Annexure I FINAL REPORT (From 01-07-2015 to 30-06-2018 ...dspace.cusat.ac.in/jspui/bitstream/123456789/13183... · synthesis and study of new organocatalysts for asymmetric michael

Annexure I

FINAL REPORT

(From 01-07-2015 to 30-06-2018)

SYNTHESIS AND STUDY OF NEW ORGANOCATALYSTS FOR ASYMMETRIC

MICHAEL ADDITION REACTIONS

Submitted to

UGC

Ref : UGC sanction letter No F. 43-251/2014(SR) dated 03-12-2015

PRINCIPAL INVESTIGATOR

Dr. N. MANOJ

Associate Professor

DEPARTMENT OF APPLIED CHEMISTRY

COCHIN UNIVERSITY OF SCIENCE AND TECHNOLOGY

KOCHI 682 022

2

FINAL REPORT

(From 1st July 2015 to 30

th June 2018)

INTRODUCTION

The quest of environmentally benign strategies and methodologies in organic synthesis is

a crucial aspect of present day research in organic chemistry. Organocatalysis is such an area of

research which has been emerged as an area that offers practical alternatives or complementary

technologies to the conventional transition metal catalyzed reactions. Organocatalysis involves

the catalyzing of an organic reaction using small organic molecules.1-8

It is low in toxicity and

less expensive in terms of procurement, handling and storage. This has resulted in making this a

very popular area of research as reflected from the recent spurt in publications in this important

domain9. Development of newer, efficient tunable organic catalyst is of conceptual and practical

importance as it might lead to the discovery of a sophisticated method of catalysis of organic

reactions. Some of the major classes of organocatalysis methods are a) enamine and iminium

catalysis, b) SOMO and radical enamine catalysis, c) amine and phosphine based catalysis, d)

catalysis based on guanidine, amidine, and Cinchona alkaloids, e) catalysis using Bronsted acids,

thiourea and peptides and f) phase transfer catalysis. A vast majority of these systems use

supramolecular association via non-covalent interaction of one of the reactant molecule with the

catalyst. This eventually led to modification of its reactivity and thereby alters the kinetics of a

reaction. Some of these catalyst systems use their hydrogen bond forming ability with the

substrate for taking part in reactions as a catalyst. The catalytic activity of such compounds based

on the formation of hydrogen bonding has been reported recently.10

The reported work was about

the catalytic action inspired by guanine nucleobase structure and its ability to develop explicit

hydrogen bonding in biological systems.

Michael addition reaction is particularly one reaction which obtained a lot of attention

from the point of view of asymmetric organocatalysis. Michael reaction or more often, Michael

addition is simply the nucleophilic 1-4 addition of a resonance stabilized carbanion or another

nucleophile to an α, β-unsaturated carbonyl compound or other similar compounds. It belongs to

the larger class of conjugate additions. This is one of the most useful methods for the mild

formation of C-C bonds, an important atom-economical method for diastereoselective and

enantioselective C-C bond formation. The nucleophile and electrophile in these reactions are

popularly known to be Michael donor and Michael acceptor respectively. Michael addition is a

thermodynamically controlled reaction.

3

Scheme 1

Michael donors are usually active methylenes such as malonates, nitroalkanes, etc. The

electron withdrawing groups (EWG) attached to the donors may be groups such as acyl,

cyano,etc. making the methylene hydrogen more acidic forming the carbanion on reaction with

base and the acceptors are activated olefins such as α,β-unsaturated carbonyl compounds,

alkenes possessing nitro groups etc.

Donors

Chart 1

Acceptors

Chart 2

Mechanism

Scheme 2

4

Step 1

Scheme 3

Deprotonation of 9 by base leads to carbanion 13 stabilized by its electron-withdrawing

groups. This carbanion reacts with the electrophilic alkene 10 to form the product in a conjugate

addition reaction.

Step 2

Scheme 4

Proton abstraction from the conjugate acid of the base (or solvent) by the enolate ion

leads to the formation of final product. As illustrated it is often an excellent method for the

creation of stereogenic centers in molecules. Much effort has focused on the development of

catalytic, asymmetric versions of Michael reaction.

Objectives of the project

Getting inspired from the multipoint hydrogen bonding in DNA by the nucleobases the

proposed work involves design, synthesis and study of a new class of organocatalysts based on a

1,3,5-triazine core which is a much cheaper and synthetically viable scaffold. The objective is

the development of a newer class of Michael addition catalyst system based on a much cheaper

5

core system that can bind to Michael acceptors via single or multipoint hydrogen bonding with

potential for tuning the solubility, electron demand and hydrophobicity. Chart 3 shows the

triazine framework and the proposed hydrogen bonded assembly.

Chart 3

Methodology

The proposed catalyst system can be synthesised from 2,4,6-tricholo-1,3,5-triazine a

cheap synthone which has inherent activation towards aromatic nucleophilic substitution reaction

in the presence of suitable nucleophiles.11-16

The general scheme adopted for the synthesis of the

catalyst system is illustrated in scheme 5, which uses aliphatic or aromatic amines as

nucleophiles for the substitution of chlorine on the triazine framework. The number of

substitutions can be effectively controlled by choosing appropriate temperature.

Monosubstitution can be achieved by carrying out the reaction at 0oC and around room

temperature disubstitution and trisubstitution at elevated temperatures. Disubstitution and

trisubstitution with amino groups is essential for the triazine frame work to act as a hydrogen

donor to Michael acceptors. Aromatic or aliphatic amines are to be chosen according to the

requirement of electron demand, solubility hydrophobicity and chiral induction.

Scheme 5

Summary of the work done

To prove the concept we set the objective to synthesise a series of molecules where the

substituents R1 and R2 should have structural features favourable for hydrogen bonding

interaction with potential Michael acceptors. For example substituents such as amino groups as

R1 and R2 can lead to the hydrogen bonded assembly showed in chart 3 with a Michael acceptor

such a trans-β-nitrostyrene.

6

The groups R1 and R2 were chosen such that they should have structural features to

favour hydrogen bonding as well as introduce required hydrophobicity to enhance binding

efficiency with Michael acceptors when used in polar solvents such as methanol or water. With

this objective we have accomplished the synthesis of following molecules as showed in Chart 4.

