177

Chapter 6

Synthesis of highly functionalized triazatricyclo [6.2.2.01, 6

]

dodecane-9, 12 -dione

6.1 INTRODUCTION

In this chapter, we present the development of a simple and efficient method for the

synthesis of multifunctionalized 2-benzylidene-4-benzyl-7-phenyl-4, 10, 11-

triazatricyclo [6.2.2.01, 6

] dodecane-9, 12-dione from a simple starting material N-

Benzyl-4-piperidone (NBP), aryl aldehyde and cyanoacetamide. This four-component

domino reaction provides the following fascinating features: (i) easily accessible

precursor of NBP, aryl aldehydes and cyanoacetamide. (ii) eco-friendly and simple

reaction in which mild base is used as catalyst; (iii) rate of the reaction is fast thereby

enabling the product formation within 30-60 min, thus the consumption of energy and

manpower for future pharmaceutical and industrial production, and (iv) a reaction

with easy workup which requires only neutralisation and extraction with organic

solvent which is then subjected to column chromatography. This domino reaction

gives quick access to synthesise highly functionalized triazatricyclo [6.2.2.01, 6

]

dodecane-9, 12-dione (tricyclo dilactam) in which two quaternary carbon-amino

functionalities among four stereogenic centres are there. This reaction is more

fascinating since it gives access to tricyclo dilactams possessing two quaternary

amino functionalities among four stereogenic centers. Such observation is truly

interesting and very rare in organic chemistry. We are the first to report such skeletal

arrangement of tricyclic dilactam using four components via a Domino reaction.

Figure 6.1 Structure of synthesized tricyclo dilactam and multifunctionalized

Tricyclo dilactam

178

6.2 LITERATURE DISCUSSION

Synthesis of fused cyclic amide ring has been the most challenging objective in

synthetic organic chemistry for the past few decades, because such derivatives are

considerably important scaffolds for synthesis and drug design as they can directly

serve in pharmaceutical research. Paquette and co-worker in 1973 reported the

synthesis of mono- and disubstituted bicyclo [4.2.2] deca-2, 4, 7, 9-tetraenes and

studied their reactivity (Paquette et al., 1973). This group synthesised unsaturated

bicyclo [4.3.1] - decane moiety through tricyclic lactam in which carbon framework

underwent rearrangement. On treating this tricyclic lactam with trimethyloxonium

fluoroborate they produced imino ether of lactam. Furthermore, triplet-sensitized

irradiation on this imino ether of lactam clearly gave a product in which the

cyclobutene ring was formed from isomers of butadiene unit as shown in Scheme 6.1.

ν

Scheme 6.1 Synthesis of bicyclo [4.2.2] deca-2, 4, 7, 9-tetraenes

In 1978, Sammes et. al. discussed the synthesis of dihydroxy pyrimidines by

intramolecular cycloaddition reaction of mono- and dihydroxy pyrimidines via

bicyclic dilactam bridged adduct (Sammes et al., 1978). This group had isolated the

bridged bicyclic dilactam adduct under milder conditions along with pyridine, but on

further heating adduct smoothly decomposed to form pyridone as shown in Scheme

6.2. Bridged adduct is very unstable and even this conversion would be possible over

chromatography silica gel in polar solvent. This group had tested the generality of this

cycloaddition process to a variety of derivatives. Among these derivatives 5-(hex-5-

179

en-1-yl)-2-methylpyrimidin-4(3H)-one was one of the homologues for which they

carried out thermolysis at 198°C and got 3-methyloctahydro-1H-3,8a-

(epiminomethano) isoquinoline-1,9-dione adduct as shown in Scheme 6.3.

Scheme 6.2 Synthesis of pyridone via bridged bicyclic dilactam adduct

Scheme 6.3 Thermolysis of pyrimidin-4(3H)-one to produce bridged bicyclic

dilactam adduct

Mukherjee et. al., in 1983, described the preparation of tricyclo [6.3.1.01, 6

] dodecane

and tricyclo [6.2.2.01, 6

] dodecane ring systems which involves intramolecular

cyclisation of diazomethyl ketones (Mukherjee et al., 1983). Tricyclo [6.2.2.0 l, 6

]

dodecane framework was synthesised from bridged carboxylic systems related to

diterpenes by incorporating methyl groups at C-2 and C-8 and oxygen function at C-9

and dienone synthesised from β-naphthoic ester by reductive methylation followed by

intramolecular cyclisation of diazomethyl ketone as shown in Scheme 6.4.

Scheme 6.4 Thermolysis of pyrimidin-4(3H)-one to produce bridged bicycle

In 1990, Hickmott et. al., reported the synthesis of tricyclo [8.4.0.01, 6

] tetradecane and

Tricyclo [6.2.2.01, 6

] dodecane ring systems for the first time (Hickmott et al., 1990).

180

At δ-position of the dienamine, the reaction happens mostly at the less reactive centre

and in methanol solvent whereas when the reaction was carried out at β-position (C-1)

of the dienamine with methyl propenoate and propenenitrile with dienamine occurs at

the more reactive site in all solvents. However, this group did not propose any

mechanism of the subsequent cyclisation but they suggested that enolate anion would

be formed initially which might be involved in a prototropic shift to give 4a-methyl-7-

(pyrrolidin-1-ium-1-ylidene)-1, 2, 3, 4, 4a, 5, 6, 7- octahydronaphthalen-1-yl) butan-

2-olate followed by cyclisation onto C-8a of the eniminium salt thus producing the

quaternary centre. For the first time, this group developed a method to access novel

[8.4.0.01, 6

] tetradecane ring system as shown in Scheme 6.5.

