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CHAPTER-5

SYNTHESIS, CHARACTERIZATION OF SOME NEW

HOMOALLYLAMINES AND β-AMINO KETONES

153

5.1. Introduction

Multicomponents reactions (MCRs) are those reactions in which three or more reactants come

together in a single reaction vessel to form a new product which contains portions of all the components.

First 'officially' reported MCR was the Strecker synthesis (Sheme-5.1) of α-amino nitrile in 1850 [1].

During this one and a half century period, some notable achievements include the discovery of the

Biginelli [2], the Mannich [3], and the Passerini [4] reactions culminating in 1959 when Ugi published

probably the most versatile MCR based on the reactivity of isocyanides [5]. Multicomponent reactions

(MCRs) have recently emerged as valuable tools in the preparation of structurally diverse chemical

libraries of drug-like heterocyclic compounds. In view of the increasing interest for the preparation of

large heterocyclic compound libraries, the development of new and synthetically valuable

multicomponent reactions remains a challenge for both academic and industrial research teams.

R H

ONH3 HCN

R

NH2

CN

R = Aromatic, aliphatic, hetetocyclic substituents

264 265

Scheme-5.1: Strecker synthesis

The condensation of activated carbonyl compounds with in-situ formed iminium species, called

the Mannich reaction, provides β-amino carbonyl compounds. Using these multicomponent reactions

we have prepared two series of compounds i.e, homoallylamines and β-amino ketones in microwave and

studied their animicrobial activity.

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5.1.1 Biological importance of homoallylamines and β-amino ketones

Allylamines, (266) are fundamental building blocks in organic chemistry and their synthesis is

an important industrial and synthetic goal. The allylamine fragment can be encountered in natural

products, but often the allylamine is transformed to a range of products by fictionalization, reduction, or

oxidation of the double bond.

R

NR1 R2

R3

266

R, R1, R2, R3 = Aromatic, Aliphatic, Hetetocyclic

Fig. 5.1: Functionalised homoallylamines

Homoallylic amines are valuable intermediates in organic synthesis [6] as starting materials in

the preparation of biologically active substances [7] as resolving agents [8], and as chiral auxiliaries for

asymmetric synthesis [9]. They are used for the synthesis of β-amino acids [10], as well as β-lactams

[11] and HIV-protease inhibitors [12]. The homoallylic amine moiety is not widely present in natural

products, however, compounds like Eponemycin [13], which exhibits potent activity against B16

melanoma cells, or a depsipeptide cryptophycin 337 [14], which is an analog of a potent anti-tumor

compound Cryptophycin, contain this subunit.

On the other hand, homoallylic amines are excellent building blocks for the synthesis of

numerous nitrogen-containing natural products [15]. Chiral homoallylic amines were utilized as the key

intermediates in the preparation of many natural products, such as an amino-sugar vancosamine isolated

from Vancomycin [16], a spirocycle alkaloid alichlorine isolated from a Japanese sponge Halichondria

okadai Kadota [17], an alkaloid from Prosopis africana, desoxoprosopinine [18], and many others [19].

With the utilization of ring-closing metathesis methodology, numerous piperidine alkaloids can be

easily prepared from the corresponding aminodienes [20]. Preparation of β-amino acids is of particular

155

interest to medicinal and bioorganic chemists as various β-amino acid moieties can be found in taxoids,

β-lactam antibiotics and other compounds.

A plethora of synthetic methods have been devised for the preparation of homoallylic amines.

All methods for their synthesis can be divided into four groups: a) nucleophilic addition to imines and

iminium ions. b) [3,3]-Sigmatropic rearrangement of N-protected amino acid allylic esters. c) [2,3]-

Sigmatropic rearrangements of N-allyl α-amino esters or allylic ammonium salts. d) Miscellaneous

synthesis.

Acid catalyzed alkylation of N-acyl-a-alkoxyamines with a variety of nucleophiles has

extensively studied and well demonstrated to be an excellent alternative method to alkylation of imines

by Naoki et al, (1994) [21]. This type of reaction provides a convenient method for the synthesis of

homoallyl- and homopropargyl amines and β-amino esters.

NHCO2Me

OMe

R1 R2-Br

NHCO2Me

R2

R1Zn

THF

267 268 269

Where R1 = Me, Ph, i-Pr, H: R2 = PhCH2, Allyl, Vinyl.

Scheme - 5.2: Preparation of homoallylamines

Lanthanide triflates are used as effective catalysts for the allylation of imines with

allyltributylstannane to afford homoallylamines (Scheme-5.3) in moderate to good yields by Cristina et

al, (1995) [22].

R NR1 Sn(Bu)3

Ln(OTf)3 R

HNR1

270 271272

Where R = Me, Ph,H: R1= 4-OCH3Ph, Benzyl

156

Scheme-5.3: Preparation of homoallylamines using lanthanide catalysts.

Billet et al, (2001) have used crotylsilane in a three-component reaction for the synthesis of

homoallylamines (Scheme-5.4) from aldehydes. A moderate to good syn:anti 5:1 diastereoselectivity

was observed. The obtained homoallylamines were transformed into pyrrolidines or piperidines [23].

R H

O

H2N R1 SiMe3

Lewis acid

R

HNR1

R

HNR1

273 274 275276 277

Where R, R1 = Ph, PhCH2, PhCHCH2, -OMePh

Scheme - 5.4: Preparation of homoallylamines using crotylsilane.

A complete conformational analysis of 4-methyl-2-(3-pyridyl)quinoline (278)) and structurally

related compounds with known antifungal properties was carried out using ab initio and DFT

calculations by Villagra et al, (2003) [24].

R1

NH

R

278

Where R, R1 = Ph, PhCH2, PhCHCH2, -Cl, Br

Fig. 5.2: Cyclised derivatives of homoallylamines

Ella-Menye et al, (2005) have reported the three-component “aza Sakurai–Hosomi” reaction

performed on (±) O-protected mandelic aldehydes and observed the unexpected syn hydroxy

homoallylamines (280) and (281) as the major adducts [25].

157

CHO

OR

OH

NHCBz

OH

NHCBz

SiMe3

CBzNH2, Lewis acid

280

281

279

Where R = Tributyldimethyl silane, Tributyl diphenyl silane, Teteraisopropyl silane

Scheme 5.5: Preparation of homoallylamines using “aza Sakurai–Hosomi” reaction

Fernando et al, (2006) studied the synthesis and in vitro evaluations and structural activity

relationship of homoallylamines and related derivatives as antifungal agents. Among them few

derivatives (282 and 283) showed excellent antifungal activity against dermatophytes [26].

Br

NH

O

282

Cl

NH

O

283

Fig. 5.3: N-(1-(Furan-2-yl) but-3-enyl)benzenamine derivatives

Vladmir et al, (2008) reported the synthesis of homoallylamines bearing furan ring and studied

their antifungal, cytotoxic activity against (MCF-7) and lung (H-460) activity. Compound N-(1-(furan-

2-yl)but-3-enyl)pyridin-4-amine (284) showed excellent activity [27].

N

NH

O

284

Fig. 5.4: N-(1-(Furan-2-yl)but-3-enyl)pyridin-4-amine

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Bismuth (III) nitrate pentahydrate catalyzes efficiently the three-component condensation of

aldehydes, amines, and allyltributylstannane at room temparature to afford the corresponding

homoallylic amines (Scheme-5.6) in excellent yield, Ponnaboina et al, (2009) [28].

R H

O

H3CO

NH2SnBu3

R

HN

OCH3

CH3CN

Bi(NO3)3.5H2O

285 286 287288

Where R = Ph, PhCH2, -OMePh

Scheme 5.6: Preparation of homoallylamines using Bismuth (III) nitrate catalyst

Gonzalez et al, (2010) used indium metal and titanium tetraethoxide for the synthesis of

homoallylamines (Scheme-5.7) similar homoallylamines are used in the synthesis of naturally occurring

ring alkaloids [29].

BrR H

O

t-BuSNH2

O

In, Ti(OEt)4

THF, 60oC R

NHS

O

t-Bu

289

290 291

292

Where R = Ph, Bn, 4-ClPh, 4-OMe- Ph

Scheme 5.7: Preparation of homoallylamines using Indium catalyst

Yamaguchi et al, (2011) have reported a nuclephilic allylation of 2- aminotetrahydrofuran and 2-

aminotetrahydropyran with allylic alcohols to provide α-hydroxyhomoallylamines (Scheme - 5.8) in

high yields using Pd/Et3B and Pd/Et2Zn [30].

