CHAPTER: III
Diastereoselective synthesis of 1,1,4-
trisubstituted 2,3,4,9-tetrahydrospiro-β-
carbolines via glacial acetic acid catalyzed
Pictet-Spengler reaction
Chapter III
75
Diastereoselective synthesis of 1,1,4-trisubstituted 2,3,4,9-
tetrahydrospiro-β-carbolines via glacial acetic acid catalyzed Pictet-
Spengler reaction
Introduction:
β-Carboline is a basic heterocyclic ring system found1-9
in several families of
natural products as well as in the synthetic alkaloids. There are many simple natural
products like harman, harmine and also complex β-carbolines alkaloids like canthine-6-
ones, eudistomidins, manzamines and eudistomins reported in literature. The increasing
interest in the synthesis and reactivity study of β-carbolines is due to the wide range of
biological activities possessed by this class of compounds.
Similar to β-carbolines, tetrahydro-β-carbolines (THβCs) are also naturally
occurring and biologically active compounds. 1,2,3,4-THβCs are naturally occurring
compounds produced during food production, storage and processing. They have been
identified in soy sauces, beers, wines, chocolates and cocoa.10-13
These alkaloids have been
demonstrated to exhibit antioxidant properties and to inhibit platelet aggregation,10
monoamine oxidiase, monoamine uptake and as a binding to the benzodiazepine
receptor.14,15
THβCs as potential neuroactive alkaloids were found in chocolates and
cocoa.16
THβC derivatives I-IV are present in biological tissues and fluids.17
NH
NH
R2
R1
R3
I R1 = CH3, R2 = COOH, R3 = OH 6OHMTHβC
II R1 = CH3, R2 =H = R3 = H THCA
III R1 = CH3, R3 = H, R2 = COOH MTCA
IV R1 = R2 = CH3, R3 = H MTHβC
Chart I
THCA (II) and MTCA (III) shown in Chart I are widespread in commercial
foods, in raw or cooked fish and meat and in alcoholic and smoked products.18
MTCA
(III) is a precursor of mutagenic N-nitroso compounds and may cause certain neuronal cell
death in vitro.18
They have been shown to bind with nanomolar affinity19
to serotonin
Chapter III
76
receptors and also bind to GABA, a receptor ion channel and modulate molecular
mechanisms controlling anxiety, convulsions and sleep.20,21
Literature survey revealed that THβCs have wide occurrence range in nature like
simple 1,6-dihydroxy-1,2,3,4-THβC which is isolated from Hyrtios erectus and H.
reticulates.22
An inherently unstable 1,2,3,4-tetrahydro-β-carboline alkaloid, (+) Jafrine
has been isolated from the flowers of Tagetes patula.23
A racemic mixture of
haploscleridamine has been isolated from a Micronesian sponge of the order
Haplosclerida.24
It has moderate potency as an inhibitor of cathepsin K.
NH
NHNH
NHNH
NH
OH
HO
MeOH Me
R
NH
N
O
HO
1,6-dihydroxy-1,2,3,4-THβC Jafrine (R = pentyl) Haploscleridamine
Harmicine was isolated from Kopsia griffithii.25
Trypargimine has been found from
Eudistoma sp. Ascidian.26
Barchycerine was isolated from the leaves of Psychotria
brachyceras (Rubiaceae).27
NH
NNH
NHNH
NHH
n(H2C)
NH
NH2
COOH
HNO
H H
HO
H
H OGlc
COOMe
n = 3
Harmicine Trypargimine Barchycerine
Lycoperodine-1 was isolated from tomato fruits (Lycopersicon esculentum).28
Cytotoxic alkaloid (-) Hyrtioerectine B has been isolated from a Red Sea specimen of the
marine sponge Hyrtios erectus.29
NH
NH
HO COOH
CH3
NH
NH
COOH
Lycoperodine-1 (-) Hyrtioerectine B
Chapter III
77
Yohimbine type indole alkaloid V was isolated from the stem bark of Mitragyna
africanus collected in Nigeria.30
Yohimbinic acid and isorauhimbinic acid are found in the
dried roots of Rauwolfia serpentina.31
Yohimbinic acids showed no effect as inhibitors of
topoisomerases I and II inhibitors. Both Yohimbinic acid and isorauhimbinic acid inhibited
human promyelocytic leukemia (HL-60) cell growth.
NH
NNH
N
OMe
H
H
H
OH
MeOOC
H
OH
HOOC
V Yohimbinic acid 3S, 16R, 20R
Isorauhimbinic acid 3R, 16S, 20R
Tetrahydrospiro-β-carbolines (THSβCs) are known to be important compounds
since they show various biological activities. A series of novel spirocondensed indoline-
carbolines like VI and VII show anticonvulsants structure-activity relationships.32
NH
NH
HN
NH
NH
HN
Me
BrNH
NH
X
HN
R
R1O
X = -CH2-, -CH2-CH2-
R = H, Me
R1 = H, Br
VI VII VIII
The hydrochlorides of VIII [Spiro-(β-carbolineindolones) and Spiro-
(indoleindolo[2,3-c]azepinones) exhibited antispasmodic activity.33
Also Spiro-(β-
carbolinepyrrolidines) IX and related compounds showed GHSR inhibitory activity with
Ki = 60 nM.34
NR5
X
N
NH
NR3
R4
R7
R3
R6R8
R
R2 (CH2)nR1
IX X
Chapter III
78
Pyridoindoles X (R = H, halogen, alkyl, alkoxy, CF3; R1 = alkoxycarbonyl, amido;
R2 = H, alkyl, alkoxycarbonyl; R3 = H, acyl, alkyl, amido; n = 0, 1) are useful as
antidepressants.35
Alkaloids containing THSβC and THβC ring systems represent an important class
of compounds, which exhibit interesting biological activities. Due to the wide range of
biological activities possessed by this class of compounds, there are several methods
reported for the synthesis of these systems. Important synthetic methods include Pictet
Spengler cyclisation and Bischler-Napieralski reaction.
Pictet-Spengler reaction36
has been extensively studied in the area of synthesis of
different biologically important heterocyclic systems.37
Asymmetric Pictet-Spengler
reaction has attracted much attention38-45
because it is an important and useful tool to
construct chiral synthons containing tetrahydroisoquinolines or tetrahydro-β-corbolines
structural moieties. Therefore, the main challenge of this cyclization is stereoselectivity
and the ratio of isomers. Different conditions by changing temperature, solvent and acid-
catalysts were studied to improve the selectivity of Pictet-Spengler reaction.46-50
Other
synthetic strategies used to influence the stereoselectivity of the Pictet-Spengler
condensation include the use of chiral catalysts,41
chiral auxiliaries43,51
or optically active
carbonyl compounds.52
Some examples of reported synthetic methods are depicted below.
Reported methods:
1. Kusurkar et al (2008)
53
NH
NH2 NH
NHSi(CH3)3Cl, DCM
PhCHO
ArR
Ar
R
NH
NH
Ph
Ph Ar
R
+
88 h, 0 - 25 oC
2. Brandt et al (2006)
54
NH
NH2 NH
NH
COOH
R
Cyclohexanone
Tetralinreflux
Chapter III
79
3. Herrera et al (2005)
55
NH
NH2
Ph
NH
NH
Ph
TFA, reflux
Ph
PhCHO
4. Hsung and co-workers (2005)56
NH
HNNH
NTs
O
EtO O
O
O
Ts
NH
N O
OH
Ts
NH
N O
Ts
H
NaH, THF+
NaBH4, MeOH
THF
BF3Et2O, MgSO4
CH2Cl2
5. Semenov et al (2004, 2005)57-59
NH
NH2
Ph
NH
NH
Ph
R2 R1
Aldehyde or Ketone
H2SO4, reflux
6. Tietze et al (2004)60
NH
NHNH
NH
CO2Me
O
NOMe
OMe
H
H
HO
N
H
OMe
OMe
H
H
POCl3, PhH
reflux
Chapter III
80
7. Joullie and co-workers (2003)61
NH
NH2NH
NH
CO2Me
O
O
CO2Me
Ninhydrin
o1 N HCl, rt
8. Söderberg and co-workers (2003)62
N
R1NO2
R
NH
NR1
R
Pd(dba)2, dppp
1,10-Phenanthroline
Co Ligand, DMF
9. Laronze and co-workers (2000)63
NH
NH2NH
NHtoluene, (H+),
Cyclohexanone
RCOOt-Bu
R
COOt-Bu
10. Bonjoch and co-workers (1998)64
NH
N O
H
CN
H
NH
N H
NC
H
POCl3
NaBH4
11. Hoornaert and co-workers (1998)65
N
N
NH
O
R1
R2
Cl
R
NH
N
R
R2
R1
O
NH
N
R
R2
Cl
C6H5Br
reflux
+
Chapter III
81
12. Lévy and co-workers (1997)66
NH
NH
NH2 NHCN
CN CN
H2, Pd/C
Present work:
Amongst the variously substituted THβCs very few reports are available typically
for 1,4-disubstituted THβCs53,55,58
and also for 1,1,4-trisubstituted THSβCs.57,59
Therefore,
we planned to study the reactions in which spiro THβCs with different substituents at the
1 and 4 positions would be synthesised. In the earlier work53
from our laboratory, Pictet
Spengler cyclization was used for synthesising 1,4-disubstituted THβCs. In continuation
with that work, it was decided to use the same method for the synthesis of new 1,1,4-
trisubstituted spiro THβCs.
Various different acid catalysts have been used for the Pictet Spengler cyclization
in which sulphuric acid and TFA are the most common ones. We used trimethylsilyl
chloride for our earlier work. As glacial acetic acid is a mild acid it was decided to use it
for the Pictet Spengler cyclizations in the present work.
Result and discussion:
Having the nitro compounds 35-41 in hands (see Chapter II, Part B), it was
decided to reduce the nitro group to get variously substituted tryptamine derivatives. Thus
reduction of 2-(3-indolyl)-2-phenyl-1-nitroethane 35 using freshly prepared Raney Nickel
in methanol and hydrogen gas at 70 psi in Parr low pressure hydrogenation apparatus was
carried out for 2 hrs (Scheme I).
NH
NO2
Ar
NH
NH2
Ar
Raney Nickel
H2, MeOH
35 - 41 52 - 55, 57 - 59
NH
NO2
Ar
+
56
35, 52. Ar = phenyl, 36, 53. Ar = 3,4-dimethoxyphenyl, 37, 54. Ar = 3,4-methylenedioxy-
phenyl, 38, 55. Ar = 4-methoxyphenyl, 39. Ar = 4-nitrophenyl, 56, 57. Ar = 4-amino-
phenyl, 40, 58. Ar = 2-furyl, 41, 59. Ar = 2-thienyl.
Scheme I
Chapter III
82
This was also possible using a balloon filled with H2 gas and stirring overnight. Usual
work up resulted in a thick brown liquid which after addition of ether gave a brown solid
melting at 130 οC (lit.
43 mp. 130
οC) in 95% yield. This product showed following spectral
data. IR (KBr) showed broad bands at 3411, 3348 and 3143 cm-1
corresponding to indole
>NH and -NH2. 1H NMR (Fig. 13a) showed (i) a broad singlet at 1.38 (exchangeable with
D2O) corresponding to two protons of NH2 (ii) two multiplets at 3.3 and 3.44 for two
C1H2, (iii) a multiplet at 4.22 for C2H (iv) signals of ten aromatic
protons at 6.91-7.46 and (v) a broad singlet at 8.54 due to indole
>NH (exchangeable with D2O). 13
C NMR showed (i) strong signal
at 47.1 for methylene and methine carbons (methylene carbon has
shifted up field as compared to that in the nitro compound 35 at
79.4) (ii) twelve signals between 111.0-142.9 corresponding to
fourteen aromatic carbons (two carbons were resonating at the same chemical shift to give
a strong signal). All the above spectral data confirmed the structure of the product as 52.
