NAFION AS A CATALYST IN ORGANIC...

Chapter I

12

NAFION AS A CATALYST IN ORGANIC SYNTHESIS

The Nafion catalyst, a perfluroalkanesulfonic acid resin was developed by

DuPont chemists in early 1960 during work with General Electric on a fuel cell.1 The

IUPAC nomenclature of Nafion is tetrafluoroethylene-perfluoro-3,6-dioxa-4-methyl-

7-octensulfonic acid and the chemical formula is shown in Figure 1.

CF2

F2C

CF

F2C

OF2C

CF

CF3

OCF2

F2C

SO

OOH

n

m

Figure 1

Where is the value of m could be as low as 1 and the value of n ranges

between 6 to 13.2 It has hydrophobic (-CF2-CF2-) and hydrophilic (-SO3H) regions in

its structure and its super acidity due to the electron withdrawing effect of the

perfluoroalkyl backbone to which the sulfonic acid group is attached. The estimated

Hammett (H0) value for Nafion-H is comparable to that of 96-100% sulfuric acid

(H0 = -12.0).3

Nafion was first synthesized by the copolymerization of tetrafluoroethylene

(TFE) i.e. monomer in Teflon and the derivatives of a perfluoro (alkyl vinyl ether)

with sulfonic acid fluoride. The resulting product is an -SO2F- containing

thermoplastic that is extracted into films. Hot aqueous NaOH converted these sulfonyl

fluoride (-SO2F-) groups into sulfonate groups (-SO3-Na+). This form of Nafion is

referred to as a neutral or salt form, is finally converted to the acid form containing

the sulfonic acid (-SO3H) groups.

Chapter I

13

Nafion, the acidic form of the polymeric fluorinated sulfonic acid has been

widely investigated as an acidic catalyst for organic reactions.4 Nafion containing

substantial amount of water has been shown to be composed principally a source of

RfSO3-.H3O+ ion pairs and is potentially a source of H+aq. However, in its catalytic

chemistry, the material behaves as a much stronger acid than H+aq. The composition

of the materials explains its catalytic behavior.

Nafion is a heterogeneous recyclable Bronsted solid acid catalyst, acts as

water tolerant ion exchange resin. The swelling properties of the dried Nafion in

different solvents (i.e. methanol, water and trigyceride) were examined. Swelling in

water was investigated because it may be present in lower-quality biodiesel feed-

stocks. The kinetics of transesterification of vegetable oils, a highly refined olive oil

(acid value = 0.04) is also used, as a solvent for comparison. The catalyst dimensions

(obtained with a vernier caliper) and weights were measured for several Nafion

cylindrical-shaped pellets before and after soaking in the pure solvent at 60 °C

(typical transesterification reaction temperature) until equilibrium were reached.

Irreversible swelling after cooling has been proved to be a good assumption for this

type of system.5 The volume increase was measured and also estimated using the

relationship suggested6 to consider that the Nafion and the solvent volume are

additive. The resin was treated in methanol resulted in the high degree of swelling as a

result of physicochemical changes. Water showed a moderate capability for swelling

the resin, which is advantageous from the standpoint of greater acid site accessibility.

However, water may also lower the acid strength of the active sites7 or cause

deactivation via hydrolysis, as has been suggested for related sulfonic acid catalytic

materials.8 It has been reported that the mixture of short-chain alcohols and water

cause a greater degree of swelling than either the short chain alcohol or alone.

Chapter I

14

THF/water mixture provides the great degree of swelling of the Nafion resin (as

communicated by DuPont). Both short chain (triacetin) and long chain (olive oil)

triglycerides showed essentially no swelling capability for the perfluorinated resin,

which is analogous to the swelling characteristics obtained with free fatty acids such

as oleic acid.9 A change in color from transparent to dark amber was observed when

Nafion was soaked in either short-chain or long-chain triglycerides, indicating the

presence of possible side reactions (formation of carbonaceous deposits).

Nafion is unaffected by strong bases, strong oxidizing and reducing acids,

chlorine, oxygen, hydrogen, and hydrogen peroxide at temperature up to 125 °C.10 It

is thermally stable to about 170 °C in the acid form and stable to higher temperature

200-235 °C on replacement of protons by metal counter-ions.11

Nafion is a recyclable Bronsted acid catalyst and hence is able to catalyze a

variety of organic reactions such as transalkylation, ether synthesis, esterification, the

condensation of ketones, Pinacol-Pinacolone and Fries rearrangements.

The perfluorinated resin sulfonic acid (Nafion) is a recyclable heterogeneous

Bronsted acid catalyst which facilitates the various organic synthesis. Due to this

reason, it has received more attention in the area of organic synthesis.

Friedel-Crafts alkylation of benzene (1) with substituted alkenes (2) was

catalyzed by Nafion-H at 125-210 °C to yield the substituted benzene (3)

(Scheme 1).12

HC CH2R Nafion-H125-210 oC+

CHCH3

R

R = H, CH3

(3)(2)(1)

Scheme 1

Chapter I

15

Subsequently, Olah et al. has reported the use of Nafion-H in the Friedel-

Crafts acylation of aroyl chlorides (4) with toluene (5) to give substituted

methylbenzophenones (6) (Scheme 2).13

Nafion-H

R = H, 4-CH3, 2-F, 3-F, 4-F, 3-Cl(4) (5) (6)

ClC

ORCH3 C

O

CH3

R+

Scheme 2

The synthesis of mesitylene (8) and bromotoluene (9) was carried out by the

nucleophilic reaction of bromomesitylene (7) with toluene (5) in the presence of

Nafion-H catalyst under heating condition (Scheme 3).14

BrCH3H3C

CH3 CH3

BrCH3

Nafion-H,+ +

(7) (5) (8) (9)

CH3H3C

CH3

Δ

Scheme 3

Christian et al. has described the formation of pyrylium salts (12) from tertiary

and secondary alcohols (10) with carboxylic acid anhydrides (11) in the presence of

perfluorinated resinsulphonic acid Nafion-H (Scheme 4).15

OC

O

R1CO

R1R OH +

N

R

R1R1

Nafion-HCCl4, NH4OH

(10) (11) (12)R = t-Butyl alcohol, 2-Methylbutan-2-ol, 2-Methylpentan-2-ol, 3-Methylpentan-3-olR1 = Me, Et

Scheme 4

Chapter I

16

The 1,1-diacetates (15) were generally prepared by the equivalent amount of

aldehydes (13) and freshly distilled acetic anhydride (14) using catalytic amount of

Nafion-H at ambient temperature (Scheme 5).16

+ OC

O

CO

O

R

H

CH3

CH3

Nafion-H

(13) (14) (15)

CO

C

C

O

CH3

CH3

O

R H

O

R = Ph, p-O2NC6H4, p-ClC6H4, p-FC6H4, CH3, c-C6H11, Cl3C, C4H3O, o-ClC6H4, PhCH=CH-

Scheme 5

Fries rearrangement of phenol esters (16) to hydroxyphenyl ketones (17) was

carried out in the presence of Nafion-H (Scheme 6).17

Nafion-H

(16) (17)R = H, 4-CH3, 3-Cl; R1 = H, 4-CH3; X = OH, 2-OH

OC

O

C

O R1R R1 R

Scheme 6

The reductive cleavage of acetals (18) to the corresponding ethers (20) and

triethylsilane alkylethers (21) were carried out under Nafion-H catalysis with

triethylsilane (19) in refluxing dichloromethane solution (Scheme 7).18

CR1

R2 OR3

OR3Nafion-H CHO

R1

R2R3 (Et)3SiO R3

(20) (21)(18)