159

Ph H

O

RNH2

Pd catalyst

Ph

NHR

OH

Et3B

293 294 295296

Where R = Ph, Bn, 4-ClPh, 4-OMe -Ph, 4-Me-Ph

Scheme 5.8: Preparation of homoallylamines using Pd/Et3B catalyst

Highly enantioselective asymmetric synthesis (Scheme-5.9) of highly optically pure 2-

substituted piperidines was developed by Piao et al, (2012) using aldehydes, amines and allyl bromides

[31].

NH

R NH

R NH2R

R O

InBr

NH3

Where R = Ph, 4-F-Ph, 4-NO2-Ph, 2-Br-Ph, 2-OMe- 3-ClPh, -OMePh.

298

299

300301302

Scheme 5.9: Retro synthetic pathway of 2- substituted piperidines

In general homoallylic amines are prepared either by the addition of organometallic reagents to

imines or by nucleophillic addition of allylsilanes, allyltin, allylboron or allyl germane reagents to

imines in the presence of different Lewis acid catalysts as discussed in the above examples. The

common drawback in the reported methods is generation of aldehyde sideproduct because of unstable

intermediate imine. Also in some processes the removal of catalyst is difficult. Moreover the reported

yields are less because of decomposition of some catalyst sensitive aldehydes. Most of the synthesis

protocols reported so far requires long reaction times, stringent conditions, and highly toxic

reagents/catalysts, the catalysts are often expensive and tedious to prepare. The reactions are often

characterized by low yields. Therefore, there is a need for the development of simple, convenient and

environmentally benign approaches for the synthesis of homoallylic amines.

160

Nitrogen containing molecules are significant synthetic targets owing to their wide range of

applications as pharmaceutical and bioactive compounds. Mannich reaction has been one of the classical

methods for the synthesis of nitrogenous compounds, especially β- amino carbonyl compounds that are

versatile intermediates for the synthesis of β- amino alcohols and β- amino acids, which have the great

deal of biological importance.

In 1987 Gennari et al, have reported the synthesis of enantio- and diastereo-controlled synthesis

of the β-lactums by the addition silyl ketene acetal derived from (lS,2R)-N-methylephedrine-0-

propionate to imines using TiCl4 as a catalyst (Scheme-5.10) [32].

NMe2

OH

H

Ph

Me

OSiMe3 N

Me H H

Ph

PhO

PhN

H Ph

303 304

Scheme-5.10: Asymmetric synthesis β-lactums

Manabe et al, (1999) reported the three-component Mannich-type reactions of aldehydes,

amines, and ketones were efficiently catalyzed by dodecylbenzenesulfonic acid at ambient temperature

in water to get various β-amino ketones in good yields [33].

RCHO R1NH2 R3

O

R2

Dodecylbenzenesulfonic acid

R

NH

R2R3

OR1

Where R = Ph, Furfuraldehyde, Isovaleraldehyde

R1 = Ph, -OMePh, 4-Cl-Ph

R2, R3 = H, Ph, Cyclohexanone

305 306 307308

Scheme 5.11: Synthesis of β-amino ketones

161

The synthesis of β-amino ketones from aldehydes has been achieved in water using indium

trichloride as catalyst (Scheme-5.12) by Loh et al, (2000). The catalyst was recovered after the reaction

was complete and reused for a repeat reaction without any significant drop in reactivity [34].

PhCHO

Ph

NH

Ph

OPh

PhNH2

OTMS

Ph

InCl3

309 310 311 312

Scheme-5.12: Synthesis of β-amino ketones using InCl3 catalyst

Chiral β -amino alcohol units are useful as chiral building blocks for various biologically active

compounds. Matsunaga et al, (2003) have reported a highly enantio- and diastereoselective direct

catalytic asymmetric Mannich-type reaction to provide anti-amino alcohols. The process worked well

with from as little as 0.25 to 1 mol % of catalyst loading [35].

NPPh2

O

OO

OH

NH

OH

OPh2P

O

Et2Zn/S,S-Binol

313 314315

Scheme-5.13: Synthesis of anti amino alcohols

The transition metal salt-catalyzed direct three component Mannich reactions of aryl aldehydes,

aryl ketones, and carbamates are described by Xu et al, (2004). The RuCl3.xH2O, AuCl3-PPh3, and

AuCl3-catalyzed direct Mannich reactions (Scheme-5.14) led to the synthesis of N-protected β -aryl- β -

amino ketones [36].

162

CHO

R

O

R1

NH O

CBz

R R1NH2CBz

AuCl3-PPh3

316 317 318

Where R, R1 = H, 4-Cl, 4-Br, 4-Me, 4-OMe, 4-NO2

Scheme 5.14: Transition metal catalysed synthesis of β-amino ketones

Phukan et al, (2006) have reported the synthesis of Mannich reaction between an aryl aldehyde,

aryl ketone and benzyl carbamate using iodine as catalyst (Scheme 5.15). Even the less reactive amines,

also produced Cbz-protected β -aryl β -amino carbonyl compounds in high yields [37].

CHO

R

O

R1

NH O

CBz

R R1NH2CBz

Iodine, 10 mol%

319 320 321

Where R, R1 = H, 4-Cl, 4-Br, 4-Me, 4-OMe, 2-OCH3,

4-OCH3, 2,4-Dichloro

Scheme 5.15: Iodine catalysed synthesis of β-amino ketones

1-Aryl-3-phenethylamino-1-propanone hydrochlorides (Fig 5.5) which are potential potent

cytotoxic agents, were synthesized via Mannich reactions using paraformaldehyde, phenethylamine

hydrochloride as the amine component and substituted acetophenones, as the ketone component by

Mete et al, (2007) [38].

163

O

NH

RHCl

322

Where R = Ph, 4-F-Ph, 4-Me-Ph, 4-Nitro-Ph, 4-OHPh

Figure 5.5: β-Amino ketones

Small organic molecules recently emerged as a third class of broadly useful asymmetric catalysts

that direct reactions to yield predominantly one chiral product, complementing enzymes and metal

complexes. Yang et al, (2008) have synthesised β-amino aldehydes (Scheme-5.16) in extremely high

enantioselectivities and reasonable yields [39].

R H

NBoc

H

O

R

NHBoc

CHO

S-Proline

323 324 325

Where R = Ph, 4-CF3Ph, 4-MePh, 3-Nitro-Ph, Furyl, isopropyl

Scheme 5.16: Proline catalysed synthesis of β-amino aldehydes

A novel class of non-steroidal progesterone receptor antagonists with aromatic β-amino ketone

scaffold have been synthesized by Du et al, (2010).These compounds have shown high binding affinity

and great selectivity for the cognate receptor. Among all the synthesised compounds, 3-(3-

fluorophenyl)-3-(4-nitrophenylamino)-1-p-tolylpropan-1-one (Fig 5.6) found to be the most potent

progesterone receptor antagonist in contransfection assay and a model of ligand-induced decidualization

[40].

164

O

F

NH

NO2

326

Fig 5.6: 3-(3-Fluorophenyl)-3-(4-nitrophenylamino)-1-p-tolylpropan-1-one

Wang et al, (2012) have reported the synthesis and antidiabetic study of series of β-amino-

ketone containing nabumetone moiety. All the synthesised compounds are screened for antidiabetic

activity invitro, compound 4-(3-(4-hydroxyphenyl)-1-(3-methoxyphenyl)-3-oxopropylamino)-N-(5-

methylisoxazol-3-yl)benzenesulfonamide (Fig 5.7) has shown peroxisome proliferator-activated

receptor activation and α-glucosidase inhibition activity significantly [41].

O

HO

OMe

NH

SNH N

O

MeO

O

327

[PPAR activation 69.75]

Fig 5.7: 4-(3-(4-Hydroxyphenyl)-1-(3-methoxyphenyl)-3-oxopropylamino)-N-(5-methylisoxazol-3-

yl)benzenesulfonamide

Mannich bases have been widely applied as prodrugs of amine derivative drugs. The analogous

C-Mannich bases (β-aminoketones) have received rather less attention probably because, they are not

sufficiently susceptible to elimination at pH encountered in vivo. Compounds, in which there is a

thermodynamic advantage to elimination, may be an exception. Further from the literature, it was

observed that, β-aminoketones are biologically potent molecules such as, antibacterial, antifungal,

analgesic, anti-inflammatory, and as antivirals.

