CHAPTER: IV - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/3208/13/13...Chapter IV 145...

CHAPTER: IV

Synthesis of tetrahydro-5-azaindoles and

5-azaindoles using Pictet-Spengler

reaction – appreciable difference in products

using different acid catalysts

Chapter IV

139

Synthesis of tetrahydro-5-azaindoles and 5-azaindoles using Pictet-

Spengler reaction – appreciable difference in products

Introduction:

The indole nucleus is arguably one of the most important heterocycles and is a key

structural element for a vast number of biologically active molecules. The widespread

utility of indole heterocycles in life sciences has stimulated the development of numerous

methodologies for its synthesis.1 Replacing one of the carbon atoms at positions 4 - 7 in

the indole template with a nitrogen atom gives 4-, 5-, 6-, or 7-azaindoles respectively

which are typically pyrrolopyridines. The correct nomenclature and structures are shown

in Chart 1.

NH

NH

N

NH

N

NH

NNH

N NH

Indole

Azaindoles

N

1H-Pyrrolo[3,2-b]pyridine

(4-azaindole)

1H-Pyrrolo[3,2-c]pyridine

(5-azaindole)

1H-Pyrrolo[2,3-c]pyridine

(6-azaindole)

1H-Pyrrolo[2,3-b]pyridine

(7-azaindole)

2

34

5

6

7

2

34

5

6

7

Chart 1

The interest in azaindoles originated primarily from their medicinal relevance and

applications in material synthesis and coordination chemistry. They are frequently

exploited as indole bioisosteres in the design of biologically interesting molecules.2 Most

of the azaindole derivatives are synthetic products, although some azaindole containing

compounds do exist in nature,3,4

like variolins, martinelline and martinellic acid.

Many of the 5-azaindoles show diverse biological activities such as compound I

has been discovered as novel factor VIIa inhibitor with a potency of 0.22 µM for fVIIa and

>10-fold selectivity against the antitargets.5 Compound II, which was made as a direct

comparison of I has further improved potency (fVIIa Ki = 0.081 µM) and selectivity

(>400-fold against antitargets).5 Installation of various acid substitutions at the central aryl

Chapter IV

140

ring improved potency against fVIIa like compound III. Compound III gave the best

potency against fVIIa as well as ex vivo efficacy as measured by PT.

NHN

HNHO

O

OH NHN

HNHO

O

OH

H2N

COOH

NHN

HNHO

O

OH

H2N

I II III

1,2-Disubstituted azaindole derivatives possess basic amine moieties as novel

series of active site directed thrombin inhibitors.6 Interestingly, the more rigid and less

basic amide moiety of the N1 side chain in IV showed modestly better activity than the

methylene amine linkage in V in the azaindole series.

N

N1

OMe

O N

N

N1

OMe

O N

O

NN

IV V

A series of pyrrolo[3,2-c]pyridine derivatives are isosteres of the thieno[3,2-

c]pyridine antithrombotic agents like ticlopidine and its derivatives clopidogrel, which

have been proven to be effective in the treatment and/or prevention of platelet-dependent

disorders.7 Tetrahydropyrrolo[3,2-c]pyridines are known as inhibitors of ADP-stimulated

platelet aggregation in vitro, their activity being related to the lipophilicity.8a

Within the

limits of this screening, the closest analogue VI of ticlopidine and the 2-formyl derivative

VII showed the highest activities.

Chapter IV

141

N

N

HCCH2

H

O

NH

N

VI VII

A novel series of 2-(tetrahydropyrrolo[3,2-c]pyridine-3-yl)-ethylamine derivatives

VIII and IX were designed as GnRH receptor antagonists that were both potent against

human and rat receptors in vitro.8b

N

NH

R1

HN

N

N

NH

HN R2

OF

CF3N

N

R4

R1R2

R3

R5

VIII IX X

Azaindoles have been used for various pharmaceutical agents. Interestingly,

pyrrolo[3,2-c]quinoline ring system X is a very important skeleton,9 due to their diverse

biological activities such as antitumor properties,10

gastric (H‏+/K

+,ATPase inhibitor-(‏

11

anti-inflammatory activities12

and bradykinin receptor antagonist.13

Alkaloids containing tetrahydroazaindole and azaindole 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. Some of the reported methods are

given below.

Reported Methods:

1. Arai and Yokoyama (2009)14

NH

NH

R

NH

H2N

DCM, 40 oC

RCHO, TFA

Chapter IV

142

2. Zhu and co-workers (2007)8b

N

O

Boc

N

NH

Boc

1) pyrrolidine,toluene, reflux

2) a, DIPEA, THF, reflux

O

Br

3) ammonium acetate, EtOH

a =

,

3. Riether and co-workers (2005)15

N

R

NHBoc

N

NH

RDBU

MeOH, H2O

65-85 oC

4. Mingoia et al (2004)9

OMe

O

R2

NO2

1. R1NH2, AcOH

reflux, 3-8 hrs

NR2

MeR1

NH2N

N

R3

R2

MeR1

2. H2, 10%, Pd/C

EtOH, rt, overnight

R3CHO, DMF

15 mol% p-TsOH

100 oC, 3hrs

5. Yum and co-workers (2004)16

NI

N Ph

Pd(OAc)2, n-Bu4NCl

i-Pr2NEt, DMF, 120 oC

R

N

N

R

Ph

R1R1

6. Xi and co-workers (2004)17

Me2Si

Ar

Ar

C

N

R1

C

N

R1

C

N

R1

+++1) Cp2Zr (II)

2) H2O N

HN

Ar

R1

R1Ar

R1

Chapter IV

143

7. Altomare et at (2000)8a

N

N

R

R

R5

OH

HC CH

KOH, DMSO

80-90 oC, 4-6 hrs

N

N

R

R

R5

R1

N

N

R

R

R5

R1

R2Cu(NO3)2, Ac2O, rt, 5 hrs

PoCl3, DMF, rt, 5 hrs

or

8. Xu et al (1998)18

NI

NHBoc

N

R

NHBoc

N

N

R

Boc

Pd(PPh3)2Cl2

CuI, Et3N, rt

R

CuI (0.02eq)

DMF, 80 oC

9. Ujjainwalla et al (1998)19

R1

NI

NH2

N

NH

R2

Pd(dppf)Cl3

LiCl, Na2CO3

DMF, 100 oC

R2

R1

10. Hands et al (1996)20

N

NHBoc

N

Li

NLi

Boc

N

N

N

NH

R

OH

Boc

Rn-BuLi

or t-BuLi

DMF or

R

O

NOMe

Me

HCl

11. Yamanaka and co-workers (1992)21

NBr

NHAc

Bu3Sn OEt

Pd(PPh3)2Cl2

Et4NCi

CH3CN, reflux

N

NHAcOEt

HCl, MeOH

reflux

N

NH

Chapter IV

144

12. Robinson et al (1991)22

H2, 10%, Pd/C

EtOH, 60 oCN

NO2

Me

O

N

NO2

O

NMe2

N

HN

Me2NCH(OMe)2

DMF, 90 oC

13. Herz and Tocker (1955)23

NH

NH

H2N HNR

O

NH

N

R

NH

N

R

Pd/CPOCl3

Present Work:

The chemistry of azaindoles has been previously described.24

A few classical

methods such as Fischer, Madelung and Reissert procedures are the traditional methods

used for the synthesis of most of the azaindoles which suffer from harsh reaction

conditions and modest yields.25

Azaindoles have been synthesised from terminal alkynes

using Sonogashira reaction,26

from internal alkynes using heteroannulation27

and by Heck

reaction.28

Recently, organometallic chemistry and other synthetic strategies have been

used for the preparation of azaindole derivatives.29

The Pictet-Spengler reaction30

is an important acid-catalyzed transformation

frequently used for the synthesis of tetrahydroisoquinolines or tetrahydro-β-carbolines

from carbonyl compounds and phenyl ethylamines or tryptamines, respectively.31

In

general, the classical Pictet-Spengler reaction is a two step method and involves acid

catalyzed condensation of an aliphatic amine attached to a sufficiently reactive aromatic

nucleus with aldehydes. In the first step an imine is formed, which may be activated by

acid and in the second step endo cyclization between a carbon nucleophile of a sufficiently

reactive aromatic moiety and the activated iminium ion resulting in a heterocyclic ring via

a new C–C bond formation.

There is only one report14,32

each for the synthesis of 5 and 6-azaindoles by Pictet-

Spengler reaction [reported method No. 1 for 5-azaindole]. It was planned to achieve the

Chapter IV

145

synthesis of tetrahydro-5-azaindoles and 5-azaindoles with different substituents at the 4

and 7-positions by building nitrogen containing six membered ring on pre existing pyrrole

ring using Pictet-Spengler reaction. As the 2-aryl-2-(2-pyrrolyl)-l-nitroethanes are already

prepared as described in Chapter II, Part A, those could be easily converted to

corresponding amines. These 2-aryl-2-(1H-pyrrol-2-yl)ethanamines serve as starting

materials for the Pictet-Spengler reaction with aromatic aldehydes expecting the formation

of tetrahydro-5-azaindoles.

Result and Discussion:

Having the nitro compounds 21a, 22a, 24a and 26a in hands (see Chapter II, part

A), it was decided to reduce the nitro group to get variously substituted amino derivatives.

Hydrogenation of 2-[2-nitro-1-(4-methoxyphenyl)ethyl]-1H-pyrrole 24a was carried out

using balloon filled with H2 gas and Raney Nickel as a catalyst (Scheme I).

NH

O2N

ArNH

H2N

Ar

Raney Nickel

MeOH / H2

21a, 22a, 24a, 26a 78, 79, 80, 81

24a,78. Ar = 4-methoxyphenyl; 21a, 79. Ar = phenyl; 22a, 80. Ar = 3,4-dimethoxyphenyl;

26a, 81. Ar = 2-furyl,

Scheme I

Usual work up resulted in a thick brown liquid which after addition of ether

furnished a semisolid. Recrystalization from hexane gave white crystals melting at 94-6 oC

in 91% yield. The compound was characterised by spectral and analytical data. The

compound analyzed for C13H16N2O. IR (KBr) showed three peaks at 3460, 3412 and 3389

cm-1

corresponding to -NH2, and pyrrole >NH. 1

H NMR (Fig. 33a) showed (i) a broad

signal at 1.46 (exchangeable with D2O) corresponding to >NH2 protons, (ii) two doublet of

doublets, one at 3.18 with J = 6.6, 12.1 Hz and the other at 3.3 with J = 6.6, 12.1 Hz for

C1H2 protons, (iii) a singlet at 3.78 for -OCH3, (iv) a triplet at 3.98 with J = 6.6 Hz for C2H

(The formation of the product was also confirmed by comparing the position of these

protons which were further up-field than those in starting compound 24a at 4.69-4.85 and

4.94 respectively), (v) two broad singlets at 5.92 and 6.67 and one doublet at 6.13 with J =

Chapter IV

146

2.5 Hz for three protons of pyrrole, (vi) two doublets, one at 6.84 with J = 8.5 Hz and the

other at 7.1 with J = 8.5 Hz for four aromatic protons, (vii) a broad singlet at 8.84 due to

pyrrole >NH (exchangeable with D2O). 13

C NMR (Fig. 33b) showed (i) three signals at

45.3, 46.5 and 55.3 for methylene, methine and methoxy carbons respectively (it was clear

here that methylene carbon was shifted up field as compared to that in the nitro compound

24a at 79.3), (ii) eight singlets between 105.5-158.5 corresponding to ten aromatic carbons

(two carbons were resonating at the same chemical shift to give strong signals which is

ortho and meta to methoxy group). M+ at m/z 216, base peak at 186 obtained by the loss of

-CH2-NH2. All the above spectral and analytical data confirmed the structure of the

product as 78.