These catalysts systems were used in the Michael addition reaction and optimized the conditions.

Chart 4

A new set of catalysts designed where aromatic amines were used as groups R1 and R2 to

understand the role of electron demand in the catalysis process. A series of catalysts were

prepared and characterised are given in Chart 5. A significant road block we faced was with the

solubility of these molecules. They are sparingly soluble in o-dichlorobenzene.

7

Chart 5

For chiral catalysis we synthesized a series of triazine molecules bearing alkyl esters of

aminoacids. We choose L-alanine and L-phenyl alanine as the aminoacid unit for the preparation

of chiral triazine catalysts for Michael addition reaction.

Chart 6

8

We have synthesized triazine derivative 37 with N,N diethylethylene diamine, which act

as a potential hydrogen bond donors with an internal amino groups which can assist

deprotonation of the Michael donors.

9

Brief Report on the Work Done:

Starting materials and reagents such as 1,3,5-trichlorotriazine, n-propylamine, n-

butylamine, n-pentylamine, cyclohexylamine, n-hexylamine, n-octlyamine, n-dodecylamine,

aniline, p-anisidine, 5-aminoisophthalic acid, 1-aminobiphenylamine, 1-naphthylamine D and L-

Alanine, trans-β-nitrostyrene etc., were purchased from Sigma-Aldrich or Alfa Aesar and were

used as received. The solvents used in the synthesis procedures were obtained from Spectrochem

Ltd and were dried and distilled prior to use. All reactions and chromatographic separations were

monitored by thin layer chromatography (TLC). Glass plates coated with dried and activated

silica gel or aluminium sheets coated with fluorescent silica gel (Merck) were used for thin layer

chromatography. Visualization was achieved by exposure to iodine vapour or UV radiation.

Solvent removal was done on an IKA Model RV-10B or Heidolph Model Hei-VAP rotary

vacuum evaporator. Infrared spectra were recorded on JASCO 4100 model, FTIR spectrometer.

The 1H NMR spectra were recorded on 400 MHz on Bruker Avance III FT-NMR spectrometer

with tetramethylsilane (TMS) as internal standard. Chemical shifts were reported in parts per

million (ppm) downfield to tetramethylsilane. Molecular mass was determined by Waters 3100

mass detector with an Electro-Spray-Ionization unit. The Michael addition reactions were

monitored by an Agilent Model 7890A GC with FID or 5975C MS detector.

Synthesis of N2,N

4,N

6-tripropyl-1,3,5-triazine-2,4,6-triamine (22)

Scheme 6

1.84 g of 2,4,6-tricholo-1,3,5-triazine (0.01 mol) was dissolved into 20 ml of acetonitrile

and the solution was cooled to an inner temperature of 10°C, n-propylamine (0.03 mol) in 10 ml

of acetonitrile was added dropwise such that the inner temperature was maintained at 30°C.

Then, sodium carbonate (0.03 mol) was added and the mixture was heated to reflux for 12 hours.

After completion, the solvent was removed under reduced pressure and the contents were

extracted with dichloromethane. The organic layer was dried with sodium sulfate, filtered, and

concentrated under reduced pressure. The residues obtained were recrystallized from a mixture

of an ethyl acetate and a methanol to produce a white solid in 91% yield. mp: 57 oC; IR (KBr,

cm-1

) 3278, 2959, 2931, 1571, 1516, 1464, 1348, 812; 1

H NMR (400MHz, CDCl3) δ 5.12 (br,

3H), 3.23 (br, 6H), 1.51-1.42 (m, 6H), 0.86-0.82(t, 9H); 13

C NMR (100MHz, CDCl3) δ 165.1,

41.4, 22.0,10.4; MS (ESI) m/z 253.18 (M + H)+.

10

Figure 1. 1H NMR of compound 22

Figure 2. 13

C NMR of compound 22

Synthesis of N2,N

4,N

6-tributyl-1,3,5-triazine-2,4,6-triamine (23)

11

Scheme 7

Cyanuric chloride (0.01mol) was dissolved into 20 ml of acetonitrile and the solution was

cooled to an inner temperature of 10°C, n-butylamine (0.03mol) in 10 ml of acetonitrile was

added dropwise such that the inner temperature was maintained at 30°C. Then, sodium carbonate

(0.03mol) was added and the mixture was heated to reflux for 12 hours. After completion, the

solvent was removed under reduced pressure and the contents were extracted with 50 mL of

dichloromethane. The organic layer was dried with sodium sulfate, filtered, and concentrated

under reduced pressure to yield the product 23 as colorless oil. Yield 92%; IR (KBr, cm-1

) 3283,

2956, 2866, 1585, 1517, 1421, 1356, 1115; 1H NMR (400 MHz, CDCl3) δ 5.21 (br, 3H), 3.25

(br, 6H), 1.46-1.39 (m, 6H), 1.31-1.22 (m, 6H), 0.84-0.81 (t, 9H); 13

C NMR (100 MHz, CDCl3) δ

165.0, 39.3, 31.0, 19.0, 12.7; MS (ESI,+ve) m/z 296.26 (M + 2H)+.


12

Figure 4. 13


Synthesis of N2,N

4,N

6-tripentyl-1,3,5-triazine-2,4,6-triamine (24)

Scheme 8

2,4,6-tricholo-1,3,5-triazine (0.01mol) was dissolved into 100 ml of acetonitrile and the

solution was cooled to an inner temperature of 10°C, n-pentylamine (0.03mol) in 20 ml of

acetonitrile was added dropwise such that the inner temperature was maintained at 30°C. Then,

sodium carbonate (0.03mol) was added and the mixture was heated to reflux for 16 hours. After

completion, the solvent was removed under reduced pressure and the contents were extracted

with 50 mL of dichloromethane. The organic layer was dried with sodium sulfate, filtered, and

concentrated under reduced pressure, to yield the product 24 as colorless oil. Yield 92%; IR

3273, 2930, 2862, 1519, 1352, 1174, 812; 1H NMR (400MHz, CDCl3) δ 4.75(br, 3H), 3.32(br,

6H), 1.55-1.52(m, 6H), 1.34-1.32(m,12H), 0.91-0.88(m, 9H); 13

C NMR (100MHz, CDCl3) δ

165.0, 39.6, 28.5, 28.1, 21.4, 12.9; MS (ESI,+ve) m/z 337.28 (M + H)+.

