 (s, 2H, CH2), 7.13 (dd, J = 1.7, 8.5 Hz, 2H,
CH), 7.25 (d, J = 8.5 Hz, 1H, CH), 7.62 (d, J = 1.5 Hz, 1H, CH),
11.15 (b, 1H, NH); ms: m/z 323 (M)+, 325 (M+2)+.
CH2), 3.08 (s, 3H, CH3), 4.07 (q, J = 7.1 Hz, 2H, CH2), 7.66 (d, J
= 8.7 Hz, 2H, CH), 7.81 (d, J = 8.7 Hz, 2H, CH); ms: m/z 340
(M+H)+, 381 (M+CH3CN+H)+.
Anal. Calcd. for C15H21N3O4S: C, 53.08; H, 6.24; N, 12.38.
Found: C, 52.73; H, 6.12; N,. 12.56.
4-Piperidinone 4-Methanesulfonylphenylhydrazone Monohydro-
chloride (16c).
8-Bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole Monohydro-
chloride (9c).
This compound was obtained at 95% yield according to
method A; mp 189° (methanol); Rf = 0.10 (methanol); yellow
solid; ir (neat): 3328 (NH+), 1292 (SO2CH3), 1143 (SO2CH3)
This compound was obtained at 70% yield according to
method A; mp > 230° (ethanol) lit [31] 282-284°; Rf = 0.63
(methylene dichloride:methanol+ammonia, 9:1, v/v); brown
1
cm-1; uv: ꢀ max 300 nm; H nmr (DMSO-d6): ꢁ 2.63 (t, J = 5.9
1
solid; ir (neat): 3222 (NH+) cm-1; uv: ꢀ max 240 nm; H nmr
Hz, 2H, CH2), 2.83 (t, J = 5.9 Hz, 2H, CH2), 3.09 (s, 3H, CH3),
3.23 (m, 4H, CH2), 7.23 (d, J = 8.8 Hz, 2H, CH), 7.68 (d, J = 8.8
Hz, 2H, CH), 9.44 (b, 2H, NH), 9.99 (b, 1H, NH+); ms: m/z 268
(M-HCl+H)+.
Anal. Calcd. for C12H17N3O2S•HCl•0.5H2O: C, 46.03; H, 6.07;
N, 13.43. Found: C, 46.27; H, 5.96; N, 13.59.
(DMSO-d6): ꢁ 3.03 (t, J = 5.2 Hz, 2H, CH2), 3.42 (t, J = 5.2 Hz,
2H, CH2), 4.24 (s, 2H, CH2), 7.32 (m, 2H, CH), 7.68 (s, 1H,
CH), 9.79 (b, 2H, NH), 11.55 (b, 1H, NH+); ms: m/z 250
(M-HCl-H)+, 252 (M-HCl+H)+.
Anal. Calcd. for C11H11BrN2•HCl: C, 45.94; H, 4.21; N, 9.74.
Found: C, 46.02; H, 4.45; N, 9.51.
1-Ethoxycarbonylpiperidinone 4-Sulfamoylphenylhydrazone
Monohydrochloride (17b).
Ethyl 1,3,4,5-Tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (11b).
This compound was obtained at 95% yield according to
method A; mp 121° (ethanol 95%) lit [10] 121-123°; Rf = 0.68
(methylene dichloride:methanol, 9:1, v/v); orange solid; ir
(neat): 3300 (NH), 1667 (C=O) cm-1; uv: ꢀ max 265 nm; 1H nmr
(deuteriochloroform): ꢁ 1.32 (t, J = 7.1 Hz, 3H, CH3), 2.86 (t, J =
5.8 Hz, 2H, CH2), 3.87 (t, J = 5.8 Hz, 2H, CH2), 4.21 (q, J = 7.1
Hz, 2H, CH2), 4.71 (s, 2H, CH2), 7.15 (m, 2H, CH), 7.32 (d, J =
7.8 Hz, 1H, CH), 7.47 (d, J = 7.1 Hz, 1H, CH), 7.88 (b, 1H,
NH); ms: m/z 245 (M+H)+.