NH

H2N

OMe

78

12

Further, this method was used for the synthesis of various other amines. Thus the

reactions using Michael adducts 21a, 22a and 26a were carried out as shown in Scheme I,

to get amino compounds 79, 80 and 81 in good yield. The spectral data for these

compounds is collected in Table I and Experimental section.

Table I: Spectral data, mps and yields of amino compounds 78, 79, 80 and 81

Prod.

No.

IR

cm-1

M.P

C

Yield

%

1H NMR

13C NMR

C1H C1H C2H C1 C2

78 Fig. 33a,b 3460, 3412, 3389 94-6 91 3.18 dd 3.3 dd 3.98 t 45.3 46.5

79 Fig. 34a 3427 (br) 106-08 94 3.21 dd 3.32 dd 4.01 t 46.9 47.0

80 Fig. 35a 3365 (br) 84-6 90 3.2 dd 3.33 dd 3.94 t 46.4 46.9

81 Fig. 36a,b 3340, 3286 59-61 89 3.21 s 4.08 bs 41.5 45.7

Chapter IV

147

Fig. 33a: (300 MHz, CDCl3)

1H NMR Spectrum of Compound 78

Fig. 33b: (75 MHz, CDCl3)

13C NMR Spectrum of Compound 78

NH

H2N

OMe78

NH

H2N

OMe78

Chapter IV

148





NH

H2N

79

NH

H2N

80

OMe

OMe

Chapter IV

149





NH

H2N

81

O

NH

H2N

81

O

Chapter IV

150

Keeping in view tetrahydro-5-azaindoles as target molecules, Pictet-Spengler

cyclization was attempted initially using conventional catalysts namely TMSCl and TFA.

In the beginning when the reaction was performed using one equivalent of benzaldehyde,

it was very slow and afforded a complex mixture. Thus excess of benzaldehyde was used

for these reactions.

Pictet-Spengler cyclization of amine 78 using TMSCl - Formation of unexpected 2-

benzyl and 2,3-dibenzyl-5-azaindoles:

Treatment of amine 78 (0.002 mol) with benzaldehyde (0.006 mol) in the presence

of TMSCl in dichloromethane under nitrogen atmosphere at room temperature furnished

two products, one as yellow crystals, melting at 175-77 οC and the other as an oily liquid

(Scheme II). To our surprise the molecular ions in the mass spectrum were at m/z 390 and

480 respectively clearly indicating that neither of these was the expected product. The

spectral data also showed that both the products were different from the expected product.

NH

H2N

OMe

0 - 25 oC

Si(CH3)3Cl

DCM, 48 hrs

PhCHO

+

78 82 83

mp 175-77 oC

M+ 390

oily liquid

M+ 480

Scheme II

The compound mp 175-77 oC analyzed for C27H22N2O. It displayed IR (KBr) band

at 3367 cm-1

for >NH. 1H NMR (Fig. 37a) showed (i) a singlet at 3.81 for -OCH3, (ii)

singlet at 4.12 for -CH2-, (iii) a singlet at 6.65 for C3H of

pyrrole ring, (iv) signals of fifteen aromatic protons at

6.97 to 8.28 and (v) a broad singlet exchangeable with

D2O at 8.67 for >NH of pyrrole ring. This spectral data

suggested structure 82 for this compound. The 13

C NMR

(Fig. 37b) was consistent with this structure as it showed

signals for twenty five carbons in the aromatic region and

signals at 34.5 and 55.3 for -CH2- and -OCH3

respectively. The assignment of the latter two signals was confirmed by DEPT (Fig. 37c).

NH

N

OMe82

2

3

4

6a

Chapter IV

151

Based on this structure the singlet at 4.12 was assigned to the aCH2 which is attached to

two aromatic rings whereas the singlet at 8.25 was assigned to C6H.

The oily liquid which analysed for C34H28N2O had IR band at 3450 cm-1

for >NH.

1H NMR (Fig. 38a) showed (i) three singlets at 3.84, 3.88 and 4.06 for -OCH3 and 2×CH2

protons, (ii) signals of twenty aromatic protons at 6.66 to 8.25 and (iii) a broad singlet

exchangeable with D2O at 8.33 for >NH of pyrrole ring. 13

C NMR (Fig. 38b) showed (i)

singlets at 30.4, 32.4 and 55.4 for 2×CH2 and -OCH3 respectively and (ii) singlets in the

region 111.4 to 159.3 for thirty one aromatic carbons. DEPT (Fig. 38c) confirmed the

presence of two CH2 groups and one -OCH3 group at 30.4, 32.4 and 55.4 respectively, as

expected for compound 83. The two singlets at 3.88 and 4.06 (protons a/b) were consistent

with CH2 groups attached to two aromatic rings while the singlet at 8.25 was assigned to

C6H.

NH

N

OMe83

2

36

4

a

b

The formation of 82 and 83 can be explained by an amazing one pot four steps

reaction sequence involving first Pictet-Spengler cyclization followed by substitution at C2

and C3 with one or two molecules of benzaldehyde along with dehydration and subsequent

dehydrogenation to give trisubstituted-5-azaindole 82 or tetrasubstituted-5-azaindole 83

respectively (Scheme III). Support for this mechanism is provided at the end of this

chapter.

Chapter IV

152

NH

H2N

NH

NH

ArNH

N

Ar

Ar1 H

O Ar1 Ar1

Ar

H

NH

NH

Ar1

Ar

Ar1 H

O

X

NH

NH

Ar1

Ar

O

Ar1

X

NH

NH

Ar1

Ar

O

Ar1

X

HNH

NH

Ar1

ArAr1

NH

N

Ar1

ArAr1

H

H

NH

N

Ar1

ArAr1

H

NH

N

Ar1

ArAr1

H

NH

N

Ar1

ArAr1

NH

N

Ar1

ArAr1

H

Ar1 H

O

X

NH

N

Ar1

ArAr1

H

Ar1

O

X

NH

N

Ar1

ArAr1

H

Ar1

NH

N

Ar1

ArAr1

Ar1

H

NH

N

Ar1

ArAr1

Ar1

H

A

A

X = H, Si(CH3)3

H

Scheme III

Chapter IV

153





NH

N

OMe82

NH

N

OMe82

Chapter IV

154

Fig. 37c: (75 MHz, CDCl3) DEPT Spectrum of Compound 82

NH

N

OMe82

Chapter IV

155





NH

N

OMe83

NH

N

OMe83

Chapter IV

156

Fig. 38c: (75 MHz, CDCl3) DEPT Spectrum of Compound 83

NH

N

OMe83

Chapter IV

157

Pictet-Spengler cyclization of amine 78 using TFA:

TFA is the other commonly used catalyst for Pictet-Spengler cyclization. As the

reaction using TMSCl was giving unexpected products and targeted compound as

tetrahydro -5- azaindole was not obtained, it was thought to study the reaction using TFA.

In this reaction excess of benzaldehyde was used since mixture of products was obtained

by using one equivalent of benzaldehyde. Thus, reaction of amino compound 78 (0.002

mol) with benzaldehyde (0.004 mol) carried out in TFA for 15 hrs in DCM at room

temperature furnished only one product as yellow crystals mp 175-77 oC in 69% yield

(Scheme IV). The elemental analysis, mp, and spectral data established the identity of this

compound as 82 mp 175-77 oC obtained in the reaction with TMSCl.

NH

N

OMe

NH

H2N

OMe

rt

TFA

DCM, 4 hrs

PhCHO

78 82

Scheme IV

Thus, the reaction using TFA furnished selectively trisubstituted-5-azaindole as the

only product. To verify the generality of tandem four steps reaction sequence during

Pictet-Spengler cyclization, reactions of amines 79, 80, and 81 were carried out with

benzaldehyde and with substituted benzaldehydes using TFA as a catalyst. Condensation

of the amines 79, 80, and 81 with benzaldehyde provided the expected trisubstituted-5-

azaindoles 84, 85 and 86 respectively as single product (Scheme V).

Surprisingly, reactions using substituted benzaldehydes with amino compound 81

led to different results in Pictet-Spengler cyclization. Trisubstituted-5-azaindole 87 was

obtained exclusively in the reaction of amine 81 with 4-methoxybenzaldehyde (Scheme

V). The spectral data, mps and yields for all trisubstituted-5-azaindole are recorded in

Table II.

Chapter IV

158

NH

N

Ar

Ar1

Ar1

NH

H2N

Arrt

DCM, 12-24 hrs

79, 80, 81 84, 85, 86, 87, 88

Ar1CHO, TFA

79, 84. Ar and Ar1 = phenyl; 80, 85. Ar = 3,4-dimethoxyphenyl, Ar1 = phenyl; 81, 86. Ar =

2-furyl, Ar1 = phenyl; 87. Ar = 2-furyl, Ar1 = 4-methoxyphenyl; 88. Ar = 2-furyl, Ar1 = 4-

chlorophenyl + product with mp 164-166 oC.

Scheme V

Table II: Spectral data, mps and yields of trisubstituted-5-azaindoles 82, 84-88

The reaction of amine 81 with 4-chlorobenzaldehyde afforded two solids, having

mp 170-72 oC and 164-66

oC (Scheme VI). The compound mp 170-72

oC was readily

identified from its spectral data to be the 2-aryl-5-azaindole 88 (Scheme V, Table II).

NH

H2N

rt

DCM, 24 hrs

81 88

TFA+

89

O

mp 170-72 oC mp 164-66 oC

CHO

Cl

+

Scheme VI

The compound mp 164-66 °C analyzed for C17H15ClN2O. In IR (KBr) it showed

bands at 3362, 3248 cm-1

for >NH groups. 1H NMR (Fig. 43a) exhibited (i) a broad singlet

exchangeable with D2O at 1.93 for >NH, (ii) two doublet of doublets at 3.17 with J = 8.3,

Prod.

No.

IR

cm-1

M.P

C

Yield

%

1H NMR

13C NMR

-CH2- C3H C6H -CH2- C6

82 Fig. 37a,b,c 3367 175-77 69 4.12 s 6.65 s 8.28 s 34.5 140.2

84 Fig. 39a,b 3444 170-72 74 4.06 s 6.61 s 8.27 s 34.4 140.0

85 Fig. 40a,b 3348 185-87 70 4.17 s 6.69 s 8.35 s 34.5 139.9

86 Fig. 41a,b 3462 Oily liquid 68 4.23 s 6.68 s 8.65 s 34.4 141.9

87 Fig. 42a,b 3456 Oily liquid 61 4.16 s 6.63 bs 8.61 s 33.7 141.8

88 3363 170-72 31 4.19 s 6.56 s 8.61 s 33.9 141.6

Chapter IV

159

12.4 Hz and at 3.45 with J = 5.2, 12.4 Hz each for one proton at C6, (iii) a triplet at 4.23

with J = 7.2 Hz for C7H, (iv) doublet at 5.02 with J = 1.7 Hz for C4H, (v) signals between

5.73 to 7.37 for nine aromatic protons and (vi) a broad singlet exchangeable with D2O at

8.22 for >NH of pyrrole ring. This spectral data suggested that this compound is the

expected product 89 of the Pictet-Spengler reaction. In agreement with this suggestion the

13C NMR (Fig. 43b) showed singlets at 34.9, 47.7 and 57.6 for C7, C6 and C4 respectively.