13


Figure 6. 13


14

Synthesis of N2,N

4,N

6-trihexyl-1,3,5-triazine-2,4,6-triamine (25)

Scheme 9

Cyanuric chloride (0.01mol) was dissolved into 20 ml of acetonitrile and the solution was

cooled to an inner temperature of 10°C, n-hexylamine (0.03mol) in 20 ml of acetonitrile was

added dropwise such that the inner temperature was maintained at 30°C. Then sodium carbonate

(0.03mol) was added and the mixture was heated to reflux for 24 hours. After completion, the

solvent was removed under reduced pressure and the contents were extracted with 50 mL of

dichloromethane. The organic layer was dried with sodium sulfate, filtered, and concentrated

under reduced pressure, to yield colorless oil. Yield 85%; IR (KBr, cm-1

) 3272, 2927, 1516,

1353, 1170, 811. 1H NMR (400 MHz, CDCl3) δ 4.75 (br, 3H), 3.32 (br, 6H), 1.55-1.49 (m, 6H),

1.36-1.27 (m, 18H), 0.90-0.86 (m, 9H); 13

C NMR (100 MHz, CDCl3) δ 166.13, 40.67, 31.57,

29.84, 26.62, 22.59, 14.01; MS (ESI,+ve) m/z 379.31 (M + H)+.


15

Figure 8. 13


Synthesis of N2,N

4,N

6-trioctyl-1,3,5-triazine-2,4,6-triamine (26)

Scheme 10

2,4,6-tricholo-1,3,5-triazine (0.01mol) was dissolved into 20 ml of toluene and the

solution was cooled to an inner temperature of 10°C, n-octylamine (0.03mol) in 20 ml of toluene

was added dropwise such that the inner temperature was maintained at 30°C. Then, sodium

hydroxide (0.03mol) was added and the mixture was heated to reflux for 8 hours. After


with dichloromethane. The organic layer was dried with sodium sulfate, filtered, and

concentrated under reduced pressure, to afford the desired product as white solid in 90% yield.

mp 55 oC; IR (KBr, cm

-1) 3449, 3278, 2955, 2854, 1564, 1515, 1465, 1353, 1161;

1H NMR

(400MHz, CDCl3) δ 4.87 (br, 3H), 3.34 (br, 6H), 1.56-1.51 (m, 6H), 1.31-1.28 (m, 30H), 0.91-

0.87 (m, 9H); 13

C NMR (100MHz, CDCl3) δ 166.20, 40.66, 31.83, 29.89, 29.35, 29.26, 26.96,

22.64, 14.07; MS (ESI): m/z 463.42 [M + H]+.

16


Figure 10. 13


Synthesis of N2,N

4,N

6-tridodecyl-1,3,5-triazine-2,4,6-triamine (27)

17

Scheme 11

Cyanuric chloride (0.01mol) was dissolved into 20 ml of toluene and the solution was

cooled to an inner temperature of 10°C, n-dodecylamine (0.03mol) in 20 ml of toluene was

added dropwise such that the inner temperature was maintained at 30°C. Then, sodium

hydroxide (0.03mol) was added and the mixture was heated to reflux for 12 hours. After



concentrated under reduced pressure, to afford the desired product as white solid in 90% yield.

mp 78 oC; IR (KBr, cm

-1) 3409, 3264, 2968, 2933, 2872, 2810, 1566, 1514, 1382, 1068, 812;

1H

NMR (400 MHz, CDCl3): δ 4.72 (br, 3H), 3.32(br, 6H), 1.54-1.49 (m, 6H), 1.30-1.25 (m, 54H),

0.84-0.81 (m, 9H); 13

C NMR (100 MHz, CDCl3) δ 166.2, 40.6, 31.9, 29.9, 29.6, 29.3, 26.9, 22.6,

14.0; MS (ESI,+ve) m/z 631.61 (M + H)+.


18

Figure 12. 13


Synthesis of N2,N

4,N

6-triphenyl-1,3,5-triazine-2,4,6-triamine (28)

Scheme 12

The reactions were carried out in a 100 mL autoclave under autogenous pressure. The

reactor was charged with acetone (50 mL), cyanuric chloride (10mmol), aniline (30mmol) and

NaHCO3 (30mmol). The reaction mixture was heated at 100°C for 10 h. After cooling to room

temperature, the precipitate was collected by filtration and washed with acetic acid to give 28 as

white solid. Yield 89%; mp 230 oC; IR (KBr, cm

-1) 3035, 1582, 1525, 1117, 840;

1H NMR (400

MHz, DMSO-d6) δ 9.22 (s, 3H), 7.80 (m, 6H), 7.31-7.27 (m, 6H), 7.02-6.98 (m, 3H); 13

C NMR

(100 MHz, DMSO-d6) δ 164.0, 139.8, 128.3, 122.0, 120.3; MS (ESI, +ve) m/z 355 (M + H)+.

19


Figure 14. 13


20

Synthesis of N2,N

4,N

6-tricyclohexyl-1,3,5-triazine-2,4,6-triamine (29)

Scheme 13

In a round-bottom-flask coupled with a water condenser, magnetic stirrer and nitrogen

inlet, was added 50 ml of tetrahydrofuran (THF), cyanuric chloride (0.01mol) and Na2CO3

(0.03mol). The mixture was stirred for 30 min at room temperature and then cyclohexylamine

(0.03mol) was added dropwise. The mixture was refluxed for 16 h to obtain a white solid

extracted with chloroform-H2O. The chloroform extracts were then dried with anhydrous sodium

sulfate and evaporated under reduced pressure to give 29 as white solid, Yield: 85%; mp 190oC;

IR (KBr, cm-1

) 3424, 3245, 2925, 1524, 1364, 1166, 814; 1H NMR (400 MHz, CDCl3) δ 4.63 (s,

3H), 3.76-3.75.(m, 3H), 1.73-1.70 (m, 6H), 1.62-1.58 (m, 6H) 1.40-1.31 (m, 6H), 1.20-1.14(m,

9H); 13

C NMR (100 MHz, CDCl3) δ 165.5, 49.7, 33.4, 25.7, 24.9; MS (ESI, +ve) m/z 373 (M +

H)+.