CH2Cl2,(Et)3Si H

(19)

+ +

R1 = H, Ph, CH3(CH2)8; R2 = H, CH3; R3 = CH3, C2H5

R1 = R2 =

Δ

,

Scheme 7

Chapter I

17

The Ritter reaction of alcohols (10) with nitriles (22) was described by Olah et

al. to yield the corresponding amides (23) using recyclable Nafion-H catalyst

(Scheme 8).19

R1 OH R1 HN RC

O

R C N Nafion-H,+

(10) (22) (23)

R = PhCH2, 2,4-Dimethyl-benzyl,1-Adamantane, 2-Adamantane, 2-Norbornane, exo-2-Phenyl-2-norbornaneR1 = CH3, Ph

Δ

Scheme 8

Nafion-H was reported an effective acid resin catalyst for the intramolecular

aromatic substitution of N-aryldiazoacetamides (24) to form the corresponding 2(3H)-

indolinones (25) in refluxing chloroform (Scheme 9).20

N

R1 N2

ZO

Nafion- H

(24)

R

N

R1

O

Z(25)

R = H, 2,3-(CH3)2, m-CH3, 3,4-CH2(O)2, α-NaphthylR1 = H, Et, Ben; Z = H, CH3CO

R

Scheme 9

The condensation of acetophenones (26) to 1,3,5-triarylbenzenes (27) was

catalyzed by Nafion-H under relatively mild reaction conditions at 145-150 °C

(Scheme 10).21

Chapter I

18

R1

R2

R1

R2

R2

R1

CH3O

R1

R2

Nafion-H145-150 oC

(26) (27)

R1 = H, CH3, CH3CH2, t-Bu, OCH3, Br, Cl, NO2; R2 = H, Br, OCH3

Scheme 10

Nafion-H was found to be an excellent acid catalyst for the direct conversion

of acetals (18) to thioacetals (28) with 1,2-ethanedithiol in methylene chloride

solution (Scheme 11).22

CR1

R2

OR3

OR3

HSCH2CH2SHNafion-H

CH2Cl2, reflux

CR1

R2

S

S

(18) (28)

R1 = Ph, CH3CH2CH2, CH3(CH2)5, (CH2)2, (CH2)5, (CH2)6 R2 = H, CH3, Ph, CH3CH2CH2, CH3(CH2)5, (CH2)2, (CH2)5, (CH2)6 R3 = MeO, EtO, ; R1 = R2 =

Scheme 11

Friedel-crafts reaction of substituted calix[4]arenes (29) with diphenyl ether in

the presence of Nafion-H resulted in the formation of [9,9]spirobixanthene (30)

(Scheme 12).23

Chapter I

19

OH HOOHOHR R

R

R

Nafion-H(Ph)2O C

O

O

(29) (30)R = t-Bu, H

Scheme 12

Kobayashi et al. has described Sc-Nafion catalyzed allylation reaction of

carbonyl compounds (31) with tetraallyltin (32) to afford the desired homoallylic

alcohols (33) in high yields at room temperature (Scheme 13).24

Sn

4

+ Nafion-ScCH3CN, rt R

OH

(33)(31)R = Ph, PhCH2, Ph(CH2)2, 2-Pyridine, PhHC=CHR1 = H, CH3, COOMe; (31) = D-arabinose, D-ribose, D-glucose

(32)

R R1

O

R1

Scheme 13

Nafion-H was found to be an highly efficient solid acid catalyst for the

biomolecular conversion of alcohols (10) to ethers (34) in excellent yields (Scheme 14).25

2 R OH Nafion-H,O RR-H2O

(10) (34)R = CH3(CH2)4, CH3(CH2)5, CH3(CH2)6, CH3(CH2)7, CH3(CH2)8, CH3(CH2)9, 3-MeC4H9, 2-EtC6H12, 3,7-Me2C8H15, 3,5,5-Me3C6H10, c-C6H11, 1-MeC4H8, 1-EtC4H8, 1-MeC7H14,

Δ

Scheme 14

Chapter I

20

Mukaiyama aldol condensation was carried out between aromatic aldehydes

(35) and the Danishefsky diene (36) which undergo Diels-Alder cyclization to form

the 2,3-dihydro-γ-pyridones (38) through the formation of imine intermediate (37) in

the presence of Nafion-H (Scheme 15).26

Me3SiO

OMe

+

XH

Nafion-HOMe

XSiMe3O

RX

O

(36)(35) (37) (38)

R

X = O, NPh; R = H, 3-CH3, 2-NO2, C4H3O, 4-CH3, 4-OCH3, 4-Br, RC6H4 = 2-Furyl, 3-PyridylR

Scheme 15

Vankar et al. has reported that the catalytic amount of Nafion-H along with

NaI (1 equiv.), in methanol cleaved a variety of tert-butyldimethyl silyl ether

(TBDMS) (39) readily in to corresponding alcohols (10) in high yields

(Scheme 16).27

Nafion-H, NaIMethanol

(39) (10)R OTBDMS R OH

R = Alkyl, Aryl, Cyclic

Scheme 16

The deprotection of trimethylsilyl ethers (40) to their corresponding alcohols

(10) was carried out in the presence of Nafion-H and wet SiO2 in n-hexane at room

temperature (Scheme 17).28

Chapter I

21

R OTMSNafion-H,

n-Hexane, rt R OH(40) (10)

R = 4-CH3OC6H4CH2, 4-(CH3)2CHC6H4CH2, 4-(CH3)3CC6H4CH2, 2-ClC6H4CH2, 2,4-Cl2C6H3CH2, 2-BrC6H4CH2, 2-O2NC6H4CH2, 3-O2NC6H4CH2, 4-O2NC6H4CH2, n-C7H15, n-C8H17, PhHC=CHCH2,

wet SiO2

H2C

O

O

CH2

H2C

H2C

O CH2

H2C

CH2

CH3

H2C

,

,,

,

,,

,

Scheme 17

The one-pot three-component synthesis of 2,3-disubstituted 4-(3H)-

quinazolinones (44) from o-aminobenzoic acid (41), alkyl/aryl-trietoxymethanes (42)

and aromatic amines (43) was catalyzed by Nafion-H under solvent-free microwave

irradiation conditions (Scheme 18).29

OH

NH2O

NH2

R C

OEt

OEt

OEt R1+ + Nafion-HMW

N

N

OR1

R

(44)(41) (42) (43)

R = H, Me, Et, Ph; R1= 3-CF3, 4-CF3, 2,4-(NO2)2, 2-Cl-5-CF3

Scheme 18

The multicomponent reaction of cyclic β-diketones (45), urea (46) and

aldehydes (13) was reported for the synthesis of octahydroquinazolinone derivatives

(47 & 48) over Nafion-H with good yield and selectivity (Scheme 19).30

Chapter I

22

Nafion-HEthanol, refluxH2N NH2

O

(46)

+

O

OR

R

(13)