Apart from these, the region between 105 to 155 could account for fourteen aromatic

carbons.

NH

NH

89

O

Cl

2

3

4

6

7

The 1H and

13C NMR clearly indicated that this compound was a single

diastereomer. Later studies indicated that it was the trans isomer. The structure of

compound mp 164-66 °C was further confirmed by its dehydrogenation to afford 92 as

shown in Scheme VII. The results of dehydrogenation are collected later.

NH

NH

89

O

Cl

NH

NPd/C

xylene

92

O

Cl

12 hrs

reflux,

Scheme VII

When 4-nitrobenzaldehyde was used for the condensation reaction with amine 81

in presence of TFA, a mixture of two products was obtained. Importantly, in this case

separation of these could be achieved successfully using column chromatography to

Chapter IV

160

furnish a solid product mp 163-64 oC and an oily liquid in 34% and 24% yield respectively

(Scheme VIII).

NH

H2N

24 hrs

DCM, TFA, rt

81

NH

NH

91

NH

NH

O O

90

O2NO2N

O

+

CHO

O2N

Scheme VIII

The spectral properties described below suggested that these compounds were

diastereomers 90 and 91. The solid product melting at 163-64 oC analyzed for C17H15N3O3

and showed IR (KBr) bands at 3351, 3219 cm-1

for both >NH and 1518, 1344 cm-1

for -

NO2 group. 1H NMR (Fig. 44a) revealed (i) a broad singlet exchangeable with D2O at 2.50

for >NH, (ii) a doublet at 2.98 with J = 6.9 Hz for C6H and the other proton of C6H

overlapping with DMSO-d6 at 3.25, (iii) two broad singlets at 4.19 and 5.09 for C7H and

C4H, (iv) signals between 5.46 to 8.19 for nine aromatic protons and (v) a broad singlet



three singlets at 34.3, 47.4 and 56.4 for C7, C6 and C4 respectively, (ii) strong singlets at

122.9 and 128.9 corresponding to four aromatic carbons which are ortho and meta to nitro

group and (iii) ten more singlets for ten aromatic carbons. Mass spectrum showed no M+;

the peak at highest mass M+-29 at m/z 280 (base peak) was obtained by the loss of

NH=CH2. This spectral data required this compound to be either 90 or 91 (trans or cis).

The oily liquid which analyzed for C17H15N3O3 showed IR (KBr) bands at 3416

(broad) cm-1

for both >NH and 1518, 1346 cm-1

for -NO2 group. 1H NMR (Fig. 45a)

exhibited (i) a broad singlet exchangeable with D2O at 2.69 for >NH, (ii) a multiplet at

3.21-3.4 for two protons of C6H2, (iii) two broad singlets at 4.11 and 5.15 for C7H and

C4H, (iv) signals between 5.74 to 8.14 for nine aromatic protons and (v) a broad singlet



three singlets at 34.1, 46.2 and 56.8 for C7, C6 and C4 respectively, (ii) strong singlets at

Chapter IV

161

123.6 and 129.2 corresponding to four aromatic carbons which are ortho and meta to nitro

group and (iii) ten singlets for ten aromatic carbons. Mass spectrum showed, M+-28 at m/z

281 and base peak at m/z 280 obtained by the loss of NH=CH2. All the above data

confirmed the structure to be either 90 or 91 (trans or cis).

The two diastereomers showed difference in 1H NMR. The solid product showed

three separate signals for two C6H and C7H while in the spectrum of the oily liquid the

same three protons resonate at 3.21-3.4 as a multiplet and 4.11 as a broad doublet.

Further proof that the two compounds were diastereomers was obtained by their

dehydrogenation with Pd/C to furnish the same product 93 mp 155-57 oC. The details of

the dehydrogenation are described later.

NH

N

93

O

O2N

The studies reported later in this chapter suggest that the solid is the trans isomer

90 and the oily liquid is the cis isomer 91.

By analyzing the results of Pictet-Spengler reactions, it was observed that in case

of benzaldehyde and 4-methoxybenzaldehyde the reactions were rapid to furnish the

trisubstituted-5-azaindoles by tandem four steps reaction sequence. While using 4-

nitrobenzaldehyde due to the presence of electron-withdrawing group, reaction was slow

and hence afforded only Pictet-Spengler cyclization furnishing two diastereomers of

tetrahydro-5-azaindoles. In the reaction with 4-chlorobenzaldehyde due to lower

withdrawing effect of chloro as compared nitro group, both the products namely

trisubstituted-5-azaindole and tetrahydro-5-azaindole were formed. The formation of

products in all the reactions can be explained by a probable mechanism shown in Scheme

III.

Chapter IV

162

It may be pointed that in the earlier report14

of the Pictet-Spengler reaction using

TFA in DCM at 40 oC, only the trans isomer of tetrahydro-5-azaindole was resulted.

However these workers had carried out reaction only with two aldehydes.

Dehydrogenation studies:

Further dehydrogenation of tetrahydro-5-azaindoles was carried out using 5% Pd/C

to get the 5-azaindoles. Thus, dehydrogenation of tetrahydro-5-azaindoles 89 using 5%

Pd/C refluxed in xylene gave product 92 as a white solid melting at 180-82 °C (Scheme

VII), while that of the mixture of 90 and 91 gave 5-azaindole 93 as a yellow solid melting

at 155-57 oC along with some amount of starting 90. It was interesting to observe the ease

of dehydrogenation of both the individual isomers. Dehydrogenation of 90 furnished 93

after 15 hours along with 15% recovered starting, while 91 got dehydrogenated completely

within 2 hours (Scheme IX).

Pd/C

reflux, xylene+

15 hrs NH

N

Pd/C, reflux, xylene, 15 hrs

93

O

O2N

15% of isomer 90 recovered

Pd/C, reflux, xylene, 2 hrs

NH

NH

91

NH

NH

O O

90

O2NO2N

mp 163 - 64 oC oily liquid

Scheme IX

This indicated that 91 reacted faster than 90 which suggested cis arrangement of

the aryl and furyl groups at C4 and C7 respectively in 91 and trans in 90 (Chart II). The

instability due to the cis arrangement of the bulky groups at C4 and C7 in 91 forces the

molecule to react faster to achieve the stable aromatic structure. Furthermore, abstraction

of cis hydrogen by the catalyst is facilitated as approach of catalyst to this compound is

Chapter IV

163

facile. The identity of dehydrogenated compounds 92 and 93 was confirmed by spectral

and analytical data (Fig. 46a, 46b, 47a and 47b / Table IV and Experimental section).

HN

H

H

H

HHN

H

H

H

HO2N

NO2

OO

90 91

47

Chart II

In case of Pictet-Spengler reaction with 4-chlorobenzaldehyde, the small amount of

the cis isomer initially formed might be getting dehydrogenated rapidly during the Pictet-

Spengler reactions, hence it could not be isolated. The product 89 obtained might be the

trans isomer which could be isolated as it is dehydrogenated slowly.

It was not possible to achieve the synthesis of targeted tetrahydro-5-azaindoles

selectively using TMSCl or TFA in the Pictet-Spengler cyclizations, except the reactions

(using TFA) with benzaldehydes having electron withdrawing substituents.

Chapter IV

164





NH

N

84

NH

N

84

Chapter IV

165





NH

N

85

OMe

OMe

NH

N

85

OMe

OMe

Chapter IV

166





NH

N

86

O

NH

N

86

O

Chapter IV

167





NH

N

87

O

MeO

MeO

NH

N

87

O

MeO

MeO

Chapter IV

168





NH

NH

O

89

Cl

NH

NH

O

89

Cl

Chapter IV

169

Fig. 44a: (300 MHz, DMSO-d6)


Fig. 44b: (75 MHz, DMSO-d6)


NH

NH

O

90

O2N

NH

NH

O

90

O2N

Chapter IV

170





NH

NH

O

91

O2N

NH

NH

O

91

O2N

Chapter IV

171

Fig. 46a: (300 MHz, CDCl3/DMSO-d6)


Fig. 46b: (75 MHz, CDCl3/DMSO-d6)


NH

N

O

92

Cl

NH

N

O

92

Cl

Chapter IV

172





NH

N

O

93

O2N

NH

N

O

93

O2N

Chapter IV

173

Pictet-Spengler cyclization of amine 78 using glacial acetic acid:

With the aim to synthesise selectively only tetrahydro-5-azaindoles, glacial acetic

acid was used as a milder catalyst for this cyclization. Thus reaction of amine 78 with

benzaldehyde in the presence of glacial acetic acid in dichloromethane for 36 hrs at room

temperature furnished a white solid in 68% yield (Scheme X).

NH

N

NH

H2N

24 hrs

DCM, rt

78 95

NH

NH

94

PhCHO, AcOH

OMe OMe OMe

Pd/C

reflux, xylene

Scheme X

The white solid melted at 152-54 οC and analyzed for C20H20N2O. IR (KBr)

displayed bands at 3398 (br) cm-1

for both >NH. 1H NMR (Fig. 48a) showed (i) a broad

singlet exchangeable with D2O at 2.7 for >NH, (ii) two doublet of doublets at 2.94, J = 9.7,

12.3 Hz and at 3.39, J = 5.2, 12.3 Hz for C6H2, (iii) singlet at 3.78 for -OCH3, (iv) a

triplet at 4.1 with J = 5.8 Hz for C7H, (v) doublet at 5.11 with J = 1.4 Hz for C4H, (vi)

signals between 5.74 to 7.44 for eleven aromatic protons and (vii) a broad singlet


C NMR (Fig. 48b) exhibited (i)

singlets at 41.3, 52.7, 55.3 and 58.8 for C7, C6, -OCH3 and C4, and (ii) strong singlets at

114.0, 128.2, 128.3 and 129.3 corresponding to eight carbons (four of them are ortho and

meta to methoxy group and piperidine ring) and eight other signals for eight carbons. Mass

spectrum showed, M+-29 as base peak at m/z 275 obtained by the loss of NH=CH2. From

this spectral and analytical data the product was shown to be one isomer of 4-phenyl-7-(4-

methoxyphenyl)-tetrahydro-5-azaindole 94. The reason to assign the trans geometry

shown in 94 is described later.

Acetic acid acts as a mild catalyst amongst other catalysts like TMSCl or TFA. The

formation of a diastereoselective product can be attributed to the mild nature of the

catalyst. In addition to the above product some amount of starting along with very minor

amount of an unknown product was seen on TLC which was identified in the later part.

Chapter IV

174

Dehydrogenation of tetrahydro-5-azaindole 94:

4-Phenyl-7-(4-methoxyphenyl)-tetrahydro-5-azaindole 94, 5% Pd/C and dry xylene were

mixed and refluxed for 9 hrs. Usual work up and chromatographic separation on neutral

alumina using pet-ether and ethyl acetate as eluents furnished an unreported solid product

as a white crystalline compound melting at 195-97 οC in 81% yield. From the mode of

formation and spectral data, the compound was shown to be 4-phenyl-7-(4-

methoxyphenyl)-5-azaindole 95.