21

Figure 16. 13


Synthesis of N2,N

4,N

6-tri(naphthalen-1-yl)-1,3,5-triazine-2,4,6-triamine (30)

Scheme 14


reactor was charged with acetone (50 mL), cyanuric chloride (10 mmol), 1-naphthyl amine (30

mmol) and NaHCO3 (30 mmol). The reaction mixture was heated at 100°C for 10 h. After

cooling to room temperature, the precipitate was collected by filtration and washed with acetic

acid to yield 30 as white crystalline solid. Yield: 84%; mp 210 oC; IR (KBr, cm

-1) 3390, 1552,

1480, 1420, 1264; 1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 3H), 8.04-8.02 (m, 3H), 7.90-7.88

(m, 3H), 7.68-7.66 (m, 3H), 7.53-7.50 (m, 9H), 7.32-7.31 (m. 3H); 13

C NMR (100 MHz, DMSO-

d6) δ 165.8, 134.1, 133.3, 128.5, 127.8, 126.0, 125.8, 125.5, 125.0, 121.5, 121.2; MS (ESI, +ve)

m/z 505 (M + H)+.

22


Figure 18. 13


23

Synthesis of N2,N

4,N

6-tris(4-methoxyphenyl)-1,3,5-triazine-2,4,6-triamine (31)

Scheme 15

Compound 31 was synthesised by a reported procedure.17

2,4,6-tricholo-1,3,5-triazine

(0.01 mol) was added to a stirred solution of p-anisidine (0.033 mol) in 75 mL of glacial acetic

acid, and the mixture was refluxed (118°C) for 5 hours. The product precipitated from solution

was filtered, washed several times with boiling water to neutral pH and dried at 90°C in air to

afford the desired product as white solid. Yield: 82%; mp 216 oC; IR (KBr, cm

-1) 3230, 1580,

1510, 1240; 1H NMR (400MHz, DMSO-d6) δ 8.96(s, 3H), 7.64(m, 6H), 6.87-6.85(m, 6H),

3.73(s, 9H); 13

C NMR (100 MHz, DMSO-d6) δ 164.0, 154.5, 132.9, 121.9, 113.5, 55.1; MS (ESI,

+ve) m/z 445 (M + H)+.


24

Figure 20. 13


Synthesis of N2,N

4,N

6-tris(4-nitrophenyl)-1,3,5-triazine-2,4,6-triamine (32)

Scheme 16

Cyanuric chloride (10 mmol), p-nitroaniline (30 mmol), and K2CO3 (30 mmol) were

mixed in 80 mL of 1,4-dioxane. The mixture was refluxed for 24 h, and then the solid product

was separated from the reaction mixture by filtration. After being washed successively with

water (100 mL × 3), methanol (50 mL × 3), and toluene (50 mL × 3), the solid was dried under

reduced pressure overnight. White solid; Yield: 85; mp > 300 °C; IR (KBr, cm-1

) 3340, 1630,

1590, 1510, 1340, 1240; 1H NMR (400 MHz, DMSO-d6): δ 10.31 (s, 3H), 8.23-8.21 (d, 6H),

8.11-8.09 (d, 6H); MS (ESI, +ve) m/z 490 (M + H)+.

25


Synthesis of N2,N

4,N

6-tri([1,1'-biphenyl]-4-yl)-1,3,5-triazine-2,4,6-triamine (33)

Scheme 17


reactor was charged with acetone (50 mL), cyanuric chloride (10mmol), biphenylamine

(30mmol) and NaHCO3 (30mmol). The reaction mixture was heated at 100 °C for 10 h. After

cooling to room temperature, the precipitate was collected by filtration and washed with acetic

acid to yield 33 as white solid. Yield: 75%; mp 255 oC; IR (KBr, cm

-1) 3401, 1594, 1523, 1232;

1H NMR (400 MHz, DMSO-d6) δ 9.44(s, 3H), 7.96-7.94(d, 6H), 7.68-7.62(q, 12H), 7.47-7.44(t,

26

6H), 7.35-7.31(t, 3H); 13

C NMR (100 MHz, DMSO-d6) δ 164.0, 139.9, 139.4, 133.7, 128.8,

126.7, 126.5, 126.1, 120.6. MS (ESI, +ve) m/z 583 (M + H)+.


Figure 23. 13


27

Synthesis of 5,5',5''-((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))triisophthalic acid (34)

Scheme 18

Compound 34 was synthesised by a reported procedure18

. 5-aminoisophthalic acid (15.2

g, 0.084 mol), NaOH (5.36 g, 0.134 mol), and NaHCO3 (8.74 g, 0.104 mol) were added to 140

mL H2O. The mixture was stirred at 0 ºC for 30 min, followed by dropwise addition of cyanuric

chloride (3.68 g, 0.02 mol) in 1,4-dioxane (70 mL). The mixture was then heated at 100 ºC for

24h. The resulting solution was adjusted to pH=2 with HCl solution. The solid was collected by

filtration, rinsed several times with distilled water, and dried. Yield: 55%; mp >300. IR (KBr,

cm-1

) 3312, 1700, 1630, 1533,1400, 1214,1134, 1066. MS (ESI, -ve) m/z 617 (M - H)+.