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However, the drastic reaction conditions for the classical intermolecular Mannich reaction limit

its synthetic usefulness. Therefore, numerous modifications of this reaction have been developed to

overcome the drawbacks. Many metal complexes have been used as Lewis acid catalysts to promote the

reaction under anhydrous conditions as discussed earlier and few water-compatible Lewis acids were

reported. However, these catalysts suffer from some disadvantages such as requiring a large amount of

Lewis acid (usually more than 10 mol %), a long reaction time, and/or atmosphere sensitive reagents.

There is increasing interest in developing environmentally benign reactions and atom-economic

catalytic processes that employ unmodified ketones, amines, and aldehydes for Mannich-type reaction

in recent years. Cerium chloride is used in many organic reactions as a catalyst, as a reagent. Since it is

highly soluble in water can be easily removed from the reaction by water wash. These properties of

cerium chloride prompted us to try Mannich reaction using cerium chloride as a catalyst. In view of

these facts and in continuation of our research on pharmaceutically important heterocycles, we prepared

a rapid and efficient three-component synthesis of β-aminoketones via a CeCl3 (1 mol %) catalyzed one

pot reaction in microwave, in 3 minutes duration. The product formed can be easily isolated just by

pouring in to water.

5.2. Results and discussions

An efficient catalytic three-component reaction of aldehydes, amines and allyltributylstannate

has been successfully developed to produce homoallylic amines at 25oC, in excellent yields, in the

presence of 1 mol % of trifluoroacetic acid (Scheme 5.17). Newly synthesized compounds were

confirmed by spectral studies. This is a convenient and environmentally benign approach for the

synthesis of homoallylic amines.

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R CHO R1 NH2

SnBu3

TFA 1 mol%

RT R NH

R1

328(a-q) 329(a-q)

330331(a-q)

Scheme 5.17: CF3CO2H catalysed synthesis of Homoallylamines

R NR1

HOCF3

O

R NR1

SnBu3

RHN R1

SnBu3

NHR

R1

HSnBu3

OCF3

O

H

H

HO

CF3

O

Scheme 5.17a: Proposed mechanism for CF3CO2H catalysed synthesis of Homoallylamines

The reaction of benzaldehyde, 1-naphthylamine, and allyltributyl in the presence of 0.1

equivalents CF3COOH (TFA) in acetonitrile at 25˚C resulted in the formation of the homoallylic

amines in 68-98 % yield. The scope and generality of this process is illustrated with respect to different

substrates. Both Aromatic, aliphatic, cyclic and heterocyclic aldehydes reacted smoothly with different

amines to afford the corresponding homoallylic amines in high to excellent yields of the products within

25-60 min, whereas ketones did not yield any product even after long reaction times (15-29 hrs.)

Compounds containing an electron withdrawing group on the aldehydes reacted more efficiently

resulting with higher yields. Amines bearing an electron donating group also favoured the reaction

under the standard reaction conditions to give products less than 1 hour. Furthermore acid-sensitive

aldehyde, furfuraldehyde worked well without any decomposition under the reaction conditions because

of low concentration of acid and at ambient temperature. Enolizable aldehydes, such as

cyclohexanecarboxaldehyde also produced the corresponding homoallylamines in good yields. In all

cases, no homoallylic alcohol (the adduct of aldehyde and allyltributyltin) was obtained under these

167

reaction conditions due too rapid formation and activation of imines in the presence of catalytic amount

of CF3COOH. Results are summarized in Table-5.1.

Table-5.1: Newly synthesized homoallylic amines (331 a-q)

S. No R

R1 Reaction time(min)Yield (%)

331a Phenyl Napthyl 30 95

331b

2-Benzofuran

3,4-Diflurobenzyl

35

90

331c

Cyclopropyl 4-t-Butylphenyl

30

98

331d

2,4-Difluorophenyl 2,4,5-Trifluorophenyl 45

89

331e

2-Benzofuran

Napthyl

30

90

331f

2,4-Difluorophenyl 4-t-Butylaniine

45

95

331g 2-Fluoro-5-methoxyphenyl 3-Fluorophenyl 45

82

331h

Cyclopropane carboxaldehyde

4-Fluoro-3-trifluoromethyl-Phenyl

30

85

331i

Cyclohexane carboxaldehyde 4-Morpholinophenyl 60

78

331j

Cyclohexane carboxaldehyde 2,5-Dimemethylphenyl

30

88

331k 2-Allyloxyphenyl 4-(4-Chlorophenoxy) Phenyl45 75

331l

5-(2-Chlorophenyl)furan-2-carbaldehyde

4-(4-Chlorophenoxy) phenyl60

73

331m 1-Acetyl-1H-3-indolyl Benzo[d]thiazol-7-amine 60

68

331n

2,4-Difluorophenyl 2,4-Difluorophenyl 45

75

331o

2,6-Difluorophenyl 4-Chloro-3-fluorophenyl 30

78

331p

2-Thiophenyl 4-Cyanophenyl

45

68

331q 3-Ethoxyphenyl 4-Fluorophenyl 30 72

All aldehydes, amines, allyltributyltin, CF3CO2H and solvents are purchased from commercial

sources and all the aldehydes and solvents were distilled before use. Reactions were monitored on TLC

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by comparison with the starting materials. Yields refer to the isolated yields of the products after

purification by flash chromatography.

All the reactions are monitored by mass analysis of crude reaction mixture and by TLC using

ethylacetate: hexane as eluent. An unambiguous structure proof of compound (331o) was achieved by

an examination of the crystal structure of compound (331o). In the molecule of the title homoallylic

amine, C16H13ClF3N, the dihedral angle between the two benzene rings is 84.63 (4)o. Weak

intramolecular N—H-----F hydrogen bonds generate S(6) and S(5) ring motifs. In the crystal structure,

weak intermolecuar N—H-----F hydrogen bonds link molecules into centrosymmetric dimers which are

arranged in molecular sheets parallel to the ac plane. Fig.-5.11 shows crystal structure of compound

(331o). In 1H NMR spectra, presence of triplet proton at 4.5-4.7 clearly confirmed the formation of

homoallylamine, and it is supported by 13 C NMR spectra where single peak at 48-50 indicates the

junction carbon of the homo allylamine. In case of compound (331a) LCMS of the compound shows

97.9% purity and also molecular ion peak 274, which confirms the molecular weight of the compound.

In 1H NMR peak at 4.55-4.61 (m, 1H, CH) indicates the junction –CH of homoallylamine. Also in the

aromatic region presence 4 set of multiplets indicates the presence of naphthalene and phenyl rings in

the compound.

Three-component Mannich reaction of ketones, aldehydes and different amines in microwave

irradiation afforded corresponding β-amino carbonyl compounds in good yields (Scheme 5.18).

Solvent Free, 83-95%

O O HN

R

R1

CeCl3/Microwave, 3 minR CHO R1 NH2

332 333(a-k) 334(a-k) 335(a-k)

Scheme 5.18: CeCl3 catalysed synthesis of β-amino ketones

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The different substituent used and yield of the reactions are mentioned in Table-5.2.

Proposed mechanism for CeCl3 catalysed Synthesis of β-amino ketones

R1

NH2

NR1

R

CeCl3

O O

CeCl3

O

R

HNR1

CeCl3

R H

O

CeCl3

R NH2

OHR1

CeCl3

R NH

OH

R1

-H2O

Table-5.2: Newly synthesized β-aminoketones (335 a-k)

S.No R R1 Yield (%)a Anti/Synb

335a Phenyl t-Butylphenyl 87 100:0 335b 4-Fluorophenyl 2,4-Difluorophenyl 86 100:0 335c 2-Chlorophenyl 4-Cyanophenyl 95 100:0

335d 2-Fluoro-5-methoxy phenyl 2,4-Difluorophenyl 92 100:0 335e 2-Fluorophenyl 3,4-Difluorophenyl 88 100:0 335f 2-Allyloxyphenyl 3-Fluorophenyl 85 100:0 335g 2-Hydroxy-3-methyl phenyl 3-Methoxyphenyl 93 100:0 335h 4-Ethylphenyl 3,4,5-Trifluoro-methyl phenyl95 100:0 335i 4-Ethylphenyl 4-Methyl-3 nitro phenyl 90 60:40

335j 2-Benzofuran Napthyl 83 100:0 335k 4-Pyridyl 2-Methyl-5-aminoindole 88 100:0

170

In our initial experiments, substituted benzaldehyde (333a), substituted aniline (334), and

cyclohexanone (332) in acetonitrile were stirred for 4 hours in the presence of catalytic amount (1 mol

%) of CeCl3 at room temperature. Even after 4 hours, no product was observed in mass analysis; further

reaction mixture was heated to 80oC for 8 hours, which gave the corresponding β-aminoketones (335a)

in very low yield (25 %), with unreacted imine. Even after increasing the quantity of catalyst loading to

10 mol %, no any sign of improvement of the reaction. Further in our study we have used substituted

benzaldehyde (333a), aniline (334a), cyclohexanone (332), and 1 mol % of CeCl3 in microwave tube,

sonicated for 1 min, and irradiated in microwave for 3 min. Mass analysis of crude reaction mixture

showed formation of only product with no starting material or side product.