The compound analyzed for C20H16N2O and showed IR (KBr) band at 3201 cm-1

for >NH. 1H NMR (Fig. 49a) displayed (i) a singlet at 3.22 for -OCH3, (ii) singlet at 7.66

for C6H, (iii) a broad singlet at 10.07 (exchangeable with D2O) for >NH of pyrrole ring,

(iv) signals between 6.27 to 7.42 for eleven aromatic protons. In 13

C NMR (Fig. 49b) all

carbons showed signals in the aromatic region except one signal at 55.0 for -OCH3. The

structure was also confirmed by the M+ at m/z 300 as base peak and other fragments at m/z

285, 269, 190, 114 and 77.

Encouraged by the success in the diastereoselective cyclization reaction with

glacial acetic acid, the substituents at C4 and C7 were changed to generalize the

stereoselectivity in this reaction. Thus, condensation of the amines 80 and 81 with

benzaldehyde in glacial acetic acid gave tetrahydro-5-azaindoles 96 and 97 respectively as

major products. Reactions with amine 81 and 4-chlorobenzaldehyde, 4-nitrobenzaldehyde

and 4-methoxybenzaldehyde furnished new compounds 89, 90 and 98 respectively in

diastereoselective manner (Scheme XI). The spectral data, mps and yields of all

tetrahydro-5-azaindoles are recorded in Table III and Experimental section.

NH

N

Ar

Ar1

NH

H2N

Ar overnight

DCM, rt

80,81

NH

NH

Ar

Ar1

89, 90, 96, 97, 98

Ar1CHO, AcOH Pd/C

reflux, xylene

92, 93, 99, 100, 101

9-15 hrs

89, 92. Ar = 2-furyl, Ar1 = 4-chlorophenyl, 90, 93. Ar = 2-furyl, Ar1 = 4-nitrophenyl, 96,

99. Ar = 3,4-dimethoxyphenyl, Ar1 = phenyl, 97, 100. Ar = 2-furyl, Ar1 = phenyl, 98, 101.

Ar = 2-furyl, Ar1 = 4-methoxyphenyl.

Scheme XI

Chapter IV

175

In all these reactions only one diastereomer was obtained however the

stereochemistry of the product could not be decided. The stereochemistry of 96 was

unambiguously investigated using single crystal X-ray analysis. It indicated trans

geometry as R, S configuration at C4 and C7 respectively to the diastereomer 96 (Fig. 50c).

As in all reactions using glacial acetic acid only one diastereomer was obtained, by

analogy with the trans isomer 96 and considering the similarity in the spectral data, all

diastereomers obtained in the reaction using glacial acetic acid were probably having trans

geometry. The compounds mp 164-66 oC and 163-64

oC in the TFA reaction were found to

be identical with 89 and 90 obtained using glacial acetic acid. This suggested that these

compounds obtained in the TFA reaction should probably have trans geometry.

Figure 50c. ORTEP diagram of sulphate 96 ellipsoid is drawn at 50% probability

Chapter IV

176

In the last step, refluxing 4,7-disubstituted-tetrahydro-5-azaindoles 89, 90 and 96-

98 with 5% Pd/C in xylene furnished 4,7-disubstituted-5-azaindoles 92, 93 and 99-101

respectively. The spectral data, mps and yields of these compounds are recorded in Table

IV. Comparing the time required for the dehydrogenation reaction of all tetrahydro

compounds (Table IV) it was observed that the trans isomers were dehydrogenated slowly

(9-15 h) and the time required was similar for all compounds indicating similar geometry

of all tetrahydro products.

The very minor product obtained in the reaction of amine 78 with benzaldehyde in

the presence of glacial acetic acid was shown to be identical with the dehydrogenated

product 95. During the Pictet-Spengler reaction of amine 81 with 4-methoxybenzaldehyde,

aromatic product 101 was detected in 10% yield along with 4,7-disubstituted tetrahydro-5-

azaindole 98. In all other similar reactions, TLC indicated the presence of little amount of

dehydrogenated product. As the cis isomer was shown to dehydrogenate faster, probably

the initially formed cis isomer might be getting converted to the 4,7-disubstituted-5-

azaindole.

To support the mechanism suggested in Scheme III, the 4,7-disubstituted-

tetrahydro-5-azaindole 94 obtained in the reaction using acetic acid was treated with

benzaldehyde in the presence of TFA in dichloromethane for 24 hrs at room temperature

(Scheme XII). The product obtained was shown to be 82 using 1H NMR spectrum. The

same reaction using TMSCl furnished products, 82 and 83 which were confirmed by TLC

(Scheme XII).

24 hrs

NH

N

Ph

Ph

Ph

NH

N

Ph

Ph

+

48 hrs

DCM, rt

PhCHO

82 83

TMSClNH

NH

Ph

94OMe

TFA

DCM, rtNH

N

Ph

Ph

82

PhCHO

OMe OMeOMe

Scheme XII

Chapter IV

177

Table III: Spectral data, mps and yields of tetrahydro-5-azaindoles 89-91, 94 and 96-98.

Table IV: Spectral data, mps and yields of disubstituted-5-azaindoles 92, 93 and 99-101.

Prod.

No.

IR

cm-1

M.P

C

Yield

%

1H NMR

13C NMR

C6H C6H C7H C4H C7 C6 C4

89 Fig. 43a,b 3362, 3248 164-66 59 3.17

dd

3.45

dd

4.23

t

5.02

d

34.9 47.7 57.6

90 Fig. 44a,b 3351, 3219,

1518, 1344

163-64 52 2.98

d

3.25

brs

4.19

brs

5.09

brs

34.3 47.5 56.4

91 Fig. 45a,b 3416 (br),

1518, 1346

Oily

liquid

24 3.21-3.4 m 4.11

bd

5.15

brs

34.1 46.2 56.8

94 Fig. 48a,b 3398 (br) 152-54 68 2.94

dd

3.39

dd

4.1

t

5.11

d

41.3 52.7 58.8

96 Fig. 50a,b 3553, 3277 169-71 66 3.04

T

3.49

dd

4.27

brs

5.67

s

39.4 50.4 57.6

97 Fig. 51a,b 3356, 3259 129-31 60 3.19

dd

3.49

dd

4.24

t

5.07

d

35.0 47.8 58.3

98 Fig. 52a,b 3362, 3248 146-48 61 2.9

dd

3.26

dd

4.16

brs

4.84

s

34.4 48.0 56.8

Prod. No. Dehydrogenation

time (h)

IR

cm-1

M.P

C

Yield

%

1H NMR

13C NMR

C6H C6

92 Fig. 46a,b 12 3257 180-82 55 8.66 s 139.6

93 Fig. 47a,b 15 3217, 1518, 1377 155-57 46 8.78 s 146.0

95 Fig. 49a,b 9 3201 195-97 81 7.66 s 139.6

99 Fig. 53a,b 11 3335 163-65 68 8.37 s 139.2

100 Fig. 54a,b 9 3222 162-64 63 8.4 s 142.6

101 Fig. 55a,b 9 3215 170-71 65 8.64 s 142.0

Chapter IV

178





NH

NH

94OMe

NH

NH

94OMe

Chapter IV

179

10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5

2.242.05 1.581.051.00 0.95

DMSO-d6

2.5

0

3.2

2

6.2

66.2

8

6.3

96.4

46.6

96.7

06.8

76.8

96.9

36.9

76.9

87.0

17.4

07.4

17.4

37.4

47.6

6

10.0

7



170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

DMSO-d6Chloroform-d

39.6

0

55.0

3

76.9

7

102.2

2

114.2

7

119.8

6

122.2

0

126.4

2127.9

8128.1

9128.4

2129.2

8

138.4

4138.7

2139.6

4

150.1

0

159.0

6



NH

N

95 OMe

NH

N

95 OMe

Chapter IV

180





NH

NH

96 OMe

OMe

NH

NH

96 OMe

OMe

Chapter IV

181





NH

NH

O

97

NH

NH

O

97

Chapter IV

182





NH

NH

O

98

MeO

NH

NH

O

98

MeO

Chapter IV

183





NH

N

99 OMe

OMe

NH

N

99 OMe

OMe

Chapter IV

184

11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5

4.922.52 1.27 1.15 1.12 1.031.000.83

6.3

26.3

36.3

3

6.5

66.5

7

6.7

16.7

3

7.1

57.1

77.1

87.1

87.2

07.2

47.2

77.3

67.4

1

7.7

07.7

37.7

4

8.4

0

10.8

3



150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DMSO-d6Chloroform-d39.9

0

77.9

3

102.1

9

106.6

6110.5

0111.9

4

122.9

5127.4

7128.5

7128.7

4135.6

9136.3

1139.8

8142.5

8

150.4

6150.5

7



NH

N

100

O

NH

N

100

O

Chapter IV

185





NH

N

101

O

MeO

NH

N

101

O

MeO

Chapter IV

186

Conclusion

1. A diastereoselective method was established for the synthesis of 4,7-disubstituted

tetrahydro-5-azaindoles using glacial acetic acid as a mild catalyst during Pictet–

Spengler reaction. The stereochemistry of one of the diastereomers was

unambiguously confirmed by single crystal X-ray analysis.

2. The method was used for synthesizing six 4,7-disubstituted tetrahydro-5-

azaindoles. All of these 89, 90, 94 and 96-98 were dehydrogenated to 4,7-

disubstituted-5-azaindoles 92, 93, 95 and 99-101.

3. In a unprecedented tandem four steps reaction sequence using stronger acid TFA,

unreported 2,4,7-trisubstituted-5-azaindoles 82, 84-87 and 88 were obtained in

good yields.

4. A similar tandem four steps reaction sequence was also observed in presence of

TMSCl to furnish a 2,4,7-trisubstituted and 2,3,4,7-tetrasubstituted-5-azaindoles

82 and 83 respectively.

Chapter IV

187

Experimental section

Expt. No. 4.1 - General procedure for Catalytic hydrogenation

NH

O2N

ArNH

H2N

Ar

Raney Nickel

MeOH / H2

21a, 22a, 24a, 26a 78, 79, 80, 81 2-Aryl-2-(2-pyrrolyl)-l-nitroethane (0.002 mol) was dissolved in methanol and

Raney Nickel (1.5g) was added to it. The reaction mixture was treated with hydrogen

using balloon for 3-12 hrs. The catalyst was filtered off through celite bed and the filtrate

was concentrated by vacuum distillation. Ether was added so that the product readily

separated out, and recrystalized from hot hexane.