Synthesis of (2S,2'S,2''S)-trimethyl 2,2',2''-((1,3,5-triazine-2,4,6-triyl) tris(azanediyl))tri

propanoate (35)

Scheme 19

L-alanine methyl ester hydrochloride (30 mmol) and Na2CO3 (30 mmol) was added to 50

mL THF maintained at 0–5 oC and allowed to stand for temperature equilibration (20

oC). A

solution of cyanuric chloride (10 mmol) in THF (30 mL) was added with vigorous stirring. The

reaction mixture was then refluxed for 24 h. After completion, the solvent was removed under

reduced pressure and the contents were extracted with 50 mL of dichloromethane. The organic

layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure, to yield a

white solid. Yield: 74%; mp 120 oC; IR (KBr, cm

-1) 3371, 3262, 2960, 1739, 1569, 1509, 1438,

28

1260, 1177, 1085, 806; 1

H NMR (400MHz, CDCl3): δ 6.11 (br, 3H), 4.51 (m, 3H), 3.66 (s, 9H),

1.35-1.33 (m, 9H); 13

C NMR (100MHz, CDCl3) δ 173.4, 164.1, 51.1, 48.2, 17.3; MS (ESI, +ve)

m/z 385.16 (M + H)+.


Figure 25. 13


29

Synthesis of (2S,2'S,2''S)-trimethyl 2,2',2''-((1,3,5-triazine-2,4,6-triyl)tris(azanediyl))tris(3-

phenylpropanoate) (36)

Scheme 20

A mixture containing cyanuric chloride (1.0 mmol), L-phenylalanine methyl ester (3.6

mmol) and DIPEA (6.0 mmol) in 50 mL toluene was stirred at reflux for 12 hours. Then,

volatiles were removed to dryness in vacuum and the residue was dissolved in ethyl acetate (20

mL) and washed with a saturated NH4Cl solution. The organic layer was dried over anhydrous

sodium sulfate, filtered, and evaporated under reduced pressure, to afford the desired product as

white solid in 82% yield. mp: 230 oC; IR (KBr, cm

-1) 3282, 3062, 3028, 2927, 1735, 1601, 1496,

1229, 746; 1H NMR (400 MHz, DMSO-d6) δ 10.51 (bs, 3H), 7.32-7.01 (m, 15H), 4.51-4.47 (m,

3H); 13

C NMR (100MHz, DMSO-d6) δ 172.6, 137.3, 129.2, 128.1, 126.4, 53.4.

Synthesis of N2,N

4,N

6-tris(2-(diethylamino)ethyl)-1,3,5-triazine-2,4,6-triamine(37)

Scheme 21

Cyanuric chloride (0.01mol) was dissolved into 20 ml of toluene and the solution was

cooled to an inner temperature of 10°C, N,N-diethylethylenediamine (0.03mol) in 20 ml of

toluene was added dropwise such that the inner temperature was maintained at 30°C. Then,

sodium hydroxide (0.03mol) was added and the mixture was heated to reflux for 12 hours. After


30


concentrated under reduced pressure, to afford the desired product as yellowish oil. Yield 85%;

IR (KBr, cm-1

) 3409, 3264, 2968, 2933, 2872, 2810, 1566, 1514, 1382, 1068, 812; 1H NMR (400

MHz, CDCl3) δ 4.77 (br, 3H), 3.40 (m, 6H), 2.54-2.52 (m, 18H), 1.03-0.99(m, 18H); 13

C NMR

(100 MHz, CDCl3) 165.8, 51.9, 38.2, 38.1, 11.5; MS (ESI, +ve) m/z 424.36 (M + H)+.


Figure 27. 13


31

Study of Michael addition reaction in the presence of prepared catalysts

To establish catalysis, Michael addition reaction between trans-β-nitrostyrene and diethyl

malonate were carried out in presence of base (triethylamine) and catalyst and also without

catalyst at room temperature in THF as solvent. Reactions were monitored in every 30 minutes.

To compare the catalytic activity of the catalyst, a graph is plotted with time against

concentration of the product formed (Figure 28). From the graph it is clear that the synthesized

catalyst enhances the reaction rate in comparison to the reaction without catalyst

Figure 28. Effect of Catalyst 25 on the Michael Addition

reaction of trans-β-nitrostyrene with diethyl malonate in THF.

Optimization of the amount of catalyst.

For the optimization of the amount of catalysts required we carried out Michael addition

reaction using catalyst 27. Table 1 shows the effect of catalyst concentration on conversion in

Michael addition reaction. From the table 1 it is found that about 10mol% of the catalyst is the

optimal amount of the catalyst to catalyse the reaction.

Table 1. Optimisation of the amount of catalyst (27) in o-dichlorobenzene.

Entry Amount of Catalyst Yield(%)*

32

1a none 0%

2b 100mol% 19%

3b 50mol% 18%

4b 25mol% 17%

5b 10mol% 17%

6c 100mol% 88%

7c 50mol% 87%

8c 25mol% 87%

9c 10mol% 87%

aabsence of the base and the catalyst,

bpresence of

catalyst, no base, cpresence of an equivalent amount of

base triethylamine and the catalyst (27). * Determined

by GC analysis.

Optimization of the catalyst

Catalysts 25, 28-34 were screened to identify the optimal catalyst for Michael addition reaction

between diethylmalonate and trans-β-nitrostyrene. In the absence of the catalyst and in the

presence of triethylamine the reaction gave 45% yield at room temperature for a reaction time of

12 hours. In the presence of the catalyst and triethylamine, results show that catalyst 25 gave

maximum yield of Michael adduct. The results are tabulated in Table 2.

Table 2. Screening of catalystsa

Entry Catalyst Time(h) Yield(%)b

1 none 12 45

2 25 12 76

3 28 12 68

4 29 12 63

5 30 12 48

6 31 12 45

7 32 12 49

33

8 33 12 47

9 34 12 50

aAll reactions were carried out using trans-β-

nitrostyrene (0.2 mmol) and diethyl malonate(0.4

mmol) in the presence of different catalyst (0.02mmol,

10 mol %) and 1 equiv. triethylamine in o-

dichlorobenzene (1 mL) at rt. bDetermined by GC

analysis.

Since the catalyst 25 with hexyl chain gives maximum yield compared with other

compounds, we further synthesized catalysts with different alky chains and studied the effect of

alkyl chain in Michael addition reaction. From the table 3 catalysts with long alkyl chain gives

maximum yield. From these results it can be identified the importance of the length of the alkyl

chain on the catalyst molecule. This points to the fact that hydrophobicity and the polarity of the

micro environment around the hydrogen bonds has a significant role in the catalysis process.