Using this method various β-substituted tryptamines 53-55 and 57-59 were
synthesized in good yield as shown in Scheme I. In the case of nitro compound 39, initial
reduction of aromatic nitro group furnished product 56. After continuing the reaction for
longer time, both the nitro groups were reduced to get product 57. The characterisation of
all these tryptamines was carried out by using the spectral data as well as matching the
data with the reported53
values (see Table I, Experimental section).
Table I: Spectral data, mps and yields of amino compounds 52-59
Prod. No. IR,
cm-1
M.P
C
Yield
%
1H NMR
13C NMR
C1H C1H C2H C1 C2
52 Fig. 13a 3411, 3348, 3143 130 95 3.3 m 3.44 m 4.22 m 47.1
53 3275 (br) 193-95 91 3.25 m 3.40 m 4.20 t 42.3 45.1
54 3325 (br) 217-18 87 3.32 bs 4.2 t 42.5 44.2
55 Fig. 14a 3645, 3570 (br) Oily 81 3.24 dd 3.39 dd 4.21 t 45.8 47.1
56 3425, 3348, 3288,
1547, 1380
139 10 4.80 dd 4.93 - 5.05 m 40.9 79.8
57 3645, 3570 broad 126-28 79 3.13 dd 3.28 dd 4.07 t 44.7 46.2
58 3356, 3292 broad 141-42 94 3.26 - 3.42 m 4.33 t 40.9 45.9
59 3450, 3358, 3296 122 90 3.28 - 3.5 m 4.52 t 38.7 39.0
52
NH
NH2
Chapter III
83
Fig. 13a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 52
Fig. 14a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 55
55
NH
NH2
OMe
52
NH
NH2
Chapter III
84
To synthesise the spiro THβCs, cyclic ketones were used in the Pictet-Spengler
condensation reactions.
Pictet-Spengler reaction using symmetric ketones:
Initially it was planned to carry out Pictet-Spengler condensation using symmetric
ketones like cyclohexanone or cyclopentanone. To check the catalytic activity of glacial
acetic acid in Pictet-Spengler cyclization, first the condensation reaction of amine 52 and
cyclohexanone in the presence of catalytic amount of glacial acetic acid was carried out by
refluxing in toluene (Scheme II).
1
34
NH
NH
NH
NH2
Ar
NH
Ar
reflux, 9.5-13.5 hrsAcOH,Toluene N
Ar
60 - 6852 - 55, 57 - 59
n(H2C)n(H2C)
n = 1, 2
n(H2C)
O
52, 60. Ar = phenyl, n = 2; 53, 61. Ar = 3,4-dimethoxyphenyl, n = 2; 54, 62. Ar = 3,4-
methylenedioxyphenyl, n = 2; 55, 63. Ar = 4-methoxyphenyl, n = 2; 57, 64. Ar = 4-
aminophenyl, n = 2; 58, 65. Ar = 2-furyl, n = 2; 59, 66. Ar = 2-thienyl, n = 2; 52, 67. Ar =
phenyl, n = 1; 54, 68. Ar = 3,4-methylenedioxyphenyl, n = 1.
Scheme II
Usual work-up with neutralization and chromatographic separation yielded a
yellowish solid, melting at 185-87 oC in 91% yield. From the mode of formation and the
spectral data, the new compound was shown to be 60. The compound 60 analyzed for
C22H24N2. IR (KBr) showed broad band at 3402 cm-1
for both >NH. 1H NMR (Fig. 15a)
showed (i) a multiplet at 1.48-1.95 for 11 protons [-(CH2)5-, including NH (partially
exchangeable with D2O)], (ii) two doublet of doublets at 3.02, J = 5.5, 13.5Hz and at 3.39,
J = 5.2, 13.5 Hz for two geminally and vicinally coupled C3H2, (iii) a triplet at 4.15 with J
= 5.2 Hz for C4H, (iv) signals of nine aromatic protons at 6.84 to 7.30 and (v) a broad
singlet exchangeable with D2O at 7.85 for >NH of indole ring. 13
C NMR (Fig. 15b)
showed (i) signals at 21.4, 25.8, 36.4, 37.2, 40.0, 48.5 and 52.3 for eight carbons (two
signals overlap at 21.4), (ii) strong signals at 128.1 and 128.2 corresponding to four
aromatic carbons and (iii) ten signals for ten carbons. Mass spectrum showed (i) M+ at m/z
316 (ii) base peak at 273 (obtained by the loss of CH2-CH2-CH3). In the 13
C NMR, signal
Chapter III
85
at 52.3 was assigned to the spiro carbon (C1) which was absent in the DEPT experiment
where all protonated carbons are seen. One CH at 40.8 (C4) and five -CH2 groups at 21.4,
25.8, 36.4, 37.2 and 48.5 with one strong signal at 21.4 were observed in the aliphatic
region in the DEPT experiment (Fig. 15c). This data supported for the formation of
compound 60 during Pictet-Spengler cyclization in presence of glacial acetic acid.
NH
NH1
345
78
60
Similar Pictet-Spengler cyclization of amine 52 with cyclopentanone carried out
under same conditions for 13.5 hrs yielded a brown solid, melting at 133-35 oC in 82%
yield (Scheme II). On the basis of spectral and analytical data, the structure of unreported
product was assigned as 67 as follows. The compound analyzed for C21H22N2. IR (KBr)
showed band at 3425 broad cm-1
for both >NH. 1H NMR (Fig. 16a) showed (i) a multiplet
at 1.81-2.15 for nine protons [-(CH2)4-, including NH (partially exchangeable with D2O)]
(ii) two doublet of doublets at 3.03, J = 5.5, 13.5 Hz and at 3.43, J = 5.0, 13.5 Hz for two
geminally and vicinally coupled C3H2, (iii) a triplet at 4.14 with J = 5.0 Hz for C4H, (iv)
signals of nine aromatic protons at 6.83 to 7.35 and (v) a broad singlet exchangeable with
D2O at 7.75 for >NH of indole ring. 13
C NMR (Fig. 16b) showed (i) signals at 25.1, 40.2,
40.07, 40.9, 50.0 and 61.8 for seven carbons (two signals overlap at 25.1), (ii) strong
signals at 128.1 and 128.2 corresponding to four aromatic carbons, (iii) strong signal at
110.5 corresponding to two carbons and (iv) other nine signals for nine carbons. Mass
spectrum showed (i) M+ at m/z 302 (ii) base peak at 273 obtained by the loss of NH=CH2.
NH
NH1
345
7
8
67
Chapter III
86
Fig. 15a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 60
Fig. 15b: (75 MHz, CDCl3)
13C NMR Spectrum of Compound 60
60
NH
NH
60
NH
NH
Chapter III
87
Fig. 15c: 75 MHz DEPT Spectrum of Compound 60
60
NH
NH
Chapter III
88
Fig. 16a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 67
Fig. 16b: (75 MHz, CDCl3)
13C NMR Spectrum of Compound 67
67
NH
NH
67
NH
NH
Chapter III
89
After establishing the route for the synthesis of 60 and 67 THSβCs, the method was
generalized using various β-substituted tryptamines 53-55 and 57-59 with cyclohexanone
and tryptamine 54 with cyclopentanone which furnished seven new 1,1,4-trisubstituted
THSβCs 61-66 and 68 respectively as shown in Scheme II. It is well known that the two
rings of spiro compounds are orthogonal and the groups attached at the two ends define
planes at right angles to each other. These compounds are known to show dissymmetry,
however they do not have any dissymmetric atom. In the present case as the ketones used
were symmetric, only one racemic product was expected. The spectral data for these
compounds is collected in Table II and Experimental section.
Table II: Spectral data, mps and yields of THSβCs 60-68
Prod. No. IR cm-1
M.P C Yield % 1H NMR
13C NMR
C3H C3H C4H C1 C3 C4
60 Fig. 15a,b 3402 br 185-87 91 3.02 dd 3.39 dd 4.15 t 52.3 48.5 40.8
61 Fig. 17a,b 3358 br 260-62 88 3.01 dd 3.35 dd 4.08 t 51.4 47.7 39.7
62 Fig. 18a,b 3412 br 201-03 89 2.98 dd 3.38 dd 4.09 t 51.5 47.6 39.6
63 Fig. 19a,b 3373, 3308 187-89 90 2.95 dd 3.35 dd 4.11 t 51.6 47.8 39.7
64 Fig. 20a,b 3458,
3346, 3225
224-26 71 2.75 dd 3.15 dd 3.90
brs
52.2 48.5 40.3
65 Fig. 21a,b 3300 br 260-62 85 3.18 bs 4.08 bs 52.3 44.4 37.9
66 Fig. 22a,b 3410, 3273 78-80 87 3.05dd 3.30 dd 4.30 t 52.3 48.5 37.9
67 Fig. 16a,b 3425 br 133-35 82 3.03 dd 3.43 dd 4.14 t 61.8 50.0 40.9
68 Fig. 23a,b 3412 br 245-47 79 2.90 dd 3.26 dd 3.98 bd 61.7 50.0 40.8
Chapter III
90
Fig. 17a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 61
Fig. 17b: (75 MHz, CDCl3/DMSO-d6)
13C NMR Spectrum of Compound 61
61
NH
NH
OMe
OMe
61
NH
NH
OMe
OMe
Chapter III
91
Fig. 18a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 62
Fig. 18b: (75 MHz, CDCl3/DMSO-d6)
13C NMR Spectrum of Compound 62
62
NH
NH
OO
62
NH
NH
OO
Chapter III
92
Fig. 19a: (300 MHz, CDCl3/DMSO-d6)
1H NMR Spectrum of Compound 63
Fig. 19b: (75 MHz, CDCl3/DMSO-d6)
13C NMR Spectrum of Compound 63
63
NH
NH
OMe
63
NH
NH
OMe
Chapter III
93
Fig. 20a: (300 MHz, DMSO-d6)
1H NMR Spectrum of Compound 64
Fig. 20b: (75 MHz, DMSO-d6)
13C NMR Spectrum of Compound 64
64
NH
NH
NH2
64
NH
NH
NH2
Chapter III
94
Fig. 21a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 65
Fig. 21b: (75 MHz, CDCl3)
13C NMR Spectrum of Compound 65
65
NH
NH
O
65
NH
NH
O
Chapter III
95
Fig. 22a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 66
Fig. 22b: (75 MHz, CDCl3)
13C NMR Spectrum of Compound 66
66
NH
NH
S
66
NH
NH
S
Chapter III
96
Fig. 23a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 68
Fig. 23b: (75 MHz, CDCl3)
13C NMR Spectrum of Compound 68
NH
NH
OO
68
NH
NH
OO
68
Chapter III
97
Pictet-Spengler reaction using unsymmetrical ketones:
As the spiro compounds show dissymmetry it would be possible to get selectively
only one diastereomer of the spiro compound if it does not have any element of symmetry.
To check the stereoselectivity in reaction it was necessary to use unsymmetrical ketones
for the Pictet-Spengler cyclization. Isatin, α-tetralone and 2-methylcyclopentane-1,3-dione
were selected for this purpose. Thus treatment of amino compound 52 with isatin in
presence of catalytic amount of glacial acetic acid furnished 69 as a solid product (Scheme
III).