This compound was obtained at 72% yield according to
method A; mp 187° (ethanol); Rf = 0.84 (methylene dichloride:
ethyl acetate, 1:1, v/v); yellow solid; ir (neat): 3663 (NH+), 1713
(C=O), 1322 (SO2NH2), 1155 (SO2NH2) cm-1; uv: ꢀ max 290
nm; 1H nmr (DMSO-d6): ꢁ 1.19 (t, J = 6.6 Hz, 3H, CH3), 2.42 (t,
J = 6.0 Hz, 2H, CH2), 2.53 (t, J = 5.9 Hz, 2H, CH2), 3.50 (m, 4H,
CH2), 4.06 (q, J = 6.6 Hz, 2H, CH2), 7.11 (d, J = 8.8 Hz, 2H,
CH), 7.59 (d, J = 8.8 Hz, 2H, CH); ms: m/z 341 (M-HCl+H)+.
Anal. Calcd. for C14H20N4O4S•HCl: C, 44.62; H, 5.62; N,
14.87. Found: C, 44.77; H, 5.75; N, 14.82.
2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole Monohydrochloride (11c).
4-Piperidinone 4-Sulfamoylphenylhydrazone (17c).
This compound was obtained at 80% yield according to
method A; mp > 230° (ethanol); Rf = 0.34 (ethyl acetate:ethanol,
9:1, v/v); white solid; ir (neat): 3293 (NH+) cm-1; uv: ꢀ max 275
nm; 1H nmr (deuteriochloroform): ꢁ 2.47 (m, 2H, CH2), 2.94 (s,
2H, CH2), 3.70 (s, 2H, CH2), 6.67 (m, 2H, CH), 6.97 (m, 2H,
CH), 9.69 (b, 1H, NH+); ms: m/z 214 (M-HCl+CH3CN+H)+.
Anal. Calcd. for C11H12N2•HCl: C, 63.31; H, 6.28; N, 13.42.
Found: C, 63.50; H, 6.14; N, 13.12.
This compound was obtained at 95% yield according to
method B; mp 200° (isopropyl alcohol); Rf = 0.50 (methylene
dichloride:methanol, 9:1, v/v); yellow solid; ir (neat): 3191
(NH), 3072 (NH), 1713 (C=O), 1322 (SO2NH2), 1155 (SO2NH2)
1
cm-1; uv: ꢀ max 290 nm; H nmr (DMSO-d6): ꢁ 1.89 (s, 4H,
CH2), 1.96 (s, 4H, CH2), 7.02 (b, 2H, NH2), 7.12 (d, J = 8.5 Hz,
2H, CH), 7.60 (d, J = 8.5 Hz, 2H, CH), 9.16 (b, 1H, NH); ms:
m/z 269 (M+H)+.
Anal. Calcd. for C11H16N4O2S•0.25H2O: C, 48.38; H, 6.05;
Found: C, 48.70; H, 6.02.
4-Piperidinone 4-Nitrophenylhydrazone Monohydrochloride (15c).
This compound was obtained at 85% yield according to
method A; mp > 230° (ethanol 95%); Rf = 0.10 (methanol);
yellow solid; ir (neat): 3221 (NH+), 1305 (NO2) cm-1; uv: ꢀ max
2,3,4,5-Tetrahydro-8-methoxy-1H-pyrido[4,3-b]indole Mono-
hydrochloride (7c).
1
395 nm; H nmr (DMSO-d6): ꢁ 2.64 (t, J = 6.1 Hz, 2H, CH2),
2.84 (t, J = 6.1 Hz, 2H, CH2), 3.25 (m, 4H, CH2), 7.20 (d, J = 9.4
Hz, 2H, CH2), 8.10 (d, J = 9.4 Hz, 2H, CH), 9.31 (b, 2H, NH),
10.37 (b, 1H, NH+); ms: m/z 235 (M-HCl+H)+, 276 (M-HCl+
CH3CN+H)+.
This compound was obtained at 75% yield according to
method B; mp > 230° (ethanol) lit [31] > 250°; Rf = 0.49
(methylene dichloride:methanol+ammonia, 9:1, v/v); white
1
solid; ir (neat): 3302 (NH+) cm-1; uv: ꢀ max 230 nm; H nmr
Anal. Calcd. for C11H14N4O2•HCl: C, 48.80; H, 5.58; N, 20.70.
Found: C, 48.65; H, 5.68; N, 20.81.