2-(4-Methoxyphenyl)-2-(1H-pyrrol-2-yl)ethanamine 78

Time : 12 hrs

Mp. : 94-6 oC, white crystals

Yield : 91 %

IR (KBr) : 3460, 3412, 3389 cm-1

for NH2 and NH

MS : m/z 216 [M+], 199, 186 (100%), 171

Elemental analysis : for C13H16N2O, requires: C, 72.19; H, 7.46; N, 12.95. Found: C,

72.41; H, 7.66; N, 13.32%

1H NMR (Fig. 33a)

1.46 brs (Ex. with D2O) 2H >NH2 3.18 dd (J=6.6,12.1H) 1H C1H

3.3 dd (J = 6.6, 12.1 Hz) 1H C1H 3.78 s 3H OCH3

3.98 t (J = 6.6 Hz) 1H C2H 5.92 brs 1H C3''H

6.13 d (J = 2.5 Hz) 1H C4''H 6.67 brs 1H C5''H

6.84 d (J = 8.5 Hz) 2H C3'H,C5'H 7.1 d (J = 8.5 Hz) 2H C2'H,C6'H

8.84 brs (Ex. with D2O) 1H >NH

13C NMR (Fig. 33b)

45.3 C1 46.5 C2 55.3 OCH3

105.5 C3'' 108.0 C4'' 114.1(str.) C3', C5'

116.9 C5'' 129.0 (str.) C2', C6' 132.7 C2''

133.0 C1' 158.5 C4'

NH

H2N

OMe

78

12

1'2'

3'

4'5'

6'

2''

3''4''

5''

Chapter IV

188

2-Phenyl-2-(1H-pyrrol-2-yl)ethanamine 79

Time : 3 hrs


Yield : 94 %

IR (KBr) : 3427 (br) cm-1

for NH2 and NH

MS : m/z 186 [M+], 156 (100%), 141, 91

Elemental analysis : for C12H14N2, requires: C, 77.38; H, 7.58; N, 15.04. Found: C,

77.18; H, 7.75; N, 15.26%

1H NMR (Fig. 34a)

1.33 brs (Ex. with D2O) 2H >NH2 3.21 dd (J = 6.3, 12.4 Hz) 1H C1H

3.32 dd (J = 6.3, 12.4 Hz) 1H C1H 4.01 t (J = 6.3 Hz) 1H C2H

5.94 brs 1H C3''H 6.13 d (J = 2.8 Hz) 1H C4''H

6.67 brs 1H C5''H 7.13-7.35 m 5H ArH


13C NMR

46.9 C1 47.0 C2 105.3 C3''

107.8 C4'' 116.7 C5'' 126.7 C4'

128.0 (str.) C2', C6' 128.5 (str.) C3', C5' 133.0 C2''

141.5 C1'

2-(3,4-Dimethoxyphenyl)-2-(1H-pyrrol-2-yl)ethanamine 80

Time : 12 hrs


Yield : 90 %

IR (KBr) : 3365 (br) cm-1

for NH2 and NH

MS : m/z 246 [M+], 231, 216 (100%), 200, 185

Elemental analysis : for C14H18N2O2, requires: C, 68.27; H,

7.37; N, 11.37. Found: C, 68.06; H, 7.65; N, 11.59%

1H NMR ( Fig. 35a)

1.45 brs (Ex. with D2O) 2H >NH2 3.2 dd (J = 6.6, 12.1 Hz) 1H C1H

3.33 dd (J = 6.6, 12.1 Hz) 1H C1H 3.82 s 3H OCH3

NH

H2N

79

12

1'2'

3'

4'5'

6'

2''

3''4''

5''

NH

H2N

80

12

1'2'

3'

4'5'

6'

2''

3''4''

5''

OMe

OMe

Chapter IV

189

3.86 s 3H OCH3 3.94 t (J = 6.6 Hz) 1H C2H

5.94 brs 1H C3''H 6.14 d (J = 2.5 Hz) 1H C4''H

6.65-6.83 m 4H ArH 8.84 brs (Ex. with D2O) 1H >NH

13C NMR

46.4 C1 46.9 C2 55.9 (str.) OCH3

105.3 C3'' 107.9 C4'' 111.2 C2'

111.3 C5' 116.7 C5'' 120.1 C6'

133.1 C2'' 133.8 C1' 147.8, 148.9 C4', C3'

2-(2-Furyl)-2-(1H-pyrrol-2-yl)ethanamine 81

Time : 3 hrs


Yield : 89 %

IR (KBr) : 3340, 3286 (br) cm-1

for NH2 and NH

MS : m/z 176 [M+], 146 (100%), 130, 117.

Elemental analysis : for C10H12N2O, requires: C, 68.16; H, 6.86; N, 15.90. Found: C,

68.42; H, 6.52; N, 15.64%

1H NMR (Fig. 36a)

1.29 brs (Ex. with D2O) 2H >NH2 3.21 brs 2H C1H

4.08 brs 1H C2H 5.98 brs 1H C3''H

6.04 brs 1H C3'H 6.12 brs 1H C4''H

6.29 brs 1H C4'H 6.68 brs 1H C5''H

7.34 brs 1H C5'H 8.99 brs (Ex. with D2O) 1H >NH

13C NMR (Fig. 36b)

41.5 C1 45.7 C2 105.7 C3'

106.5 C3'' 107.9 C4'' 110.1 C4'

116.9 C5'' 130.5 C2'' 141.5 C5'

154.9 C2'

NH

H2N

81

12

2'

3'

4' 5'

2''

3''4''

5''

O

Chapter IV

190

Expt. No. 4.2 – Pictet-Spengler reaction using TMSCl

NH

N

Ph

ArPh

Ph

NH

N

Ph

ArPhNH

H2N

Ar

+

rt

DCM, 48 hrs

PhCHO

82 8378

TMSCl

Solution of amino compound (78, 0.002 mol) in dichloromethane was stirred at

room temperature with benzaldehyde (0.006 mol). The solution was cooled and trimethyl

silyl chloride (0.004 mol) was slowly added to it over 15 minutes.The reaction mixture

was stirred at room temperature for 48 hrs and was diluted with dichloromethane. 10%

Sodium hydroxide was added and the organic phase was separated. The aqueous phase

was extracted with dichloromethane (2 × 50 mL); the organic extracts were combined and

dried over sodium sulphate. The crude product obtained was chromatographed on silica

gel using pet-ether and ethyl acetate as an eluent yielding the pure products.

2-Benzyl-4-phenyl-7-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine 82

Time : 48 hrs

Mp. : 175-77 oC, yellow solid

Yield : 28%

IR (KBr) : 3367 cm-1

for NH

MS : m/z 390 (100%) [M+], 375, 359, 313, 299,

281, 91, 77

Elemental analysis : for C27H22N2O requires: C, 83.05; H,

5.68; N, 7.17. Found: C, 82.84; H, 5.91; N, 6.89%

1H NMR (Fig. 37a)

3.81 s 3H -OCH3 4.12 s 2H -CH2-

6.65 s 1H C3H 6.97 d (J = 7.9 Hz) 2H C3'H,C5'H

7.15-7.29 m 5H ArH 7.4 d (J = 6.3 Hz) 1H ArH

7.46-7.48 m 4H ArH 7.96 d (J = 6.6 Hz) 2H ArH

8.28 s 1H C6H 8.67 bs (Ex. with D2O) 1H >NH

NH

N

2

3

4

7

4a

7a 1'2'

3'

5'

2''

4''

6''

1'''

4'''

6

OMe

6'

82

Chapter IV

191

13C NMR (Fig. 37b)

34.5 -CH2- 55.3 -OCH3 101.6 C4a

114.6 (str.) C3', C5' 119.5 C3 122.9 C7a

126.8, 127.7 2 × ArC 128.4 (str.) 3 × ArC 128.5 (str.) 2 × ArC

128.6 (str.) 3 × ArC 128.7 (str.) 2 × ArC 129.2 (str.) C3'', C5''

137.6 C7 138.5 ArC 139.3 ArC

140.2 C6 149.2 C4 159.3 C4'

DEPT (Fig. 37c) showed the presence of one -CH2- group and one -OCH3 group.

2,3-Dibenzyl-4-phenyl-7-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine 83

Time : 48 hrs

Mp. : Oily liquid

Yield : 15 %.

IR (KBr) : 3450 cm-1

for NH

MS : m/z 480 (100%) [M+], 448, 403,

389, 374, 311, 297, 91, 77

Elemental analysis : for C34H28N2O requires: C, 84.97;

H, 5.87; N, 5.83. Found: C, 85.19; H, 6.09; N, 5.61%

1H NMR (Fig. 38a)

3.84 s 3H -OCH3 3.88 s 2H -CH2-

4.06 s 2H -CH2- 6.66 bs 2H C3'H,C5'H

6.96-7.13 m 7H ArH 7.18-7.3 m 6H ArH

7.34 t (J = 6.6 Hz) 2H ArH 7.49 d (J = 8.8 Hz) 2H ArH


13C NMR (Fig. 38b)

30.4 -CH2- 32.4 -CH2- 55.4 -OCH3

111.4 C4a 114.8 (str.) C3', C5' 119.0 C3

122.2 C7a 125.3, 126.8 C4'''', C4''' 127.5 (str.) 2 × ArC

127.6 C4'' 127.7 (str.) 2 × ArC 127.8 (str.) 2× ArC

128.0 ArC 128.4 (str.) 2 × ArC 128.8 (str.) 2 × ArC

NH

N

OMe

2

4

6

1'

4'

1''

4''

1'''

4'''

1''''

4''''3

83

Chapter IV

192

129.1 (str.) 2 × ArC 129.2 (str.) 2 × ArC 136.2, 137.6 C2, C7

138.5 ArC 138.8 ArC 140.5 ArC

140.6 C6 152.2 C4 159.3 C4'

DEPT (Fig. 38c) showed the presence of two -CH2- group and one -OCH3 group.

Expt. No. 4.3 - Pictet–Spengler reaction using TFA

NH

H2N

ArNH

NH

Ar1

ArNH

N

Ar1

ArAr1

+TFA

DCM

12-24 hrs, rt

78, 79, 80, 81 82, 84, 85, 86, 87, 88 89-91

Ar1CHO

A solution of the amino compound (78, 79, 80 or 81; 0.002 mol) in

dichloromethane was stirred at room temperature with aromatic aldehyde (0.004 mol) as

described in case of TMSCl. After completion of reaction, aqueous sodium hydrogen

carbonate was added. Usual work up furnished the products.

2-Benzyl-4-phenyl-7-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine 82

Time : 15 hrs


Yield : 69%

The spectral properties established it to be identical with 82 obtained in reaction using

TMSCl.