Scheme 6.5 Access to the novel [8.4.0.01, 6

] tetradecane ring system

Fukumoto et. al., in 1994, presented the synthesis of tricyclo [6.2.2.01, 6

] dodecane and

tricyclo [5.3.1.0 3, 8

] undecane derivatives (Fukumoto et al., 1994). This group carried

out a reaction between 6-[5(E)-6- (methoxycarbonyl) hex-5-enyl] -2-cyclohexen-l-one

and LHMDS followed by the addition of formaldehyde (one-pot) which resulted in

cascade Michael-Michael-aldol reaction, gave hydroxymethylated tricyc1o[6.2.2.01, 6

]

dodecane as shown in Scheme 6.6. They synthesised methylated tricyc1o [5.3.1.03, 8

]

undecane by a Michael-Michael-substitution reaction from 5-[4(E)-5-

(methoxycarbonyl) pent-4-enyl]-2-methyl-2-cyclohexen-l-one and LHMDS followed

by the addition of methyliodide in the presence of HMPA as shown in Scheme 6.7.

Scheme 6.6 Synthesis of tricyclo [6.2.2.01, 6

] dodecane

181

Scheme 6.7 Synthesis of tricyclo [5.3.1.0 3, 8

] undecane

In 1998, Bhat et. al., described the synthesis of novel 7, 9, l l-trimethyl-8, 10, 12-

trioxatetracyclo [5.3.2.0.4,9

.04, 11

]-dodec-1-yl]-2-butanone skeleton by treating H-

ZSM-5 with 2-acetyl-3.4- dihydro-2,5-di (3"-oxo-butyl)-6-methyl-(2H)-pyran (Bhat

et al., 1998). They obtained acid form of zeolite Na-ZSM-5 through successive ion-

exchange with 1M NH4NO3 solution and this was followed by heating for 6h at 673K.

They achieved the synthesis of tetracyclo [5.3.2.0.4,9

.04, 11

]-dodecane by reacting

methyl vinyl ketone with DABCO which gave dimer of methyl vinyl ketone, which

then underwent hetero-Diels-Alder reaction while refluxing it with o-dichlorobenzene

and gave 2-acetyl-3, 4-dihydro-2, 5-di (3'-oxobutyl)- 6-methyl-(2H)-pyran as shown

in Scheme 6.8.

Scheme 6.8 Synthesis of trioxatetracyclo [5.3.2.0.4, 9

.04, 11

]-dodec-1-yl]-2-

butanone

Ihara et. al., in 1999, accounted for the synthesis of tricyclo [5.2.1.01, 5

] decane ring

system by intramolecular double Michael reaction of 5-(5-methoxycarbonyl-4-

pentenyl)-2-cyclopenten-1- one (Ihara et al., 1999) as shown in Scheme 6.9. Also,

they synthesized ((±)-(1R*, 2R*, 5R*, 6R*, 7S*)-2, 6-dimethyl-6-

ethoxycarbonyltricyclo [5.2.1.01, 5

] - decan-9-one as a single isomer by heating 5-(1,

5-dimethyl-5-ethoxycarbonylpent-4-enyl)-2-cyclopenten-1-one with TMSCl, Et3N,

and ZnCl2 in o-dichlorobenzene at 150°C. They did not propose any mechanism for

the formation of 5-(5-methoxycarbonyl-4-pentenyl)-2-cyclopenten-1- one, but they

considered the fact that the cyclisation proceeds in a stepwise manner. In the first step,

corresponding silyl enol ether was generated from Et3N and TMSCl. The first

Michael addition was between above silyl enol ether to the α, β-unsaturated ester due

to the coordination of carbonyl oxygen of the α, β-unsaturated ester with ZnCl2. They

performed the second Michael addition continuously.

182

The same group (Ihara et. al., 2000) reported the synthesis of tricyclo [6.3.0.03, 9

]

undecan-10-one by intramolecular double Michael addition. Initially they carried out

α-Alkylation of 2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-1-one using

I(CH2)5OTBDMS followed by α-methylation, and in turn, they underwent retro Diels-

Alder reaction at a high temperature 250 °C to give enone analogue. This intermediate

was subsequently used to synthesise tricyclo [6.3.0.03, 9

] undecan-10-one as shown in

Scheme 6.10.

Scheme 6.9 Synthesis of tricyclo [5.2.1.01, 5

] decane ring system

Scheme 6.10 Synthesis of tricyclo [6.3.0.03, 9

] undecan-10-one

Guigen Li et. al., in 2010, described a domino reaction involving four components,

providing an access to highly functionalized tricyclo [6.2.2.01, 6

] dodecane derivatives

starting from cyclic ketone, cyanoacetamide and aliphatic aldehydes (Guigen et al.,

2010) as shown in Scheme 6.11. They proposed the reaction mechanism which

underwent tandem formations of two different Knoevenagel intermediates in turn

rearrangement of C-C bond, followed by [4+2] cycloaddition, intramolecular

Michael-type addition and carbonyl addition/elimination reactions. They tried the

same reaction with aromatic aldehyde to synthesis the corresponding tricyclo

[6.2.2.01, 6

] dodecane but this reaction proceeded in different way to form

183

quinazolines. This group was the first to report the access of four stereogenic centers

with one quaternary carbon-amino attachment.

Scheme 6.11 Synthesis of tricyclo [6.2.2.01, 6

] dodecane derivatives

In 2013, Xiang-Shan Wang et. al., reported the synthesis of fused tetracyclic

heterocycles containing [1, 6] naphthyridines under catalyst free conditions starting

from aromatic aldehyde, an amine, and tert-butyl 2, 4-dioxopiperidine-1-carboxylate

in EtOH at refluxing temperature (Wang et al., 2013) as represented in Scheme 6.12.

They used various heterocyclic amines like 1H-indazol-5-amine, 1H-indazol-6-amine,

1H-indol-5-amine and 1H-benzo [d] imidazol-5-amine, which gave the corresponding

naphthyridines; 11-aryl-3H-indazolo[5,4-b][1,6] naphthyridine, 11-aryl-1H-

indazolo[6,7-b] [1,6]naphthyridine, 11-aryl-3H-indolo [5,4-b] [1,6] naphthyridine and

11-aryl-3H-imidazo[4',5':3,4] benzo [1,2-b] [1,6]naphthyridine derivatives

respectively. Initially they optimized the reaction conditions at various temperatures

in different solvents. From the obtained optimal conditions, they carried out reactions

with diverse range of aldehydes and amines.