(DMSO-d6): ꢁ 3.00 (m, 2H, CH2), 3.39 (m, 2H, CH2), 3.73 (s,
3H, CH3), 4.21 (s, 2H, CH2), 6.70 (d, J = 8.6 Hz, 1H, CH), 6.98
(s, 1H, CH), 7.22 (d, J = 8.6 Hz, 1H, CH), 9.82 (b, 2H, NH),
11.14 (b, 1H, NH+); ms: m/z 203 (M-HCl+H)+.
Anal. Calcd. for C12H14N2O•HCl: C, 60.38; H, 6.33; N, 11.73.
Found: C, 60.11; H, 5.95; N, 11.86.
1-Ethoxycarbonylpiperidinone 4-Methanesulfonylphenylhydra-
zone (16b).
This compound was obtained at 90% yield according to
method A; mp 166° (methanol); Rf
dichloride:methanol, 9:1, v/v); yellow solid; ir (neat): 3325
= 0.69 (methylene
8-Fluoro-2,3,4,5-tetrahydro-2-(phenylmethyl)-1H-pyrido[4,3-b]-
indole Monohydrochloride (8a).
(NH), 1690 (C=O), 1296 (SO2CH3), 1140 (SO2CH3) cm-1; uv: ꢀ
1
max 265 nm; H nmr (DMSO-d6): ꢁ 1.21 (t, J = 7.1 Hz, 3H,
This compound was obtained at 82% yield according to method
B; mp > 230° (methanol) lit [32] 245.5-246.5°; Rf = 0.47
CH3), 2.43 (t, J = 6.1 Hz, 2H, CH2), 2.57 (t, J = 6.1 Hz, 2H,

576
A. Bridoux, L. Goossens, R. Houssin and J.-P. Hénichart
Vol 43
(methylene dichloride:methanol+ammonia, 9:1, v/v); white solid;
3.24 (b, 2H, CH2), 4.07 (s, 1H, CH2), 7.20 (m, 2H, CH), 7.41 (s,
1H, CH), 8.08 (b, 1H, NH); ms: m/z 219 (M+H)+, 260
(M+CH3CN+H)+.
Anal. Calcd. for C12H14N2S: C, 66.02; H, 6.46; N, 12.83.
Found: C, 65.98; H, 6.24; N, 12.97.
1
ir (neat): 3150 (NH+) cm-1; uv: ꢀ max 255 nm; H nmr (DMSO-
d6): ꢁ 3.16 (m, 2H, CH2), 3.38 (m, 2H, CH2), 3.69 (m, 1H, NH),
4.28 (m, 2H, CH2), 4.49 (m, 2H, CH2), 6.91 (td, J = 2.3, 9.3 Hz,
1H, CH), 7.21 (dd, J = 2.0, 9.3 Hz, 1H, CH), 7.33 (dd, J = 2.0, 2.3
Hz, 1H, CH), 7.48 (m, 3H, CH), 7.70 (m, 2H, CH), 11.42 (b, 1H,
NH), 11.47 (b, 1H, NH+); ms: m/z 281 (M-HCl+H)+.
2,3,4,5-Tetrahydro-2-(phenylmethyl)-1H-pyrido[4,3-b]indole
(11a).
8-Bromo-2,3,4,5-tetrahydro-2-(phenylmethyl)-1H-pyrido[4,3-b]-
indole Monohydrochloride (9a).
This compound was obtained at 71% yield according to
method C; mp 159° (ethanol 95%) lit [15] 158-159°; Rf = 0.43
(methylene dichloride:methanol, 9:1, v/v); white solid; ir (neat):
This compound was obtained at 92% yield according to
method B; mp > 230° (ethanol); Rf
1
3377 (NH) cm-1; uv: ꢀ max 265 nm; H nmr (deuteriochloro-
= 0.53 (methylene
dichloride:methanol, 9:1, v/v); brown solid; ir (neat): 3207
(NH+) cm-1; uv: ꢀ max 235 nm; 1H nmr (methanol-d4): ꢁ 3.41 (t,
J = 6.1 Hz, 2H, CH2), 3.50 (s, 2H, CH2), 3.87 (t, J = 6.1 Hz, 2H,
CH2), 4.62 (s, 2H, CH2), 7.43 (m, 2H, CH), 7.75 (m, 6H, CH);
ms: m/z 341 (M-HCl)+, 343 (M-HCl+2)+.
form): ꢁ 2.80 (m, 4H, CH2), 3.71 (s, 2H, CH2), 3.83 (s, 2H,
CH2), 7.30 (m, 8H, CH), 7.73 (b, 1H, NH); ms: m/z 263
(M+H)+.