Table 3. Study the effect of alkyl chain on Michael addition reactiona

Entry Catalyst Time(h) Yield(%)b

1 22 12 68

2 23 12 69

3 24 12 72

4 25 12 76

5 26 12 85

6 27 12 87

aAll reactions were carried out using trans-β-

nitrostyrene (0.2 mmol) and diethyl malonate(0.4

mmol) in the presence of different catalyst (0.02mmol,

10 mol %) and 1 equiv. triethylamine in o-

dichlorobenzene (1 mL) at rt. bDetermined by GC

analysis.

34

Optimization of solvent medium

Further we proceed to identify the optimal solvent for the reaction. By using catalyst 27

we carried out reactions in seven different solvents at room temperature. The results were

tabulated in Table 4. The results show that o-dichlorobenzene resulted into maximum yield for

the reaction when carried out for 12 hours.

Table 4. Effect of reaction solventsa

Entry Solvent Time(h) Yield(%)b

1 CH2Cl2 12 79

2 chloroform 12 79

3 THF 12 58

4 toluene 12 57

5 o-dichlorobenzene 12 87

6 dichloroethane 12 80

7 CH3CN 12 51 aAll reactions were carried out using trans-β-nitrostyrene

(0.2 mmol) and diethyl malonate(0.4 mmol) in the

presence of catalyst 27 (0.02 mmol, 10 mol %) at rt in

different solvents (1.0 mL) in presence of 1 equiv.

triethylamine at room temperature. bDetermined by GC

analysis.

From the results it appears that the halogenated solvents in particular the aromatic

halogenated solvents are suitable for carrying out the reaction in the presence of the prepared

catalyst. This may be due to the better stability of the hydrogen bonded assembly in this medium

in comparison to THF or Toluene as the solvent.

Optimization of base

The optimization of the base for the Michael addition reaction of trans-β-nitrostyrene

with diethylmalonate in presence of catalyst 27 under identical condition was carried out. From

the results, we observed that triethylamine is more effective than the bases, such as DIPEA,

Na2CO3, pyridine and DABCO.

35

Table 5. Screening of base on the reaction of trans-β-nitrostyrene

on the reaction of diethylmalonatea

Entry Base Catalyst Time Yield(%)b

1 Na2CO3 27 12 43

2 DIPEA 27 12 76

3 triethylamine 27 12 87

4 DABCO 27 12 70

5 Pyridine 27 12 62 aAll reactions were carried out using trans-β-nitrostyrene (0.2

mmol) and diethylmalonate(0.4 mmol) in the presence of

catalyst 27 (0.02 mmol, 10 mol %) and 1 equiv. base in o-

dichlorobenzene (1 mL) at rt. bDetermined by GC analysis.

Effect of additives in the Michael addition reaction

With the selected catalyst 27, solvent and base, the effect of additives on Michael

addition reaction was investigated. As shown in Table 6, the addition of additives could not gave

improved results.

Table 6. Effect of additives on the reaction of trans-β-nitrostyrene on the

reaction of diethylmalonatea

Entry Additives catalyst Time Yield(%)b

1 Trifluoroacetic acid 27 12 88

2 Acetic acid 27 12 86

3 Benzoic acid 27 12 87

4 4-nitrobenzoic acid 27 12 86

5 p-nitrophenol 27 12 86 aAll reactions were carried out using trans-β-nitrostyrene (0.2 mmol) and

diethyl malonate(0.4 mmol) in the presence of catalyst 27 (0.02 mmol, 10

mol %) and 1 equiv. triethylamine in o-dichlorobenzene (1 mL) at rt. bDetermined by GC analysis.

36

Having established optimized reaction conditions for the model reaction, the scope of this

transformation was studied on various nitroolefins and Michael donors using 27 as a catalyst.

From the observed result in Table 7, with both electron-withdrawing and electron-donating

groups present on the aryl groups of the nitroolefin, the product yield was independent of the

substitution on the aryl group. Unsubstituted β-nitroalkenes gave better yield compared with

substituted β-nitroalkenes bearing electron with-drawing or electron-donating groups on the

aromatic ring

Table 7. Substrate scopea

Entry R R1 Time Yield(%)

b

1 -H -CO2Me 12 84

2 -Cl -CO2Me 12 82

3 -Br -CO2Me 12 81

4 -OMe -CO2Me 12 78

5 -NO2 -CO2Me 12 76

6 -H -CO2Et 12 83

7 -H -CN 12 80

aAll reactions were carried out using trans-β-nitrostyrene (0.2 mmol) and

diethylmalonate(0.4 mmol) in the presence of catalyst 27 (0.02 mmol, 10

mol %) and 1 equiv. triethylamine in o-dichlorobenzene (1 mL) at rt. bIsolated yield

Asymmetric Michael addition reaction using the prepared catalyst

Catalyst bearing alkyl esters of amino acids (35 and 36) were used for catalyzing

asymmetric Michael addition reaction of diethylmalonate and trans-β-nitrostyrene. and

the results were shown on table 8. From the result both catalyst give better yield but the

Michael adducts formed was racemic mixture.

37

Table 8. Screening of chiral catalyst for Michael addition reactiona

Entry Catalyst Time Yieldb

1 35 12 80

2 36 12 75 aAll reactions were carried out using trans-β-nitrostyrene (0.2

mmol) and diethyl malonate(0.4 mmol) in the presence of

different catalyst (0.02mmol, 10 mol %) and 1 equiv.

triethylamine in o-dichlorobenzene (1 mL) at rt. bDetermined by

GC analysis.

HPLC data for chiral Michael products

HPLC separation conditions, (column: CHIRALPAK AD (0.4 cm*25 cm), eluent:

hexane/2-propanol = 8/2, flow rate: 1 ml/min, detection: UV 220 nm; retention time of

two enantiomers, 8.7 min, 11.7 min (Racemic)

Catalyst 35

Figure 29. HPLC chromatogram and data of Michael adduct

38

Catalyst 36

Figure 30. HPLC chromatogram and data of Michael adduct

Catalyst 37 with internal amino group which can assist deprotonation of the Michael

donors was studied using diethylmalonate and trans-β-nitrostyrene. From the obtained

result the catalyst gives a yield of 84%.