R = H, CH3R1 = C6H5, 4-H3CC6H4, 3-ClC6H4, 4-ClC6H4, 2-BrC6H4, 3-BrC6H4, 4-BrC6H4, 4-O2NC6H4, 4-CH3OC6H4, 4-FC6H4, 3-FC6H4, 2,4-Cl2C6H3, 3-Pyridine, 4-Pyridine

R1 H

O

O

NH

HN O

R1O

O O

R

R

R1

R

R

R

R

+

(45)

(48)

(47)

Scheme 19

Narsaiah et al. has developed a one-pot multicomponent condensation of aryl

aldehydes (13), enolisable ketones (49) and acetyl chloride (50) using Nafion-H

catalyst for the synthesis of β-acetamido ketones in acetonitrile (51) at room

temperature (Scheme 20).31

R1

O

CH3COCl Nafion-HCH3CN, rt

R R1

ONHAc

+ +

(13) (49) (50) (51)R= Ph, 4-FC6H4, 4-O2NC6H4, 2-O2NC6H4, 3-O2NC6H4, 4-MeOOCC6H4, 2-ClC6H4, 4-MeOC6H4, 4-ClC6H4, 4-H3CC6H4R1 = Ph, 4-ClC6H4, 4-H3CC6H4, 4-MeOC6H4, 4-O2NC6H4, 4-BrC6H4; R2 = H

R H

O R2

R2

Scheme 20

The hydroamination of vinylpyridines (52) with aliphatic and aromatic amines

(53) was developed for the synthesis of disubstituted-(2-pyridin-2-yl-ethyl)-amines

(54) using cation exchange resin Nafion-NR50 under milder reaction conditions

(Scheme 21).32

Chapter I

23

N

+ NH

R1

R2

Nafion-NR50Ethanol, reflux

NN

R1

R2

(52) (53) (54)R1= H, Aryl, Alkyl; R2 = Aryl, Alkyl

Scheme 21

A novel one-pot solvent-free synthesis of 1,3,4-oxadiazoles (57) was

reported by the condensation of acid hydrazides (55) and triethyl orthoalkanates

(56) using solid supported Nafion®NR50 under microwave irradiation

(Scheme 22).33

Nafion NR50

R1 = H, F, OMe, 2-Furyl, 2-Thienyl, 4-Pyridyl; R2 = H, Et, C6H5

N N

O R2

R1

NHNH2

O

R1O O

R2 O

(55) (56) (57)

+ MW

®

Scheme 22

The Ritter reaction of nitriles (58) and alcohols (59) was reported for solvent-

free synthesis of amides (60) catalyzed by Nafion®NR50 under microwave irradiation

(Scheme 23).34

Nafion NR50MW, 130 oC

CR1 N R2

OH

NH

R2

O

R1+

R1 = H, MeO, Cl; R2 = H, Me, MeO, Cl, Naphthyl, Adamantyl

(58) (59) (60)

®

Scheme 23

Chapter I

24

The one-pot synthesis of nitrones (62) via direct condensation/oxidation of

aldehydes (13) and primary amines (61) using Nafion immobilized MoOCl4 as

catalyst and solid urea-hydrogen peroxide (UHP) as oxidant was described under very

mild reaction conditions (Scheme 24).35

R1 H

O

+ H2N R2 Nafion-MoUHP, MeOH, rt N+ R2

O-

R1

(13) (61) (62)

R1 = Ph, 4-MeOC6H4, 4-O2NC6H4, 2-Furyl, CH3(CH2)2CH2 R2 = PhCH2, n-Bu, t-Bu

Scheme 24

Kidwai et al. has reported the synthesis of 2-aminothiazoles (65) from α-

bromoketones (63) with thiourea derivatives (64) using Nafion-H as a solid acid

catalyst coupled with aqueous PEG-400 system (Scheme 25).36

CH2Br

O

+ CH2N NHR1

S

PEG:water (60:40)N

SNHR1

(65)(63) (64)

R = H, p-Me, p-BrR1 = H, Ph, 2-Naphthyl, p-BrC6H4, p-MeOC6H4, p-MeC6H4, p-HOC6H4, p-O2NC6H4

Nafion-H, 50 oC

R

R

Scheme 25

Chapter I

25

PROPARGYLAMINES

Propargylamine or propargylic amines (66) are highly useful building blocks

in organic synthesis and the corresponding structural motif has been found in various

natural products and compounds of pharmaceutical relevance.37

NH

(66)

The classical methodologies for the preparation of propargylic amines have

usually exploited the relatively high acidity of terminal acetylenic C-H bond to form

alkynes-metal reagents by the reaction with strong base.

Propargylamines are versatile synthetic intermediates for organic synthesis,

especially for the synthesis of heterocyclic compounds such as oxazolidinones,

imidazoles and pyrroles etc.

4-Methylene-2-imidazolidinones (69) were obtained by the base catalyzed

cyclization of propargylic ureas (68), which were synthesized by the reaction of 3-

alkylamino-1-butyne (67) with isocyanate (Scheme 26).38

HNH

H3C

R1R2NCO NaOCH3

HN

H3C

R1NHR2

ON

N

O

R2

R1

H3C

CH2

(67) (68) (69)

R1 = c-C6H11, (CH3)3C-CH2-(CH3)2C; R2 = 4-ClC6H4, 2,5-Cl2C6H3

Scheme 26

Reaction of β-oxodithioesters (70) with propargylamine (71) afforded the

corresponding 2-(acylalkylidene)-5-(methylene)thiazolidines (72) (Scheme 27).39

Chapter I

26

R SMe

O S+ HC C CH2NH2

EtOHR S

O HN

(70) (71) (72)R = CH3, C6H5, 4-MeOC6H4

Δ

Scheme 27

Reaction of 1-(N-methyl-N-phenylaminomethyl) benzotriazole (73)

with alkynylalkylaluminates (74) gave corresponding propargylamines (75)

(Scheme 28).40

(73) (74) (75)

N

NN

NPh

R)2NaEt2Al(+R

N Ph

R = H, C6H5

Scheme 28

Copper(I)-catalyzed direct alkyne-imine addition reaction of N-

benzylideneanilines (77) with phenylacetylene (76) was carried out in the presence of

H2O resulted in the formation of propargylamines (78) (Scheme 29).41

R H2O or Toluene

R = Ph Ar' = C6H5, 4-MeC6H4, 4-ClC6H4, 4-BrC6H4Ar = C6H5, 4-MeC6H4, 4-EtC6H4, 4-ClC6H4, 4-BrC6H4

(76) (77) (78)

+H 10 mol% Cu(OTf)

Ar

NHAr'

Ph

N

Ar

Ar'

Scheme 29

Chapter I

27

Enantioselective, Copper(I)-catalyzed three-component reaction of alkynes

(76), aldehydes (13) and secondary amines (53) was reported to afford the

corresponding propargylamines (79) in toluene at room temperature by using CuBr (5

mol%) and (R)-quinap (R)-2 (5.5 mol%) (Scheme 30).42

R

R = C6H5, n-Bu, 4-BrC6H4, SiMe3, c-Hex; R1 = Ph, i-Bu, i-Pro, c-Hex, 1-Ethylpropayl, 4-MeOC6H4, 4-F3CC6H4, 2-H3CC6H4, 3-Furanyl, 3-Benzothiphenyl; R2 = R3 = Bn, Allyl