1H-NMR and 13C-NMR spectra were recorded on 400-MHz and 300-MHz Bruker

spectrometers, respectively. Elemental analysis was performed on a Thermo Finnigan FLASH EA 1112

CHN analyzer. Melting points were recorded (uncorrected) on a Buchi Melting Point B-545 apparatus.

All the compounds (335a-k) were synthesized in-house from the corresponding commercially available

aldehydes, amines and ketone. The products were characterized by1H-NMR, 13C-NMR, MS, and

elemental analysis. The structure of compound (335a) was further confirmed by single-crystal X-ray

analysis. In the molecule of the title compound, C23H29NO, the cyclohexanone ring has been distorted

from the standard chair conformation by the ketone group such that part of the ring is almost flat. The

remaining [(4-tert-butylanilino)(phenyl) methyl] portion of the molecule is in an equatorial position on

the cyclohexanone ring. The dihedral angle between the two benzene rings is 81.52 (8)o. In the crystal

packing, molecules are linked by N-H…O hydrogen bonds into infinite one-dimensional chains along

the axis and these chains are stacked down the c axis. The crystal structure is further stabilized by weak

C-H…O and C-H interactions. In this method major anti-isomer was formed except in the case of

compound (335i), where 1:1 mixture of syn and anti-isomers formed, confirmed by 13C-NMR, where

171

two distinct peaks for C=O is observed at 211 and 212. This may due to electron donating and electron

withdrawing groups present in the same molecule. The anti and syn isomers were identified by the

coupling constants (J) of the vicinal protons adjacent to C=O and NH in their 1H-NMR spectra. In

general, the coupling constants for anti-isomers are greater than that for syn isomers. The ratio of the

isomers was determined by integration of the corresponding peaks in 1H NMR spectra. For example in

case compound (335b) triplet peaks at 4.59 in 1H NMR indicates the junction –CH and the same carbon

is observed at 57.3 in 13C NMR, also C=O peak is seen at 211.8. LCMS of the compound shows 99.3%

purity and molecular ion peak at 336 which confirmed the molecular weight of the compound.

5.3. Synthesis

5.3.1. General procedures

5.3.1. General Procedure synthesis of Homoallylamines (331a-q)

To a mixture of aldehyde (10 mmol), amine (10 mmol) and allyltributyltin (10 mmol) in

acetonitrile (5 mL), CF3COOH (1 mmol) was added. The reaction mixture was stirred at 25˚C under

nitrogen atmosphere for an appropriate time. After completion of the reaction, as indicated by TLC and

mass analysis, the reaction mixture was extracted with diethyl ether (3×20 ml). The combined organic

layers were concentrated in vacuum and purified by flash chromatography to afford the pure

homoallylic amines (331a-q).

5.3.2. General procedure for synthesis of β-amino ketones (335a-k)

A mixture of aldehyde (1 mmol), amine (1 mmol), cyclohexanone (1 mmol) and cerium chloride

(1 mol %) were taken in a sealed pressure regulation 10-mL pressurized vials with“snap-on” cap and

sonicated for 2 min; resulting mixture was irradiated in the single-mode microwave synthesis system at

120W power and 100 ºC temperature for 3 minutes. Completion of reaction was confirmed by mass

172

analysis and TLC. Reaction mixture was diluted with water and the solid separated was filtered, dried

and recrystalised using ethyl acetate to yield pure product (335 a-k).

5.4. Characterization

5.4.1. Experimental Data:

5.4.1.1. Naphthalene-1-y-(1-phenyl –but-3-enyl)- amine (331a)

Yield; 95%, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5), Thick liquid. 1H NMR (400 MHz, CDCl3,

24oC):δ = 2.72-2.83 (m, 2H, CH2), 4.55-4.61 (m, 1H, CH), 5.18-5.22 (d, 1H, J = 16 Hz), 5.31-5.36 (m,

1H, CH2), 5.80-5.90 (m, 1H, CH2), 6.36 (br. s, 1H, NH), 7.14-7.27 (m, 4H, Ar-H), 7.31-7.38 (m, 2H,

Ar-H), 7.41-7.78 (m, 4H, Ar-H), 7.93-7.7.95 (m, 1H, Ar-H). 13C NMR (100 MHz, CDCl3,24oC): δ =

43.4, 57.0, 106.3, 117, 118.6, 119.7, 123.4, 124.7, 125.6, 126.2, 127.0, 128.7, 128.9, 134.2, 134.7,

141.8, 143.0. LCMS (97.9%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm

5µm, RT = 3.4 min, m/z = 274 [M + H]+). Anal. Calc. for C20H19N: C 87.91, H 6.96, N 5.13. Found: C

87.9, H 6.95, N 5.11%.

5.4.1.2. (1-Benzofuran-2-yl-but-enyl)-(3,5-difluoro-benzyl)-amine (331b)


24oC): δ= 2.59-2.75 (m, 2H, CH2), 3.71-3.75 (m, 1H,), 3.83-3.3.92 (m, 2H, CH2), 5.08- 5.17 (m, 2H,

CH2), 5.71-5.81 (m, 1H, CH), 6.64 (s, 1H, NH), 6.77-6.84 (m, 2H, Ar-H), 7.24-7.37 (m, 3H, Ar-H),

7.48-7.50 (m, 1H, Ar-H), 7.55-7.57 (m, 1H, Ar-H). 13C NMR (100 MHz, CDCl3,24oC): δ = 39.12, 44.3,

55.4, 103.4, 104, 110.9, 111, 118, 120.7, 122, 123, 128, 131.13, 134.2, 154.8, 158, 159.8, 162. LCMS

(96.3%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT=1.0 min,

m/z = 314 [M + H]+). Anal. Calc. for C19H17F2NO; C 72.84, H 5.43, N 4.47. Found: C 72.82, H 5.44, N

4.45%.

173

5.4.1.3. (4-Tert-butyl-phenyl)-(1-cyclopropyl-3-but-enyl)-amine (331c)


24oC): δ = 0.330.35 (m, 2H, CH2), 0.50 (m, 2H, CH2), 1.09 (m, 1H, CH), 1.29 (s, 9H, t-butyl), 2.44-2.47

(m, 2H, CH2), 2.95-2.97 (m, 1H, CH), 3.5 (bs, 1H, NH), 5.12 (m, 2H, CH2), 5.97-5.99 (m, 1H, CH),

6.60-6.62 (d, 2H, J = 8 Hz, Ar-H), 7.237.24 (d, 2H, J = 8 Hz, Ar-H). 13C NMR (100 MHz,

CDCl3,24oC): δ= 2.6, 3.40, 16, 31.6, 39.7,56.8, 113, 117, 125.9, 135.2, 139.9, 145.4. LCMS (95%,

Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 4.1 min, m/z = 244

[M + H]+). Anal. Calc. for C17H25N;C 83.95, H 10.29, N 5.76. Found: C 83.97, H 10.26, N 5.75%

5.4.1.4. [1-(2, 4-Diflurophenyl)-but-3-enyl]- (2, 4, 5-trifluoro-phenyl)-amine (331d)


24oC): δ = 2.47-2.2.63 (m ,2H, CH2), 4.13-4.26 (m, 2H, 2CH), 5.20-5.24 (m, 2H, CH2), 5.70-5.77 (m,

1H, CH), 6.11-6.5 (m, 1H, Ar-H), 6.84-6.88 (m, 1H, Ar-H), 7.09-7.73 (m, 3H, Ar-H). 13C NMR (100

MHz, CDCl3,24oC): δ = 42.9, 56.5, 101, 104, 115, 117, 119, 122, 132, 139, 139.7, 144, 147, 150. LCMS

(94.6%, Method; 0.1% HCOOH; ACN, Flow 0.8mL/min, Column C 18 75X4.6mm 5µm, RT = 3.8 min,

m/z = 312 [M -H]). Anal. Calc. for C16H12F5N;C 61.34, H 3.83, N4.47. Found: C 61.33, H 3.84, N

4.45%.