Scheme 6.12 Synthesis of fused tetracyclic heterocycles of [1, 6] naphthyridines

184

6.3 RESULTS AND DISCUSSION

We report the synthesis of highly functionalized triazatricyclo [6.2.2.01, 6

] dodecane-9,

12 –dione starting from NBP, cyanoacetamide and aryl aldehydes using sodium

hydroxide as catalyst in methanol via domino reaction (Aldol reaction / condensation /

cyclisation by dehydration). This reaction offers several advantages such as use of

simple precursors, low cost, less reaction time, consumption of less energy, good

yield and easy work up. Initially, we carried out this reaction using similar condition

as followed in the previous chapter (chapter 5) to obtain tricyclo dilactam

fluorophore, but unexpectedly we got non-fluorescence compound of highly

functionalized triazatricyclo [6.2.2.01, 6

] dodecane-9, 12 –dione. In order to investigate

further we focused on the mechanism to study the path in which the reaction

proceeded and suggested that the mechanism followed Aldol reaction / condensation /

cyclisation followed by dehydration to give the desired product.

Scheme 6.13 Synthesis of highly functionalized triazatricyclo [6.2.2.01, 6

]

dodecane-9, 12 -dione

6.3.1 OPTIMISATION OF REACTION CONDITION

In our initial study, we investigated the optimal condition to evaluate the efficiency of

the catalyst for this reaction under various conditions. In order to optimize the

reaction conditions, several metal hydroxides were screened in this reaction. When

the reaction was performed in the absence of base catalyst, the reaction did not

proceed but when the reaction was performed using any of the metal hydroxides, the

reaction proceeded to form highly functionalized triazatricyclo [6.2.2.01, 6

] dodecane-

9, 12 -dione. When sodium hydroxide was used as catalyst it was significant to note

that the reaction provided remarkable yield. We carried out the reaction with 0.25

mol% and increased this up to 2 mol% of catalyst to examine further on the catalyst

185

efficiency and the required molar percentage of the catalyst to generate excellent

yield. When 0.5 mol% of NaOH was used as catalyst, a high yield was observed

whereas it did not further improve the yield significantly when the quantities of

catalyst were inceased, and thus we used 0.5 mol% of NaOH as catalyst in this

reaction.

Table 6.1 Screening of catalyst and solvent effect for the synthesis of tricyclic

dilactamsa

Entry Catalyst (mol %) Solvent (ml) Yield (%)b

1 None Methanol -

2 LiOH (1) Methanol 21

3 LiOH (0.5) Methanol -

4 KOH (1) Methanol 39

5 KOH (0.5) Methanol 28

6 NaOH (2) Methanol 71

7 NaOH (1) Methanol 70

8 NaOH (0.5) Methanol 70

9 NaOH (0.25) Methanol 58

10 NaOH (0.5) None 51

11 NaOH (0.5) CH3CN -

12 NaOH (0.5) DCM -

13 NaOH (0.5) Ethanol 53

14 NaOH (0.5) IPA 48

15 NaOH (0.5) Benzene -

16 NaOH (0.5) Hexane -

aReaction conditions: N-benzyl-4-piperidone (10 mmol); benzaldehyde (20 mmol)

and cyanoacetamide (20 mmol) at room temperature (30oC).

bIsolated yield.

186

Table 6.2 Domino reaction for the synthesis of tricyclic dilactamsa

Entry ArCHO Product Yield (%)b

1 2a

19a

70

2 2g

19b

72

3 2u

19c

60

4 2s

19d

68

187

5 2b

19e

66

6 2t

19f

58

7 2c

19g

62

8 2f

19h

71

9 2r

19i

70

188

10 2d

19j

56

11 2e

19k

48

12 2h

19l

59

13 2q

19m

55

14 2j

19n

61

aReaction conditions: N-benzyl-4-piperidone (10 mmol); aryl aldehydes (20

mmol) and cyanoacetamide (20 mmol) in NaOH (0.5 mol%), MeOH at room

temperature (30oC).

bIsolated yield

189

The solvent was the major factor which influenced the formation of the product and

also affected the product yield. Thus, we carried out this reaction with a variety of

solvents such as polar protic, aprotic and nonpolar solvents using 0.5 mol% of NaOH

as the catalyst (Table 6.1, entry 8, 10–16) in order to investigate the best solvent

suitable for this reaction. We obtained good yields with polar protic solvents such as

ethanol, methanol and isopropyl alcohol (IPA) but the product was not obtained in the

absence of solvent, with polar aprotic solvents like acetonitrile, dichloromethane

(DCM) and nonpolar solvents like hexane, benzene. Thus, the optimal solvent for

these reaction transformations was methanol. The appropriate optimal condition for

these reaction transformations was 0.5 mol% of sodium hydroxide as catalyst and

methanol as solvent. We also investigated the scope and the limitation of these

reactions. To evaluate the generality of this reaction in other system, this reaction was

carried out using a diverse range of aromatic aldehydes under the same conditions.

The results obtained are summarized in Table 6.2. We also tried with aliphatic

aldehydes instead of aryl aldehydes, but failed to get expected product. We even tried

to synthesise the various tricyclic dilactam using various cyclic ketone. In each case

the product obtained fascinated us, and further studies are being conducted in our

laboratories.

6.3.2 MECHANSITIC INSIGHT

Initially, we expected that the synthesised tricyclic dilactam would be a fluorophore

motif, but it did not show any fluorescence properties. So, we focused on the

mechanism of the path in which the reaction proceeded to form tricyclic dilactam

(19a).

Scheme 6.14 Several reactions for the formation of 19a via int6a and int6b.

190

Scheme 6.15 Synthesis of tricyclic dilactam (19a) via int6a and int6b.

There are two mechanisms possible for the formation of tricyclic dilactam (19). One

possible mechanism is the formation of aldol product in the first step; the second step

is the formation of malonamide from the condensation of cyanoacetamide and the

third step is the cyclisation of these two intermediates to give the desired product.