1
34
NH
NH
NH
NH2
Ar
NH
Ar
reflux
tolueneN
Ar
69, 72, 73 and 74
52, 54, 55 and 59
HN
HN
ONH
NH
NH
Ar
O
O
isatin, AcOH
[AB]B
18-18.5 hrs
69: phenyl, 72: Ar = 3,4-methylenedioxyphenyl, 73: Ar = 4-methoxyphenyl, 74: Ar = 2-
thienyl.
Scheme III
Usual workup and chromatographic separation yielded a pale yellow solid, melting
at 199-201 oC in 88% yield. The structure of the base 69 was confirmed using spectral and
elemental analytical data. The compound analyzed for C24H19N3O. IR (KBr) showed bands
at 3296 (br), 3263 for three >NH and band at 1722 cm-1
for carbonyl group. 1H NMR (Fig.
24a) showed (i) a broad singlet exchangeable with D2O at 1.69 for >NH, (ii) two doublet
of doublets at 3.56, J = 5.5, 13.4 Hz and at 3.75, J = 6.7, 13.4 Hz for two geminally and
vicinally coupled C3H2, (iii) a triplet at 4.41 with J = 6.7 Hz for C4H, (iv) signals of
thirteen aromatic protons at 6.89 to 7.42 and (v) two broad singlets exchangeable with D2O
at 7.61 for >NH of indole ring and at 8.1 for >NH of isatyl ring. 13
C NMR (Fig. 24b)
showed (i) signals at 40.3, 48.3 and 61.8 for C4, C3 and C1, (ii) strong signals at 128.3 and
Chapter III
98
128.4 corresponding to four aromatic carbons, and (iii) seventeen singlets for seventeen
carbons. Mass spectrum showed, (i) M+ at m/z 365, (ii) base peak at 337 obtained by the
loss of carbonyl group (C=O).
1
34
NH
NH
69
HNO
The product 69 was a single diastereomer and it was necessary to find the absolute
stereochemistry of the spiro product. Single crystal X-ray analysis was carried out for this
purpose which revealed that the base 69 has R, R configuration at C1 and C4 (Figure 24c).
Thus by using glacial acetic acid as a catalyst probably due to the mildness of the catalyst
only one diastereomer of base 69 was obtained selectively and a stereoselective reaction
could be achieved.
Figure 24c. ORTEP diagram of base 69 ellipsoids is drawn at 50% probability
Chapter III
99
Fig. 24a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 69
Fig. 24b: (75 MHz, CDCl3)
13C NMR Spectrum of Compound 69
69
NH
NH
NH
O
69
NH
NH
NH
O
Chapter III
100
Concomitant literature survey revealed57,59
that there is a report for the formation of
mixture of the two diastereomers of sulfate form of base 69 in a similar Pictet-Spengler
condensation using sulfuric acid in water as a catalyst in 46% yield. In the above report
59
the major diastereomer was shown to have R, R configuration using 2D NMR of the
mixture without isolating the individual isomers. However, in the present study by using
acetic acid as a catalyst we could achieve the formation of only one diastereomer of base
69 in 88% yield exclusively and also confirmed the stereochemistry of 69 as R, R
unambiguously using single crystal X-ray analysis. The sterically preferred spiro
transition state (Scheme III) having the trans arrangement of substituents at C1 and C4 in
presence of glacial acetic acid as a mild acidic catalyst explained the exclusive formation
of one diastereomer 69.
Formation of salts (sulfate and hydrochloride) from base 69:
To compare the reported59
and the present results, base 69 was treated with sulfuric
acid (conc.) in methanol (Scheme IV). The mixture was heated with stirring till the
solution became clear and was kept at room temperature for 24 h to furnish the
corresponding sulphate in 95% yield as colourless crystals, melting above 300 oC. The
1H
NMR (Fig. 25a) and 13
C NMR (Fig. 25b) data of sulphate 70 was consistent with that of
the reported59
major isomer.
The report33
of good biological activity for the hydrochloride of similar base
without substituent at 4-position tempted us to covert base 69 to the hydrochloride 71 by
treating the base 69 with HCl (conc.) as shown in Scheme IV. The product crystallized out
from the solution and was shown to be the expected product 71 as colourless crystals,
melting at 255-57 oC in 94% yield.
1
34
NH
NH
Ph
69
HNO
1
34
NH
NH2
Ph
HNO
X
70, X = HSO4
71, X = Cl
H2SO4 or HCl
Conc.
heating
rt, 24 hrs
Scheme IV
Chapter III
101
In 1H NMR of salts 70 (Fig. 25a) and 71 (Fig. 26a), the assignments of C3H2 and
C4H are different than those of base 69 as shown in Table III. In both the salts, the protons
at C3 are shifted downfield due to the proximity of positive nitrogen. C4H appeared as a dd
with J = 6.1 and 12.1 Hz as Ja,e and Ja,a respectively showing coupling with two protons
at C3. This indicated the axial position of C4H in both the salts 70 and 71. However, in
base 69 C4H appeared at 4.41 as a triplet, J = 6.7 Hz, indicating rapid flipping of the
nitrogen containing ring in solution.
Table III: Comparison of 1H NMR spectra of compounds 69, 70 and 71
Entry Assignment Base 69 Sulphate 70 Hydrochloride 71
C3H C3H C4H C3Ha C3He C4H C3Ha C3He C4H
1 Chemical shift (δ) 3.56 3.75 4.41 4.14 4.72 3.84 4.17 4.83 3.71
2 Multiplicity dd dd t t dd dd t dd dd
3 J Hz 5.5,
13.4
6.7,
13.4
6.7 10.7 6.1,
10.7
6.1,
12.1
11.3 6.1,
10.6
6.1,
12.1
As compared to the chemical shift of C4H in base, this proton, being axial was
shifted to up field position in both the salts. In contrast to this, the stereochemistry of salts
70 and 71 was shown to be same as that of the base 69 having R, R configuration at C1 and
C4 using X-ray analysis (Figure 25c and Figure 26c). This can be revealed by the
overlapping of X-ray structures of 69, 70 and 71 as shown in Chart I. The difference in
the two results from 1H NMR and X-ray analysis can be attributed to the solution state
where rapid flipping is possible in 1H NMR and rigid solid state in X-ray analysis. The
structures of 70 and 71 were unambiguously finalized using spectral data and elemental
analyses (Table IV).
To generalize the reactions, the substituents at 1 and 4-positions were changed.
Treatment of amino compounds 54, 55 and 59 with isatin afforded new compounds 72, 73
and 74 respectively in diastereoselective manner (Scheme III). The spectral data, mps and
yields of the products are recorded in Table IV and Experimental section.
Chapter III
102
Fig. 25a: (300 MHz, DMSO-d6)
1H NMR Spectrum of Compound 70
Fig. 25b: (75 MHz, DMSO-d6)
13C NMR Spectrum of Compound 70
NH
N
NH
O
HH
HSO4
70
NH
N
NH
O
HH
HSO4
70
Chapter III
103
The molecule is refined aniotropically
except the disordered (HSO4-) moiety. X-
ray analysis revealed the configuration at
C1 and C4 as R and R.
Figure 25c. ORTEP diagram of sulphate 70 ellipsoid is drawn at 50% probability
Chapter III
104
Fig. 26a: (300 MHz, DMSO-d6)
1H NMR Spectrum of Compound 71
Fig. 26b: (75 MHz, DMSO-d6)
13C NMR Spectrum of Compound 71
NH
N
NH
O
HH
Cl
71
NH
N
NH
O
HH
Cl
71
Chapter III
105
The complex crystallizes with one
solvent methanol along with half
disordered water molecule. X-ray
analysis revealed the configuration at C1
and C4 as R and R.
Figure 26c. ORTEP diagram of sulphate 71 ellipsoid is drawn at 50% probability
Chapter III
106
Base
Hydrochloride
Sulphate
Chart I. Overlapping of the molecules for compounds 69, 70 and 71
Further, instead of isatin, α-tetralone was used in the Pictet-Spengler condensation
reaction with amino compounds 52 and 55 under same condition which resulted in
compounds 75 and 76 exclusively indicating the diastereoselective reaction in these cases
also (Scheme V).
NH
NH
NH2
Ar
NH
Ar
reflux, 18-18.5 hrs
AcOH,Toluene
75, 7652 and 55
tetralone
75: phenyl, 76: Ar = 4-methoxyphenyl
Scheme V
The structures of 75 and 76 were also confirmed using spectral and elemental analysis
(Table IV and Experimental section). Compound 75 showed in
IR (KBr) bands at 3437, 3421 cm-1
for two >NH. 1H NMR (Fig.
24a) showed (i) three broad singlets at 1.87, 2.05 and 2.17 for -
(CH2)3- protons, (ii) two doublet of doublets at 3.81, J = 6.6, 13.2
Hz and at 4,04, J = 6.6, 13.2 Hz for two geminally and vicinally
coupled C3H2, (iii) a triplet at 4.4 with J = 7.6 Hz for C4H, (ii) a broad singlet
1
34
NH
NH
Ph
75
Chapter III
107
exchangeable with D2O at 5.71 for >NH, (iv) signals of thirteen aromatic protons at 7.05 to
7.42 and (v) one broad singlet exchangeable with D2O at 8.64 for >NH of indole ring. 13
C
NMR (Fig. 24b) showed (i) signals at 14.1, 22.5, 30.1, 36.7 and 67.8 for six carbons (two
signals overlap at 22.5), (ii) strong signals at 133.6, 129.0, 126.5, 124.7, 120.4 and 113.6
corresponding to fourteen aromatic carbons and (iii) six singlets for six carbons. Mass
spectrum showed, (i) M+ and base peak at m/z 364.
It is to be noted that the reaction gave only one diastereomer 75 as seen from the
spectral data. Since the NMR spectra of both the products 75 and 76 were similar to that of
69, probably these isomers also have R, R stereochemistry at C1 and C4 similar to the
isomer 69.
Table IV: Spectral data, mps and yields of THSβCs 69-76
Subsequently, the substituent at 1-position was changed by using 2-
methylcyclopentane-1,3-dione as an unsymmetric ketone for the Pictet-Spengler
condensation. Thus the treatment of amino compound 52 with 2-methylcyclopentane-1,3-
Prod. No. IR cm-1
M.P C Yield % 1H NMR
13C NMR
C3H C3H C4H C1 C3 C4
69
Fig.24a,b
3296 (br),
3263, 1722
199-201 88 3.56 dd 3.75 dd 4.41 t 61.8 48.3 40.3
70
Fig. 25a,b
3389, 3244
(br), 1725
above
300
95 4.72 dd 4.14 t 3.84 dd 59.5 44.7 36.8
71
Fig. 26a,b
3306, 3248,
3217 (br),
1739
255-57 94 4.83 dd 4.17 t 3.71 dd 60.9 48.3 38.8
72
Fig. 26a,b
3398 (br),
3288, 1730
266-68 85 3.28 dd 3.45 dd 4.25 t 61.6 48.9 39.8
73
Fig. 28a,b
3610, 3342,
3286, 1732
280-81 84 3.26 dd 3.50 dd 4.33 t 61.0 48.5 39.9
74
Fig. 29a,b
3390, 3280,
3186, 1718
134-36 81 3.44
brs
3.53 dd 4.62 t 61.1 48.8 35.1
75
Fig. 30a,b
3437, 3421 183-85 76 3.81 dd 4.04 dd 4.4 t 65.8 48.1 36.7
76
Fig. 31a,b
3404, 3302 Oily 72 3.79 m 4.03 dd 4.38 t 66.7 48.3 34.2
Chapter III
108
dione, under the same conditions led to the formation of a new product melting at 191-93
oC in 89% yield.