2,3,4,5-Tetrahydro-8-nitro-2-(phenylmethyl)-1H-pyrido[4,3-b]-
indole Monohydrochloride (18a).
2,3,4,5-Tetrahydro-8-methylthio-2-(phenylmethyl)-1H-pyrido-
[4,3-b]indole (10a).
This compound was obtained at 20% yield from hydrazine 12
(base), according to method C; the precipitate obtained after
reaction with hydrochloric acid-glacial acetic acid was directly
recrystallized; mp > 230° (ethanol:water, 1:1, v/v); Rf = 0.61
(methylene dichloride:methanol+ammonia, 9:1, v/v); yellow
solid; ir (neat): 3088 (NH+), 1336 (NO2) cm-1; uv: ꢀ max 255
nm; 1H nmr (DMSO-d6): ꢁ 2.89-3.27 (m, 2H, CH2), 3.55 (m, 2H,
CH2), 4.40 (m, 2H, CH2), 4.53 (m, 2H, CH2), 7.51 (m, 4H, CH),
7.69 (m, 2H, CH), 8.02 (m, 1H, CH), 8.53 (s, 1H, CH), 11.25 (b,
1H, NH), 12.10 (s, 1H, NH+); ms: m/z 308 (M-HCl+H)+.
Anal. Calcd. for C18H17N3O2•HCl: C, 62.88; H, 5.28; N,
12.22. Found: C, 62.63; H, 5.33; N, 12.21.
This compound was obtained at 88% yield according to
method B; chromatography eluent: cyclohexane:ethyl acetate
(4:1, v/v); mp 187° (ethanol 95%); Rf = 0.68 (methylene
dichloride:methanol, 9:1, v/v); brown solid; ir (neat): 3144 (NH)
cm-1; uv: ꢀ max 240 nm; 1H nmr (deuteriochloroform): ꢁ 2.50 (s,
3H, CH3), 2.78 (m, 2H, CH2), 2.89 (t, J = 5.2 Hz, 2H, CH2), 3.71
(s, 2H, CH2), 3.82 (s, 2H, CH2), 7.15 (s, 1H, CH), 7.37 (m, 7H,
CH), 8.04 (b, 1H, NH); ms: m/z 309 (M+H)+.
Anal. Calcd. for C19H20N2S: C, 73.99; H, 6.54; N, 9.08.
Found: C, 74.12; H, 6.39; N,8.87.
Ethyl 2,3,4,5-Tetrahydro-8-methylthio-2H-pyrido[4,3-b]indole-
2-carboxylate (10b).
Ethyl 1,3,4,5-Tetrahydro-8-nitro-2H-pyrido[4,3-b]indole-2-
carboxylate (18b).
This compound was obtained at 61% yield according to
method B; chromatography eluent: cyclohexane:ethyl acetate
(4:1, v/v); Rf = 0.57 (methylene dichloride:ethyl acetate, 1:1,
v/v); oil; ir (neat): 3291 (NH), 1668 (C=O) cm-1; 1H nmr
(deuteriochloroform): ꢁ 1.32 (t, J = 7.0 Hz, 3H, CH3), 2.52 (s,
3H, CH3), 2.83 (t, J = 5.1 Hz, 2H, CH2), 3.86 (m, 2H, CH2), 4.22
(q, J = 7.0 Hz, 2H, CH2), 4.68 (s, 2H, CH2), 7.22 (m, 2H, CH),
7.45 (s, 1H, CH), 8.02 (b, 1H, NH); ms: m/z 291 (M+H)+.
Anal. Calcd. for C15H18N2O2S: C, 62.04; H, 6.25; N, 9.65.
Found: C, 61.85; H, 6.16; N, 9.48.
This compound was obtained at 3% yield from hydrazine 12
(base), according to method C; chromatography eluent:
methylene dichloride:ethyl acetate (9:1, v/v); the oil was diluted
in chloroform and precipitated from a mixture isopropyl alcohol-
ethyl ether; mp 200° (ethanol); Rf = 0.52 (methylene dichloride:
ethyl acetate, 1:1, v/v); yellow solid; ir (neat): 3249 (NH), 1658
(C=O) cm-1; uv: ꢀ max 255 nm; 1H nmr (deuteriochloroform): ꢁ
1.36 (t, J = 7.3 Hz, 3H, CH3), 2.92 (m, 2H, CH2), 3.92 (m, 2H,
CH2), 4.23 (q, J = 7.3 Hz, 2H, CH2), 4.75 (s, 2H, CH2), 7.35 (d, J
= 8.8 Hz, 1H, CH), 8.11 (dd, J = 2.3, 9.0 Hz, 1H, CH), 8.28 (b,
1H, NH), 8.45 (d, J = 2.3 Hz, 1H, CH); ms: m/z 290 (M+H)+,
331 (M+CH3CN+H)+.