5.4.1.5. (1-Benzofuran-2-yl-but-3-eny)-napthalen-1-yl-amine (331e)


24oC): δ = 2.93 (t, 2H, J = 8 Hz, CH2), 4.90 (t, 1H, J = 4 Hz, CH), 5.35 (m, 2H, CH2), 5.94 (m, 1H, CH),

6.64 (m, 1H, Ar-H), 7.23-7.29 (m, 2H, Ar-H), 7.44-7.50 (m, 5H, Ar-H), 7.8(m, 1H, Ar-H), 7.90 (m, 1H,

Ar-H). 13C NMR (100 MHz, CDCl3,24oC): δ = 39.2, 51.69, 102, 106, 111, 118, 119, 120, 123, 124,

174

125.2, 126, 128, 133, 134, 154.3, 158. Anal.Calc. for C22H19NO; C 84.35, H 6.07, N 4.47. Found: C

84.32, H 6.06, N 4.46%.

5.4.1.6. (4-tert-Butyl-phenyl)- [1-(2, 4-difluoro-phenyl)-but-3-eny]-amine (331f)


24oC): δ = 1.36 (s, 9H, t-butyl), 2.52 (m, 2H, CH2), 4.35 (q, 1H, J = 8 Hz, CH), 5.29 (m, 2H, CH2), 6.02

(m, 1H, Ar-H), 6.52 (d, 2H, J = 8 Hz, Ar-H), 7.18-7.23 (m, 4H, Ar-H), 7.32 (m, 1H, Ar-H). 13C NMR

(100 MHz, CDCl3,24oC): δ = 31.6, 33.7, 43.3, 56.77, 113, 115, 117, 118, 122, 125, 134, 140, 141, 144,

150. LCMS (90%, Method; 0.1% HCOOH; ACN, Flow 0.8mL/min, Column C 18 75X4.6mm 5µm,

RT=4.3min, m/z = 316 [M +H]+).Anal. Calc. for C20H23F2N; C 76.19, H 7.30, N 4.44. Found: C 76.16,

H 7.28, N 4.42%.

5.4.1.7. [1-(2-Fluoro-6-methoxy-phenyl)-but-3-enyl]- (3-fluorophenyl)-amine (331g)

Yield; 82%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.7), Thick liquid. 1H NMR (400 MHz, CDCl3,

24oC): δ = 2.4 (m, 1H, CH2), 2.5 (m, 1H, CH2), 3.6 (s, 3H,-OCH3), 4.59 (t, 1H, J = 4 Hz, CH), 5.1 (m,

2H, CH2), 5.6 (m, 1H, CH), 6.1 (dd, 1H, J = 4 Hz, Ar-H), 6.39 (m, 2H, Ar-H), 6.6 (m, 1H, Ar-H), 6.7

(m, 1H, Ar-H), 6.9 (m, 2H, Ar-H). 13C NMR (100 MHz, CDCl3,24oC): δ = 40.9, 51.2, 55.8, 100.2,

104.4, 112.8, 113, 115, 116, 127, 128, 130, 133, 148, 152. LCMS (90%, Method; 0.1% HCOOH; ACN,

Flow 0.8mL/min, Column C 18 75X4.6mm 5µm, RT = 3.5 min, m/z = 290 [M +H]+). Anal.Calc. for

C17H17F2NO; C 70.59, H 5.88, N 4.84. Found: C 70.60, H 5.85, N 4.83%.

5.4.1.8. (1-Cyclopropyl-but-3-enyl)-(4-fluoro-3-trifluoromethyl-phenyl)-amine (331h)


24oC): δ = 0.330.35 (m, 2H, CH2), 0.50 (m, 2H, CH2), 2.4 (q, 2H, J = 8 Hz, CH), 2.9 (q, 1H, J = 8 Hz,

CH), 5.2 (m, 2H, CH2), 5.9 (m, 1H, CH), 6.68 (t, 1H, J = 4 Hz, Ar-H), 6.76 (t, 1H, J = 4 Hz, Ar-H), 7.0

175

(m, 1H, Ar-H). 13C NMR (100 MHz, CDCl3, 24oC): δ = 2.8, 3.1, 15.8, 39.3, 57, 110, 117.2, 118, 118.5,

121.5, 134, 144, 153. LCMS (93.5%, Method; 0.1% HCOOH; ACN, Flow 1.0mL/min, Column C 18

75X4.6mm 5µm, RT = 1.9 min, m/z = 272 [M -H]). Anal. Calc. for C14H15F4N; C 61.54, H 5.49,N 5.13.

Found: C 61.57, H 5.47, N 5.11%.

5.4.1.9. (1-Cyclohexyl-but-3-enyl)- (4-morpholin-4-yl-phenyl)-amine (331i)


24oC): δ = 1.0-1.32 (m, 4H, 2CH2), 1.5 (m, 2H, CH2), 1.6-1.8 (m, 5H, CH2), 2.2 (m, 2H, CH2), 2.95-3.3

(bs, 4H, -NCH2), 3.75 (m, 4H, -OCH2), 5.2 (m, 2H, CH2), 5.75 (m, 1H, CH), 6.5-7.0 (bs, 4H, Ar-H). 13C

NMR (100 MHz, CDCl3, 24oC): δ = 26.8, 29.5, 35.6, 41.2, 51.0, 58.2, 68.9, 114.1,116, 118, 128, 129,

142. LCMS (96%, Method; 0.1% HCOOH; ACN, Flow 0.8mL/min, Column C 18 75X4.6mm 5µm, RT

= 3.9 min, m/z = 315 [M + H]+). Anal.Calc. for C20H30N2O; C 76.43, H 9.55, N 8.92. Found: C76.41, H

9.54, N 8.91%.

5.4.1.10. (1-Cyclohexyl-but-3-enyl)- (2, 5-dimethyl-phenyl)-amine (331j)


24oC): δ = 1.1-1.3 (m, 5H, CH2), 1.7 (m, 1H, CH2), 1.75 (m, 1H, CH2), 1.82 (m, 3H, CH2), 1.92 (d, 1H,

J = 12 Hz, CH2), 2.15 (s, 3H, Ar-CH3), 2.3 (m, 1H, CH2), 2.35 (s, 3H, Ar-CH3), 2.42 (m, 1H, CH2), 3.9

(q, 1H, J = 4 Hz, CH), 5.12(m, 2H, CH2), 5.8 (m, 1H, CH), 6.48 (d, 2H, J = 8Hz, Ar-H), 6.97 (d, 1H, J =

8 Hz, Ar-H). 13C NMR (100 MHz, CDCl3, 24oC): δ = 17.2, 21.7, 26.5, 26.7, 29.5, 35.8, 41.2, 57.0,

110.8, 116.4, 117.1, 117.5, 130.2, 135.2, 135.7, 136.6. LCMS (96%, Method; 0.1% HCOOH; ACN,

Flow 0.8mL/min, Column C 18 75X4.6mm 5µm, RT=3.9 min, m/z = 258 [M + H]+).Anal. Calc. for

C18H27N; C 84.05, H 10.51, N 5.45. Found: C 84.02, H 10.50, N 5.43%.

5.4.1.11. [1-(2-Allyloxy-phenyl)-but-3-enyl]-[4-(4-chloro-phenoxy)-phenyl]-amine (331k)

176


24oC): δ = 2.55 (m, 1H, CH2), 2.75 (m, 1H, CH2), 4.3 (bs, 1H, NH), 4.68 (t, 2H, J = 4 Hz, -OCH2), 5.3

(m, 1H, CH), 5.36- 5.39 (m, 2H, CH2), 5.51 (d, 1H, J = 16 Hz, CH), 5.84 (d, 1H, J = 13.6 Hz, CH2), 5.9

(m, 1H, CH), 6.13-6.20 (m, 1H, Ar-H), 6.54 (d, 2H, J = 12 Hz, CH), 6.82-6.9 (m, 4H, Ar-H), 6.9 (m,

2H, Ar-H), 7.2 (m, 3H, Ar-H), 7.39 (d, 1H, J = 8 Hz, Ar-H). 13C NMR (100 MHz, CDCl3, 24oC): δ=

40.6, 52.0, 68.5, 11.6, 114.2, 117.0, 117.6, 118.2, 120.8, 123, 126.5, 127.1, 127.7, 130.2, 130, 133.2,

135.2, 144.2, 147.0, 155.6, 157.7. LCMS (98%, Method; 0.1% HCOOH; ACN, Flow 1.0mL/min,

Column C 18 75X4.6mm 5µm, RT = 2.6 min, m/z = 406 [M + H]+). Anal.Calc. for C25H24ClNO2; C

73.98, H 5.92, N 3.45. Found: C 73.97, H 5.90, N3.44%.