Another possible mechanism is the formation of two different intermediates of

Knoevenagel condensation, which in turn rearranges C-C bond followed by [4+2]

cycloaddition. Subsequently, this undergoes intramolecular Michael-type addition

followed by the attack of aryl aldehyde via aldol condensation to give the desired

product. Thus, to investigate the exact mechanism, we carried out several reactions

under the same conditions. Initially we carried out a few reactions to synthesise aldol

product of NBP with benzaldehyde (int6a), condensation of cyanoacetamide (int6b),

two different Knoevenagel product of NBP with cyanoacetamide (int6c) and

benzaldehyde with cyanoacetamide (int6d) under the same condition.

Scheme 6.16. Several reactions for the formation of 19a via int6c, int6d and

int6e.

191

Scheme 6.17. Synthesis of tricyclic dilactam (19a) via int6c, int6d and int6e.

Finally, we carried out two reactions under the same condition. One was the reaction

between int6a and int6b; the other was between int6c and int6d. In the first reaction

we successfully got the expected product (19a), whereas, in the second reaction we

did not get the expected intermediate (int6e) which could be further reacted with

benzaldehyde to give the product (19a). This reaction schemes and their mechanisms

are represented in Scheme 6.14-6.15 and Scheme 6.16-6.17 respectively. Hence, from

these two reactions, we concluded that the mechanism for this reaction proceeded

only via aldol reaction/ condensation of cyanoacetamide followed by cyclisation and

in turn by dehydration. But, the mechanism for the formation of tetracyclic dilactam

discussed in the previous chapter proceeded in other way. This could be the major

reason for not getting fluorophore for the synthesised tricyclic dilactam (19).

192

Scheme 6.18. A most feasible mechanism for the formation of product (19a).

Most functionalities of the resulting tricyclo diamide products (19a) offer great

flexibility for further structural modifications and the synthesised products are indeed

lactam analogues that are directly useful for drug design in pharmaceutical sciences.

193

6.4 SPECTRAL DISCUSSION

Characterization of compound 19a was discussed as a representative compound of

this class of compounds 19a – 19n.

Figure 6.2: Structure of 2-benzylidene-4-benzyl-7-phenyl-4, 10, 11-triazatricyclo

[6.2.2.01, 6

] dodecane-9, 12-dione (19a)

2-benzylidene-4-benzyl-7-phenyl-4, 10, 11-triazatricyclo [6.2.2.01, 6

] dodecane-9, 12-

dione (19a): White solid obtained by slow evaporation from ethanol and THF (1:1)

mixture. The yield and the melting point were 70 and > 300 ⁰C respectively. FT-IR

spectra of compound 19a, showed the absorption band at 3541 cm-1

representing one

of the amide N-H stretching. A band at 3309 cm-1

indicated another amide N-H

stretching. A band at 3045 cm-1

represented the aromatic C-H stretching. The

absorption band at 2870 cm-1

represented the aliphatic C-H stretching. A band at 1687

cm-1

confirmed the presences of C=O stretching (Spectra 6.1). 1H,

13C-NMR spectra,

DEPT-90 and DEPT-135 were recorded in 400 MHz Bruker using DMSO as solvent.

1H-NMR spectra of compound 19a showed peak at 1.19-1.23 ppm corresponding to

H1 and H2 proton. Peaks at 1.92-1.99 ppm showed singlet corresponding to H5 and H6

proton. Peaks at 2.14 and 2.76 ppm showed singlet corresponding to H3 and H4 proton

respectively. Peaks at 3.94 and 4.04 ppm showed singlet corresponding to H7 and

NBP’s CH2 proton respectively. The vinylic protons exhibited a singlet peak at 6.05

ppm. The other aromatic CH proton appeared at 6.98-7.49 ppm. Peak at 9.43 ppm

showed singlet corresponding to amide NH proton (Spectra 6.2). 13

C-NMR spectrum

of compound 19a showed peak at 26.36, 28.90, 49.68, 58.39 and 70.91 ppm

corresponding to aliphatic carbons. Peak at 126.48-137.32 ppm corresponded to

aromatic carbons. Peaks at 169.60 and 169.73 ppm indicated two amide carbonyl

194

carbons. (Spectra 6.3). To confirm the structural arrangements of the compound 2D-

NMR of DEPT-90, DEPT-135, mass and HRMS were recorded. DEPT-135 spectra of

compound 19a showed negative peaks at 26.39 and 28.92 corresponding to NBP’s

aliphatic CH2 carbons and positive peaks at 41.44, 49.69 and 58.40 ppm

corresponding to aliphatic CH carbons. Aromatic carbons showed positive peaks at

126.50-129.68 ppm (Spectra 6.4). DEPT-90 spectra of compound 19a had positive

peaks at 41.44, 49.69 and 58.40 ppm corresponding to aliphatic CH carbons, and

aromatic carbons showed positive peak at 126.50-129.68 ppm (Spectra 6.5). Thus,

this clearly shows that the arrangements of the structure would be tricyclic dilactam.

Mass (Spectra 6.7) and HRMS (Spectra 6.8) pattern of the compound 19a including

its fragmentation pattern it confirms the structure of the synthesised compound. The

structures of all the synthesised compounds (19a – 19n) were confirmed using FT-IR,

1H,

13C-NMR, Mass and HRMS analysis (Table 6.6) and the purity of the synthesised

compound was checked using HPLC.