NH
NH2
Ph
NH
N
Ph
AcOH
52
O
O
O
NH
NH
Ph
O77
toluene, reflux
Scheme VI
The above product showed IR (KBr) bands at 3367 (br) cm-1
for two >NH. 1H
NMR showed (i) a singlet at 1.52 for -CH3 protons, (ii) multiplet at 2.62-2.15 for -(CH2)2-
protons (iii) two doublet of doublets at 3.85, J = 6.4, 13.8 Hz and at 4.02, J = 6.3, 12.7 Hz
for two geminally and vicinally coupled C3H2, (iv) a triplet at 4.49 with J = 7.2 Hz for
C4H, (v) a broad singlet exchangeable with D2O at 6.63 for >NH, (vi) signals of ten
aromatic protons at 6.89 to 7.55, and (vii) one broad singlet exchangeable with D2O at
10.46 for >NH of indole ring. 13
C NMR showed, (i) signals at 6.7, 23.8, 32.5, 43.4, and
48.5 for five carbons, (ii) two signals at 105.1 and 173.1 for olefinic carbons, (iii) a strong
singlet at 128.0 corresponding to three aromatic carbons, (iv) eleven singlets for eleven
carbons and (v) one singlet at 199.5 for carbonyl carbon. This spectral data was not
consistent with the expected structure as well as the intermediate imino compound.
Considering the product as the imino compound, attempts for cyclization using strong acid
TFA were also unsuccessful (Scheme VI). Thus single crystal X-ray analysis was carried
out from which structure 77 was assigned to the new unexpected product (Fig. 32). The
formation of compound 77 can be explained by bond isomerisation in imine intermediate
to achieve the stable conjugated system. Thus no spiro THβC could be obtained in this
reaction.
Fig. 32. ORTEP diagram of compound 77 ellipsoids is drawn at 50% probability.
Chapter III
109
Fig. 27a: (300 MHz, DMSO-d6)
1H NMR Spectrum of Compound 72
Fig. 27b: (75 MHz, CDCl3/DMSO-d6)
13C NMR Spectrum of Compound 72
72
NH
NH
NH
O
OO
72
NH
NH
NH
O
OO
Chapter III
110
Fig. 28a: (300 MHz, DMSO-d6)
1H NMR Spectrum of Compound 73
Fig. 28b: (75 MHz, DMSO-d6)
13C NMR Spectrum of Compound 73
73
NH
NH
NH
O
OMe
73
NH
NH
NH
O
OMe
Chapter III
111
Fig. 29a: (300 MHz, CDCl3/DMSO-d6)
1H NMR Spectrum of Compound 74
Fig. 29b: (75 MHz, CDCl3/DMSO-d6)
13C NMR Spectrum of Compound 74
74
NH
NH
NH
O
S
74
NH
NH
NH
O
S
Chapter III
112
Fig. 30a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 75
Fig. 30b: (75 MHz, CDCl3)
13C NMR Spectrum of Compound 75
75
NH
NH
75
NH
NH
Chapter III
113
Fig. 31a: (300 MHz, CDCl3)
1H NMR Spectrum of Compound 76
Fig. 31b: (75 MHz, CDCl3)
13C NMR Spectrum of Compound 76
76
NH
NH
OMe
76
NH
NH
OMe
Chapter III
114
Conclusion
1. Catalytic activity of glacial acetic acid in Pictet–Spengler reaction has been
demonstrated using symmetrical ketones like cyclohexanone and cyclopentanone.
New spiro products were furnished during these reactions.
2. Using the same catalyst with unsymmetrical ketones like isatin and tetralone,
exclusively one diastereomer of new THSβCs were obtained.
3. Structures of base 69, sulfate 70 and hydrochloride 71 were confirmed using single
crystal X-ray analysis from which the absolute configuration of the products 69, 70
and 71 was confirmed as R, R.
4. A diastereoselective and high yielding method for the synthesis of THSβCs was
established using glacial acetic acid.
Chapter III
115
Experimental Section
Expt. No. 3.1 - General procedure for catalytic hydrogenation of 2-aryl-2-(3-indolyl)-
l-nitroethane
NH
NO2
Ar
NH
NH2
Ar
Raney Nickel
H2, MeOH
35 - 41 and 46 52 - 55, 57 - 59
2-Aryl-2-(3-indolyl)-l-nitroethane (35-41, see Chapter: II - Part B, 0.002 mol)
was dissolved in methanol and Raney Nickel (1.5g) was added to it. The reaction mixture
was treated with hydrogen at 70 psi in Parr low pressure hydrogen apparatus for 2-48 hrs
or treated with hydrogen using balloon for 2-12 hrs. The catalyst was filtered off and the
filtrate was concentrated by vacuum distillation. Ether was added so that the product
readily separated out.
2-Phenyl-2-(3-indolyl)-1-aminoethane 52
Time : 2 hrs using H2 apparatus or 12 hrs using H2 in balloon
Mp. : 130 C(lit.53
mp. 130 °C)
Yield : 95 %, white crystals
IR (KBr) : 3411, 3348, 3143 cm-1
for NH2 and NH
MS : m/z 236 (M+), 206 (100%)
1H NMR (Fig. 13a)
1.38 brs (Ex. with D2O) 2H >NH2 3.3 m 1H C1H
3.44 m 1H C1H 4.22 m 1H C2H
6.93 s 1H ArH 6.99 t (J = 7.7 Hz) 1H ArH
7.06-7.19 m 2H ArH 7.21-7.29 m 5H ArH
7.42 d (J = 8.0 Hz) 1H ArH 8.54 brs (Ex. with D2O) 1H >NH
13C NMR
47.1 (str.) C1, C2 111.0 C7' 117.2 C3'
119.1, 119.2 C4', C6' 121.2, 121.9 C5', C2' 126.2, 126.9 C4'', C4'a
128.0 (str.) C2'', C6'' 128.4 (str.) C3'', C5'' 136.3 C7'a
NH
NH2
12
1'
2'
3'4'a4'
5'
6'
7'7'a
1''
2''
3''
4''
5''
6''
52
Chapter III
116
142.9 C1''
2-(3,4-Dimethoxyphenyl)-2-(3-indolyl)-1-aminoethane 53
Time : 48 hrs using H2 apparatus or 10 hrs using H2 in balloon.
Mp. : 193-95 C (lit.53
mp. 195 °C)
Yield : 91%, white crystals
IR (KBr) : 3275 (br) cm-1
MS : m/z 296 (M+), 266(100%), 265, 250, 234,
204, 178, 130, 76.
1H NMR
1.88 brs (Ex. with D2O) 2H >NH2 3.25 m 1H C1H
3.40 m 1H C1H 3.8 s 3H OCH3
3.85 s 3H OCH3 4.20 t (J = 6.3 Hz) 1H C2H
6.72-6.9 m 3H ArH 6.94-7.08 m 2H ArH
7.13 t (J = 7.4) 1H ArH 7.30 d (J = 7.7 Hz) 1H ArH
7.44 d (J = 7.7 Hz) 1H ArH 8.28 brs (Ex. with D2O) 1H >NH
13
C NMR
42.3 C1 45.1 C2 56.5 (str.) 2 × OCH3
112.5 C7' 112.9, 113.2 C2'', C5'' 114.9 C3'
119.5, 120.0 C6'', C4' 121.4 C6' 122.8, 123.1 C5', C2'
127.5 C4'a 134.5 C1'' 138.4 C7'a
149.7 C4'' 151.0 C3''
2-(3,4-Methylenedioxyphenyl)-2-(3-indolyl)-1-aminoethane 54
Time : 48 hrs using H2 apparatus or 10 hrs using
H2 in balloon
Mp. : 217-18 C (lit.53
mp. 219 °C)
Yield : 87 %, white crystals
IR (KBr) : 3325 (br) cm-1
MS : m/z 280 (M+) 278, 252, 250 (100%), 220,
204, 191, 115
53
NH
NH2
12
1'
2'
3'4'a4'
5'
6'
7'7'a
1''
2''3''
4''5''
6''
OMe
OMe
54
NH
NH2
12
1'
2'
3'4'a4'
5'
6'
7'7'a
1''
2''3''
4''5''
6''
OO
Chapter III
117
1H NMR
3.14 brs (Ex. with D2O) 2H >NH2 3.32 m 2H C1H2
4.2 t (J = 6.6 Hz) 1H C2H 5.84, 5.86 (2 x brs) 2H -OCH2O-
1.1. 6.55-6.8 m 3H ArH 6.9-7.02 m 2H ArH
7.1 t (J = 7.4 Hz) 1H ArH 7.3 d (J = 8.0 Hz) 1H C7'H
7.38 d (J = 8.0 Hz) 1H 1.2. C4'H 8.4 brs (Ex. with D2O) 1H >NH
13C NMR
42.5 C1 44.2 C2 99.2 -OCH2O-
106.5, 106.8 C7', C2'' 110.0 C5'' 113.9 C3'
117.0, 117.2 C6'', C2' 119.5, 119.8 C4', C6' 120.2 C5'
125.1 C4a' 135.1 (str.) C7'a, C1'' 144.4 C4''
146.0 C3''
2-(4-Methoxyphenyl)-2-(3-indolyl)-1-aminoethane 55
Time : 25 hrs using H2 apparatus or 7 hrs using H2
in balloon.
Mp. : Oily
Yield : 81 %
IR (KBr) : 3645, 3570 broad cm-1
1H NMR (Fig. 14a)
2.02 bs (Ex. with D2O) 2H -NH2 3.24 dd (J = 7.7, 12.4 Hz) 1H C1H
3.39 dd (J = 7.4, 12.7 Hz) 1H C1H 3.75 s 3H -OCH3
4.21 t (J = 7.4 Hz) 1H C2H 6.82 d (J = 8.3 Hz) 2H C3''H,C4''H
6.92 s 1H C2'H 7.05 t (J = 7.4 Hz) 2H ArH
7.1-7.31 m 3H ArH 7.46 d (J = 8.0 Hz) 1H ArH
8.93 bs (Ex. with D2O) 1H >NH
13C NMR
45.8 C1 47.1 C2 55.1 -OCH3
111.1 C7' 113.7 (str.) C3'', C5'' 117.1 C3'
118.9, 119.1 C4', C6' 121.2, 121.7 C5', C2' 126.7 C4'a
55
NH
NH2
12
1'
2'
3'4'a4'
5'
6'
7'7'a
1''
2''3''
4''5''
6''
OMe
Chapter III
118
128.8 (str.) C2'', C6'' 134.8 C1'' 136.3 C7'a
157.8 C4''
2-(4-Aminophenyl)-2-(3-indolyl)-1-nitroethane 56
Time : 10 hrs using H2 apparatus or 2 hrs using H2 in balloon
Mp. : 139 C (lit.53
mp. 138-40 °C), Orange
crystals
IR (KBr) : 3425, 3348, 3288, 1547, 1380 cm-1
MS : m/z 281 (M+), 247, 234, 221(100%), 204,
143, 130,117
1H NMR
3.57 brs (Ex. with D2O) 2H -NH2 4.80 dd (J = 7.7, 11.3 Hz) 1H C1H
4.93-5.05 m 2H C1H,C2H 6.55 d (J = 7.4 Hz) 2H C3''H,C5''H
6.89 s 1H C2' H 7.03 m 3H ArH
7.13 t (J = 7.7 Hz) 1H C6'H 7.26 d (J = 8 Hz) 1H C7'H
7.40 d (J = 7.7 Hz) 1H C4'H 8.03 brs (Ex. with D2O) 1H >NH
13C NMR
40.9 C2 79.8 C1 111.2 C7'
114.7 C3' 115.3 (str.) C3'', C5'' 118.9 C4'
119.7 C6' 121.4 C5' 122.4 C1''
136.3 C7'a 145.5 C4''
2-(4-Aminophenyl)-2-(3-indolyl)-1-aminoethane 57
Time : 20 hrs using H2 apparatus or 5 hrs using H2
in balloon.