(76) (13) (53) (79)

NHR2

R3+H

R2 N

R3

RR1

R1 H

O

+(R)-quinap (R)-2

(5.5 mol%)

CuBr (5 mol%)Toluene, rt

Scheme 30

Substituted propargylamides (82) were obtained by the metal catalyzed

coupling of imines (80) with alkynes (76) and acid chlorides (81) (Scheme 31).43

R CH3CN, rt

R = C6H5, (CH3)3Si, CH2Cl, n-C4H9R1 = 4-H3CC6H4, 4-H3CSC6H4, 4-BrC6H4R2 = Bn, H2COOCCH3, C2H5; R3 = C6H5, CH3, i-Pr

+HCuI, i-Pr2NEt

O

R3 ClR1 H

NR2

+N

R1

R

R2

O

R3

(76) (80) (81) (82)

Scheme 31

Reaction of activated quinolines (83) with terminal acetylenes (76) in the

presence of copper iodide and i-Pr2NEt afforded the corresponding 2-alkynyl-1,2-

dihydroquinolines (84) (Scheme 32).44

Chapter I

28

R

R = C6H5, CH3(CH2)4CH2, CH2OH

HCuI

+

(76) (83) (84)

CH2Cl2, rti-Pr2NEt

N

OEtO

Cl-N

OEtOR

Scheme 32

Reaction of alkynes (76) to N-tert-butanesulfinimines (85) in the presence of a

base lithium hexamethyldisilazide (LiHMDS) provided the corresponding N-tert-

butylsulfinylpropargylamines (86) (Scheme 33).45

R n-Hexane

R = C6H5, (CH3)3Si, n-C4H9R1 = C6H5, 4-CH3OC6H4, n-Bu, t-Bu, i-Pr, trans-PhCH=CH

HLiHMDS

R1 H

NS

+HN

R1

R(76) (85) (86)

O

-78 oC to rt

S

O

Scheme 33

α-[4-(1-Substituted)-1,2,3-triazol-4-yl]benzylacetamides (88) were obtained

via microwave-assisted Cu(I)-catalyzed reaction of chiral propargylamines (87) with

phenyl azide or sodium azide (Scheme 34).46

NHR1

R

NHR1

N

NN

n1. Ac2O, Et3N, CH2Cl2, rt2. NaN3, C6H5CH2Cl

sodium ascorbate/(CuSO4),H2O/t-ButOH, MW

R = H, 4-F, 4-Br, 4-Cl; R1 = Ac, H; n = 0,1

(87) (88)

R

Scheme 34

Chapter I

29

Au-nanoparticles were catalyzed multicomponent A3-coupling reaction of

aldehydes (13), amines (53) and alkynes (76) to give the propargylamines (89) in

excellent yields at 70-80 oC under nitrogen atmosphere (Scheme 35).47

R

R = C6H5, 4-MeC6H4, 4-MeOC6H4, 3-ClC6H4, 4-BrC6H4, 2-Furfuryl, 2-Thiophenyl, 3-Pyridenyl R2R3NH = Piperidine, Morpholine, Pyrrolidine

(13) (53) (76) (89)

NH

R2

R3

+ H

R2

NR3

R

R1 H

O

+R1

10 mol% Au-np (18 2 nm)±THF 75-80 oC, N2, 1 atm

Scheme 35

Addition of lithium trifluoromethylacetylide (90), in situ prepared from

lithium diisopropylamide and 2-bromo-3,3,3-trifluoropropene to various N-tert-

butanesulfinyl imines (91) provided the corresponding trifluoromethylated propargyl

sulfinamides (92) (Scheme 36).48

Li

R1 = CH3 ; R2 = C2H5, C6H5, i-Pr, i-Bu

F3CMe3Al

(90) (91) (92)

Toulene+S

N R2

O R1NH

SO

R2

R1

CF3

Scheme 36

Propargylamines (94) were obtained by the reaction of phenylacetylene (93)

and aldehydes (13) with heterocyclic amines (53) using zinc titanate nanopowder in

aqueous medium at 100 oC (Scheme 37).49

Chapter I

30

R = Ph, 4-ClC6H4, 4-BrC6H4, 2-HOC6H4, 3,4-(MeO)2C6H3, 4-Me2NC6H4, 4-ClC6H4, CH3CH2CH2 R1R2NH = Piperidine, Pyrrolidine, Morpholine, Piperazine, N-Methylpiperazine

(93) (13) (53) (94)

NHR1

R2

+

H R1

NR2

R H

O

+Rwater (5 mL)

100 oC

Zinc titanatenanopowder

(5 mol%)

Scheme 37

NiCl2-catalyzed A3-coupling reaction of alkynes (76), aldehydes (13) and

amines (53) gave the corresponding propargylamines (89) in quantitative yields

(Scheme 38).50

R

R = Ph, CH3(CH2)5, 4-MeC6H4, (CH3)3Si R1 = H, C6H5, 4-O2NC6H4, 3-O2NC6H4, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, Cyclohexyl, 2-ClC6H4, 3-ClC6H4, 2,4-Cl2C6H3, Me2CH, 2-Thiophene R2R3NH = Piperidine, Pyrrolidine, Morpholine, Piperazine, N-Methylpiperazine, N-Methylaniline, Aniline, Dibenzyl amine, N-Methylpiperazine, Ammonia, Benzylamine, Methyl amine, n-Butylamine, Ethyl-1-piperazinecarboxylate

(76) (13) (53) (89)

NHR2

R3

+H

R2

NR3

R

R1 H

O

+

R1Toluene, 100 oC

NiCl2

Scheme 38

Fe3O4 nanoparticle-supported copper(I) pybox-catalyzed enantioselective

direct-addition reactions of terminal alkynes (76) to imines (95) gave the

corresponding propargylamines derivatives (96) (Scheme 39).51

Chapter I

31

N

R1

R

HN

R2

R2H

Fe3O4 nanoparticle-supported copper(I)pybox catalyst

(10 mol%)CH2Cl2

R

R1

+

(95) (76) (96)

R = H, p-Br, p-Cl, p-CF3; R1 = H, p-Br; R2 = Ph, p-MeC6H4

Scheme 39

The synthesis of various propargylamines (97) was achieved by the simple

Barbier–Grignard-type reaction of phenylacetylene (93) with a variety of aldimines

(80) catalyzed by a bimetallic In–Cu system under aqueous condition (Scheme 40).52

NR1

R

HN

R1

R+

(93) (80) (97)

R = R1 = H, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4, 4-O2NC6H4, 4-MeC6H4SO2

In-CuH2O, 40 oC

Scheme 40

Gold nanoparticles impregnated on alumina catalyzed A3-coupling reaction of

aldehydes (13), amines (53) and alkynes (76) to give corresponding propargylamines

(89). The aldimine (98) formation was catalyzed by Montmorillonite K10 beforehand

(Scheme 41).53

R2NH

R1

R1

HR H

O

+N

R1

R

R1

NR1

R2R

R1

Au-np@Al2O3 80 oCMM K-10 25 oC

(76)

(13) (53) (98) (89)R = C6H5, C5H5N, C4H3O, C6H5CH2CH2, CH3(CH2)5R1R1NH = Piperidine, Morpholine, Pyrrolidine, Diethylamine, 2-(Methylamino)ethanolR2 = C6H5