19

5

Sp

ectra 6

.1: F

T-IR

of 2

-ben

zylid

ene-4

-ben

zyl-7

-ph

enyl-4

, 10, 1

1-tria

zatricy

clo [6

.2.2

.01

, 6] dod

ecan

e-9, 1

2-d

ion

e (19a)

19

6

Sp

ectra 6

.2: 1H

– N

MR

of 2

-ben

zylid

ene-4

-ben

zyl-7

-ph

enyl-4

, 10, 1

1-tria

zatricy

clo [6

.2.2

.01

, 6] dod

ecan

e-9, 1

2-d

ion

e (19

a)

19

7

Sp

ectra 6

.3: 1

3C –

NM

R o

f 2-b

enzy

liden

e-4-b

enzy

l-7-p

hen

yl-4

, 10, 1

1-tria

zatricy

clo [6

.2.2

.01

, 6] dod

ecan

e-9, 1

2-d

ion

e (19a)

19

8

Sp

ectra 6

.4: D

EP

T-1

35 sp

ectra o

f 2-b

enzy

liden

e-4-b

enzy

l-7-p

hen

yl-4

, 10, 1

1-tria

zatricy

clo [6

.2.2

.01

, 6] dod

ecan

e-9, 1

2-d

ion

e (19a)

19

9

Sp

ectra 6

.5: D

EP

T-9

0 sp

ectra o

f 2-b

enzy

liden

e-4-b

enzy

l-7-p

hen

yl-4

, 10, 1

1-tria

zatricy

clo [6

.2.2

.01

, 6] dod

ecan

e-9, 1

2-d

ion

e (19a)

200

Spectra 6.6: HPLC data for compound (19a) in acetonitrile

20

1

Sp

ectra 6

.7: M

ass sp

ectra

of 2

-ben

zylid

ene-4

-ben

zyl-7

-ph

enyl-4

, 10, 1

1-tria

zatricy

clo [6

.2.2

.01

, 6] dod

ecan

e-9, 1

2-d

ion

e (19a)

20

2

Sp

ectra 6

.8: H

RM

S sp

ectra

of 2

-ben

zylid

ene-4

-ben

zyl-7

-ph

enyl-4

, 10, 1

1-tria

zatricy

clo [6

.2.2

.01

, 6] dod

ecan

e-9, 1

2-d

ion

e (19a)

20

3

Tab

le 6.3

Sp

ectral D

ata

of co

mp

ou

nd

19a –

19n

Pro

du

ct

cod

e

FT

-IR

(cm-1)

Rf - T

LC

(EA

:

hex

ane)

1H-N

MR

(δ) in

pp

m

13C

-NM

R (δ

) in p

pm

HR

MS

M

P

(⁰C)

Ca

lcula

ted

Fo

un

d

19

a

35

41

,

33

09

,

30

45

,

28

70

,

16

87

0.6

7 (6

0%

)

1.1

9-1

.23

(dd

, CH

2 , 2H

), 1.9

2 (s, C

H, 1

H), 1

.99 (s,

CH

, 1H

), 2.4

1 (s, C

H2 , 1

H), 2

.76

(s, CH

2 , 1H

),

3.9

4

(s, C

H,

1H

), 4

.04

(s,

CH

2 , 2

H),

6.0

5

(s,

vin

ylic

-H,

1H

), 6

.98

-7.4

9

(ArH

, 1

5H

), 9

.43

(s,

am

ide N

H, 2

H)

26

.36

, 2

8.9

0,

49

.68

, 5

8.3

9,

70

.91

, 12

6.4

8,

12

7.6

8,

12

8.0

4,

12

8.9

5, 1

29

.08

, 12

9.6

6, 1

31

.50

,

13

3.3

5, 1

37

.32

169

.60

, 169.7

3

C2

9 H2

7 N3 O

2

([M]

+)

44

9.2

10

3

44

9.2

10

2

>3

00

19

b

35

82

,

32

97

,

30

89

,

28

30

,

16

98

0.4

7 (6

0%

)

2.1

3-2

.17

(dd

, CH

2 , 1H

), 2.3

8-2

.42

(dd

, CH

2 , 1H

),

2.7

0-2

.74

(d

, C

H,

1H

), 2

.97-2

.99

(m

, C

H,

1H

),

3.1

6-3

.20

(dd, C

H, 1

H), 3

.59 (s, C

H2 , 2

H), 3

.66

-

3.7

1 (m

, CH

2 , 2H

), 6.8

9 (s, v

inylic

-H, 1

H), 7

.03

-

9.1

2 (A

rH, 1

3H

), 7.8

0 (s, am

ide N

H, 2

H)

37

.40,

37

.45,

39.7

9,

50

.60

, 5

0.6

7,

54

.68, 5

7.7

3, 6

4.6

0, 1

14

.90

, 11

5.0

9,

11

5.8

0,

12

4.5

4,

126

.01

, 12

6.4

4,

12

7.5

5,

12

8.9

9,

129

.86

, 13

0.2

8,

13

8.8

4,

14

1.5

7,

158

.94

, 16

0.8

2,

16

1.4

7, 1

63

.35

, 17

9.2

1

C2

9 H2

5 F2 N

3 O2

([M]

+)

48

5.1

91

5

48

5.1

91

4

>3

00

19

c

35

01

,

32

87

,

29

92

,

28

04

,

16

81

0.4

9 (6

0%

)

2.1

5-2

.19

(dd

, CH

2 , 1H

), 2.3

5-2

.39

(dd

, CH

2 , 1H

),

2.6

8-2

.72

(d

, C

H,

1H

), 3

.01-3

.03

(m

, C

H,

1H

),

3.1

3-3

.17

(dd, C

H, 1

H), 3

.61 (s, C

H2 , 2

H), 3

.64

-

3.6

9 (m

, CH

2 , 2H

), 6.6

2 (s, v

inylic

-H, 1

H), 6

.93

-

7.4

1 (A

rH, 1

3H

), 7.9

1 (s, am

ide N

H, 2

H)

39

.81,

42

.09,

50.6

8,

54

.72

, 5

7.7

8,

64

.52,

11

3.0

3,

113

.93,

11

4.3

3,

11

7.2

2,

12

5.0

3,

127

.55

, 12

8.8

1,

13

4.3

5,

14

0.0

3,

143

.29

, 16

0.3

9,

16

1.9

2, 1

62

.91

, 16

4.4

3, 1

74.5

1

C2

9 H2

5 F2 N

3 O2

([M]

+)