5.4.1.12. [4-(4-Chloro-phenoxy)-phenyl]-{1-[5-(2-chloro-phenyl)-furan-2-yl]-but-3-enyl}-amine

(331l)


24oC): δ= 2.7 (bs, 2H, CH2), 4.50 (t, 1H, J = 4 Hz, CH), 5.0 (m, 2H, CH2), 5.6 (m, 1H, CH), 6.25 (s, 1H,

Ar-H), 6.76 (m, 2H, Ar-H), 7.16 (m, 4H, Ar-H), 7.18 (d, 1H, J = 4 Hz, Ar-H), 7.23 (m, 3H, Ar-H), 7.3

(m, 1H, Ar-H), 7.35 (d, 1H, J = 4 Hz, Ar-H), 773 (d, 1H, J = 4 Hz, Ar-H). 13C NMR (100 MHz, CDCl3,

24oC): δ = 40, 60, 100, 111.6, 118.5, 118.8, 120, 126, 127.6, 127.9, 129, 129.4, 130.7, 133.5, 144.5,

149, 150, 157. Anal.Calc. for C26H21Cl2NO2; C 69.33, H 4.67, N 3.11. Found: C 69.34, H 4.65, N

3.10%.

5.4.1.13. 1-{3-[1-(Benzothiazol-7-ylamino)-but-3-enyl]-indol-1-yl}-ethanone (331m)


24oC): δ = 2.5 (s, 1H, CH3), 2.72 (m, 1H, CH2), 2.88 (m, 1H, CH2), 4.78 (q, 1H, J = 4 Hz, CH), 5.26 (m,

2H, CH2), 5.85 (m, 1H, CH), 6.87 (d, 1H, J = 8 Hz, Ar-H), 7.0 (s, 1H, Ar-H), 7.27-7.41 (m, 3H, Ar-H),

7.7 (m, 1H, Ar-H), 7.89 (d, 2H, J = 8 Hz, Ar-H), 8.46 (bs, 1H, NH), 8.67 (s, 1H, Ar-H). 13C NMR (100

177

MHz, CDCl3, 24oC): δ= 26.9, 40.4, 50.4, 103.8, 105, 105.7, 115.1, 117.0, 118.9, 122.5, 123.6, 123.7,

123.8, 125.5, 128, 134, 135.7, 136.6, 145.6, 146.1, 168.6.LCMS (76%, Method; 0.1% HCOOH; ACN,

Flow 1.0mL/min, Column C 18 75X4.6mm 5µm, RT = 3.7 min, m/z = 362 [M + H]+).Anal. Calc. for

C21H19N3OS: C 69.81, H 5.26, N 11.63. Found: C 69.79, H 5.25, N 11.60%.

5.4.1.14. (2, 4-Difluoro-phenyl)- [1-(2, 4-difluoro-phenyl)-but-3-enyl]-amine (331n)


24oC), δ= 2.5-2.6 (m, 2H, CH2), 4.3 (bs, 1H, NH), 4.69 (m, 1H, CH), 5.24 (m, 2H, CH2), 5.74 (m, 1H,

CH), 6.34 (m, 1H, Ar-H), 6.59 (m, 1H, Ar-H), 6.64-6.87 (m, 3H, Ar-H), 7.3 (m, 1H, Ar-H). 13C NMR

(100 MHz, CDCl3, 24oC): δ = 41.2, 50.7, 103, 110, 11.4, 112.9, 119.0, 125.2, 128.5, 131.6, 133.4,

149.6, 152.1, 153.3, 155.6, 160.7 LCMS (94.7%, Method; 0.1% HCOOH; ACN, Flow 0.8mL/min,

Column C 18 75X4.6mm 5µm, RT = 3.9 min, m/z = 295.9 [M + H]+). Anal.Calc. for C16H13F4N; C

65.08, H 4.41, N4.75. Found: C 65.10, H 4.39, N 4.73%.

5.4.1.15. (4-Chloro-2-fluoro-phenyl)- [1-(2, 6-difluoro-phenyl)-but-3-enyl]-amine (331o)

Yield; 78%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.65), White solid; m.p. 126-127oC. 1H NMR (400

MHz, CDCl3, 24oC): δ = 2.72 (m, 1H, CH2), 2.87 (m, 1H, CH), 4.95 (m, 1H, CH), 5.28 (m, 1H, CH2),

5.71(m, 2H, CH2, NH), 5.81(m, 1H, CH), 6.68 (m, 1H, Ar-H), 6.8-6.9 (m, 4H, Ar-H), 7.2 (m, 1H, Ar-

H). 13C NMR (100 MHz, CDCl3): δ = 39.5, 48.3, 111.6, 113.0, 115.3, 117.5, 118.3, 121.2,124.4, 128.9,

129.0, 133.7, 152, 160, 162.5. LCMS (99.5%, Method; 0.1% HCOOH; ACN, Flow 0.8 mL/min,

Column C 18 75X4.6mm 5µm, RT = 4.2 min, m/z = 311.9 [M + H]+).Anal.Calc. for C16H13ClF3N: C

61.64, H 4.17, N 4.49. Found: C 61.61, H 4.14, N 4.47%.

5.4.1.16. 4-(1-Thiophen-2-yl-butylamino)-benzonitrile (331p)

178


24oC): δ = 2.7 (m, 2H, CH2), 4.77 (m, 1H, CH), 5.2 (m, 2H, CH2), 5.7 (m, 1H, CH), 6.56 (d, 2H, J =

8.Hz, Ar-H), 6.97 (d, 2H, J = 4 Hz, Ar-H), 7.20 (d, 1H, J = 4 Hz, Ar-H), 7.38 (d, 2H, J = 8 Hz, Ar-H).

13C NMR (100 MHz, CDCl3): δ = 42.6, 52.7, 99.4, 113.1, 119.3, 120.3, 124.0, 124.4, 127.0, 133.3, 133.,

146.6, 150.1. LCMS (96.0%, Method; 0.1% HCOOH; ACN, Flow 0.8 mL/min, Column C 18

75X4.6mm 5µm, RT = 2.6 min, m/z = 355 [M + H]+). Anal.Calc. for C15H14N2S; C 70.87, H 5.51, N

11.02. Found: C 70.85, H 5.50, N 11.01%

5.4.2.1. 2-((4-Tert-butylphenylamino)(phenyl) methyl) cyclohexanone (335a)

Yield; 87%, Off white solid, M.p. 154-156oC (TLC, Pet-ether/EtOAc, 1:1, Rf= 0.3). 1H NMR

(400 MHz, CDCl3, 24oC):δ 7.41 (t, J = 8 Hz, 2H, Ar-H), 7.32 (m, 2H, Ar-H), 7.23 (m, 1H, Ar-H), 7.1 (t,

j = 8 Hz, 2H, Ar-H), 6.5 (t, J = 8.8 Hz, 2H, Ar-H), 4.63 (d, J = 7.2 Hz, 1H, CH), 2.8 (m, 1H, CH), 2.3-

2.5 (m, 2H,CH2), 1.8 (m, 4H,2CH2), 1.6 (m, 2H, CH2), 1.23 (s, 9H, 3CH3).13C-NMR (100 MHz, CDCl3,

24oC): δ 212.8, 144.8, 142.0, 140.1, 128.4, 127.3, 127.1, 125.8, 113.2, 58.1, 57.5, 41.7, 33.7, 31.5, 31.1,

27.8, 23.5. IR (neat): 1/λ = 3375, 3025, 1760, 1619 cm-1. LCMS (99.3%, Method; 0.1% HCOOH; ACN,

Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 4.4 min, m/z = 336.4 [M + H]+). Anal. Calcd for

C23H29NO (335.22): C, 82.34; H, 8.71; N, 4.18. Found: C, 82.30; H, 8.71; N, 4.20.