Scheme 41

Chapter I

32

Pargyline derivatives (99) and (100) were prepared from 8-

(methylaminomethyl)quinoline and exhibited anti-monoamine oxidase activity.54

H2C NCH2C CH

Me(99)

N

N CH2C

(100)

Me CH

The propargylamine derivative (101) potentiated tryptamine convulsions of

rats similar to Pargyline had slight stimulating effect.55

H2C NMeCH2C CH(101)

A series of 10-propargyl-5,8-dideazafolic acid derivatives (102) were

synthesized and tested for inhibition of purified L1210 thymidylate synthase and for

inhibition of L1210 cell growth in vitro.56

(102)

HN

N

CH2N

R

O CH2C CH

R2

R1

R3

R = NH2; R1 = H, Cl, MeOR2 = H, Cl, Ac, F, CN, CONH2, SO2NMe2, NO2, COCF3, OCF3 R3 = H, MeO

A series of acetylenic imidazoles (103) related to oxotremorine were prepared

and evaluated as cholinergic agents with in vitro binding assays and in vivo

pharmacological tests in mice.57

Chapter I

33

NCH2C CCH2NN

O R

R1

R = H, MeR1 = H, Me

(103)

2-Alkynyl and 2-cycloalkynyl derivatives of adenosine-5'-N-ethyluronamide

(NECA) (104) were prepared as selective A2 adenosine receptor agonists with potent

inhibitory activity on platelet aggregation.58

N

N N

N

CRC

O

OH OH

EtHNOC

R = H, Hydroxyalkyl, 1-Hydroxycyclopentyl, Aminoalkyl, 1-Aminocyclohexyl, Alkenyl, (CH2)3CN, (CH2)3Cl

(104)

NH2

Cyclo-hexapeptide analogue (105) was synthesized starting from

propargylamine and found to possess anti-parallel β-sheet structure.59

CHN

Me

NH

C

HN

O

NH

Me

C

C

Me(105)

O

Chapter I

34

2-(2,6-Difluorophenyl)-4-phenylalkynyl oxazolines (106) were prepared as a

potent insect growth regulators.60

F

F

N

OR

R = Me3C, Me3CO, H, CF3, 4-CF3SO3C6H4, 4-BrC6H4, 4-FC6H4, Ph(106)

Compound (107) related to 2-azatidinone was synthesized as single

enantiomer and found to be potent cholesterol absorption inhibitors.61

(107)

N

O

HO

F

NH

HN

O

O O

OH

HO OH

OH

O

O

O

O

COOHHO

Chapter I

35

[(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate (108) was

synthesized as anti-apoptotic-neuroprotective agent and as a novel

cholinesterasemonoamine oxidase inhibitor.62

HNO

O

N

(108)

1,8-Naphthyridine-3-carboxamide derivatives (109) were synthesized as

anticancer and anti-inflammatory agent and tested for in vitro cytotoxicity against

eight cancer cell lines and a normal cell line with IC50 = 1.37 μM for HBL-100

(breast) cell line.63

N N

O

NH

O

O O

NH

OBu-tO

CH(109)

R

R = Cl, Me

1-alkyl-N-propargyl-1,2,3,4-tetrahydroisoquinoline derivatives (110) were

synthesized from 2-phenylethylamine and showed cytotoxic effect on PC12 cells.64

N

R

R = Ph, Methyl, Ethyl, n-Propyl, n-Butyl, n-Pentyl, n-Hexyl cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, 3-Hydroxypropyl, 3-Acetoxypropyl

(110)

Rasagiline (N-propargyl-1-(R)-aminoindan) (111) was synthesized as potent

irreversible monoamine oxidase (MAO)-B inhibitor, anti-Parkinsonian drug and

Chapter I

36

effected as monotherapy or adjunct to L-Dopa for patients with early and late

Parkinson’s disease (PD).65

HN(111)

The length of synthesis is dependent upon the average molecular complexity

produced per operation, which depend in turn on the number of chemical bonds being

created. Therefore, devising reaction that achieves multi-bond formation in single

operation is becoming a major challenge in search of step economy synthesis.

Multicomponent Reactions (MCRs) found to be a straight forward route to generate

complexity with diversity in a single operation. MCRs processes66, in which three or

more reactants are combined in a single chemical process to produce product that

incorporate substantial portions of all the components, naturally comply with many of

stringent methods required for ideal organic synthesis.

MCRs, though fashionable these days, have in fact a long history. Indeed,

many important reactions such as the Strecker amino acid synthesis (1850)67, the

Hantsch dihydropyridine synthesis (1882)68, the Biginelli dihydropyrimidine (1891)69

and the Mannich reaction70 etc. are all multicomponent in nature. Inspite of the

significant contribution of MCRs to the state of the art of the modern organic

chemistry and their potential use in complex organic syntheses, little attention was

paid to the development MCRs. However, with the introduction of molecular biology

and high-throughput biological screening, the demand on the number and the quality

of compounds for drug delivery has increased enormously. By virtue of their inherent

convergence and high productivity, together with their exploratory and complexity-

Chapter I

37

generating power, MCRs became a rapidly evolving field of research and have

attracted the attention of both academic and industrial scientists.

Carbon-Carbon bond-forming reactions are arguably the most important

processes in chemistry, as they represent the key step in the building of more complex

molecules from simple precursors. In the past few years, organic chemists have

developed a plethora of reactions for carbon-carbon bond formation between saturated

sp3 C-atoms. However, until the discovery and development of metal-mediated cross-

coupling reactions, starting in 1970s, there was no simple, general direct methodology

known for carbon-carbon bond formation between unsaturated species such as aryl,

vinyl and alkynyl moieties. In other words, carbon-carbon bond formation between sp

and sp2 C-atom centers are often difficult and tedious. In the intervening 25 years, a

wide variety of cross-coupling methodologies have been developed and cross-

coupling reactions have emerged among the most powerful and useful synthetic tools

in chemistry.71

Chapter I

38

OBJECT OF THE PRESENT WORK

An increasing awareness of the environmental cost of traditional acid-

catalyzed chemical processes has created an opportunity for new solid acid-based

approaches to many important industrial reactions.72,73 The replacement of

conventional, toxic and polluting Bronsted and Lewis acid catalysts with eco-friendly

reusable solid acid heterogeneous catalysts like acidic zeolites, clays, sulfated zirconia

and ion exchange resins is an area of current interest.74-77 The use of solid acid

catalyst instead of liquid includes many advantages such as reduced equipment

corrosion, ease of product separation, recycling of the catalyst and environmentally

acceptability.