2-Benzyl-4,7-diphenyl-1H-pyrrolo[3,2-c]pyridine 84

Time : 12 hrs

Mp. : 170-72 oC, white solid

Yield : 69 %

IR (KBr) : 3444 cm-1

for NH

MS : m/z 360 (100%) [M+], 283, 269, 205, 113,

91, 77

Elemental analysis : for C26H20N2 requires: C, 86.64; H, 5.59; 4'

NH

N

84

2

3

4

7

4a

7a 1'2'

3'

5'

2''

4''

6''

1'''

4'''

6

6'

Chapter IV

193

N, 7.77. Found: C, 86.41; H, 5.39; N, 8.03%

1H NMR (Fig. 39a)

4.06 s 2H -CH2- 6.61 s 1H C3H

6.98-7.29 m 6H Ar-H 7.32-7.49 m 5H Ar-H

7.52 d (J = 7.2 Hz) 2H C2'H, C6'H 7.91 d (J = 7.2 Hz) 2H C2''H, C6''H

8.27 s 1H C6H 9.13 brs (Ex. with D2O) 1H >NH

13C NMR (Fig. 39b)

34.4 -CH2- 101.5 C4a 119.7 C3

122.9 C7a 126.7, 127.8 C4''', C4'' 128.1 (str.) 2 × ArC

128.3 (str.) 2 × ArC 128.4 (str.) 2 × ArC 128.5 (str.) 2 × ArC

128.6 (str.) 3 × ArC 129.1 (str.) 2 × ArC 135.7, 137.6 C7, C2

138.9 ArC 139.1 ArC 139.4 ArC

140.0 C6 149.9 C4

2-Benzyl-4-phenyl-7-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine 85

Time : 15 hrs


Yield : 70 %

IR (KBr) : 3348 cm-1

MS : m/z 420 (100%) [M+], 419, 403, 389,

343, 91, 77

Elemental analysis : for C28H24N2O2 requires: C, 79.98; H,

5.75; N, 6.66. Found: C, 80.23; H, 5.59; N, 6.91%

1H NMR (Fig. 40a)

3.82 s 3H OCH3 3.92 s 3H OCH3

4.17 s 2H -CH2- 6.69 s 1H C3H

6.96-7.01 m 2H C2'H, C5'H 7.12 d (J = 8.3 Hz) 1H C6'H

7.19-7.36 m 5H ArH 7.42 t (J = 7.2 Hz) 1H C4''H

7.5 t (J = 7.4 Hz) 2H C3''H, C5''H 7.99 d (J = 7.4 Hz) 2H C2''H, C6''H

8.32 brs (Ex. with D2O) 1H >NH 8.35 s 1H C6H

4'

NH

N

85

2

3

4

7

4a

7a 1'2'

3'5'

2''

4''

6''

1'''

4'''

6

6'OMe

OMe

Chapter IV

194

13C NMR (75 MHz, CDCl3, Fig. 40b)

34.5 -CH2- 55.8 (str.) 2×OCH3 101.3 C4a

111.1, 111.6 C3, C2' 119.6, 120.4 C5', C6' 122.8 C7a

126.7, 128.23 C4''', C4'' 128.26 ArC 128.33 (str.) 2 × ArC


137.7, 138.8 C7, C2 139.2 ArC 139.6 ArC

139.9 C6 148.6 C4' 149.3, 149.6 C3', C4

2-Benzyl-4-phenyl-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine 86

Time : 16 hrs

Mp. : Oily liquid

Yield : 68 %

IR (KBr) : 3462 cm-1

for NH

MS : m/z 349 [M+-1, 100%], 319, 273, 259, 91,77.

Elemental analysis : for C24H18N2O requires: C, 82.26; H, 5.18;

N, 7.99. Found: C, 82.02; H, 5.43; N, 7.69%

1H NMR (Fig. 41a)

4.23 s 2H -CH2- 6.58 m 1H C3'H

6.68 brs 1H C3H 6.84 d (J = 3.6 Hz) 1H C4'H

7.23-7.4 m 5H ArH 7.44 d (J = 7.2 Hz) 1H ArH

7.52 t (J = 7.4 Hz) 2H ArH 7.57 brs 1H C5'H

8.01 d (J = 7.2 Hz) 2H C2''H, C6''H 8.65 s 1H C6H


13C NMR (Fig. 41b)

34.4 -CH2- 101.0 C4' 105.4 C4a

109.5 C3 111.6 C3' 123.2 C7a

126.7 ArC 128.1 ArC 128.3 (str.) 2 × ArC


136.3, 136.4 C2, C7 137.6 ArC 139.7 ArC

139.9, 141.9 C5', C6 149.9 C4 151.4 C2'

4'

NH

N

86

2

3

4

7

4a

7a 2'

3'5'

2''

4''

6''

1'''

4'''

6

O

Chapter IV

195

2-(4-Methoxybenzyl)-4-(4-methoxyphenyl)-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine 87

Time : 20 hrs

Mp. : Oily liquid

Yield : 61 %

IR (KBr) : 3456 cm-1

MS : m/z 410 [M+, 100%], 395, 381, 303, 108,

91, 77

Elemental analysis : for C26H22N2O3 requires: C, 76.08; H,

5.40; N, 6.82. Found: C, 76.31; H, 5.57; N, 7.09%

1H NMR (Fig. 42a)

3.82 s 3H OCH3 3.89 s 3H OCH3

4.16 s 2H -CH2- 6.56 m 1H C3'H

6.63 brs 1H C3H 6.81 d (J = 3.6 Hz) 1H C4'H

6.88 d (J = 8.5 Hz) 2H C3'''H, C5'''H 7.05 d (J = 8.8 Hz) 2H C3''H, C5''H

7.19 d (J = 8.5 Hz) 2H C2'''H, C6'''H 7.57 brs 1H C5'H

7.95 d (J = 8.8 Hz) 2H C2''H, C6''H 8.61 s 1H C6H


13C NMR (Fig. 42b)

33.7 -CH2- 55.2 OCH3 55.3 OCH3

100.8 C4' 105.1 C4a 109.0 C3

111.6 C3' 113.8 (str.) C3''', C5''' 114.0 (str.) C3'', C5''

122.8 C7a 129.5 (str.) 2 × ArC 129.7 (str.) 2 × ArC

132.6 C7 136.3 C2 136.4 (str.) 2 × ArC

139.9, 141.8 C5', C6 149.7 C4 151.6 C2'

158.2, 159.6 C4''', C4''

4'

NH

N

87

2

3

4

7

4a

7a 2'

3'5'

2''

4''

6''

1'''

4'''

6

O

MeO

MeO

Chapter IV

196

2-(4-Chlorobenzyl)-4-(4-chlorophenyl)-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine 88

Time : 24 hrs

Mp. : 170-72 oC, yellowish solid

Yield : 31 %

IR (KBr) : 3363 cm-1 for NH

1H NMR*

4.19 s 2H -CH2- 6.56 bs 1H C3H

6.81 d (J = 3.0 Hz) 1H C3'H 7.13-7.42 m 6H ArH

7.46 d (J = 6.9 Hz) 1H ArH 7.58 bs 1H C5'H

7.9 d (J = 6.9 Hz) 2H C2''H, C6''H 8.61 s 1H C6H

9.31 bs (Ex. with D2O) 1H >NH

13C NMR*

33.9 -CH2- 100.7 C4' 105.9 C4a

109.6 C3 110.8 C3' 121.8 C7a

126.9 (st.) 2 × ArC 127.5 (st.) 2 × ArC 128.9 (st.) 2 × ArC

129.2 (st.) 2 × ArC 130.9, 132.9 C7, C2 134.5 ArC

135.2 ArC 136.4 ArC 137.3 ArC

140.7, 141.6 C5', C6 147.8 C4 149.1 C2'

* Additional signals of 89 were also seen in the spectrum of this compound.

4-(4-Chlorophenyl)-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine 89

Time : 24 hrs


Yield : 33%

IR (KBr) : 3362, 3248 cm-1

for both >NH

MS : m/z 269 [M+-29] (100%), 240, 234, 205, 151, 51.

Elemental analysis : for C17H15ClN2O requires: C, 68.34; H, 5.06; N,

9.38. Found: C, 68.09; H, 4.89; N, 9.11.

NH

NH

O

89

Cl

2'

3'

4'5'

2''

4''

6''

2

3

4

7

4a

7a

6

4'

NH

N

88

2

3

4

7

4a

7a 2'

3'5'

2''

4''

6''

1'''

4'''

6

O

Cl

Cl

Chapter IV

197

1H NMR (Fig. 43a)

1.93 bs (exch. with D2O) 1H >NH 3.17 dd (J = 8.3, 12.4 Hz) 1H C6H


5.02 d (J = 1.7 Hz) 1H C4H 5.73 t (J = 2.5 Hz) 1H ArH

6.06 d (J = 3.3 Hz) 1H ArH 6.32 m 1H C4'H

6.62 t (J = 2.8 Hz) 1H C2H 7.28-7.34 m 4H ArH

7.37 m 1H C5'H 8.22 bs (Ex. with D2O) 1H >NH

13C NMR (43b)

34.9 C7 47.7 C6 57.6 C4

105.7 C3' 106.0 C3 110.2 C4'

116.8 C4a 119.3 C2 125.9 C7a

128.4 (str.), 129.6 (str.) C3'', C5'', C2'', C6'' 132.9 C4''

141.8 C1'' 142.6 C5' 154.9 C2'

4-(4-Nitrophenyl)-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine 90

Time : 24 hrs


Yield : 34 %

IR (KBr) : 3351, 3219 cm-1

for both >NH and 1518, 1344

cm-1

for –NO2 group

MS : m/z 280 [M+-29] (100%), 279, 263, 233, 217, 51

Elemental analysis : for C17H15N3O3 requires: C, 66.01; H, 4.89; N,

13.58. Found: C, 65.79; H, 5.15; N, 13.36%

1H NMR (Fig. 44a)

2.50 brs (exch. with D2O) 1H >NH 2.98 d (J = 6.9 Hz) 1H C6H

3.25 brs with DMSO 1H C6H 4.19 brs 1H C7H

5.09 brs 1H C4H 5.46 brs 1H ArH

6.09 brs 1H ArH 6.38 brs 1H C4'H

6.53 brs 1H C2H 7.55 brs 1H C5'H

7.60 d (J = 7.7 Hz) 2H C2''H,C6''H 8.19 d (J = 7.7 Hz) 2H C3''H,C5''H


NH

NH

O

90

O2N

2'

3'

4'5'

2''

4''

6''

2

3

4

7

4a

7a

6

Chapter IV

198

13C NMR (Fig. 44b)

34.3 C7 47.5 C6 56.4 C4

104.5 C3' 105.8 C3 110.1 C4'

116.7 C4a 118.1 C2 122.9 (str.) C2'', C6''

124.9 C7a 128.9 (str.) C3'', C5'' 141.4 C5'

146.1 C1'' 152.9 C4'' 155.3 C2'


Time : 24 hrs

Mp. : Oily liquid

Yield : 24 %

IR (KBr) : 3416 (br) cm-1

for both >NH and 1518, 1346 cm-

1 for –NO2 group

MS : m/z 281 [M+-28], 280(100%), 263, 233, 217, 51


13.58. Found: C, 66.32; H, 4.59; N, 13.42%

1H NMR (Fig. 45a)

2.69 brs (Ex. with D2O) 1H >NH 3.21-3.4 m 2H C6H2

4.11 bd (J = 4.7 Hz) 1H C7H 5.15 brs 1H C4H


6.29 t (J = 1.7 Hz) 1H C4'H 6.68 t (J = 2.5 Hz) 1H C2H

7.34 brs 1H C5'H 7.52 d (J = 8.5 Hz) 2H C2''H,C6''H

8.14 d (J = 8.5 Hz) 2H C3''H,C5''H 8.32 brs (Ex. with D2O) 1H >NH

13C NMR (Fig. 45b)

34.1 C7 46.2 C6 56.8 C4

105.7 C3' 106.3 C3 110.2 C4'

117.3 C4a 117.7 C2 123.6 (str.) C2'', C6''

125.6 C7a 129.2 (str.) C3'', C5'' 141.8 C5'

147.1 C1'' 150.9 C4'' 155.2 C2'

NH

NH

91

O

O2N

2'

3'

4'5'

2''

4''

6''

2

3

4

7

4a

7a

6

Chapter IV

199

Expt. No. 4.4 - Pictet–Spengler reaction using AcOH

NH

H2N

ArNH

NH

Ar1

Ar

AcOH

36-48 hrs, rt

DCM

78, 80, 81 89-91, 94, 96-98

Ar1CHO

The reaction was carried out as described in Expt. No. 4.3. Usual work up afforded

the products.

