diastereoselective synthesis of 1,1,4- trisubstituted 2,3...

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



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. 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





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. 17b: (75 MHz, CDCl3/DMSO-d6)


61

NH

NH

OMe

OMe

61

NH

NH

OMe

OMe

Chapter III

91





62

NH

NH

OO

62

NH

NH

OO

Chapter III

92

Fig. 19a: (300 MHz, CDCl3/DMSO-d6)




63

NH

NH

OMe

63

NH

NH

OMe

Chapter III

93

Fig. 20a: (300 MHz, DMSO-d6)


Fig. 20b: (75 MHz, DMSO-d6)


64

NH

NH

NH2

64

NH

NH

NH2

Chapter III

94





65

NH

NH

O

65

NH

NH

O

Chapter III

95





66

NH

NH

S

66

NH

NH

S

Chapter III

96





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





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





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





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





72

NH

NH

NH

O

OO

72

NH

NH

NH

O

OO

Chapter III

110





73

NH

NH

NH

O

OMe

73

NH

NH

NH

O

OMe

Chapter III

111

Fig. 29a: (300 MHz, CDCl3/DMSO-d6)




74

NH

NH

NH

O

S

74

NH

NH

NH

O

S

Chapter III

112





75

NH

NH

75

NH

NH

Chapter III

113





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


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)


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)


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


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


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)



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.


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.


76.39; H, 6.58; N, 7.98%.

1H NMR (Fig. 18a)



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


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.


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)



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.


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)


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.


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)


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)



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


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.


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)



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


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.


Yield : 79%

IR (KBr) : 3412 (br) cm-1

.

MS : m/z 346 (M‏+), 317(100%), 304, 288.


76.06; H, 6.61; N, 7.92.

1H NMR (Fig. 23a)



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


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.


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


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


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.


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


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.


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


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.


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


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


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.


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


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


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.


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


4.49 t (J = 7.2 Hz) 1H C4H 6.63 brs (Ex. with D2O) 1H >NH


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)


4.72 dd (J = 5.8, 10.7 Hz) 1H C3H 6.54 d (J = 7.7 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


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

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diastereoselective synthesis of 1,1,4- trisubstituted 2,3...

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