In recent years, resins containing perfluorosulphonic acid group such as

Nafion®NR5078 (copolymer of tetrafluroethylene and perfluoro-2-

(fluorosulfonylethoxy) propyl vinyl ether), which is strongly acidic in nature and

chemically as well as thermally stable has been found to be an excellent catalyst for a

variety of major organic reactions like alkylation, acylation, esterification,

etherification, dehydration and nitration.79,80

Multicomponent coupling reactions (MCRs) provide a powerful synthetic

strategy to access complicated structure from rather simple starting material via a one-

pot methodology, and in particular, exhibit high atom economy and selectivity.81 As

continuation, a very good example of such a process that has been studied widely in

recent years is three-component coupling of aldehydes, amines and alkynes (A3-

coupling) via C-H activation.82,83 The propargylamines that result from A3-coupling

reactions are versatile building blocks for organic synthesis. They are generally used

as precursors for the synthesis of N-containing heterocyclic compounds such as

pyrrolidines, oxazoles and pyrroles84 and also act as key intermediates85 for the

Chapter I

39

construction of biologically active compounds like isosteres, β-lactams, oxotremorine

substrates, conformationally restricted peptides and therapeutic drug molecules.86

Traditionally, propargylamines are synthesized by nucleophilic attack of lithium

acetylides or Grignard reagents to imines.87 In recent years, enormous progress has

been made in expanding the scope of the direct addition of alkynes to carbon-nitrogen

double bonds either from prepared imines or from aldehydes and amines in one-pot

procedure by several transition-metal catalysts via C-H activation of terminal alkynes.

These include Ag(I) salts88, Au(I)/Au(II) salts89, Au(III)-salen complexes90, Cu(I)

salts91, Hg2Cl292 and Cu/Ru93 bimetallic system under homogeneous conditions.

Recently, Au(III)94, Ag(I)95, in ionic liquids and Cu-supported hydroxyapatite96 were

used to catalyze A3-coupling reactions. Also, more sophisticated alternative energy

sources like microwave91 and ultrasonic97 radiation has been used in the presence of

Cu(I) salt.

Unfortunately, these reagents used in stoichiometric amounts are often lost at

the end of the reaction (non-recyclable) and required drastic reaction conditions. Most

of these reactions were carried out either in toxic solvents88 or in the presence of

expensive solvents.98 Thus, there has been an ongoing interest to develop solid acid

catalysts for C-H bond activation of terminal alkynes99 under mild reaction

conditions.

As a part of our ongoing program on the development of new synthetic

methods and the use of recyclable heterogeneous catalyst in organic synthesis100,101

herein, we wish to report for the first time a simple and highly efficient methodology

for the synthesis of propargylamines in excellent yields using Nafion®NR50 as

recyclable and heterogeneous solid acid catalysts.

Chapter I

40

RESULTS AND DISCUSSION

As a model reaction, we initially examined an efficient and environmentally

benign protocol for A3-coupling of benzaldehyde (112a) (1.0 mmol), piperidine

(113a) (1.2 mmol) and phenylacetylene (114) (1.5 mmol) in the presence of

Nafion®NR50 in acetonitrile at 70-80 oC under nitrogen atmosphere (Scheme 42). As

a result, the expected reaction proceeded clearly to produce the desired

propargylamine in 96% yield (115a).

The effect of catalyst loading was studied by carrying out the experiments

with different amounts of Nafion®NR50. Increasing the loading of catalyst up to 0.35

gm gave desired propargylamines in 96% yield. However, the increase in the

concentration of catalyst not only promotes the reaction but also results in an increase

of the yield with decrease in the time (Table 1).

In addition, it was found that at higher temperature Nafion®NR50 showed

good catalytic activity at 70-80 °C, 96% yield was obtained, however at room

temperature lower yields were obtained even after longer reaction times. Comparable

results were obtained when the reaction was carried out at 70-80 oC with 0.25 gm of

Nafion®NR50. Thus, to reduce the amount of catalyst, all optimization was carried

out at 70-80 oC with 0.25 gm of Nafion®NR50.

The nature of reaction media has an important role in A3-coupling reaction in

the presence of Nafion®NR50 (0.25 gm). Among the various solvents studied such as

acetonitrile, methanol, THF, DCM and dioxane, acetonitrile was found to be the most

efficient solvent of choice (Table 2, Entry 1) and no products were obtained when

the reaction was carried out in dichloromethane or dioxane.

Chapter I

41

A possible mechanism was proposed 88c,89b,91a,98 involving the activation of C-

H bond of the terminal alkyne by Nafion®NR50 catalyst (Scheme 43). The sulfur

acetylide intermediate thus generated will react with the iminium ion prepared in situ

from aldehyde and secondary amine to produce the corresponding propargylamines,

water and Nafion®NR50. The regenrated Nafion®NR50 participates further in the

reaction and completes the catalytic cycle.

For the practical application of the catalyst Nafion®NR50, the life-time of the

catalyst and its level of reusability are important factors. The catalyst showed

excellent recyclability and could be reused for three to four runs with only slight drop

in activity. After completion of fresh reaction the catalyst was recovered by forceps,

washed with dichloromethane, dried and new reaction was then performed under

similar reaction conditions (Table 3).

After completing the search of optimized conditions, we chose a variety of

structurally different aldehydes, and amines possessing a wide range of functional

group to understand the scope and generality of Nafion®NR50 promoted A3-

coupling reaction. A variety of aromatic aldehydes were coupled with secondary

amines and phenylacetylene and it was found that aryl aldehydes possessing an

electron withdrawing groups (Table 4, Entries 4-6) afforded better yields with

good reactivity and lesser reaction times than those with electron donating groups

(Table 4, Entries 2 and 3) bound to the benzene ring required longer reaction

times. Heterocyclic aldehyde (Table 4, Entry 7) also displayed high reactivity

with good yield.

Chapter I

42

+R-CHO +Nafion®NR50, CH3CN

70-80 oC, N2 atmR1R2NH

NR2

R1

R

(112) (113) (114) (115a-n)

(a) R = C6H5; R1R2NH = Piperidine, (b) R = 4-MeC6H4; R1R2NH = Piperidine(c) R = 4-MeOC6H4; R1R2NH = Piperidine(d) R = 4-BrC6H4; R1R2NH = Piperidine(e) R = 4-ClC6H4; R1R2NH = Piperidine(f) R = 4-NO2C6H4; R1R2NH = Piperidine(g) R = 2-Furfuryl; R1R2NH = Piperidine(h) R = Cyclohexyl; R1R2NH = Piperidine(i) R = C6H5; R1R2NH = Morpholine(j) R = 4-MeC6H4; R1R2NH = Morpholine(k) R = 4-MeOC6H4; R1R2NH = Morpholine(l) R = 4-ClC6H4; R1R2NH = Morpholine(m) R = C6H5; R1R2NH = Pyrrolidine(n) R = 4-MeOC6H4; R1R2NH = Pyrrolidine

Scheme 42: Coupling of aldehydes, secondary amines and phenylacetylene catalyzed by Nafion®NR50.

Ph H

R-CHO + R1R2NHN

R

R1 R2

RfSO3-Ph SO3Rf

N

CHR

R1 R2

Ph

H2O

OH-

Rf = CF2-CF2 CF CF2

O CF2 CF O

CF3

n

m+ H

+

Scheme 43: Tentative mechanism for A3-Coupling.

Chapter I

43

EXPERIMENTAL

In a 50 mL round bottom flask, aromatic aldehydes/heterocylic aldehydes (1

mmol), secondary amines (1.2 mmol) and phenylacetylene (1.5 mmol) in CH3CN (5

mL) was taken. To this Nafion®NR50 (0.25 gm) was added and the reaction mixture

was stirred at 70-80 oC for the appropriate time mentioned in Table 4 under nitrogen

atmosphere. The progress of reaction was monitored by TLC. After completion of the

reaction, the reaction mixture was cooled. The organic layer was extracted with

diethyl ether and the remaining Nafion®NR50 was reused for further reactions. The

organic layer was dried over anhydrous Na2SO4 and the solvent was removed in

vacuo. The crude product was subjected to purification by silica gel column

chromatography using 20% ethyl acetate and 80% hexane as an eluent to yield the

propargylamines (115a-n, Table 4). The structures of all the products were

unambiguously established on the basis of their spectral analysis (IR, 1H NMR, 13C

NMR and mass spectral data).