4-(4-Chlorophenyl)-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine 89

Time : 48 hrs


Yield : 59 %


TFA.


Time : 48 hrs


Yield : 52 %


TFA.

4-Phenyl-7-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine 94

Time : 36 hrs


Yield : 68 %

IR (KBr) : 3398 (br) cm-1

for both NH

MS : m/z 304 [M+], 275 (100%), 260, 244, 198, 91

Elemental analysis: for C20H20N2O requires: C, 78.92; H, 6.62; N,

9.20. Found: C, 78.71; H, 6.84; N, 8.96%

1H NMR (Fig. 48a)

2.7 brs (Ex. with D2O) 1H >NH 2.94 dd (J= 9.7, 12.3 Hz) 1H C6H

NH

NH

94 OMe

1' 2'

3'

4'5'

6'

2''

4''

6''

2

3

4

7

4a

7a

6

Chapter IV

200

3.39 dd (J = 5.2, 12.3 Hz) 1H C6H 3.78 s 3H -OCH3

4.1 t (J = 5.8 Hz) 1H C7H 5.11 d (J = 1.4 Hz) 1H C4H

5.74 t (J = 2.3 Hz) 1H C3H 6.55 t (J = 2.6 Hz) 1H C2H

6.84 d (J = 8.5 Hz) 2H C3'H,C5'H 7.08 d (J = 8.5 Hz) 2H C2'HC6'H

7.21-7.44 m 5H Ar-H 7.89 brs (Ex. with D2O) 1H >NH

13C NMR (Fig. 48b)

41.3 C7 52.7 C6 55.3 -OCH3

58.8 C4 105.8 C3 114.0 (str.) C3', C5'

116.5 C4a 120.2 C2 127.4 ArC

128.2 (str.) 2 × ArC 128.3 (str.) 2 × ArC 128.7 ArC

129.3 (str.) 2 × ArC 133.9 C1' 144.0 C1''

158.6 C4'

4-Phenyl-7-(3,4-dimethoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine 96

Time : 36 hrs


Yield : 66 %.

IR (KBr) : 3553, 3277 cm-1

for both NH

MS : m/z 333 [M+-1], 305, 290, 274, 259, 243, 77

Elemental analysis : for C21H22N2O2 requires: C, 75.42; H, 6.63;

N, 8.38. Found: C, 75.69; H, 6.85; N, 8.67%

1H NMR (Fig. 50a)

3.04 t (J = 11.7 Hz) 1H C6H 3.49 dd (J = 4.7, 12.0 Hz) 1H C6H

3.79 s 3H OCH3 3.84 s 3H -OCH3

4.27 brs 1H C7H 5.35 brs (Ex. with D2O) 1H >NH

5.67 s 1H C4H 6.61 s 1H C3H

6.72 m 2H ArH 6.82 d (J = 7.9 Hz) 1H C6'H

7.25-7.39 m 3H ArH 7.44 t (J = 6.5 Hz) 2H ArH

7.94 d (J = 7.3 Hz) 1H ArH 9.51 brs (Ex. with D2O) 1H >NH

NH

NH

96 OMe

1' 2'

3'4'5'

6'

2''

4''

6''

2

3

4

7

4a

7a

6

OMe

Chapter IV

201

13C NMR (Fig. 50b)

39.4 C7 50.4 C6 55.0 -OCH3

55.1 -OCH3 57.6 C4 104.5 C3

110.6 C2' 110.7 C5' 116.6 C4a

117.2 C6' 119.8 C2 126.8 ArC

127.0 ArC 127.5 ArC 128.1 ArC

128.6 ArC 130.3 C7a 133.3 C1'

140.9 C1'' 147.2, 148.2 C4', C3'

4-Phenyl-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine 97

Time : 36 hrs

Mp. : 129-31oC, white solid

Yield : 60 %

IR (KBr) : 3356, 3259 cm-1

for both NH

MS : m/z 235 [M+-29] (100%), 218, 206, 191, 77, 51.

Elemental analysis : for C17H16N2O requires: C, 77.25; H, 6.10; N,

10.60. Found: C, 77.54; H, 6.36; N, 10.89%

1H NMR (Fig. 51a)

2.0 brs (Ex. with D2O) 1H >NH 3.19 dd (J = 8.2, 12.3 Hz 1H C6H


5.07 d (J = 1.5 Hz) 1H C4H 5.79 t (J = 2.6 Hz) 1H C3H

6.08 d (J = 3.3 Hz) 1H C3'H 6.34 m 1H C4'H

6.61 t (J = 2.3 Hz) 1H C2H 7.25-7.41 m 6H ArH


13C NMR (Fig. 51b)

35.0 C7 47.8 C6 58.3 C4

105.6 C3 106.1 C3' 110.2 C4'

116.6 C4a 119.6 C2 125.8 C4''

127.3 C7a 128.2 (str.) 2 × ArC 128.3 (str.) 2 × ArC

141.7 C1'' 144.0 C5' 155.1 C2'

NH

NH

O

97

2'

3'

4'5'

2''

4''

6''

2

3

4

7

4a

7a

6

Chapter IV

202

4-(4-Methoxyphenyl)-7-(2-furyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine 98

Stirring time : 48 hrs


Yield : 61 %

IR (KBr) : 3362, 3248 cm-1

for both NH

MS : m/z 295 [M++1], 283, 207, 110, 41.

Elemental analysis: for C18H18N2O2 requires: C, 73.45; H, 6.16; N,

9.52. Found: C, 73.19; H, 6.38; N, 9.22%

1H NMR (Fig. 52a)

1.87 brs (Ex. with D2O) 1H >NH 2.9 dd (J = 8.2, 12.3 Hz) 1H C6H

3.26 dd (J = 5.3,12.3

Hz)

1H C6H 3.71 s 3H OCH3

4.16 brs 1H C7H 4.84 s 1H C4H

5.46 s 1H C3H 6.08 d (J = 2.9 Hz) 1H C3'H

6.38 m 1H C4'H 6.50 s 1H C2H

6.83 d (J = 8.5 Hz) 2H C3''H,C5''H 7.21 d (J = 8.5 Hz) 2H C2''H,

C6''H

7.56 d (J = 0.9 Hz) 1H C5'H 10.38 bs (Ex. with D2O) 1H >NH

13C NMR (Fig. 52b)

34.4 C7 48.0 C6 55.0 -OCH3

56.8 C4 104.8, 105.9 C3, C3' 110.3 C4'

113.2 (str.) C3'', C5'' 116.6 C4a 119.5 C2

124.8 C7a 129.2 (str.) C2'', C6'' 136.6 C1''

141.7 C5' 155.6 C2' 158.2 C4''

NH

NH

O

98

2'

3'

4'5'

2''

4''

6''

2

3

4

7

4a

7a

6

MeO

Chapter IV

203

Expt. No. 4.5 - General procedure for dehydrogenation of disubstituted-tetrahydro-5-

azaindoles

NH

N

Ar

Ar1

NH

NH

Ar

Ar1

89, 90, 91, 94, 96, 97, 98

Pd/C

reflux, xylene

92, 93, 95, 99, 100, 101

A mixture of tetrahydro-5-azaindoles (89-91, 94 and 96-987; 0.10 g), 5% Pd/C (50

mg) and dry xylene (5 ml) was refluxed for 2-15 hrs. The reaction mixture was cooled and

ethyl acetate (10 ml) was added to it. The catalyst was filtered off through celite and the

filtrate was concentrated by vacuum distillation. The crude product obtained was

chromatographed on neutral alumina using pet-ether and ethyl acetate as an eluent yielding

disubstituted-5-azaindoles (92, 93, 95 and 99-101).

4-(4-Chlorophenyl)-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine 92


Yield : 55 %

IR (KBr) : 3257 cm-1

for NH

MS : m/z 294 [M+], 293, 260 (100%), 192, 116, 76

Elemental analysis : for C17H11ClN2O requires: C, 69.28; H, 3.76; N,

9.50. Found: C, 69.51; H, 3.99; N, 9.78%

1H NMR (Fig. 46a)

6.59 t (J = 1.7 Hz) 1H Ar-H 6.82 brs 1H Ar-H

7.02 d (J = 3.0 Hz) 1H Ar-H 7.37-7.43 m 1H C2H

7.5 t (J = 8.0 Hz) 2H C3''H,C5''H 7.68 brs 1H C5'H

7.98 d (J = 8.0 Hz) 2H C2''H,C6''H 8.66 s 1H C6H


13C NMR (Fig. 46b)

101.4 C3 106.3 C4' 109.8 C3'

111.4 C4a 122.3 C2 126.9 C7

NH

N

O

92

2'

3'

4'5'

2''

4''

6''

2

3

4

7

4a

7a

6

Cl

Chapter IV

204


134.9 C1'' 136.0 (str.) C5', C7a 139.6 C6

142.0 C4 149.8 C2'

4-(4-Nitrophenyl)-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine 93


Yield : 46 %

IR (KBr) : 3217 cm-1

for NH and 1518, 1377 cm-1

for NO2

MS : m/z 305 [M+], 304, 275 (100%), 259.


13.76. Found: C, 67.11; H, 3.42; N, 14.03 %

1H NMR (Fig. 47a)

6.77 t (J = 3.3 Hz) 1H ArH 6.98 brs 1H ArH

7.31 d (J = 3.8 Hz) 1H ArH 7.69 d (J = 2.8 Hz) 1H C2H

7.94 brs 1H C5'H 8.32 d (J = 8.8 Hz) 2H C2''H,C6''H

8.4 d (J = 8.8 Hz) 2H C3''H,C5''H 8.78 s 1H C6H


13C NMR (Fig. 47b)

101.4 C3 108.2 C4' 111.1 C3'

112.4 C4a 123.1 C2 123.9 (str.) C3'', C5''

129.4, 129.6 (str.) C7, C2'', C6'' 135.1 C7a

136.5 C1'' 143.8 C5' 146.0 C6

146.8 C4'' 147.1 C4 149.4 C2'

4-Phenyl-7-(4-methoxyphenyl)-1H-pyrrolo[3,2-c]pyridine 95

Mp. : 195-97 oC, white crystalline

Yield : 81 %

IR (KBr) : 3201 cm-1

for >NH

MS : m/z 300 (100%) [M+], 285, 269, 190, 114, 77


9.33. Found: C, 79.72; H, 5.16; N, 9.08%

NH

N

95OMe

1' 2'

3'

4'5'

6'

2''

4''

6''

2

3

4

7

4a

7a

6

NH

N

O

93

2'

3'

4'5'

2''

4''

6''

2

3

4

7

4a

7a

6

O2N

Chapter IV

205

1H NMR (Fig. 49a)

3.22 s 3H -OCH3 6.27 d (J = 4.0 Hz) 1H C3H

6.41 d (J = 10.0 Hz) 2H ArH 6.67-6.95 m 4H ArH

6.98 d (J = 8.0 Hz) 2H C3'H,C5'H 7.42 d (J = 8.0 Hz) 2H C2'HC6'H

7.66 s 1H C6H 10.07 brs (Ex. with D2O) 1H >NH

13C NMR (Fig. 49b)