48

5.1

91

5

48

5.1

91

5

>3

00

20

4

19

d

34

92

,

33

13

,

30

33

,

28

63

,

16

48

0.5

7 (6

0%

)

1.9

2-1

.94

(dd

, CH

2 , 1H

), 2.0

6-2

.10

(dd

, CH

2 , 1H

),

2.3

9-2

.43

(dd

, CH

, 1H

), 2.8

0-2

.82

(m, C

H, 1

H),

3.2

1-3

.25

(dd, C

H, 1

H), 3

.69 (s, C

H2 , 2

H), 3

.75

-

3.8

0 (m

, CH

2 , 2H

), 6.7

3 (s, v

inylic

-H, 1

H), 7

.11

-

7.7

4 (A

rH, 1

3H

), 8.0

1 (s, am

ide N

H, 2

H)

38

.73,

40

.91,

49.1

8,

52

.85

, 5

6.9

3,

65

.48,

11

4.7

4,

115

.12,

12

6.9

6,

12

7.8

7,

12

8.3

1,

129

.97

, 13

1.3

2,

13

3.2

9,

13

7.6

6,

140

.31

, 16

0.7

3,

16

1.8

2, 1

62

.81

, 16

4.7

3, 1

75.7

8

C2

9 H2

5 F2 N

3 O2

([M]

+)

48

5.1

91

5

48

5.1

91

3

>3

00

19

e

35

48

,

33

01

,

30

96

,

28

78

,

16

99

0.5

2 (6

0%

)

2.0

1-2

.05

(dd

, CH

2 , 1H

), 2.2

6-2

.30

(dd

, CH

2 , 1H

),

2.4

6 (s, C

H3 , 3

H) 2

.63

-2.6

7 (m

, C

H, 1

H), 2

.84

-

2.8

6 (d

, CH

, 1H

), 3.0

8-3

.12

(dd

, CH

, 1H

), 3.4

3 (s,

CH

2 , 2

H),

3.8

2-3

.87

(m

, C

H2 ,

2H

), 6

.98

(s,

vin

ylic

-H,

1H

), 6

.95

-7.2

7

(ArH

, 1

3H

), 8

.21

(s,

am

ide N

H, 2

H)

19

.32,

19

.60,

38.0

1,

39

.67

, 5

0.5

4,

54

.74, 5

7.8

1, 6

4.8

2, 1

24

.35

, 12

6.3

2,

12

6.3

5,

12

7.1

6,

128

.89

, 12

9.8

9,

13

0.2

9,

13

3.6

4,

134

.43

, 13

5.4

4,

13

6.4

4, 1

40

.07

, 14

1.7

2, 1

78.6

5

C3

1 H3

1 N3 O

2

([M]

+)

47

7.2

41

6

47

7.2

41

6

>3

00

19

f

35

91

,

32

84

,

30

02

,

28

12

,

16

74

0.8

3 (6

0%

)

2.1

0-2

.14

(dd

, CH

2 , 1H

), 2.2

9-2

.33

(dd

, CH

2 , 1H

),

2.4

4 (s, C

H3 , 3

H) 2

.65

-2.6

9 (m

, C

H, 1

H), 2

.89

-

2.9

2 (d

, CH

, 1H

), 3.1

2-3

.16

(dd

, CH

, 1H

), 3.4

9 (s,

CH

2 , 2

H),

3.8

5-3

.89

(m

, C

H2 ,

2H

), 6

.82

(s,

vin

ylic

-H,

1H

), 6

.97

-7.5

4

(ArH

, 1

3H

), 8

.07

(s,

am

ide N

H, 2

H)

20

.78,

39

.81,

42.0

8,

50

.67

, 5

4.8

8,

57

.92,

66

.84

, 1

25

.81,

12

6.6

1,

12

6.7

4,

12

7.7

2,

128

.31

, 12

9.7

0,

13

4.2

8,

139

.83

, 1

41

.74,

14

3.3

8,

17

9.0

4

C3

1 H3

1 N3 O

2

([M]

+)

47

7.2

41

6

47

7.2

41

5

>3

00

19

g

35

56

,

30

67

,

28

89

,

16

97

0.7

8 (6

0%

)

1.9

5 -2

.00

(dd

, CH

2 , 1H

), 2.1

8-2

.22

(dd

, CH

2 , 1H

),

2.3

5 (s, C

H3 , 3

H) 2

.57

-2.6

0 (d

, CH

, 1H

), 2.7

9-2

.82

(m,

CH

, 1

H),

3.0

0-3

.04

(d

d,

CH

, 1

H),

3.2

9 (s,

CH

2 , 2

H),

3.7

8-3

.82

(m

, C

H2 ,

2H

), 6

.54

(s,

vin

ylic

-H,

1H

), 7

.00

-7

.29

(A

rH,

13

H),

8.0

1 (s,

21

.28,

34

.83,

40.3

8,

49

.78

, 5

2.9

4,

58

.93,

68

.14

, 1

26

.78,

12

7.8

3,

12

8.7

4,

12

8.9

3,

129

.13

, 13

3.6

8,

13

9.2

9, 1

40

.38

, 17

9.8

7

C3

1 H3

1 N3 O

2

([M]

+)

47

7.2

41

6

47

7.2

41

3

>3

00

20

5

am

ide N

H, 2

H)

19

h

35

62

,

33

72

,

30

64

,

28

41

,

16

72

0.3

8 (6

0%

)

1.8

2-1

.86

(dd

, CH

2 , 1H

), 2.0

1-2

.05

(dd

, CH

2 , 1H

),

2.4

5-2

.47

(d

, C

H,

1H

), 2

.83

-2.8

7 (d

d,

CH

, 1

H),

3.0

4-3

.06

(m, C

H, 1

H), 3

.64

(s, CH

2 , 2H

), 3.7

2-

3.7

6 (m

, CH

2 , 2H

), 6.9

3 (s, v

inylic

-H, 1

H), 7

.07

-

7.3

1 (A

rH, 1

3H

), 8.5

6 (s, am

ide N

H, 2

H)