Chapter I

44

Table 1: Optimization of Concentration of Nafion®NR50 for A3-coupling.a

+ + Nafion®NR50, CH3CN70-80 oC, N2 atm.

N

NH

CHO

Entry Catalyst Time (h) Yield (%)b

1 0 18 0

2 0.05 12 83

3 0.10 10 90

4 0.20 5 92

5 0.25 5 96

6 0.35 4 96 aReaction Conditions: benzaldehyde (1.0 mmol), piperidine (1.2 mmol), phenylacetylene (1.5 mmol), Nafion®NR50 (0.05-0.35 gm); solvent CH3CN (5 mL); temperature 70-80 oC, N2 atm. bIsolated yields.

Table 2: Effect of solvent on A3-coupling.a

Entry Solvent Time (h) Yield (%)b

1 Acetonitrile 5 96

2 Methanol 5 92

3 Tetrahydrofuran 5 87

4 Dichloromethane 5 0

5 Dioxane 5 0 aReaction Conditions: benzaldehyde (1.0 mmol), piperidine (1.2 mmol), phenylacetylene (1.5 mmol), Nafion®NR50 (0.25 gm); solvent (5 mL); temperature 70-80 oC, N2 atm. bIsolated yields.

Table 3: Recycling of Nafion®NR50.a

No. of cyclesa Fresh Run 1 Run 2 Run 3 Run 4

Yield (%)b 96 96 95 93 92

Time (h) 5 5 5 5 5 aReaction Conditions: benzaldehyde (1.0 mmol), piperidine (1.2 mmol), phenylacetylene (1.5 mmol), Nafion®NR50 (0.25 gm); solvent CH3CN (5 mL); temperature 70-80 oC, N2 atm. bIsolated yields.

Chapter I

45

Table 4: Nafion®NR50 catalyzed A3-coupling.a

Entry Amine R Product Time (h) Yield (%)b

1 Piperidine C6H5 115a 5.0 96

2 Piperidine 4-MeC6H4 115b 5.5 92

3 Piperidine 4-MeOC6H4 115c 6.0 88

4 Piperidine 4-BrC6H4 115d 4.5 94

5 Piperidine 4-ClC6H4 115e 4.0 93

6 Piperidine 4-O2NC6H4 115f 4.5 95

7 Piperidine 2-Furfuryl 115g 4.0 90

8 Piperidine Cyclohexyl 115h 3.5 88

9 Morpholine C6H5 115i 5.0 85

10 Morpholine 4-MeC6H4 115j 6.5 91

11 Morpholine 4-MeOC6H4 115k 7.0 87

12 Morpholine 4-ClC6H4 115l 4.5 90

13 Pyrrolidine C6H5 115m 6.5 87

14 Pyrrolidine 4-MeOC6H4 115n 7.5 84 aReaction Conditions: aldehydes (1.0 mmol), secondary amines (1.2 mmol), phenylacetylene (1.5 mmol), Nafion®NR50 (0.25 gm); solvent CH3CN (5 mL); temperature 70-80 oC, N2 atm. bIsolated yields.

Chapter I

46

Spectroscopic data of synthesized propargylamines (115a-n)

1-(1,3-Diphenyl-prop-2-ynyl)-piperidine (115a): Yellowish oil; IR (film/cm-1): νmax

= 3051, 2936, 2253, 1617, 1520, 1451, 1320, 1160; 1H NMR (CDCl3, 400 MHz): δ =

7.16-7.35 (m, 10H, 2Ph), 4.56 (s, 1H, CH), 2.56-2.62 (m, 4H, 2CH2), 1.85-1.91 (m,

4H, 2CH2), 1.35-1.50 (m, 2H, CH2); 13C NMR (CDCl3, 100 MHz): δ = 138.7, 132.1,

128.5, 128.2, 128.1, 127.6, 123.4, 88.1, 86.3, 62.5, 50.9, 26.3, 24.5; m/z 275.68 (M+1,

C20H21N requires 275.17).

1-[1-(4-Methylphenyl)-3-phenyl-prop-2-ynyl]-piperidine (115b): Slightly yellowish

oil; IR (film/cm-1): νmax = 2939, 2815, 2278, 1580, 1510, 1319, 1154; 1H NMR (CDCl3,

400 MHz): δ = 7.56-7.61 (m, 9H, 2Ph), 4.78 (s, 1H, CH), 2.52-2.61 (m, 4H, 2CH2), 2.40

(s, 3H, CH3), 1.64-1.73 (m, 4H, 2CH2), 1.45-1.58 (m, 2H, CH2); 13C NMR (CDCl3, 100

MHz): δ = 137.3, 135.8, 132.1, 129.0, 128.7, 128.5, 127.1, 123.6, 87.9, 86.6, 62.8, 62.4,

50.9, 26.4, 24.7, 21.4; m/z 290.19 (M+1, C21H23N requires 289.18).

1-[1-(4-Methoxyphenyl)-3-phenyl-prop-2-ynyl]-piperidine (115c): Slightly yellowish

oil; IR (film/cm-1): νmax = 3015, 2943, 2812, 2203, 1523, 1318, 1168, 1041; 1H NMR

(CDCl3, 400 MHz): δ = 7.69-7.81 (m, 9H, 2Ph), 4.80 (s, 1H, CH), 3.74 (s, 3H, OCH3),

2.55-2.65 (m, 4H, 2CH2), 1.74-1.80 (m, 4H, CH2), 1.45-1.59 (m, 2H, CH2); 13C NMR

(CDCl3, 100 MHz): δ = 158.3, 132.2, 130.4, 129.3, 128.6, 128.2, 123.0, 114.0, 85.6, 82.6,

58.8, 55.3, 26.1, 24.2; m/z 305.90 (M+1, C21H23NO requires 305.18).

1-[1-(4-Bromophenyl)-3-phenyl-prop-2-ynyl]-piperidine (115d): Yellowish oil; IR

(film/cm-1): νmax = 3040, 2955, 2815, 2780, 2270, 1544, 1495, 1314, 1169, 1052; 1H

NMR (CDCl3, 400 MHz): δ = 7.89-7.92 (m, 9H, 2Ph), 4.81 (s, 1H, CH), 2.52-2.66 (m,

4H, 2CH2), 1.66-1.79 (m, 4H, 2CH2), 1.46-1.50 (m, 2H, CH2); 13C NMR (CDCl3, 100

MHz): δ = 138.1, 132.1, 130.1, 128.4, 128.3, 123.1, 121.5, 88.6, 88.5, 61.8, 52.9, 26.3,

24.5; m/z 354.17 (M+1, C20H20NBr requires 353.08).