Mechanism of catalysis

To understand the nature of hydrogen bonding, we monitored the 1H NMR

spectral changes of compound 27 in the absence and presence of different concentrations

of trans-β-nitrostyrene. We have recorded 1H NMR spectrum in CDCl3 in the presence of

increasing concentration of trans-β-nitrostyrene. Figure 31 shows 1H NMR spectrum of

compound 27 and mixtures of compound 27 and trans-β-nitrostyrene at different ratios

from 0 to 5 equivalents of trans-β-nitrostyrene. The spectrum of free compound 27 is

characterized by a broad peak corresponding to NH protons at 4.75 ppm. Analysis of the

spectra evolved in the presence of trans-β-nitrostyrene is indicated by decrease in peak

area. This may be due to the hydrogen bonding between compound 27 and trans-β-

nitrostyrene which led to deprotonation of N-H protons.

39

Figure 31. 1H NMR (expanded) spectra of the titration of catalyst 27

with trans-β-nitrostyrene in CDCl3 recorded in the following trans-β-

nitrostyrene quantities (equiv.): a) 0, b) 1, c) 2 d) 3, e) 4, and f) 5

40

General procedure for the catalytic Michael addition of nitroolefins with various Michael

donors

To a stirred solution of catalyst 27 (12.6 mg, 0.02 mmol, 10 mol%), nitroolefins (0.2

mmol) and Michael donor (dimethylmalonate, diethylmalonate and malononitrile) (0.4 mmol) in

o-dichlorobenzene (1 mL), triethylamine was added. The reaction mixture was stirred at rt for 12

hours and the reaction mixture was extracted with ethyl acetate, washed with water, then washed

with brine, dried over sodium sulfate and concentrated. The residue was purified by column

chromatography on silica gel (ethyl acetate and n-hexane as the eluent) to afford the

corresponding Michael adducts (57a-g)

Synthesis of dimethyl 2-(2-nitro-1-phenylethyl)malonate (57a)

According to general procedure, 57a was prepared from trans-β-nitrostyrene (29.8 mg,

0.2 mmol) and dimethyl malonate (46 μL, 0.4 mmol) as white solid. mp: 64 oC;

1H NMR (400

MHz, CDCl3) δ 7.34-7.27 (m, 3H), 7.23-7.21 (m, 2H), 4.95-4.84 (m, 2H), 4.27-4.21 (m, 1H),

3.86 (d, J = 9.2 Hz, 1H), 3.76 (s, 3H), 3.56 (s, 3H); 13

C NMR (100 MHz, CDCl3) 167.8, 167.2,

136.1, 129.0, 128.4, 127.8, 54.7, 53.0, 52.8, 42.9.

Figure 32. 1H NMR of dimethyl 2-(2-nitro-1-phenylethyl)malonate (57a)

41

Figure 33. 13

C NMR of dimethyl 2-(2-nitro-1-phenylethyl)malonate (57a)

Synthesis of dimethyl 2-(1-(4-chlorophenyl)-2-nitroethyl)malonate (57b)

According to general procedure, 57b was prepared from 1-chloro-4-(2-nitroethyl)benzene

(36.7 mg, 0.2 mmol) and dimethyl malonate (46 μL, 0.4 mmol) as pale yellow solid. mp: 45 oC;

1H NMR (400 MHz, CDCl3) δ 7.33-7.28 (m, 2H), 7.21-7.19 (m, 2H), 4.95-4.83 (m, 2H), 4.26-

4.24 (m, 1H), 3.84 (d, J = 9.2 Hz, 1H), 3.79 (s, 3H), 3.61 (s, 3H).

42

Figure 34. 1H NMR of dimethyl 2-(1-(4-chlorophenyl)-2-nitroethyl)malonate (57b)

Synthesis of dimethyl 2-(1-(4-bromophenyl)-2-nitroethyl)malonate (57c)

According to general procedure, 57c was prepared from 1-bromo-4-(2-nitroethyl)benzene

(45.6 mg, 0.2 mmol) and dimethyl malonate (46 μL, 0.4 mmol) as white solid. mp: 60 oC;

1H

NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.94-4.83 (m, 2H),

4.26-4.20 (m, 1H), 3.84(d, J = 8.8 Hz, 1H), 3.78 (s, 3H), 3.61 (s, 3H).

Figure 35. 1H NMR of dimethyl 2-(1-(4-bromophenyl)-2-nitroethyl)malonate (57c)

Synthesis of dimethyl 2-(1-(4-methoxyphenyl)-2-nitroethyl)malonate (57d)

According to general procedure, 57d was prepared from 1-methoxy-4-(2-

nitrovinyl)benzene (35.8 mg, 0.2 mmol) and dimethyl malonate (46 μL, 0.4 mmol) as colorless

oil. 1H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 4.93-4.81

(m, 2H), 4.24-4.18 (m, 1H), 3.85 (d, 9.2 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.59 (s, 3H).

43

Figure 36. 1H NMR of dimethyl 2-(1-(4-methoxyphenyl)-2-nitroethyl)malonate (57d)

Synthesis of dimethyl 2-(2-nitro-1-(4-nitrophenyl)ethyl)malonate (57e)

According to general procedure, 57e was prepared from 1-nitro-4-(2-nitrovinyl)benzene

(38.8 mg, 0.2 mmol) and dimethyl malonate (46 μL, 0.4 mmol) as yellow color oil. 1H NMR

(400 MHz, CDCl3) δ 8.23 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8, 2H), 4.98-4.95 (m, 2H), 4.42-4.23

(m, 1H), 4.15 (d, 1H), 3.91-3.80 (s, 3H), 3.66-3.63 (s, 3H).

44

Figure 37. 1H NMR of dimethyl 2-(2-nitro-1-(4-nitrophenyl)ethyl)malonate (57e)

Synthesis of diethyl 2-(2-nitro-1-phenylethyl)malonate (57f)

According to general procedure, 57f was prepared from trans-β-nitrostyrene (29.8 mg,

0.2 mmol) and diethyl malonate (61 μL, 0.4 mmol) as white solid. mp: 60 oC,

1H NMR (400

MHz, CDCl3) δ 7.33-7.22 (m, 5H), 4.93-4.83 (m, 2H), 4.24-4.20 (m, 3H), 4.00 (q, J = 7.2 Hz,

2H), 3.82 (d, J = 9.6 Hz, 1H), 1.25 (t, J = 7.2, 3H), 1.04 (t, J = 7.2 Hz, 3H); 13

C NMR (400 MHz,

CDCl3) δ 167.4, 166.8, 136.2, 128.9, 128.3, 128.0, 77.6, 62.1, 61.8, 55.0, 42.9, 13.9, 13.7.