Mp. : 126-28 C (lit.53
mp. 125-27 °C)
Yield : 79 %, white crystals
IR (KBr) : 3645, 3570 (br) cm-1
MS : m/z 251(M+), 221(100%), 204, 192,177.
1H NMR
2.8 bs (Ex. with D2O) 4H 2x -NH2 3.13 dd (J = 7.2, 12.4 Hz) 1H C1H
56
NH
NO2
12
1'
2'
3'4'a4'
5'
6'
7'7'a
1''
2''3''
4''5''
6''
NH2
57
NH
NH2
12
1'
2'
3'4'a4'
5'
6'
7'7'a
1''
2''3''
4''5''
6''
NH2
Chapter III
119
3.28 dd (J = 7.2, 12.4 Hz) 1H C1H 4.07 t (J = 7.7 Hz) 1H C2H
6.54 d (J = 8.0 Hz) 2H C3''H,C4''H 6.88 t (J = 7.2 Hz) 1H ArH
6.9-7.05 m 4H ArH 7.3 d (J = 8.0 Hz) 1H C7'H
7.36 d (J = 7.7 Hz) 1H C4'H 10.37 bs (Ex. with D2O) 1H >NH
13C NMR
44.7 C1 46.2 C2 110.1 C7'
113.4 (str.) C3'', C5'' 115.9 C3' 117.1, 117.7 C4', C6'
119.9, 120.1 C5', C2' 125.7 C4'a 127.3 (str.) C2'', C6''
130.8 C1'' 135.3 C7'a 144.4 C4''
2-(2-Furyl)-2-(3-indolyl)-1-aminoethane 58
Time : 2 hrs using H2 apparatus or 4 hrs using H2 in balloon.
Mp. : 141-42 C (lit.53
mp. 142-43 °C)
Yield : 94%, brown crystals
IR (Nujol) : 3356, 3292 (br) cm-1
MS : m/z 226 (M+), 196(100%), 195, 167, 115.
1H NMR
1.6 brs (Ex. with D2O) 2H >NH2 3.26-3.42 m 2H C1H2
4.33 t (J = 7.3 Hz) 1H C2H 6.12 dd (J=2.3, 0.9 Hz) 1H C3''H
6.3 t (J = 2.3 Hz) 1H ArH 7.03–7.16 m 2H ArH
7.2 t (J = 7.9 Hz) 1H ArH 7.36 bd (J = 8.5 Hz) 2H C2'H,C7'H
7.57 d (J = 7.9 Hz) 1H C4'H 8.18 brs (Ex. with D2O) 1H >NH
13C NMR
40.9 C1 45.9 C2 106.3 C3''
110.4 C4'' 111.6 C7' 114.7 C3'
119.4, 119.7 C4', C6' 122.3, 122.6 C5', C2' 126.7 C4'a
136.6 C7'a 141.6 C5'' 156.4 C2''
2-(2-Thienyl)-2-(3-indolyl)-1-aminoethane 59
Time : 10 hrs using H2 apparatus or 4 hrs using H2 in balloon.
58
NH
NH2
12
1'
2'
3'4'a4'
5'
6'
7'7'a
2''3''
4'' 5''
O
Chapter III
120
Mp. : 122C (lit.53
mp. 121 °C)
Yield : 90%, brown crystals
IR (KBr) : 3450, 3358, 3296 cm-1
MS : M+
was observed at 212 (M+- CH2NH2)
1H NMR
1.5 bs (Ex. with D2O) 2H >NH2 3.28-3.5 m 2H C1H2
4.52 t (J = 7.0 Hz) 1H C2H 6.94 d (J = 3.5 Hz) 2H C3''H, C4''H
7.1 t (J = 7.9 Hz) 1H ArH 7.05-7.24 m 3H ArH
7.38 d (J = 7.9 Hz) 1H C7'H 7.55 d (J = 7.9 Hz) 1H C4'H
8.11 bs (Ex. with D2O) 1H >NH
13C NMR
38.7 C1 39.0 C2 110.8 C7'
115.0 C3' 117.9, 118.0 C4', C6' 120.6, 121.4 C5', C2'
122.6 C5'' 123.4 C4'a 125.7 (str.) C3'', C4''
135.8 C7'a 146.7 C2''
Expt. No. 3.2 - General procedure for the Pictet-Spengler cyclization of amino
compounds towards tetrahydrospiro-β-Carbolines
1
34
NH
NH
NH2
Ar
NH
Ar
60 - 69, 72-7652 - 55, 57 - 59
reflux
Toluene
ketone, AcOH
9.5-18.5 hrs
The mixture of the amino compound (52-55 and 57-59, 0.002 mol), ketone (0.008
mol), and glacial acetic acid (0.1- 0.5 equiv.) was heated at 120 oC in dry toluene under
nitrogen atmosphere in a Dean-Stark apparatus for 9.5-18.5 hrs. Heating was continued till
the full consumption of the amino compound. Completion of the reaction was confirmed
by TLC. The reaction mixture was diluted with ethyl acetate, washed with 10% NaHCO3
and brine. The combined organic layer was dried over sodium sulfate and the solvent was
59
NH
NH2
12
1'
2'
3'4'a4'
5'
6'
7'7'a
2''3''
4'' 5''
S
Chapter III
121
evaporated under reduced pressure. The crude product obtained was purified using column
chromatography with hexane/ethyl acetate to give products 60-69 and 72-76.
4-Phenyl-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclohexane] 60
Time : 9.5 hrs.
Mp. : 185-87 C, yellowish solid
Yield : 91%
IR (KBr) : 3402 (br) cm-1
.
MS : m/z 316 (M+), 287, 273 (100%), 260, 115,
91, 77.
Elemental analysis : for C22H24N2 requires: C, 83.50; H, 7.64; N, 8.85. Found: C,
83.25; H, 7.89; N, 8.57%.
1H NMR (Fig. 15a)
1.48-1.95 m 11H -CH2-(CH2)3-CH2- + >NH (Ex. with D2O)
3.02 dd (J = 5.5, 13.5 Hz) 1H C3H 3.39 dd (J = 5.2, 13.5 Hz) 1H C3H
4.15 t (J = 5.2 Hz) 1H C4H 6.84-6.94 m 2H ArH
7.06 dt (J = 1.4, 8.0 Hz) 1H ArH 7.11-7.30 m 6H ArH
7.85 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 15b)
21.4(str.) -CH2- 25.8 -CH2- 36.4 -CH2-
37.2 -CH2- 40.8 C4 48.5 C3
52.3 C1 109.7, 110.5 C8, C4a 119.1, 119.2 C5, C7
121.3 C6 126.1, 126.8 C4', C5a 128.1, 128.2 C2', C6', C3', C5'
135.4 C1a 142.3 C8a 143.7 C1'
DEPT (Fig. 15c) showed the presence of five -CH2 groups with one strong signal at 21.4
and -CH3 group was absent.
60
NH
NH1
344a5a
5
6
78
8a 1a
1'
2'
3'4'
5'
6'
Chapter III
122
4-(3,4-Dimethoxyphenyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclohexane] 61
Time : 7.5 hrs.
Mp. : 260-62 C, white solid
Yield : 88%
IR (KBr) : 3358 (br) cm-1
.
MS : m/z 376 (M+), 347, 333 (100%), 320, 95,
77.
Elemental analysis : for C24H28N2O2 requires: C, 76.56; H, 7.50; N, 7.44. Found: C,
76.75; H, 7.65; N, 7.23%.
1H NMR (Fig. 17a)
1.49-1.98 m 11H -CH2-(CH2)3-CH2- + >NH (Ex. with D2O)
3.01 dd (J = 5.2, 13.5 Hz) 1H C3H 3.35 dd (J = 4.7, 13.5 Hz) 1H C3H
3.77 s 3H -OCH3 3.83 s 3H -OCH3
4.08 t (J = 4.7 Hz) 1H C4H 6.63 d (J = 7.9 Hz) 1H Ar-H
6.72-6.75 m 2H Ar-H 6.89 t (J = 7.4 Hz) 1H Ar-H
6.98 d (J = 7.7 Hz) 1H Ar-H 7.08 t (J = 7.7 Hz) 1H Ar-H
7.30 d (J = 7.9 Hz) 1H Ar-H 7.82 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 17b)
20.4 (str.) -CH2- 24.9 -CH2- 34.8 -CH2-
36.1 -CH2- 39.7 C4 47.7 C3
51.4 C1 54.8 (str) 2 × OCH3 107.7 C8
109.9, 110.0, 110.6 C2', C5',C4a 117.2, 117.6 C5, C7 119.1, 119.4 C6', C6
125.6 C5a 134.7 C1' 135.9 C1a
142.0 C8a 146.1 C4' 147.5 C3'
4-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclohexane]
62
Time : 7.5 hrs.
Mp. : 201-03 C, white solid
Yield : 89%
IR (KBr) : 3412 (br) cm-1
.
61
NH
NH1
344a5a
5
6
78
8a 1a
1'2'
3'
4'5'
6'
OMe
OMe
62
NH
NH1
344a5a
5
6
78
8a 1a
1'2'
3'4'
5'
6'
OO
Chapter III
123
MS : m/z 360 (M+), 331, 317(100%), 304, 94, 77.
Elemental analysis : for C23H24N2O2 requires: C, 76.64; H, 6.71; N, 7.77. Found: C,
76.39; H, 6.58; N, 7.98%.
1H NMR (Fig. 18a)
1.55-2.16 m 11H -CH2-(CH2)3-CH2- + >NH (Ex. with D2O)
2.98 dd (J = 5.5, 13.5 Hz) 1H C3H 3.38 dd (J = 5.0, 13.5 Hz) 1H C3H
4.09 t (J = 5.2 Hz) 1H C4H 5.89 brs 2H OCH2O-
6.63 d (J = 9.1 Hz) 2H ArH 6.71 d (J = 7.9 Hz) 1H ArH
6.90 t (J = 7.7 Hz) 1H Ar-H 7.00 d (J = 7.4 Hz) 1H ArH
7.09 t (J = 7.4 Hz) 1H ArH 7.30 d (J = 7.9 Hz) 1H ArH
7.83 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 18b)
20.4 (str.) -CH2- 24.8 -CH2- 34.7 -CH2-
35.7 -CH2- 39.6 C4 47.6 C3
51.5 C1 99.6 -OCH2O- 106.8 C8
107.4, 107.6 C2', C5' 109.9 C4a 117.3, 117.7 C5, C7
119.5, 119.9 C6', C6 125.4 C5a 134.9 C1'
137.2 C1a 141.8 C8a 144.6 C4'
146.3 C3'
4-(4-Methoxyphenyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclohexane] 63
Time : 7.5 hrs.
Mp. : 187-89 C, white solid
Yield : 90%
IR (KBr) : 3373, 3308 cm-1
.
MS : m/z 346 (M+), 317, 303(100%), 290, 77.