32

.45,

38

.94,

49.5

1,

55

.82

, 5

8.1

9,

68

.02,

12

5.4

7,

125

.75,

12

6.0

4,

12

6.4

2,

1

27

.71,

12

8.5

3,

12

9.3

1,

13

0.2

6,

13

1.9

2,

134

.04

, 13

9.1

4,

14

0.5

4, 1

40

.46

, 17

2.6

5

C2

9 H2

5 Cl2 N

3 O2

([M]

+)

51

7.1

32

4

51

7.1

32

4

>3

00

19

i

35

93

,

32

84

,

30

94

,

29

15

,

16

79

0.4

2 (6

0%

)

1.9

7-2

.01

(dd

, CH

2 , 1H

), 2.1

7-2

.21

(dd

, CH

2 , 1H

),

2.4

8-2

.50

(d

, C

H,

1H

), 2

.92

-2.9

6 (d

d,

CH

, 1

H),

3.2

0-3

.23

(m, C

H, 1

H), 3

.59

(s, CH

2 , 2H

), 3.7

8-

3.8

3 (C

H2 , 2

H), 6

.53

(s, vin

ylic

-H, 1

H), 7

.12

-7.4

1

(ArH

, 13

H), 8

.48

(s, amid

e NH

, 2H

)

31

.14,

37

.38,

50.4

5,

53

.48

, 5

8.4

4,

66

.95,

12

5.0

3,

125

.67,

12

6.1

2,

12

6.7

9,

1

27

.83,

12

8.3

2,

12

9.8

5,

13

0.8

6,

13

1.8

4,

134

.25

, 13

9.3

7,

14

0.7

8, 1

40

.93

, 17

8.8

3

C2

9 H2

5 Cl2 N

3 O2

([M]

+)

51

7.1

32

4

51

7.1

32

5

>3

00

19

j

34

71

,

32

93

,

29

87

,

27

60

,

16

88

0.4

0 (6

0%

)

2.0

8-2

.12

(dd

, CH

2 , 1H

), 2.1

9-2

.23

(dd

, CH

2 , 1H

),

2.3

9-2

.42

(d

, C

H,

1H

), 2

.89

-2.9

2 (d

d,

CH

, 1

H),

3.3

9-3

.42

(CH

, 1H

), 3.5

3 (s, C

H2 , 2

H), 3

.71

-3.7

4

(m,

CH

2 , 2

H),

3.8

9

(s, O

CH

3 , 3

H),

6.4

7

(s,

vin

ylic

-H,

1H

), 7

.10

-7

.39

(A

rH,

13

H),

8.3

4 (s,

am

ide N

H, 2

H)

29

.23,

35

.19,

48.8

2,

51

.52

, 5

2.8

4,

56

.13,

62

.84

, 1

24

.93,

12

5.7

3,

12

6.0

3,

126

.85

,

12

7.6

1,

12

8.5

9,

12

9.4

3,

13

0.6

9,

131

.74

, 13

4.9

2,

13

9.6

4, 1

40

.92

, 14

0.9

9, 1

79

.31

C3

1 H3

1 N3 O

4

([M]

+)

50

9.2

31

5

50

9.2

31

4

>3

00

19

k

35

45

,

30

05

,

28

64

,

0.4

9 (6

0%

)

2.1

2-2

.16

(dd

, CH

2 , 1H

), 2.2

1-2

.25

(dd

, CH

2 , 1H

),

2.4

8-2

.52

(d

d,

CH

, 1

H),

2.9

2-2

.95

(d

, C

H,

1H

),

3.4

3-3

.46

(CH

, 1H

), 3.6

8 (s, C

H2 , 2

H), 3

.82

-3.8

6

(m,

CH

2 , 2

H),

3.9

9

(s, O

CH

3 , 3

H),

6.6

1

(s,

30

.48,

32

.58,

50.3

4,

52

.38

, 5

4.8

2,

57

.48,

63

.52

, 1

25

.01,

12

5.8

4,

12

6.6

6,

126

.92

,

12

7.9

6,

12

8.2

9,

12

9.4

4,

13

0.9

4,

131

.84

, 13

4.4

2,

C3

1 H3

1 N3 O

4

([M]

+)

50

9.2

31

5

50

9.2

31

6

>3

00

20

6

16

91

vin

ylic

-H,

1H

), 7

.14

-7

.48

(A

rH,

13

H),

8.0

6 (s,

CO

NH

, 2H

)

13

8.9

9, 1

39

.94

, 14

0.4

6, 1

78

.43

19

l

35

33

,

33

03

,

30

29

,

28

60

,

16

63

0.5

9 (6

0%

)

1.3

3-1

.35

(t,

CH

3 , 3

H),

1.4

2-1

.44

(t,

CH

3 , 3

H),

2.1

2-2

.17

(dd

, CH

2 , 1H

), 2.2

9-2

.32

(s, CH

, 1H

),

2.3

8-2

.43

(dd

, CH

2 , 1H

), 2.5

5-2

.58

(s, CH

, 1H

),

2.7

0-2

.81

(m, C

H2 , 2

H), 3

.27

-3.2

9 (d

, CH

, 1H

),

3.5

4 (s, C

H, 1

H), 3

.59

(s, CH

2 , 2H

), 3.6

8-3

.70

(d,

CH

, 1H

), 4.0

6-4

.10

(q, O

CH

2 , 2H

), 4.1

5-4

.19

(q,

OC

H2 ,

2H

), 6

.89

(s,

vin

ylic

-H,

1H

), 6

.70

-7

.67

(ArH

, 13

H), 7

.82

(s, CO

NH

, 2H

)

14

.54,

32

.83,

35.5

4,

51

.75

, 5

4.8

1,

55

.63, 5

8.3

4, 6

3.2

4, 6

4.8

6, 1

15

.56,

11

6.6

2,

12

2.5

4,

123

.98

, 12

7.6

7,

12

8.6

4,

13

1.7

2,

133

.01

, 14

0.6

3,

15

7.8

4, 1

59

.64

, 16

2.8

4, 1

83.9

5

C3

3 H3

5 N3 O

4

([M]