55.0 -OCH3 102.2 C3 114.3 (str.) C3', C5'

119.9 C4a 122.2 C2 126.4 C4''

127.9, 128.1 C1', C7 128.2 (str.), 128.4 (str.) C2'', C6'', C2', C6'

129.3 (str.) C3'', C5'' 138.4 C7a 138.7 C1''

139.6 C6 150.1 C4 159.1 C4'

4-Phenyl-7-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-c]pyridine 99


Yield : 68 %

IR (KBr) : 3335 cm-1

for NH

MS : m/z 330 [M+, 100%], 315, 297, 194, 109, 77

Elemental analysis : for C21H18N2O2 requires: C, 76.34; H, 5.49;

N, 8.48. Found: C, 76.09; H, 5.71; N, 8.21%

1H NMR (Fig. 53a)

3.91 s 6H 2×OCH3 6.91 d (J = 2.2 Hz) 1H C3H

6.98 d (J = 8.3 Hz) 1H C5'H 7.12 s 1H C2'H

7.18 d (J = 8.3 Hz) 1H C6'H 7.28 brs 1H ArH

7.38-7.46 m 1H ArH 7.53 t (J = 7.4 Hz) 2H C3''H,C5''H

8.02 d (J = 7.7 Hz) 2H C2''H,C6''H 8.37 s 1H C6H


13C NMR (Fig. 53b)

55.8 2×OCH3 103.0 C3 111.3 C2'

111.5 C5' 120.3 C6' 120.5 C4a

122.3 C2 126.3 C4'' 127.8 ArC

NH

N

99OMe

1' 2'

3'4'5'

6'

2''

4''

6''

2

3

4

7

4a

7a

6

OMe

Chapter IV

206


138.5 ArC 138.8 ArC 139.2 C6

148.7 C4 149.2 C4' 150.4 C3'

4-Phenyl-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine 100


Yield : 63 %

IR (KBr) : 3222 cm-1

for NH

MS : m/z 260 (100%) [M+], 231, 204, 76


10.76. Found: C, 78.17; H, 4.89; N, 10.97%

1H NMR (Fig. 54a)


6.72 d (J = 4.0 Hz) 1H ArH 7.15-7.36 m 4H ArH

7.39 d (J = 10.0 Hz) 1H ArH 7.72 d (J = 8.0 Hz) 2H C2''H,C6''H


13C NMR (Fig. 54b)

102.2 C3 106.7 C4' 110.5 C3'

111.9 C4a 123.0 C2 127.5 C4''

128.6 (str.), 128.7 (str.) C2'', C6'', C3'', C5'' 135.7, 136.3 C7, C7a

139.9 C1'' 142.6 (str.) C6, C5' 150.5 C4

150.6 C2'

4-(4-Methoxyphenyl)-7-(2-furyl)-1H-pyrrolo[3,2-c]pyridine 101


Yield : 65 %

IR (KBr) : 3215 cm-1

for NH

MS : m/z 290 [M+, 100%], 275, 191, 115, 109


9.65. Found: C, 74.24; H, 5.11; N, 9.39%

NH

N

100

2'

3'

4'5'

2''

4''

6''

2

3

4

7

4a

7a

6

O

NH

N

101

2'

3'

4'5'

2''

4''

6''

2

3

4

7

4a

7a

6

O

MeO

Chapter IV

207

1H NMR (Fig. 55a)

3.87 s 3H -OCH3 6.56 brs 1H ArH

6.88 brs 2H ArH 7.03 d (J = 8.5 Hz) 2H C3''H,C5''H

7.36 brs 1H C2H 7.59 brs 1H C5'H

7.95 d (J = 8.5 Hz) 2H C2''H,C6''H 8.64 s 1H C6H


13C NMR (Fig. 55b)

55.3 -OCH3 102.8 C3 105.4 C4'

109.7 C3' 111.7 C4a 113.8 (str.) C3'', C5''

122.2 C2 125.8 C1'' 129.9 (str.) C2'', C6''

132.2 C7 135.9, 136.2 C7a, C5' 142.0 C6

150.5 C4 151.3 C2' 159.9 C4''

Chapter IV

208

References

1. Humphrey, G. R.; Kuethe J. T. Chem. Rev. 2006, 106, 2875.

2. Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem.

Soc. Rev. 2007, 36, 1120.

3. (a) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. G. H.; Parkin, S.;

Hope, H. Tetrahedron 1994, 50, 3987, (b) Trimurtulu, G.; Faulkner, D. J.; Perry, N.

B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro, M. G. H.; Jameson, G. B.

Tetrahedron 1994, 50, 3993.

4. Witherup, K. M.; Ransom, R. W.; Graham, A C.; Bernad, A. M.; Salvatore, M. J.;

Lumma, W. C.; Anderson, P. S.; Pitzenberger, S. M.; Varga, S. L. J. Am. Chem. Soc.

1995, 117, 6682.

5. Hu, H.; Kolesnikov, A.; Riggs, J. R.; Wesson, K. E; Stephens, R.; Leahy, E. M.;

Shrader, W. D.; Sprengeler, P. A.; Green, M. J.; Sanford, E.; Nguyen, M.; Gjerstad,

E.; Cabuslay, R.; Young, W. B. Bioorg. Med. Chem. Lett. 2006, 16, 4567.

6. Takeuchi, K.; Bastian, J. A.; Gifford-Moore, D. S.; Harper, R. W.; Miller, S. C.;

Mullaney, J. T.; Sall, D. J.; Smith, G. F.; Minsheng Zhang, M.; Fisher, M. J. Bioorg.

Med. Chem. Lett. 2000, 10, 2347.

7. Gardell, S. J. Perspect. Drug Discov. and Des. 1993, 1, 521.

8. (a) Altomare, C.; Summo, L.; Cellamare, S.; Varlamov, A. V.; Voskressensky, L. G.;

Borisova, T. N.; Carotti, A. Bioorg. Med. Chem. Lett. 2000, 10, 581; (b) Chen, M.;

Guo, Z.; Lanier, M. C.; Zhao, L.; Betz, S. F.; Huang, C. Q.; Loweth, C. J.; Ashweek,

N. J.; Liu, X.-J.; Struthers, R. S.; Bradbury, M. J.; Behan, J. W.; Wen, J.; O’Brien, Z.;

Saunders, J.; Zhu, Y.-F. Bioorg. Med. Chem. Lett. 2007, 17, 3845.

9. Mingoia, F.; Testa, M. L.; Lamartina, L. Tetrahedron 2004, 60, 5873.

10. (a) Helissey,; Parrot-Lopez, H.; Renault, J.; Cros, S. Eur. J. Med. Chem. 1987, 22,

366, (b) Helissey, P.; Giorgi-Renault, S.; Parrot-Lopez, H.; Renault, J.; Cros, S. Chem.

Pharm. Bull. 1989, 37, 2413.

11. (a) Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing, S. M.; Leach, C. A.; Parsons, M. E.;

Price, C. A.; Reavill, D. R.; Wiggall, K. J. J. Med. Chem. 1990, 33, 527; (b)

Escolano, C.; Jones, K. Tetrahedron Lett. 2000, 41, 8951.

12. Skonicki, J. S.; Kearney, R. M. US 5, 216, 162, and references cited therein.

13. Lovely, J. C.; Mahmud, H. Tetrahedron Lett. 1999, 40, 2079.

Chapter IV

209

14. Yokoyama, N.; Arai, T. Chem. Commun. 2009, 3285.

15. Harcken, C.; Ward, Y.; Thomson, D.; Riether, D. Synlett 2005, 20, 3121.

16. Sung, N.-D.; Yang, O.-K.; Kang, S. S.; Yum, E. K. Bull. Korean Chem. Soc. 2004, 25,

1351.

17. Sun, X.; Wang, C.; Li, Z.; Zhang, S.; Xi, Z. J. Am. Chem. Soc. 2004, 126. 7172.

18. Xu, L.; Lewis, I. R.; Davidsen, S. K.; Summers, J. B. Tetrahedron Lett. 1998, 39,

5159.

19. Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355.

20. Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I. F.; Wright, S. H. B.

Synthesis 1996, 877.

21. Sakamoto, T.; Satoh, C.; Kondo, Y.; Yamanaka, H. Heterocycles 1992, 34, 2379.

22. Robinson, R. P.; Donahue, K. M. J. Org. Chem. 1991, 56, 4805.

23. Herz, W.; Tocker, S. J. Am. Chem. Soc. 1955, 77. 6353.

24. (a) Herz, W.; Tocker, S. J. Am. Chem. Soc. 1955, 77. 6353–6355; (b) Okuda, S.;

Robison, M. M. J. Org. Chem.1959, 24, 1008; (c) Yakhontov, L. N.; Lapan, E. I.

Khimiya Geterotsiklicheskikh Soedinenii 1970, 1, 27; (d) Azimov, V. A.;

Krasnokutskaya, D. M.; Palant, I. N.; Yakhontov, L. N. Khimiya Geterotsiklicheskikh

Soedinenii 1979, 3, 375; (e) Sakamoto, T.; Kondo, Y.; Iwashita, S.; Yamanaka, H.

Chem. Pharm. Bull. 1987, 35, 1823.

25. (a) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I. F.; Wright, S. H.

B. Synthesis 1996, 7, 877; (b) Sakamoto, T.; Satoh, C.; Kondo, Y.; Yamanaka, H.

Heterocycles 1992, 34, 2379; (c) Mahadevan, I.; Rasmussen, M. J. Heterocycl. Chem.

1992, 29, 359; (d) Chi, S. M.; Choi, J.-K.; Yum, E. K.; Chi, D. Y. Tetrahedron Lett.

2000, 41, 919 and references cited therein.

26. Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles 1988, 27, 2225 and references

cited therein.

27. Wensbo, D.; Eriksson, A.; Jeschke, T.; Annby, U.; Gronowitz, S.; Cohen, L. A.

Tetrahedron Lett. 1993, 34, 2823.

28. Blache, Y.; Sinibaldi-Troin, M.-E.; Voldoire, A.; Chavignon, O.; Gramain, J.-C.;

Teulade J.-C.; Chapat, J.-P. J. Org. Chem. 1997, 62, 8553.

29. (a) Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem.

Soc. Rev. 2007, 36, 1120 and references cited therein; (b) Whelligan, D. K.; Thomson,

D. W.; Taylor, D.; Hoelder, S. J. Org. Chem. 2010, 75, 11; (c) Ebetino, F. H.; Mazur,

Chapter IV

210

A.; Lundy, M. W.; Russell, R. G. G. PCT Int. Appl. WO 2010033981, 2010, 40; (d)

Huestis, M. P.; Fagnou, K. Org. Lett. 2009, 11, 1357; (e) Popowycz, F.; Merour, J.-Y.;

Joseph, B. Tetrahedron 2007, 63, 8689.

30. (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030, (b) Tatsui, G. J.

Pharm. Soc. Jpn. 1928, 48, 92.

31. (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797; (b) Chrzanowska, M.;

Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341.

32. Rousseau, J.-F.; Dodd, R. H. J. Org. Chem. 1998, 63, 2731.

CHAPTER: IV - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/3208/13/13...Chapter IV 145...

Documents

Transcript of CHAPTER: IV - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/3208/13/13...Chapter IV 145...