Elemental analysis : for C23H26N2O requires: C, 79.73; H,
7.56; N, 8.09. Found: C, 79.51; H, 7.69; N, 7.85%.
1H NMR (Fig. 19a)
1.49-2.12 m 11H -CH2-(CH2)3-CH2- + >NH (Ex. with D2O)
2.95 dd (J = 5.8, 12.4 Hz) 1H C3H 3.35 dd (J = 5.2, 13.2 Hz) 1H C3H
63
NH
NH1
344a5a
5
6
78
8a 1a
1'2'
3'4'
5'
6'
OMe
Chapter III
124
3.76 s 3H OCH3 4.11 t ( J = 5.2 Hz) 1H C4H
6.76-6.99 m 4H ArH 7.04 t (J = 7.9 Hz) 3H ArH
7.32 d (J = 7.9 Hz) 1H ArH 9.59 bs (Ex. with D2O) 1H >NH
13C NMR (Fig. 19b)
20.5 (str.) -CH2- 24.9 -CH2- 34.9 -CH2-
35.8 -CH2- 39.7 C4 47.8 C3
51.6 C1 54.2 -OCH3 107.9 C8
109.9 C4a 112.6 (str.) C3', C5' 117.3, 117.8 C5, C7
119.5 C6 125.6 C5a 128.1 (str.) C2', C6'
134.9, 135.2 C1', C1a 141.9 C8a 156.8 C4'
4-(4-Aminophenyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclohexane] 64
Time : 10 hrs.
Mp. : 224-26 C, white solid
Yield : 71%
IR (KBr) : 3458, 3346, 3225 cm-1
.
MS : m/z 331(M+), 302, 288(100%), 275, 117.
Elemental analysis : for C22H25N3 requires: C, 79.72; H, 7.60;
N, 12.68. Found: C, 79.49; H, 7.35; N, 12.39.
1H NMR (Fig. 20a)
1.43-2.05 m 13H -CH2-(CH2)3-CH2- + >NH, NH2 (Ex. with D2O)
2.75 dd (J = 7.4, 13.2 Hz) 1H C3H 3.15 dd (J = 5.0, 12.7 Hz) 1H C3H
3.90 brs 1H C4H 6.45 d (J = 7.9 Hz) 2H O to -NH2
6.59-6.85 m 4H ArH 6.94 t (J = 5.5 Hz) 1H ArH
7.25d (J = 7.9 Hz) 1H ArH 10.79 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 20b)
20.9 -CH2- 21.5 -CH2- 25.5 -CH2-
35.7 (str.) -CH2- 40.3 C4 48.5 C3
52.2 C1 109.3 C8 110.8 C4a
113.9 (str.) C3', C5' 117.8, 118.6 C5, C7 120.0 C6
64
NH
NH1
344a5a
5
6
78
8a 1a
1'2'
3'4'
5'
6'
NH2
Chapter III
125
126.3 C5a 128.4 (str.) C2', C6' 131.2 C1'
135.5 C1a 142.4 C8a 146.6 C4'
4-(2-Furyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclohexane] 65
Time : 8.5 hrs.
Mp. : 260-62 C, white solid
Yield : 85%
IR (KBr) : 3300 (br) cm-1
.
MS : m/z 306 (M+), 277, 263(100%), 248, 115.
Elemental analysis : for C20H22N2O requires: C, 78.40; H, 7.24;
N, 9.14. Found: C, 78.19; H, 7.09; N, 9.02.
1H NMR (Fig. 21a)
1.39-1.99 m 11H -CH2-(CH2)3-CH2- + >NH (Ex. with D2O)
3.18 brs 2H C3H 4.08 brs 1H C4H
5.78 s 1H C3'H 6.11 s 1H C4'H
6.88 d (J = 7.2 Hz) 1H C5H 6.98 t (J = 7.4 Hz) 1H C8H
7.12 m 3H ArH 7.78 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 21b)
21.3 -CH2- 21.4 -CH2- 25.8 -CH2-
33.8 -CH2- 35.4 -CH2- 37.9 C4
44.4 C3 52.3 C1 106.6 C3'
107.8 C4' 109.9, 110.6 C8, C4a 118.6, 119.3 C5, C7
121.3 C6 126.8 C5a 135.2 C1a
141.3 C8a 142.1 C5' 156.9 C2'
4-(2-Thienyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclohexane] 66
Time : 8.5 hrs.
Mp. : 78-80 C, brown solid
Yield : 87%
IR (KBr) : 3410, 3273 cm-1
.
MS : m/z 322 (M+), 293, 279(100%), 226.
65
NH
NH1
344a5a
5
6
78
8a 1a
1'2'
3'
4' 5'
O
66
NH
NH1
344a5a
5
6
78
8a 1a
1'2'
3'
4' 5'
S
Chapter III
126
Elemental analysis : for C20H22N2S requires: C, 74.49; H, 6.88; N, 8.69. Found: C,
74.18; H, 6.56; N, 8.42.
1H NMR (Fig. 22a)
1.40-1.89 m 11H -CH2-(CH2)3-CH2- + >NH (Ex. with D2O)
3.05 dd (J = 3.3, 12.9 Hz) 1H C3H 3.30 dd (J = 3.8, 13.2 Hz) 1H C3H
4.30 d (J = 3.8 Hz) 1H C4H 6.68 d (J = 2.8 Hz) 1H ArH
6.78 t (J = 3.8 Hz) 1H ArH 6.87 t (J = 7.7 Hz) 1H ArH
7.0 d (J = 5.5 Hz) 2H ArH 7.13 d (J = 7.9 Hz) 1H ArH
7.19 d (J = 7.9 Hz) 1H ArH 7.73 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 22b)
21.3 -CH2- 21.4 -CH2- 25.9 -CH2-
35.5 (str.) -CH2- 37.9 C4 48.5 C3
52.3 C1 110.2, 110.6 C8, C4a 118.7, 119.3 C5, C7
121.4 C6 123.4 C5' 124.3 C4'
126.5 C5a 126.8 C3' 135.3 C1a
141.8 C8a 148.5 C2'
4-Phenyl-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclopentane] 67
Time : 13.5 hrs.
Mp. : 133-35 C, brown solid
Yield : 82%
IR (KBr) : 3425 (br) cm-1
.
MS : m/z 302 (M+), 287, 273 (100%), 260, 244,
91, 77.
Elemental analysis : for C21H22N2 requires: C, 83.40; H, 7.33; N, 9.26. Found: C,
83.18; H, 7.59; N, 9.05.
1H NMR (Fig. 16a)
1.81-2.15 m 9H -CH2-(CH2)2-CH2- + >NH (Ex. with D2O)
3.03 dd (J = 5.5, 13.5 Hz) 1H C3H 3.43 dd (J = 5.0, 13.5 Hz) 1H C3H
4.14 t (J = 5.0 Hz) 1H C4H 6.83-6.92 m 2H ArH
7.07 t (J = 6.1 Hz) 1H ArH 7.10-7.35 m 6H ArH
67
NH
NH1
344a5a
5
6
78
8a 1a
1'2'
3'
4'5'
6'
Chapter III
127
7.75 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 16b)
25.1 (str.) -CH2- 40.2 -CH2- 40.7 -CH2-
40.9 C4 50.0 C3 61.8 C1
110.5 C8 119.1, 119.2 (str.) C4a, C5, C7 121.4 C6
126.2, 126.8 C4', C5a 128.1 (str.) C2', C6' 128.2 (str.) C3', C5'
135.6 C1a 140.5 C8a 143.5 C1'
4-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-cyclopentane]
68
Time : 11.5 hrs.
Mp. : 245-47 C, white solid
Yield : 79%
IR (KBr) : 3412 (br) cm-1
.
MS : m/z 346 (M+), 317(100%), 304, 288.
Elemental analysis : for C22H22N2O2 requires: C, 76.28; H, 6.40; N, 8.09. Found: C,
76.06; H, 6.61; N, 7.92.
1H NMR (Fig. 23a)
1.42-2.01 m 9H -CH2-(CH2)2-CH2- + >NH (Ex. with D2O)
2.90 dd (J = 5.5, 13.2 Hz) 1H C3H 3.26 t (J = 5.0 Hz) 1H C3H
3.98 bd (J = 4.4 Hz) 1H C4H 5.77 brs 2H OCH2O-
6.45-6.65 m 3H ArH 6.75-7.05 m 3H ArH
7.15 t (J = 8.2 Hz) 1H ArH 7.76 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 23b)
25.0(str.) -CH2- 40.1 -CH2- 40.3 -CH2-
40.8 C4 50.0 C3 61.7 C1
100.7 -OCH2O- 108.0, 108.4 C8, C2' 110.4, 110.5 C5', C4a
119.0, 119.2 C5, C7 121.0, 121.4 C6', C6 126.7 C5a
135.6 C1' 137.7 C1a 140.4 C8a
145.8 C4' 147.4 C3'
NH
NH1
344a5a
5
6
78
8a 1a
1'2'
3'4'
5'
6'
OO
68
Chapter III
128
4-Phenyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one 69
Time : 18.5 hrs.
Mp. : 199-201 C, colorless crystals
Yield : 88%
IR (KBr) : 3296 (br), 3263, 1722 cm-1
.
MS : m/z 365 (M+), 337(100%), 322, 307,
274, 260, 231, 91, 116, 77.
Elemental analysis : for C24H19N3O requires: C, 78.88;
H, 5.24; N, 11.50. Found: C, 78.75; H, 5.39; N, 11.34.
1H NMR (Fig. 24a)
1.69 bs (Ex. with D2O) 1H >NH 3.56 dd (J = 5.5, 13.4 Hz) 1H C3H
3.75 dd (J = 6.7, 13.4 Hz) 1H C3H 4.41 t (J = 6.7 Hz) 1H C4H
6.89-6.96 m 3H ArH 6.99-7.1 m 2H ArH
7.15 d (J = 7.9 Hz) 1H ArH 7.21-7.3 m 3H ArH
7.33 t (J = 7.3 Hz) 2H ArH 7.41 bd (J = 6.7 Hz) 2H ArH
7.61 brs (exch. with D2O) 1H >NH 8.1 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 24b)
40.3 C4 48.7 C3 61.8 C1
110.9, 111.1 C11, C24 113.9 C19 119.2, 119.5 C22, C21
122.1, 122.9 C23, C9 124.6 C7 126.1, 126.5 C20, C8
128.1, 128.3 (str.) C16, C14, C14' 128.4 (str.) C15, C15' 129.8 C18
131.0 C10 136.3 C25 140.7 C13
142.6 C12 177.8 C6
4-(3,4-Methylenedioxyphenyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol] 2′(1′H)-
one 72
Time : 18.5 hrs.
Mp. : 266-68 C, white solid
Yield : 85%
IR (KBr) : 3398 (br), 3288, 1730 cm-1
.
MS : m/z 409 [M+, 100%], 381, 394,76.
69
1
3
NH
N
NH
O
H
4
5
67
89
10
1112
1314
15
16
15'
14'
17
18
192021
22
23
2425
72
1
3
NH
N
NH
O
H
4
5
67
89
10
1112
1314
15
1615'
14'
17
18
192021
22
23
2425
OO
Chapter III
129
Elemental analysis : for C25H19N3O3 requires: C, 73.34; H, 4.68; N, 10.26. Found: C,
73.14; H, 4.88; N, 10.01 %.