5.4.2.2. 2-((2,4-Fluorophenylamino) (4-fluorophenyl)methyl) cyclohexanone (335b)

Yield: 86%, Off white solid, M.p: 163-165ºC (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.4), 1H-NMR

(400 MHz, CDCl3, 24oC): δ 7.33 (m, 2H, Ar-H), 7.02 (m, 3H, Ar-H), 6.78 (d, J = 8 Hz, 1H, Ar-H), 6.35

(t, J = 8.8 Hz, 1H, Ar-H), 4.89 (bs, 1H, NH), 4.59 (t, J = 6.8 Hz, 1H, CH), 2.78 (m, 1H, CH), 2.3-2.5

(m, 2H, CH2), 1.6-2.2 (m, 6H, 3CH2).13C-NMR (100 MHz, CDCl3, 24oC):δ 211.8, 163.1, 160.7, 152.5,

150.1, 136.5, 134.5, 128.9, 124.3, 121.2, 115.5, 113.6, 57.3, 42.3, 31.7, 28.5, 23.8. IR (neat): 1/λ =3375,

3025, 1760, 1619 cm-1. LCMS (98.0%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18

179

75X4.6mm 5µm, RT = 3.22 min, m/z = 334.0 [M + H]+). Anal. Calcd for C19H18F3NO (333.1) C, 68.46;

H, 5.44; N, 4.20.Found: C, 68.37; H, 5.35, N, 4.18.

5.4.2.3. 4- ((2-Chlorophenyl) (2-oxocyclohexyl) methylamino) benzonitrile (335c)

Yield: 95%, Off white solid, M.p. 225-227 ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5).1H-NMR

(400 MHz, CDCl3, 24oC): δ 7.19-7.37 (m, 6H, Ar-H), 6.6 (m, 1H, Ar-H), 6.57 (m, 1H, Ar-H), 5.7 (bs,

1H, NH), 5.36 (m, 1H, CH), 2.1-2.6 (m, 7H, 3CH2), 1.8 (m, 2H, CH2).13C NMR( 100 MHz, CDCl3,

24oC): δ 211.8, 149.9, 137.3, 136.7, 135.5, 134.9, 133.6, 130.2, 128.2, 127.3, 126.4, 113.8, 100.2, 60.3,

56.1, 53.5, 27.6, 26.8, 22.6. IR (neat): 1/λ = 3348, 3028, 2243, 1730, 1629 cm-1. LCMS (90.0%,

Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 4.10 min, m/z =

339.0 [M + H]+). Anal. Calcd for C20H19ClN2O (338.12) C, 70.90; H, 5.65; N, 8.27.Found: C, 70.80;

H, 5.68; N, 8.27.

5.4.2.4. 2-((2,4-Difluorophenylamino)(2-fluoro-methoxyphenyl)methyl)cyclohexanone (335d)

Yield: 92%, Off white solid, M.p.178-180ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.3). 1H-NMR

(400 MHz, CDCl3, 24oC): δ 6.97 (m, 2H, Ar-H), 6.76 (m, 2H, Ar-H), 6.69 (m, 1H, Ar-H), 6.48 (m, 1H,

Ar-H), 4.83 (bs, 2H, CH, NH), 3.72 (s, 3H, OCH3), 2.84 (m, 1H, CH), 2.43 (m, 2H, CH2), 1.74-1.95 (m,

6H, 3CH2). 13C-NMR (100 MHz, CDCl3, 24oC): δ 212.2, 156.4, 155.9, 155.7, 154.10, 153.4, 152.5,

150.1, 132.0, 128.9, 115.8, 113.1, 110.6, 103.4, 56.155.5, 52.4, 42.2, 32.0, 28.1, 24.2. IR (neat): 1/λ =

3364, 3019, 17410, 1614, 1474 cm-1. LCMS (99.8%, Method; 0.1% HCOOH; ACN, Flow 1mL/min,

Column C 18 75X4.6mm 5µm, RT = 3.43 min, m/z = 364.1 [M + H]+). Anal. Calcd for C20H20F3NO2

(363.14) C, 66.11; H, 5.55 N, 3.85.Found: C, 66.21; H, 5.45 N, 3.88.

5.4.2.5. 2- ( ( 3,4-Difluorophenylamino)(4- fluorophenyl)methyl)cyclohexanone (335e)

180

Yield: 88%, Off white solid, M.p: 235-238 ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.4). 1H NMR

(400 MHz, CDCl3): δ 7.34 (m, 2H, Ar-H), 7.03 (m, 3H, Ar-H), 6.89 (m, 1H, Ar-H), 6.21 (m, 2H, Ar-

H), 4.76 (bs, 1H, NH), 4.46 (s, 1H, CH), 2.73 (m, 1H, CH), 2.3-2.44 (m, 2H, CH2), 1.6-1.92 (m, 6H,

3CH2).13C NMR (100 MHz, CDCl3, 24oC): δ 212.0, 162.7, 160.3, 151.5, 149.4, 143.8, 141.6, 136.4,

128.3, 116.9, 115.1, 108.5, 102.0, 57.8, 56.8, 41.8, 31.3, 27.5, 23.7. IR (neat): 1/λ = 3323, 3018, 1761,

1619, 1464 cm-1. LCMS (98.3%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18

75X4.6mm 5µm, RT = 3.22 min, m/z = 334.0 [M + H]+). Anal. Calcd for C19H18F3NO (333.13) C,

68.46; H, 5.44; N, 4.20.Found: C, 68.46; H, 5.48; N, 4.30.

5.4.2.6. 2-((3-Fluorophenylamino)(2-(allyloxy)phenyl)methyl)cyclohexanone (335f)

Yield: 85%, Brown solid, M.p. 175-177ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2). 1H NMR

(400 MHz, CDCl3, 24oC): δ 7.37 (m, 1H, Ar-H), 7.20 (m, 1H, Ar-H), 6.8-6.96 (m, 3H, Ar-H), 6.12-6.35

(m, 4H, Ar-H, CH2=CH), 5.51 (d, J = 8 Hz, 1H, CH), 5.38 (m, 1H, CH), 5.11 (m, 1H, CH), 4.96 (bs,

1H, NH), 4.67 (s, 2H, OCH2), 2.94 (m, 1H, CH), 2.34 (m, 2H, CH2), 1.58-1.96 (m, 6H, 3CH2). 13C

NMR (100 MHz, CDCl3, 24oC): δ 213.0, 164.8, 162.4, 155.6, 148.9, 132.7, 129.6, 128.8, 127.7, 120.6,

117.1, 111.05, 109.0, 103.0, 99.6, 68.3, 55.3, 52.3, 41.6, 31.6, 27.7, 23.5. IR (neat): 1/λ =3326, 3017,

1758, 1634, 1484cm-1. MS-m/z = 354.1[M+1].. nal. Calcd for C22H24FNO2 (353.18) C, 74.76; H, 6.84;

N, 3.96.Found: C, 74.76; H, 6.88; N, 3.96.

5.4.2.7. 2-((3-Methoxyphenylamino)(2-hydroxy-3-methylphenyl)methyl) cyclohexanone (335g)

Yield: 93%, Off white solid, M.p. 185-187ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2).1H NMR

(400 MHz, CDCl3, 24oC): δ 7.36 (d, 1H, J = 12 Hz, Ar-H), 7.20 (m, 2H, Ar-H), 6.71 (m, 2H, Ar-H),

6.35 (m, 1H, Ar-H,), 6.02 (s, 1H, Ar-H), 4.42 (bs, 1H, NH), 4.01 (s, 1H, CH), 3.75 (s, 3H, -OCH3), 2.85

(m, 1H, CH), 2.11 (m, 4H, CH3, CH), 1.47-1.96 (m, 6H, 3CH2).13C NMR (100 MHz, CDCl3, 24oC): δ

211.0, 16.0, 151.5, 144.6, 129.8, 128.3, 126.2, 120.0, 119.1, 114.5, 105.2, 99.84, 74.27, 54.93, 51.27,

181

38.92, 34.81, 26.2, 25.5, 22.8, 16.22. IR (neat): 1/λ = 3356, 3037, 1757, 1636, 1464cm-1. LCMS (96.5%,

Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 4.0 min, m/z =

322.0 [M -18, -OH]). Anal. Calcd for C21H25NO3 (339.18) C, 74.31; H, 7.42; N, 4.13.Found: C, 74.34;

H, 7.52; N, 4.18.