45

Figure 38. 1H NMR of diethyl 2-(2-nitro-1-phenylethyl)malonate (57f)

Figure 39. 13

C NMR of diethyl 2-(2-nitro-1-phenylethyl)malonate (57f)

Synthesis of 2-(2-nitro-1-phenylethyl)malononitrile (57g)

According to general procedure 57g was prepared from trans-β-nitrostyrene (29.8 mg, 0.2

mmol) and malononitrile (22 μL, 0.4 mmol) as white solid. mp: 56 oC;

1H NMR (400 MHz,

46

CDCl3) δ 7.48-7.42 (m, 3H), 7.25-7.22 (m, 2H), 5.14 (m, 2H), 4.32 (d, J = 9.6 Hz 1H), 4.13 (m,

1H)

Figure 40. 1H NMR of 2-(2-nitro-1-phenylethyl)malononitrile (57g)

Study the role of prepared catalyst in Henry reaction

Henry reaction (nitro aldol) is an important C-C bond forming reaction to achieve β-

nitroalcohol from aldehyde and nitroalkane, discovered in 1895 by the Belgian chemist Louis

Henry. β-nitroalcohols acts as synthetic precusors to several important compounds. In particular,

the nitro group can be converted into several other functionalities by reduction, Nef reaction and

nucleophilic displacement to generate β-hydroxy ketones, aldehydes, carboxylic acids, azides,

sulphides and many other bifunctional compounds. It has been found that, aminoalcohols

obtained by the reduction of β-hydroxy nitroalkanes have utility as chiral ligands in asymmetric

catalysis, and as an important building block of natural products as well as pharmaceuticals.19

Scheme 22

47

Mechanism

First step is the deprotonation of nitroalkane on the alpha-carbon forming a resonance stabilised

anion. This is followed by the nucleophilic addition of the newly generated anion to the carbonyl

containing substrate to form a diastereomeric β-nitro alkoxide. The protonation of the β-nitro

alkoxide by the conjugate acid of the base will yield the respective β-nitro alcohol as the product.

One of the feature of the reaction is that, only a catalytic amount of base is required for this

reaction.

Scheme 23

Study of Henry reaction in the presence of prepared catalysts

Several hydrogen-donor organic molecules have proven to be efficient catalysts in many

reactions. The screening of the reaction was made by treating benzaldehyde and nitromethane in

presence of the prepared organocatalysts in THF at room temperature for 12h. Moderate to good

yields of nitroaldol and β-nitrostyrene were obtained (Figure 41). No product was obtained when

the reaction was performed in the absence of the catalyst

48

49

Figure 41. GC MS spectrum of β-nitrostyrene and nitroalcohol

Table 9. Screening of catalyst for Henry reaction

Entry Catalyst Time h Yield% (β-NS)b

1 27 12 43

2 no catalyst 12 0

aAll reactions were carried out using benzaldehyde 32

(0.5 mmol) and nitromethane 20 (5 mmol) in the

presence of catalyst (10 mol %) in THF at rt. bDetermined by GC analysis.

Summary

A series of triaminotriazine molecules were prepared and used as organocatalyst for

Michael addition reaction. The amino groups were chosen as they possess structural features that

can favour hydrogen bonding interaction with Michael acceptors. To enhance the binding

efficiency with Michael acceptors we have synthesised molecules with different alkyl chain

length in order to control non-polar environment around the binding site. Also, a set of catalysts

were designed and synthesized with aromatic amines to understand the role of electron demand

in the catalysis process. For chiral catalysis we synthesized a series of triazine molecules bearing

alkyl esters of aminoacids. We choose L-alanine and L-phenyl alanine as the aminoacid unit for

the preparation of chiral triazine catalysts for Michael addition reaction. Also an aminotriazine

derivative having a terminal tertiary amine group, was prepared with a view to introduce an

internal base along with potential hydrogen bond donor characteristics. This internal amino

group is expected to assist deprotonation of the Michael donors and thereby one can carryout the

reaction in the absence of triethyl amine added as the external base. We examined the catalytic

properties of the prepared catalysts in the conjugate addition of diethylmalonate to different

nitroalkene derivatives. The prepared catalysts were found to catalyse the Michael addition

reaction between trans-β-nitrostyrene and diethyl malonate in presence of triethylamine at room

temperature in THF as the solvent. Control reactions were carriedout in the absence of the

catalysts to ascetrain the role of the prepared triaminotriazine derivatives in catalysing the

Michael addition reaction. The synthesized catalysts enhance the reaction rate in comparison to

the reaction in the absence of the catalyst. Optimization of the amount of catalyst required was

carried out and found that 10 mol% is the optimal amount. Catalyst with long alkyl chain

(dodecyl) was selected as an optimal catalyst with respect to the reaction outcome and this

catalyst was used to study other reaction parameters such as temperature, solvent, base and other

additives. Among solvents, we found that o-dichlorobenzene to be superior medium for the

reaction. Among the bases tested, triethylamine was more effective than DIPEA, Na2CO3,

pyridine and DABCO. Additives such as TFA, acetic acid, benzoic acid etc. did not improve the

results. Having established the optimized reaction conditions for the model reaction, the scope of

this transformation was further studied using different nitroolefins and Michael donors using the

optimized catalyst. From the observed results almost all the substituted β-nitroalkenes, bearing

either electron-donating or withdrawing substituents on the aromatic ring gave the desired

Michael adduct in very good yield.

51

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Annexure I FINAL REPORT (From 01-07-2015 to 30-06-2018 ...dspace.cusat.ac.in/jspui/bitstream/123456789/13183... · synthesis and study of new organocatalysts for asymmetric michael