+)

53

7.2

62

8

53

7.2

62

9

>3

00

19

m

35

91

,

33

24

,

30

61

,

28

82

,

16

95

0.6

1 (6

0%

)

1.3

5-1

.39

(m, C

H3 , 6

H), 2

.13

-2.1

7 (d

d, C

H2 , 1

H),

2.3

8-2

.39

(dd

, CH

2 , 1H

), 2.4

1-2

.42

(d, C

H2 , 1

H),

2.7

0-2

.74

(m, C

H, 1

H), 2

.97-3

.03

(dd

, CH

, 1H

),

3.1

6-3

.20

(dd, C

H, 1

H), 3

.59 (s, C

H2 , 2

H), 3

.65

-

3.7

0 ( C

H2 , 2

H), 4

.03

-4.0

7 (q

, OC

H2 , 4

H), 6

.73

(s,

vin

ylic

-H,

1H

), 6

.85

-7

.65

(A

rH,

13

H),

7.9

0 (s,

CO

NH

, 2H

)

14

.78,

36

.19,

41.8

4,

50

.91

, 5

4.4

9,

55

.95, 6

3.3

2, 6

4.5

7, 1

14

.95

, 11

5.0

1,

12

6.4

9,

12

7.2

3,

127

.85

, 12

8.5

1,

13

1.8

1,

13

3.9

5,

140

.01

, 15

8.7

8,

15

9.0

4, 1

84

.92

C3

3 H3

5 N3 O

4

([M]

+)

53

7.2

62

8

53

7.2

63

0

>3

00

19

n

35

45

,

33

13

,

30

56

,

28

10

,

16

53

0.6

4 (6

0%

)

2.3

1-2

.35

(dd

, CH

2 , 1H

), 2.4

7-2

.51

(dd

, CH

2 , 1H

),

2.6

3-2

.65

(d

, C

H2 ,

1H

), 2.7

8-2

.83

(m

, C

H,

1H

),

3.0

3-3

.07

(dd, C

H, 1

H), 3

.25

-3.2

9 (d

d, C

H, 1

H),

3.7

7 (s, C

H2 , 2

H), 3

.82

-3.8

4 ( C

H2 , 2

H), 6

.62

(s,

vin

ylic

-H,

1H

), 7

.25

-8

.09

(A

rH,

19

H),

8.0

1 (s,

CO

NH

, 2H

)

34

.82,

39

.95,

48.4

9,

52

.81

, 5

6.8

4,

65

.74,

12

5.9

2,

126

.21,

12

6.8

4,

12

7.2

9,

12

8.0

4,

128

.51

, 12

9.1

5,

13

0.9

5,

13

2.9

5,

133

.67

, 13

3.9

5,

13

7.1

2, 1

40

.03

, 14

1.2

9, 1

83.5

3

C3

7 H3

1 N3 O

2

([M]

+)

54

9.2

41

6

54

9.2

41

8

>3

00

207

6.5 CONCLUSION

Herein, for the first time, we report the synthesis of new series of

multifunctionalized triazatricyclo [6, 2, 2, 0 1, 6

] dodecane derivatives via a

domino reaction using sodium hydroxide as catalyst.

A wide range of easily available chemicals namely N-benzyl-4-piperidone,

aryl aldehyde and cyanoacetamide were employed as substrates, and the

reaction provided several advantages such as use of readily available

precursor, consumption of less energy, short reaction time, moderate to good

yield and convenient work up.

The mechanisms for these reactions were proposed, and mechanistic studies

were performed experimentally to investigate the exact mechanism involved

in this reaction. The mechanistic studies specified that the proposed

mechanism proceeded only via aldol condensation (between NBP and aryl

aldehyde), Knoevenagel condensation (between cyanoacetamide), which was

followed by the cyclisation and dehydration to form the desired product.

The synthesised tricyclo dilactam derivatives afford enormous flexibility for

additional structural alterations and the synthesized tricyclo dilactam

derivatives are indeed lactam analogues which are directly useful in medicinal

and pharmaceutical chemistry.

Four stereogenic centres with two quaternary carbon-amino functions were

obtained. Such observations are very rare in organic chemistry.

208

6.6 EXPERIMENTAL DISCUSSION

Chemicals were purchased from Aldrich and they were used without further

purification. TLC -Thin layer chromatography (Merck, Silica gel 60 F254) - was

performed on pre-coated silica gel on alumina plates for monitoring the reaction. FT-

IR spectra were recorded in the range of 4000-400cm-1

on JASCO-4100 spectrometer

instrument using KBr pellets. 1H,

13C NMR spectra, DEPT-90 and DEPT-135 were

recorded using a BRUKER AMX 400 FT. HPLC was performed on a water’s liquid

chromatography equipped with a dual wavelength UV detector (Deuterium lamp,

192–600 nm), using a symmetry C18 column (10 cm X 4.6mm) 5µ HPLC grade.

Mass Spectroscopy – ESI, Triple quad (Waters Quattro premier XE) was used to

analyse the ESI mass. HRMS analysis was obtained from JEOL GC Mate.

6.6.1 GENERAL PROCEDURE FOR THE SYNTHESIS OF 1-((4-METHOXY

PHENYLTHIO) (PHENYL) METHYL) PYRROLIDIN-2-ONES (19a – 19n)

A dry 100ml Erlenmeyer flask was charged with N-benzyl-4-piperidone (10 mmol);

aromatic aldehydes (20 mmol); cyanoacetamide (20 mmol); sodium hydroxide (0.5

mol %) and methanol (15 ml). The reaction mixture was stirred at room temperature

for 30-60 min. The reaction was monitored by TLC and after the completion of

reaction, the mixture was neutralised using 0.1 N HCl and extracted with DCM (3 X

20 ml). The crude reaction mixture was purified by column chromatography on silica

gel using ethyl acetate/hexane as the eluents.