2,3,4,5-Tetrahydro-8-methoxy-2-(phenylmethyl)-1H-pyrido[4,3-b]-
indole (7a).
Anal. Calcd. for C14H15N3O4: C, 58.13; H, 5.23; N, 14.53.
Found: C, 58.03; H, 5.36; N, 14.41.
This compound was obtained at 88% yield according to
method C; mp 120° (ethanol 95%) lit [15] 119-120°; Rf = 0.56
(methylene dichloride:methanol, 9:1, v/v); brown solid; ir (neat):
3387 (NH) cm-1; uv: ꢀ max 270 nm; 1H nmr (deuterio-
chloroform): ꢁ 2.82 (d, J = 5.1 Hz, 2H, CH2), 2.90 (t, J = 5.1 Hz,
2H, CH2), 3.72 (s, 2H, CH2), 3.82 (s, 2H, CH2), 3.84 (s, 3H,
CH3), 6.77 (dd, J = 2.2, 8.7 Hz, 1H, CH), 6.84 (s, 1H, CH), 7.15
(d, J = 8.7 Hz, 1H, CH), 7.39 (m, 5H, CH), 7.77 (b, 1H, NH);
ms: m/z 293 (M+H)+.
1-(Phenylmethyl)-4-piperidinone 4-Methanesulfonylphenyl-
hydrazone (16a).
This compound was obtained at 90% yield according to
method C; mp 169° (ethanol 95%); Rf = 0.34 (methylene
dichloride:methanol, 9:1, v/v); yellow solid; ir (neat): 3331
(NH), 1299 (SO2CH3), 1133 (SO2CH3) cm-1; uv: ꢀ max 290 nm;
1H nmr (deuteriochloroform): ꢁ 2.57 (m, 8H, CH2), 3.02 (s, 3H,
CH3), 3.60 (s, 2H, CH2), 7.11 (d, J = 8.7 Hz, 2H, CH), 7.33 (m,
5H, CH), 7.52 (b, 1H, NH), 7.74 (d, J = 8.7 Hz, 2H, CH); ms:
m/z 358 (M+H)+.
2,3,4,5-Tetrahydro-8-methylthio-1H-pyrido[4,3-b]indole (10c).
This compound was obtained at 20% yield according to
method C; Rf = 0.11 (methylene dichloride:methanol, 4:1, v/v);
brown oil; ir (neat): 3670 (NH) cm-1; uv: ꢀ max 235 nm; 1H nmr
(deuteriochloroform): ꢁ 2.50 (s, 3H, CH3), 2.79 (m, 2H, CH2),
Anal. Calcd. for C19H23N3O2S: C, 63.84; H, 6.49; N, 11.75.
Found: C, 63.58; H, 6.54; N, 11.82.

May-Jun 2006
Synthesis of 8-Substituted Tetrahydro-ꢀ-Carbolines
577
1-(Phenylmethyl)-4-piperidinone 4-Sulfamoylphenylhydrazone
(17a).
This compound was obtained at 70% yield according to
method F; mp > 230° (acetonitrile:water, 1:1); Rf = 0.32
(methylene dichloride:ethyl acetate+ammonia, 1:9, v/v); white
solid; ir (neat): 3251 (NH+), 1320 (SO2NH2), 1152 (SO2NH2)
This compound was obtained at 90% yield according to
method C; mp 199° (ethanol 95%); Rf = 0.17 (methylene
dichloride:methanol, 9:1, v/v); orange solid; ir (neat): 3262
(NH), 1315 (SO2NH2), 1158 (SO2NH2) cm-1; uv: ꢀ max 270 nm;
1H nmr (DMSO-d6): ꢁ 2.35 (m, 4H, CH2), 2.50 (m, 4H, CH2),
3.53 (m, 2H, CH2), 7.02 (b, 2H, NH2), 7.08 (d, J = 8.8 Hz, 2H,
CH), 7.33 (m, 5H, CH), 7.58 (d, J = 8.8 Hz, 2H, CH), 9.45 (b,
1H, NH); ms: m/z 359 (M+H)+.