5.4.2.8. 2-((3,4,5-Trifluorophenylamino)(4-ethylphenyl)methyl)cyclohexanone (335h)

Yield; 95%, Off white solid, M.p: 168-170 ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.6).1H NMR


Ar-H), 4.84 (bs, 1H, NH), 4.46 (s, 1H, CH), 2.77 (m, 1H, CH), 2.64 (m, 2H, CH2), 2.36-2.46 (m, 2H,

CH2), 1.62-2.01 (m, 6H, 3CH2), 1.23 (t, J = 4 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, 24oC): δ

212.1, 143.57, 137.6, 128.17, 127.05, 104.5, 101.8, 58.2, 57.2, 42.2, 31.7, 28.1, 27.9, 24.2, 15.2. IR

(neat): 1/λ = 3275, 3063, 2925, 1724, 1630, 1544, 1461 cm-1. LCMS (95.9%, Method; 0.1% HCOOH;

ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 3.90 min, m/z = 362.1 [M + H]+). Anal.

Calcd for C21H22F3NO (361.17) C, 69.79; H, 6.14; N, 3.88.Found: C, 69.79; H, 6.14; N, 3.88.

5.4.2.9. 2-((4-Methyl-3-nitrophenylamino)(4-ethylphenyl)methyl)cyclohexanone (335i)

Yield; 90%, Yellow solid, M.p.178-180ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2). 1H NMR


Ar-H), 4.84 (bs, 1H, NH), 4.5-5.0 (m, 1H, CH, NH), 2.78 (m, 1H, CH), 2.6 (m, 2H ,CH2), 2.06-2.36 (m,

5H, CH2, CH3), 1.62-1.9 (m, 6H, 3CH2), 1.22 (t, J = 4Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3,

24oC): δ 212.9, 211.3, 149.4, 146.4, 146.2, 143.4, 137.5, 128.1, 121.6, 118.6, 109.2, 58.07, 57.08, 56.2,

28.5, 26.8, 24.8, 23.8, 19.4, 15.2. IR (neat): 1/λ = 3470, 3367, 2955, 1719, 1544, 1461 cm-1. LCMS

(94.3%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 3.79 min,

182

m/z = 367.0 [M + H]+). Anal. Calcd for C22H26N2O3 (366.1) C, 72.11; H, 7.15; N, 7.64.Found: C, 71.99;

H, 7.18; N, 7.65.

5.4.2.10. 2-((Benzofuran-2-yl)(naphthalen-1-ylamino)methyl)cyclohexanone (335j)

Yield 83%, Brown solid, M.p. 218-220ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2).1H NMR (400

MHz, CDCl3, 24oC): δ 8.35 (m, 1H, Ar-H), 7.21-7.79 (m, 7H, Ar-H), 6.85 (m, 1H, Ar-H), 6.45 (m, 1H,

Ar-H), 4.60 (d, J = 8Hz, 1H, CH), 4.28 (bs, 1H, NH), 3.01 (m, 1H, CH), 1.5-2.59 (m, 8H, 4CH2). 13C

NMR (100 MHz, CDCl3, 24oC): δ 211.1, 158.0, 154.9, 140.0, 131.4, 128.7, 128.5, 124.2, 123.8, 122.5,

121.0, 120.9, 117.1, 113.7, 111.4, 104.5, 58.0, 53.10, 42.23, 35.01, 31.2, 26.3, 25.5, 21.10. IR (neat): 1/λ

= 3335, 3067, 1619, 1461, 1254 cm-1. Anal. Calcd for C25H23NO2 (369.17) C, 81.27; H, 6.27; N,

3.79.Found: C, 81.37; H, 6.27; N, 3.80.

5.4.2.11. 2-((2-Methyl-1H-indol-5-ylamino)(pyridin-4-yl)methyl)cyclohexanone (335k)

Yield 88%, Brown solid, M.p: 185-190ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2). 1H NMR (400

MHz, CDCl3, 24oC): δ = 8.59 (s, 1H, Ar-H), 8.52 (s, 1H, Ar-H), 7.94 (s, 1H, Ar-H), 7.8 (m, 1H, Ar-H),

7.34 (m, 1H, Ar-H), 7.01 (d, J = 12 Hz, 1H, Ar-H), 6.3-6.6 (m, 3H, Ar-H). 13C NMR (100 MHz, CDCl3,

24oC): δ = 211.3, 149.8, 149.3, 138.3, 137.8, 136.4, 135.5, 135.3, 134.0, 125.5, 122.6, 100.6, 62.2,

40.10, 27.1, 26.5, 21.4, 13.78. IR (neat): 1/λ = 3375, 3050, 2925, 1689, 1461, 1254 cm-1. MS, m/z

[M+1] 334. Anal. Calcd for C21H23N3O (333.18) C, 75.65; H, 6.95; N, 12.60.Found: C, 75.75; H, 6.98;

N, 12.6.

183

5.4.3. Spectral data

184

Fig. 5.8: 1 H NMR spectrum of compound 331p.

NH

CN

331p

S

185

Fig. 5.9: 13 C NMR spectrum of compound 331p.

NH

CN

331p

S

186

NH

CN

331p

S

187

Fig. 5.10: LCMS Data of compound 331p.

NH

CN

331p

S

Mol. Wt.: 254.35

188

Fig. 5.11: Single crystal X-ray structure of 331o

C16H13ClF3N, F000 = 640

Mr = 311.72 Dx = 1.450 Mg m−3

Monoclinic, P21/c Melting point = 399–400 K

Hall symbol: -P 2ybc Mo Kα radiation

λ = 0.71073 Å

a = 10.8980 (1) Å Cell parameters from 7434 reflections

b = 14.0073 (2) Å θ = 2.0–37.5º

c = 10.1651 (1) Å µ = 0.29 mm−1

β = 113.018 (1)ºT = 100 K

NH

F

F

F

Cl

189

Fig. 5.12: 1 H NMR spectrum of compound 331c.

NH

331c

190

Fig. 5.13: 13 C NMR spectrum of compound 331c

NH

331c

191

NH

331c

C17H25N

Mol. Wt.: 243.39

192

Fig. 5.14: LCMS Data of compound 331c

Fig. 5.15: 1 H NMR spectrum of compound 335a

O HN

335a

193

Fig. 5.16: 13 C NMR spectrum of compound 335a

O HN

335a

194

O HN

335a

C23H29NOMol. Wt.: 335.48

195

Fig. 5.17: LCMS data of compound 335a

Fig. 5.18: Crystal structure of compound 335a

Crystal data

C23H29NO Z = 2

Mr = 335.47 F000 = 364

Triclinic, P1 Dx = 1.204 Mg m−3

Hall symbol: -P 1 Melting point = 439–441 K

a = 6.5315 (2) Å Mo Kα radiation

λ = 0.71073 Å

b = 12.3946 (3) Å Cell parameters from 4449 reflections

c = 12.8853 (3) Å θ = 1.8–28.0º

α = 62.973 (1)º µ = 0.07 mm−1

β = 86.347 (2)º T = 100 K

γ = 85.103 (2)º Plate, colorless

NH

O

196

Fig. 5.19: 1 H NMR spectrum of compound 335k

HN

N

O NH

335K

197

Fig. 5.20: 13 C NMR spectrum of compound 335k

HN

N

O NH

335K

198

HN

N

O NH

335K

199

Fig. 5.21: LCMS data of compound 335k

5.5. Conclusion

HN

N

O NH

335K

Mol. Wt.: 333.43

200

This chapter describes a convenient and efficient process for the synthesis of two series of

compounds. Seventeen homoallylic amines are prepared though a three components coupling of various

aldehydes and amines with allyltributyltin in the presence of catalytic amount of CF3COOH. In addition

to its simplicity, efficiency and mild reaction conditions, this method provides high to excellent yields

of products in a short period which makes it a useful and attractive process for the synthesis of

homoallylic amines of synthetic importance. Newly synthesized compounds were characterized by 1H-

NMR, 13C-NMR, Mass spectrometry, X-ray study and elemental analyses. In another series eleven β-

amino ketone are prepared via CeCl3-catalyzed cascade reaction of anilines with various aromatic

aldehydes and carbonyl compounds. The significant features of this procedure include: facile operation,

cheap and readily available catalyst, high yields, and reasonably good diastereo selectivities, very less

reaction time. Antimicrobial activities of both the series are discussed in Chapter-6.

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