1H NMR (Fig. 27a)
3.03 brs (Ex. with D2O) 1H >NH 3.28 dd (J 5.3, 12.9 Hz) 1H C3H
3.45 dd (J 6.6, 12.9 Hz) 1H C3H 4.25 t (J 6.6 Hz) 1H C4H
5.97 brs 2H OCH2O 6.76 d (J 5.9 Hz) 2H ArH
6.8 d (J 6.6 Hz) 1H ArH 6.86 s 2H ArH
6.99-6.91 m 3H ArH 7.15 t (J 9.9 Hz) 2H ArH
7.28 t (J 7.7 Hz) 1H ArH 10.55 brs (Ex. with D2O) 1H >NH
10.58 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 27b)
39.8 C4 48.9 C3 61.6 C1
100.9 -OCH2O- 108.1, 108.9 C11, C24 110.4 C14
111.5 C15' 113.1 C19 118.7, 119.1 C22, C21
121.4, 121.5 C14', C23 122.2 C9 124.8 C7
126.3 C20 129.4 C8 132.8, 132.9 C18, C10
136.7 C13 138.2 C25 142.7 C12
146.1 C16 147.6 C15 178.4 C6
4-(4-Methoxyphenyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one 73
Time : 18 hrs.
Mp. : 280-81 C, white solid
Yield : 84%
IR (KBr) : 3610, 3342, 3286, 1732 cm-1
.
MS : m/z 395 (M+), 367 (100%), 352, 338.
Elemental analysis : for C25H21N3O2 requires: C, 75.93; H,
5.35; N, 10.63. Found: C, 75.75; H, 5.19; N, 10.45.
1H NMR (Fig. 28a)
2.50 brs (Ex. with D2O) 1H >NH 3.26 t (J = 5.0 Hz) 1H C3H
3.50 t (J = 6.6 Hz) 1H C3H 3.73 s 3H OCH3
4.33 t (J = 6.1 Hz) 1H C4H 6.63-6.78 m 2H ArH
73
1
3
NH
N
NH
O
H
4
5
67
89
10
1112
1314
1516
15'
14'
17
18
192021
22
23
2425
OMe
Chapter III
130
6.82-7.01 m 5H ArH 7.15 t (J = 7.9 Hz) 2H ArH
7.20-7.33 m 3H ArH 10.53 brs (Ex. with D2O) 1H >NH
10.57 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 28b)
48.5 C4 54.9 OCH3 61.0 C3
79.1 C1 109.7, 111.0 C11, C24 113.0, 113.4 (str.) C19, C15, C15'
118.0, 118.6 C22, C21 120.7 C23 121.6 C9
124.4 C7 125.7 C20 129.0 (str.) C8, C15, C15'
132.3, 132.5 C18, C10 135.5 C13 136.1 C25
142.2 C12 157.5 C16 177.9 C6
4-(2-Thienyl)-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one 74
Time : 18 hrs.
Mp. : 134-36 C, brown solid
Yield : 81%
IR (KBr) : 3390, 3280, 3186, 1718 cm-1
.
MS : m/z 371 [M+, 100%], 356, 343, 328.
Elemental analysis : for C22H17N3OS requires: C, 71.14;
H, 4.61; N, 11.31. Found: C, 70.91; H, 4.74; N, 11.19%.
1H NMR (Fig. 29a)
2.96 brs (Ex. with D2O) 1H >NH 3.44 bs 1H C3H
3.53 dd (J 5.4, 12.0 Hz) 1H C3H 4.62 t (J 5.5 Hz) 1H C4H
6.8 t (J 7.6 Hz) 1H ArH 6.85-7.03 m 6H ArH
7.15 t (J 10.5 Hz) 2H ArH 7.19-7.3 m 2H ArH
10.58 brs (Ex. with D2O) 2H 2×NH
13C NMR (Fig. 29b)
35.1 C4 48.8 C3 61.1 C1
109.8 C11 111.0 C24 112.6 C19
118.2, 118.4 C22, C21 120.9, 121.6 C23, C9 123.7 C16
124.3, 124.6 C15, C7 125.6 C20 126.3 C14
74
1
3
NH
N
NH
O
H
4
5
67
89
10
1112
13
14
15 16
17
18
192021
22
23
2425
S
Chapter III
131
128.9 C8 132.0, 132.4 C18, C10 136.1 C25
142.1 C12 147.3 C13 177.6 C6
4-Phenyl-2,3,4,9-tetrahydrospiro[β-carboline-1,1′-α-tetralone] 75
Time : 17.5 hrs.
Mp. : 183-85 C, white solid
Yield : 76%
IR (KBr) : 3437, 3421 cm-1
.
MS : m/z 364 [M+, 100%], 363, 349, 91, 77.
Elemental analysis : for C26H24N2 requires: C, 85.68; H,
6.64; N, 7.69. Found: C, 85.45; H, 6.89; N, 7.91 %.
1H NMR (Fig. 30a)
1.87 s 2H -CH2- 2.05 s 1H -CH-
2.17 s 3H -CH2-CH- 3.81 dd (J 6.6, 13.2 Hz) 1H C3H
4.04 dd (J 6.6, 13.2 Hz) 1H C3H 4.4 t (J 7.6 Hz) 1H C4H
5.71 brs (Ex. with D2O) 1H >NH 6.95-7.05 m 3H ArH
7.14 t (J 7.7 Hz) 2H ArH 7.22 t (J 7.7 Hz) 1H ArH
7.25-7.34 m 6H ArH 7.42 d (J 7.7 Hz) 1H ArH
8.64 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 30b)
14.1 -CH2- 22.5 (str.) -CH2- 30.1 C4
36.7 C3 67.2 C1 113.6 (st.) ArC
120.4 (str.) ArC 122.5 ArC 123.1 ArC
124.7 (str.) ArC 126.3 ArC 126.5 (str.) ArC
128.9 ArC 129.0 (str.) ArC 133.6 (str.) ArC
135.4 ArC 137.8 ArC
75
1
3
NH
NH
4
9
1011
12 1314
1516
17
4a5a5
6
78
8a 1a
1'
2'
3'4'
5'
6'
Chapter III
132
4-(4-Methoxyphenyl)-2,3, 4,9-tetrahydrospiro[β-carboline-1,1′-α-tetralone] 76
Time : 17.5 hrs.
Mp. : oily
Yield : 72%
IR (KBr) : 3404, 3302 cm-1
.
MS : m/z 394 [M+, 100%], 393, 379, 363.
Elemental analysis : for C27H26N2O requires: C, 82.20; H,
6.64; N, 7.10. Found: C, 81.93; H, 6.79; N, 7.31%.
1H NMR (Fig. 31a)
1.61 s 1H -CH- 1.91 s 2H -CH2-
2.2 s 3H -CH2-CH 3.72-3.89 m 4H C3H, OCH3
4.03 dd (J 7.6, 13.5 Hz) 1H C3H 4.38 t (J 7.6 Hz) 1H C4H
5.53 brs (Ex. with D2O) 1H >NH 6.81 t (J 8.8 Hz) 3H ArH
6.95-7.07 m 3H ArH 7.11-7.27 m 4H ArH
7.34 d (J 8.2 Hz) 1H ArH 7.42 d (J 7.6 Hz) 1H ArH
8.33 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 31b)
14.0 -CH2- 22.3 (str.) -CH2- 27.6 C4
34.2 C3 54.7 -OCH3 66.7 C1
113.6 (str.) ArC 120.3 (str.) ArC 121.4 ArC
123.3 ArC 124.0 (str.) ArC 124.9 (str.) ArC
126.6 (str.) ArC 128.5 ArC 129.1 (str.) ArC
133.7 (str.) ArC 135.2 ArC 137.8 ArC
155.1 ArC
Compound 77
Mp. : 191-93C, colourless crystals
Yield : 89%
IR (KBr) : 3367 (br) cm-1
.
MS : m/z 330 (M+), 206(100%), 124.
Elemental analysis : for C22H22N2O requires: C, 79.97; H,
76
1
3
NH
NH
4
9
1011
12 1314
1516
17
4a5a5
6
78
8a 1a
1'
2'
3'4'
5'
6'
OMe
1
3
NH
HN
O
2
1'
2'
3'4'a4'
5'
6'
7' 7'a
1''2''
3''4''
5''
6''
1'''
2'''3'''
4'''5'''
77
Chapter III
133
6.71; N, 8.48. Found: C, 79.64; H, 6.99; N, 8.26%.
1H NMR
1.52 s 3H -CH3 2.15-2.62 m 4H C4'''H,
C5'''H
3.85 dd (J = 6.4, 13.8 Hz) 1H C3H 4.02 dd (J = 6.3, 12.7 Hz) 1H C3H
4.49 t (J = 7.2 Hz) 1H C4H 6.63 brs (Ex. with D2O) 1H >NH
6.93 t (J = 7.2 Hz) 1H ArH 7.09 t (J = 7.2 Hz) 2H ArH
7.13-7.50 m 7H ArH 10.46 brs (Ex. with D2O) 1H >NH
13C NMR
6.7 -CH3 23.8 C5''' 32.5 C4'''
43.4 C3 48.5 C2 105.1 C2'''
111.3 C7' 115.3 C3' 118.2, 118.5 C4', C6'
120.9 C5' 122.0 C2' 126.1, 126.5 C4'a, C4"
128.0 (str.) C2", C3", C5", C6" 136.1 C7'a 143.1 C1"
173.1 C3''' 199.5 C1'''
Expt. No. 3.3 - General procedure for compounds 70 and 71
1
34
NH
NH
Ph
69
HNO
1
34
NH
NH2
Ph
HNO
X
70, X = HSO4
71, X = Cl
H2SO4 or HCl
Conc.
heating
rt, 24 hrs
A few drops of concentrated H2SO4 or HCl were added to compound 69 (0.2 g,
0.00055 mol) dissolved in methanol (3 ml). The reaction mixture was heated with stirring
till the solution became clear and kept at room temperature for 24 hrs. Completion of the
reaction was confirmed by TLC. The solvent was removed and the crystals were washed
twice with methanol to furnish the expected product 1,1-isatyl-4-phenyl-2,3,4,9-
tetrahydrospiro-β-carboline sulphate 70 or hydrochloride 71.
Chapter III
134
4-Phenyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one sulfate 70
Mp. : above 300 C, colorless crystals
Yield : 95%
IR (KBr) : 3389, 3244 (br), for (4×NH),
1725 cm-1
for (>C=O)
Elemental analysis : for C24H21N3O5S requires: C,
62.19; H, 4.57; N, 9.07. Found: C, 62.01; H, 4.71; N,
8.81%.
1H NMR (Fig. 25a)
3.84 dd (J = 6.1, 12.1 Hz) 1H C3H 4.14 t (J = 10.7 Hz) 1H C4H
4.72 dd (J = 5.8, 10.7 Hz) 1H C3H 6.54 d (J = 7.7 Hz) 1H ArH
6.77 t (J = 7.2 Hz) 1H ArH 7.03 t (J = 8.3 Hz) 1H ArH
7.1-7.24 m 3H ArH 7.32-7.45 m 6H ArH
7.53 t (J = 7.7 Hz) 1H ArH 10.55 2×brs (Ex. with D2O) 2H >NH
11.02 brs (Ex. with D2O) 1H >NH 11.41 brs (Ex. with D2O) 1H >NH
13C NMR (Fig. 25b)
36.8 C4 44.7 C3 59.5 C1
111.3 C11 111.9 (str.) C19, C24 119.3 (str.) C21, C22
122.4 C23 123.0 C9 124.4, 124.8 C7, C20
126.4, 126.9 C8, C16 127.6 C18 128.5 (str.) C14, C14'
128.8 (str.) C15, C15' 132.1 C10 136.9 C25
140.4 C13 143.2 C12 172.1 C6
4-Phenyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3′-indol]-2′(1′H)-one hydrochloride
71
Mp. : 255-57 C, colorless crystals
Yield : 94%
IR (KBr) : 3306, 3248, 3217 (br) cm-1
for
(4×NH), 1739 cm-1
for (>C=O).