1
cm-1; uv: ꢀ max 235 nm; H nmr (DMSO-d6): ꢁ 2.97 (m, 2H,
CH2), 3.23 (m, 2H, CH2), 3.97 (s, 2H, CH2), 4.07 (b, 2H, NH2),
4.13 (s, 2H, CH2), 7.08 (s, 2H, CH), 7.46 (m, 5H, CH), 7.81 (s,
1H, CH), 9.96 (s, 1H, NH), 11.49 (b, 1H, NH+); ms: m/z 342
(M+H)+.
Anal. Calcd. for C18H19N3O2S•0.5H2SO4•1.5H2O: C, 51.78; H,
5.15; N, 10.07. Found: C, 51.48; H, 5.39; N, 10.02.
Anal. Calcd. for C18H22N4O2S: C, 60.31; H, 6.19; N, 15.63
Found: C, 60.70; H, 6.45; N, 15.29.
The Preparation of 5-tert-Butoxycarbonyl-2,3,4,5-tetrahydro-8-
methylthio-2-(phenylmethyl)-1H-pyrido[4,3-b]indole (21).
2,3,4,5-Tetrahydro-8-methanesulfonyl-2-(phenylmethyl)-1H-
pyrido[4,3-b]indole Monosulfate (19a).
DMAP (0.46 g, 3.8 mmols) was added dropwise to carboline
10a (1.2 g, 3.8 mmols) dissolved in acetonitrile (25 mL). After
stirring for 2 hours, di-tert-butyl dicarbonate (0.83 g, 3.8 mmols)
was added portionwise. After 2 more hours, the suspension was
filtered, the solvent was removed and the residual oil was
chromatographed on silical gel (methylene dichloride:ethyl
acetate, 9:1, v/v) to give a white solid at 32% yield; mp 181°; Rf
= 0.56 (methylene dichloride:ethyl acetate, 9:1, v/v); ir (neat):
1731 (C=O) cm-1; uv: ꢀ max 255 nm; 1H nmr (deuterio-
chloroform): ꢁ 1.68 (m, 9H, CH3), 2.99 (t, J = 5.3 Hz, 2H, CH2),
3.09 (s, 3H, CH3), 3.87 (m, 2H, CH2), 4.21 (q, J = 7.1 Hz, 2H,
CH2), 4.71 (m, 2H, CH2), 7.20 (m, 1H, CH), 7.24 (m, 1H, CH),
8.04 (m, 1H, CH); ms: m/z 409 (M+H)+.
This compound was obtained at 65% yield according to
method F; mp > 230°; Rf = 0.61 (methylene dichloride:
methanol, 9:1, v/v); brown solid; ir (neat): 3346 (NH+), 1294
1
(SO2CH3), 1141 (SO2CH3) cm-1; uv: ꢀ max 240 nm; H nmr
(DMSO-d6): ꢁ 2.91 (m, 4H, CH2), 3.21 (s, 3H, CH3), 3.91 (s, 2H,
CH2), 4.02 (s, 2H, CH2), 7.29-7.61 (m, 6H, CH), 7.63 (dd, J =
1.5, 7.5 Hz, 1H, CH), 8.00 (d, J = 1.2 Hz, 1H, CH), 8.53 (b, 1H,
NH); ms: m/z 341 (M+H)+.
The Preparation of 2,3,4,5-Tetrahydro-8-methanesulfonyl-2-
(phenylmethyl)-1H-pyrido[4,3-b]indole (19a, base).