Chapter I

47

1-[1-(4-Chlorophenyl)-3-phenyl-prop-2-ynyl]-piperidine (115e): Yellowish oil; IR

(film/cm-1): νmax = 3042, 2947, 2811, 2783, 2240, 1549, 1492, 1316, 1167, 1055; 1H

NMR (CDCl3, 400 MHz): δ = 7.84-7.91 (m, 9H, 2Ph), 4.85 (s, 1H, CH), 2.50-2.65

(m, 4H, 2CH2), 1.62-1.71 (m, 4H, 2CH2), 1.43-1.51 (m, 2H, CH2); 13C NMR (CDCl3,

100 MHz): δ = 137.4, 134.2, 131.3, 130.4, 128.4, 128.3, 115.2, 86.9, 80.9, 59.2, 53.3,

25.0, 24.1; m/z 310.17 (M+1, C20H20ClN requires 309.13).

1-[1-(4-Nitrophenyl)-3-phenyl-prop-2-ynyl]-piperidine (115f): Yellowish oil; IR

(film/cm-1): νmax = 2945, 2849, 2190, 1685, 1597, 1334, 1155, 1089; 1H NMR

(CDCl3, 400 MHz): δ = 7.75-7.89 (m, 9H, 2Ph), 4.83 (s, 1H, CH), 2.48-2.59 (m, 4H,

2CH2), 1.55-1.65 (m, 4H, 2CH2), 1.41-1.53 (m, 2H, CH2); 13C NMR (CDCl3, 100

MHz): δ = 138.5, 138.0, 129.7, 128.4, 128.1, 123.6, 122.6, 86.8, 80.0, 59.1, 53.2,

25.3, 24.1; m/z 320.87 (M+1, C20H20N2O2 requires 320.15).

1-[1-(2-Furfuryl)-3-phenyl-prop-2-ynyl]-piperidine (115g): Sticky compound; IR

(film/cm-1): νmax = 2920, 2850, 2367, 2250, 1560, 1314, 1156; 1H NMR (CDCl3, 400

MHz): δ = 7.47-7.52 (m, 5H, Ph), 6.12-6.34 (m, 3H, furfuryl) 4.86 (s, 1H, CH), 2.86-

3.10 (m, 4H, 2CH2), 1.59-1.66 (m, 4H, 2CH2), 1.38-1.50 (m, 2H, CH2); 13C NMR

(CDCl3, 100 MHz): δ 152.5, 142.1, 128.2, 128.3, 122.7, 110.6, 86.8, 80.9, 60.5, 24.7,

24.5; m/z 265.93 (M+1, C18H19NO requires 265.15).

1-[1-(1-Cyclohexyl)-3-phenyl-prop-2-ynyl]-piperidine (115h): Yellowish Oil; IR

(film/cm-1): νmax = 3054, 2842, 2334, 3334, 1585, 1318, 1156, 890; 1H NMR (CDCl3,

400 MHz): δ = 7.52-7.54 (m, 2H, CH2), 7.23-7.26 (m, 3H, CH3), 3.12 (d, J = 8.2Hz,

1H), 2.44-2.65 (m, 4H, CH2), 2.14-2.34 (m, 4H), 2.15-2.19 (m, 2H), 1.70-1.83 (m,

4H), 1.37-1.48 (m, 4H), 1.12-1.35 (m, 3H); 13C NMR (CDCl3, 100 MHz): δ = 131.9,

128.3, 128.0, 122.7, 89.4, 86.6, 64.2, 38.8, 33.1, 30.5, 27.9, 26.0, 25.3, 24.9, 24.5; m/z

282.41 (M+1, C20H27N requires 281.21).

Chapter I

48

1-(1,3-Diphenyl-prop-2-ynyl)-morpholine (115i): Slightly yellowish oil; IR

(film/cm-1): νmax = 3050, 2965, 2301, 1584, 1480, 1320, 1151, 756; 1H NMR (CDCl3,

400 MHz): δ = 7.42-7.70 (m, 10H, 2Ph), 4.83 (s, 1H, CH), 2.94-3.09 (m, 4H, 2CH2),

2.57-2.67 (m, 4H, 2CH2); 13C NMR (CDCl3, 100 MHz): δ = 139.6, 131.2, 128.7,

128.3, 128.1, 127.2, 122.6, 86.7, 80.1, 66.1, 59.3, 52.3; m/z 278.22 (M+1, C19H19NO

requires 277.15).

1-[1-(4-Methylphenyl)-3-phenyl-prop-2-ynyl]-morpholine (115j): Colourless solid,

m. p. 80.5-81.5 oC; IR (film/cm-1): νmax = 3360, 3048, 2972, 2308, 1592; 1H NMR


2CH2), 2.54-2.66 (m, 4H, 2CH2), 2.33 (s, 3H, CH3); 13C NMR (CDCl3, 100 MHz): δ

= 136.2, 134.7, 128.6, 128.3, 128.2, 122.6, 86.8, 80.9, 66.0, 59.2, 52.2, 21.7. m/z

292.01 (M+1, C20H21NO requires 291.16).

1-[1-(4-Methoxyphenyl)-3-phenyl-prop-2-ynyl]-morpholine (115k): Yellowish oil;

IR (film/cm-1): νmax = 3045, 2962, 2312, 1594, 1349, 1190, 1017, 713; 1H NMR

(CDCl3, 400 MHz): δ = 7.33-7.56 (m, 9H, 2Ph), 4.73 (s, 1H), 3.73-3.89 (m, 3H), 2.16-

2.26 (m, 4H), 1.25-1.56 (m, 4H); 13C NMR (CDCl3, 100 MHz): δ = 159.1, 132.2,

128.8, 128.4, 128.2, 122.6, 112.8, 86.3, 80.6, 66.1, 55.8, 52.3; m/z 307.98 (M+1,

C20H21NO2 requires 307.16).

1-[1-(4-Chlorophenyl)-3-phenyl-prop-2-ynyl]-morpholine (115l): Yellowish oil;



2CH2), 2.59-2.62 (m, 4H, 2CH2). 13C NMR (CDCl3, 100 MHz): δ = 136.2, 134.7,

131.1, 129.1, 128.6, 122.7, 88.8, 84.3, 67.1, 59.5, 49.6; m/z 312.38 (M+1,

C19H18ClNO requires 311.11).

Chapter I

49

1-(1,3-Diphenyl-prop-2-ynyl)-pyrolidine (115m): Yellowish oil; IR (film/cm-1): νmax

= 3040, 2965, 2807, 2694, 2278, 1619, 1520, 1411, 1338, 1175, 756; 1H NMR


4CH2); 13C NMR (CDCl3, 100 MHz): δ = 139.1, 131.0, 128.6, 128.2, 126.8, 123.5,

86.1, 86.0, 59.4, 58.6, 50.5, 23.6; m/z 262.03 (M+1, C19H19N requires 261.15).

1-[1-(4-Methoxyphenyl)-3-phenyl-prop-2-ynyl]-pyrolidine (115n): Yellowish oil;


(CDCl3, 400 MHz): δ = 7.59-7.62 (m, 9H, 2Ph), 4.89 (s, 1H, CH), 3.83 (s, 3H), 1.80-

2.62 (m, 8H, 4CH2); 13C NMR (CDCl3, 100 MHz): δ =159.2, 132.2, 129.7, 128.4,

128.3, 122.6, 114.2, 86.0, 80.9, 56.9, 55.2, 23.0; m/z 292.35 (M+1, C20H21NO requires

291.16).

Chapter I

50

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