Elemental analysis : for C24H20ClN3O requires: C,
71.73; H, 5.02; N, 10.46. Found: C, 71.58; H, 4.85; N,
1
3
NH
N
NH
O
HH
HSO4
4
5
67
89
10
1112
1314
15
16
15'
14'
17
18
192021
22
23
2425
70
1
3
NH
N
NH
O
HH
Cl4
5
67
89
10
1112
1314
15
16
15'
14'
17
18
192021
22
23
2425
71
Chapter III
135
10.29%.
1H NMR (Fig. 26a)
3.71 dd (J = 6.1, 12 .4 Hz) 1H C3H 4.14 t (J = 11.3 Hz) 1H C4H
4.83 dd (J = 5.8, 10.6 Hz) 1H C3H 6.54 d (J = 8.0 Hz) 1H ArH
6.76 t (J = 7.4 Hz) 1H ArH 7.02 t (J = 7.7 Hz) 1H ArH
7.13 t (J = 7.7 Hz) 2H ArH 7.22 d (J = 8.0 Hz) 1H ArH
7.39 brs 5H ArH 7.51 t (J = 7.7 Hz) 1H ArH
7.63 d (J = 7.4 Hz) 1H ArH 10.97 brs (Ex. with D2O) 2H 2×>NH
11.4 brs (Ex. with D2O) 2H 2×>NH
13C NMR (Fig. 26b)
48.3 C4 60.9 C3 79.0 C1
109.7 C24 111.0 C11 112.6 C19
118.0, 118.5 C22, C21 120.7 C23 121.5 C9
124.4 C7 125.6 C20 126.0 C8
127.9 (str.) C14, C14' 128.0 (str.) C15, C15' 128.9 C16
132.2 C18 132.5 C10 136.0 C25
142.2 C13 143.6 C12 177.8 C6
Chapter III
136
References
1. Airaksinen, M. M.; Kari, I. Med. Biol. 1981, 59, 21.
2. Zhou, T. S.; Ye, W. C.; Wang, Z. T. Phytochemistry 1998, 49, 1807.
3. Carbrera, G. M.; Seldes, A. M. J. Nat. Prod. 1999, 62, 759.
4. Budavari, S. in: The Merck Index, Merck and Co. Inc, 11th
edn. Rahway, NJ, 1989.
5. Kusurkar, R. S.; Goswami, S. K.; Vyas, S. M. Tetrahedron Lett. 2003, 44, 4761.
6. Lippke, K. P.; Schunack, W. G.; Wenning, W.; Muller, W. E. J. Med. Chem. 1983, 26,
499.
7. Cain, M.; Weber, R. W.; Guzman, F.; Cook, J. M.; Barker, S. A.; Rice, K. C. J. Med.
Chem. 1982, 25, 1081.
8. Hagen, T. J.; Skolnick, P.; Cook, J. M. J. Med. Chem. 1987, 30, 750.
9. Dodd, R. H.; Ouannes, C.; Carvalho, L. P.; Valin, A.; Venault, P.; Chapouthier, G.;
Rossier, J.; Potier, P. J. Med. Chem. 1985, 28, 824.
10. Tsuchiya, H.; Sato, M.; Watanabe, I. J. Agric Food Chem. 1999, 47, 4167.
11. Herraiz, T. J. Agric. Food Chem. 1996, 44, 3057.
12. Gutsche, B.; Herderich, M. HPLC-MS/MS. J. Agric Food Chem. 1997, 45, 2458.
13. Gutsche, B.; Herderich, M. J. Chromatogr. A. 1997, 101.
14. Arutselvan, N.; Gopalan, S.; Kulkarni, V. G.; Balakrishna, K. Arzneim-Forsch. 1999,
49, 729.
15. Pari, K.; Sundari, C. S.; Chandani, S.; Balasubramanian, D. J. Biol. Chem. 2000, 275,
2455.
16. Herraiz, T. J. Agric. Food Chem. 2000, 48, 4900.
17. Herraiz, T. Food Additives and Contaminants 2000, 17, 859.
18. Herraiz, T. Food Additives and Contaminants 2002, 19, 748.
19. Ho, B.T. J. Pharm. Sci. 1972, 61, 821.
20. Ninan, P. T.; Insel, T. M.; Cohen, R. M.; Cook, J. M.; Skolnick, P.; Paul, S. M.
Science 1982, 218, 1332.
21. Mendelson, W. B.; Cain, M.; Cook, J. M.; Paul, S. M.; Skolnick, P. Science 1983,
219, 414.
22. Salmoun, M.; Devijver, C.; Daloze, D.; Braekman, J.-C.; van Soest, R. W. M. J. Nat.
Prod. 2002, 65, 1173.
23. Faizi, S.; Naz, A. Tetrahedron 2002, 58, 6185.
Chapter III
137
24. Patil, A. D.; Freyer, A. J.; Carte, B.; Taylor, P. B.; Johnson, R. K.; Faulkner, D. J.; J.
Nat. Prod. 2002, 65, 628.
25. Kam, T. S.; Sim, K. M. Phytochemistry, 1998, 47, 145.
26. Van Wagoner, R. M.; Jompa, J.; Tahir, A.; Ireland, C. M. J. Nat. Prod. 1999, 62, 794.
27. Kerber, A.; Gregianini, T. S.; Paranhos, J. T.; Schwambach, J.; Farias, F.; Fett, J. P.;
Fett-Neto, A. G.; Zuanazzi, J. A. S.; Quirion, J.-C.; Elizabetsky E.; Henriques, A. T. J.
Nat. Prod. 2001, 64, 677.
28. Yahara, S.; Uda, N.; Yoshio, E.; Yae, E. J. Nat. Prod. 2004, 67, 500.
29. Youssef, D. A. T. J. Nat. Prod. 2005, 68, 1416.
30. Takayama, H.; Ishikawa, H.; Kitajima, M.; Aimi, N.; Aji, B. M. Chem. Pharm. Bull.
2004, 52, 359.
31. Itoh, A.; Kumashiro, T.; Yamaguchi, M.; Nagakura, N.; Mizushina, Y.; Nishi T.;
Tanahashi, T. J. Nat. Prod. 2005, 68, 848.
32. Pogosyan, S. A.; Grigoryan, N. P.; Paronikyan, R. G. Pharm. Chem. J. 2007, 41, 527.
33. Grigoryan, N. P.; Pogosyan, S. A.; Paronikyan, R. G. Hayastani Kimiakan Handes,
2005, 58, 100.
34. Peter, B.; Ulf, B.; Roger, C.; Malin, G. N.; Annika, J. J.; Erik, R.; Terry, W. PCT Int.
Appl. WO 2005048916, 2005, 153.
35. Synthelabo, S. A. Fr. Jpn. Kokai Tokkyo Koho. JP 55145687, 1980, 9.
36. Pictet, A.; Spengler, T. Chem. Ber.1911, 44, 2030.
37. (a) Bringmann, G.; Ewers, C. T.; Walter, R. Comprehensive Organic Synthesis (Ed.
Trost, B. M.; Fleming I.) 1991, Vol. 6, pp. 736-740 (Pergamon Press: Oxford). (b)
Yoshie, H.; Masayoshi, N.; Toshiaki, S.; Takehiro, S. Chem. Pharm. Bull. 2003, 51,
1368.
38. Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
39. Chrzanowska, M.; Rozwadowska, M. D.; Chem. Rev. 2004, 104, 3341.
40. Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086.
41. Taylor, M. S.; Jacobsen, E. N.; J. Am. Chem. Soc. 2004, 126, 10558.
42. Cesati, R. R.; Katzenellenbogen, J. A.; Clingan, P. D.; Mill, T. J.; Price, R. A.;
Pritchard, R. G. Eur. J. Org. Chem. 2004, 1887.
43. Tsuji, R.; Nakagawa, M.; Nishida, A. Tetrahedron: Asymmetry 2003, 14, 177.
44. Yu, J.; Wearing, X. Z.; Cook, J. M.; Tetrahedron Lett. 2003, 44, 543.
45. Bonnet, D.; Ganesan, A. J. Comb. Chem. 2002, 4, 546.
Chapter III
138
46. Bailey, P. D.; Hollinshead, S. P.; Malcy, N. R. Tetrahedron Lett. 1987, 28, 5177.
47. Sandrin, J.; Hollinshead, S. P.; Cook, J. M. J. Org. Chem. 1989, 54, 5636.
48. Singh, K.; Deb, P. K.; Tetrahedron Lett. 2000, 41, 4977.
49. Singh, K.; Deb, P. K.; Venugopalan, P. Tetrahedron 2001, 57, 7936.
50. Jacobsen, E. N.; Klausen, R. S. Org. Lett. 2009, 11, 887.
51. Gremmen, C.; Willemse, B.; Wanner, M. J.; Koomen, G.-J. Org. Lett. 2000, 2, 1955.
52. Larghi, E. L.; Amongero, M.; Bracca, A. B.; Kaufman, T. S. ARKIVOC 2005, xii, 98.
53. Kusurkar, R. S.; Alkobati, N. A.; Gokule, A. S.; Puranik, V. G. Tetrahedron 2008,
64, 1654.
54. Brandt, S. D.; Mansell, D.; Freeman, S.; Fleet, I. A.; Alder, J. F.; Journal of
Pharmaceutical and Biomedical Analysis 2006, 41, 872.
55. Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem, Int. Ed. 2005, 44,
6576.
56. Sydorenko, N.; Zificsak, C. A.; Gerasyuto A. I.; Hsung, R. P. Org. Biomol. Chem.
2005, 3, 2140.
57. Semenov, B. B.; Novikov, K. A.; Spitsin, A. N.; Azev, V. N.; Kachala, V. V. Chem.
Nat. Comp. 2004, 40, 585.
58. Semenov, B. B.; Novikov1, K. A.; Smushkevich1, Yu. I.; Azev, V. N.; Kachala. V. V.
Chem. Heterocycl. Compd. 2005, 41, 1273.
59. Semenov, B. B.; Novikov, K. A.; Azev, V. N.; Kachala, V. V. Russ. Chem. Bull. Int.
Ed. 2005, 54, 988.
60. Tietze, L. F.ackelmann, N.; Muller, I. Chemistry - A. Eur. J. 2004, 10, 2722.
61. Leonard, M. S.; Hauze, D. B.; Carrol, P. J.; Joullie, M. M. Tetrahedron 2003, 59,
6933.
62. Dantale, S. W.; Soderberg, B. C. G. Tetrahedron 2003, 59, 5507.
63. Nemes, C.; Jeannin, L.; Sapi, J.; Laronze, M.; Seghir, H.; Auge, F.; Laronze, J.-Y.
Tetrahedron 2000, 56, 5479.
64. Quirante, J.; Escolano, C.; Merino, A.; Bonjoch, J. J. Org. Chem. 1998, 63, 968.
65. Tahri, A.; Buysens, K. J.; Vander Eycken, E. V.; Vandenberghe, D. M.; Hoornaert, G.
J. Tetrahedron 1998, 54, 13211.
66. Diker, K.; El Biach, K.; Maindreville, M. D.; Levy, J. J. Nat. Prod. 1997, 60, 791.