Bromo derivative 9a (0.3 g, 1 mmol), sodium methane-
sulfonate (0.3 g, 1.2 mmol), copper iodide (0.05 g, 0.1 mmol),
L-proline (0.06 g, 0.5 mmol) and sodium hydroxide (0.01 g, 0.2
mmol) were heated in dimethylsulfoxide at 80°. After 48 hours,
the cooled mixture was partitioned between ethyl acetate and
water. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate. The combined organic phases
were washed with brine, dried over magnesium sulfate and
concentrated. The residual oil was purified by column
chromatography (ethyl acetate:ethanol, 9:1, v/v) and carboline
was obtained at 60% yield; mp = 186° (methanol); Rf = 0.43
(methylene dichloride:methanol, 9:1, v/v); yellow solid; ir
(neat): 3346 (NH), 1340 (SO2CH3), 1149 (SO2CH3) cm-1; uv: ꢀ
max 240 nm; 1H nmr (deuteriochloroform): ꢁ 2.92 (m, 4H, CH2),
3.06 (s, 3H, CH3), 3.72 (s, 2H, CH2), 3.82 (s, 2H, CH2), 7.46 (m,
6H, CH), 7.64 (dd, J = 1.5, 7.5 Hz, 1H, CH), 8.00 (d, J = 1.2 Hz,
1H, CH), 8.38 (b, 1H, NH); ms: m/z 341 (M+H)+.
Anal. Calcd. for C24H28N2O2S: C, 70.56; H, 6.91; N, 6.86.
Found: C, 70.81; H, 6.80; N, 6.95.
The Preparation of 5-tert-Butoxycarbonyl-2,3,4,5-tetrahydro-8-
methanesulfonyl-2-(phenylmethyl)-1H-pyrido[4,3-b]indole (22).
Oxone™ (potassium peroxymonosulfate) (1.5 g, 2.5 mmols)
in water (10 mL) was added dropwise to a well stirred cooled
solution (0°) of carboline 21 in methanol (10 mL). After 30 min,
the solution was extracted with chloroform, dried over
magnesium sulfate before the solvent was evaporated. The
residual oil was chromatographed on silica gel (ethyl
acetate:ethanol, 9:1, v/v) to give a white solid at 10% yield; mp
190°; Rf = 0.54 (methylene dichloride:methanol, 9:1, v/v); ir
(neat): 1734 (C=O), 1291 (SO2CH3), 1141 (SO2CH3) cm-1; uv: ꢀ
max 235 nm; 1H nmr (deuteriochloroform): ꢁ 1.67 (s, 9H, CH3),
2.90 (t, J = 5.5 Hz, 2H, CH2), 3.07 (s, 3H, CH3), 3.16 (m, 2H,
CH2), 3.65 (s, 2H, CH2), 3.81 (s, 2H, CH2), 7.36 (m, 5H, CH),
7.79 (dd, J = 1.8, 8.8 Hz, 1H, CH), 7.91 (d, J = 1.8 Hz, 1H, CH),
8.34 (d, J = 8.8 Hz, 1H, CH); ms: m/z 441 (M+H)+.
Anal. Calcd. for C19H20N2O2S•0.25H2O: C, 66.16; H, 5.95; N,
8.12. Found: C, 66.08; H, 6.06; N, 8.20.
2,3,4,5-Tetrahydro-8-methanesulfonyl-1H-pyrido[4,3-b]indole
Monosulfate (19c).
Anal. Calcd. for C14H15N3O4: C, 58.13; H, 5.23; N, 14.53.
Found: C, 58.01; H, 5.36; N, 14.64.
This compound was obtained at 65% yield according to
method F; mp 182° (methanol); yellow solid; Rf = 0.56
(methylene dichloride:methanol, 9:1, v/v); ir (neat): 3207 (NH+),
1
1279 (SO2CH3), 1124 (SO2CH3) cm-1; uv: ꢀ max 240 nm; H
REFERENCES AND NOTES
nmr (DMSO-d6): ꢁ 3.07 (m, 2H, CH2), 3.15 (s, 3H, CH3), 3.50
(m, 2H, CH2), 4.41 (m, 2H, CH2), 7.59 (m, 2H, CH), 8.12 (s, 1H,
CH), 9.10 (b, 1H, NH+); ms: m/z 251 (M+H)+, 292
(M+CH3CN+H)+.
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H. Andree and E. A. Muth, J. Med. Chem., 30, 1818 (1987).
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Med. Chem., 29, 2093 (1986).
Anal. Calcd. for C12H14N2O2S•0.5H2SO4: C, 48.15; H, 5.03;
N, 9.36. Found: C, 48.44; H, 4.98; N, 9.02.
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2,3,4,5-Tetrahydro-2-(phenylmethyl)-8-sulfamoyl-1H-pyrido-
[4,3-b]indole Monosulfate (20a).

578
A. Bridoux, L. Goossens, R. Houssin and J.-P. Hénichart
Vol 43
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