Report on Synthesis Laboratory Work

By

Mr.T.Sothyrupan

August 2011 to August 2012

Synthesis Unit

Industrial Technology Institute

363, Baudhaloka Mawatha

Colombo 071

Content1. Synthesis of Methyl Eugenol…………………………………………………………………………………………… 3

2. Synthesis of Ethyl Paraben……………………………………………………………………………………………… 6

3. Synthesis of Propyl Paraben……………………………………………………………………………………………. 7

4. Synthesis of Cue lure………………………………………………………………………………………………………. 8

5. Designed methodology for the synthesis of pheromones and 2-AP

General Introduction ……………………………………………………………………………………………………..

a. Ferrugineol………………………………………………………………………………………………………………. 11

b. Sitophelure………………………………………………………………………………………………………………. 17

c. Serricornine……………………………………………………………………………………………………………… 24

d. 2-acetyl-1-pyrroline…………………………………………………………………………………………………. 31

6. Appendix

a. Abstract paper for the International Conference in Chemical Sciences…………………… 38

b. Extended paper for the international Conference in Chemical Sciences…………………. 39

c. Gas chromatogram of cinnamon leaf oil………………………………………………………………….. 43

d. Gas chromatogram on methyl eugenol……………………………………………………………………. 44

2

1. Synthesis of methyl eugenol

Theory:

MeO

OH

MeI, K2CO3 anhyd.

Acetone, reflux

MeO

MeO

Experimental:

Figure: Methyl eugenol reaction set up

Eugenol (Cinnamon leave oil containing 80% eugenol according to GC) 25 ml, anhydrous potassium carbonate 18 g and dry acetone 150 ml were taken in a two necked flask fitted with an efficient reflux condenser. 12 ml of methyl iodide was added to the above reaction mixture

3

and boiled under reflux for 21 hours (total time reflux = seven hours per day) using a heating mantle at inert atmosphere. Fresh portions of anhydrous potassium carbonate and methyl iodide were added every day morning before reflux. Reaction was monitored by TLC using 12% ethyl acetate in hexane as developing solvent (Vanillin sulfate as TLC detection agent). At the end of the reaction, the reaction mixture was filtered using sintered glass filter funnel and the solvent was reduced by distillation under reduced pressure using rotary evaporator (During which time most part of the acetone was removed). Condensed reaction mixture was transferred into separatory funnel and 100 ml of distilled water was added into it and organics was extracted with 60 ml portion of ethyl acetate. The ethyl acetate extract was washed with 10 % sodium hydroxide (100 ml) and the organic layer was washed with brine water (70 ml). Then the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate layer was filtered and the solvent was removed under vacuum using rotary evaporator. Yield of the product was 23 ml. Purity of the starting material and product were identified by gas chromatography.(see appendix)

. .

SF

ME

ME

E

Sample origin

IM

TLC after 7hrs 15 minutes

Developing solvent: 12% EtOAc in Hexane

. Sample origin

ME

IM

SF

TLC after 19 hours reflux

Detection: Vaniline sulfate

SF – Solvent frtont

IM – Impurities

ME – Methyl eugenol

E- Eugenol

GC – Analytical application (for the purity check):

(GC Shimadzu GC 2010)72.0% according to gas chromatogramGC specification:

4

Column type RPX – Wax (ID 0.25mm, Film thickness = 0.25 µm)Serial No: 900637Column temperature = 250oCColumn length = 30.0 m

Temperature program:Initial Temperature = 60oCFinal Temperature = 225oCTemperature gradient = 5oC / minutesInjection port temperature 230oC (initial hold time 0 minute)Detector Temperature 240oCDetector FIDTotal run time 41 minutesFinal column hold time at 225oC = 8 minutes

References:

1. Organic Synthesis Collective Volume 3, 140, (1955); Vol.25, p.9 (1945)2. Reactions and synthesis in the Organic Chemistry laboratory, Wiley-VCH 2007, Lutz

F.Tietze, Theophil Eicher, Ulf Diederichsen, Andreas Speicher, p.582, 3Ed.3. Purification laboratory chemicals by Armago, Perins and Perins

5

2. Synthesis of Ethyl Paraben

Theory:

OH

COOH

+ EtOH

Conc.H2SO4

TolueneDean-Stark apparatus

OH

COOEt

+ H2O

Experiment:

p-hydroxybenzaldehyde (10 g), pure ethanol (10 ml), toluene (50 ml) and 0.5 ml concentrated sulfuric acid were taken in a two necked round bottomed flask and refluxed under Dean-Stark apparatus for 24 hours. Reaction mixture was cool to room temperature and the solvent toluene was removed by reduced pressure distillation using rotary evaporator. A clean solid product the ethyl paraben was obtained and it was colorless.

TLC pattern:

p-hydroxy benzoic acid

sample origin

ethyl paraben

unreactedp-hydroxybenzoic acid

solvent front

TLC developing solvent Hexane: EtOAc = 3:2

Note:

Product is in active to vaniline sulfate and was detected by UV lamp (254 nm) in TLC detection. Ethanol and toluene were purified by standard procedure as described in Vogel’s.

Reference: Text book of practical organic chemistry by Vogel’s

6

3. Synthesis of propyl paraben

Theory:

OH

COOH

+ n-PrOHConc.H2SO4

tolueneDean-Stark apparatus

OH

COOPr

+ H2O

Experimental:

p-hydroxybenzaldehyde (10 g), pure n-propanol (10 ml), toluene (50 ml) and 0.5 ml concentrated sulfuric acid were taken in a two necked round bottomed flask and refluxed under Dean-Stark apparatus for 24 hours. Reaction mixture was cool to room temperature and the solvent toluene was removed by reduced pressure distillation using rotary evaporator. A clean solid product the propyl paraben was obtained and it was colorless.

TLC Pattern:

solvent front

p-hydroxy benzic acid\

Sample origin

propylparaben

TLC developing solvent Hexane : EtOAc=3:2

Note:

Product is in active to vaniline sulfate and was detected by UV lamp (254 nm) in TLC detection. N-propanol and toluene were purified by standard procedure as described in Vogel’s.

Rference: Text book of practical organic chemistry by Vorgel’s

7

4. Synthesis of Cue-Lure from p-hydroxy benzaldehyde

Theory:

OH

CHO

+ CH3

O

CH3

1. NaOH (aq)

2. Dil.HCl

OH

CH CH CH3

O

+ H2O

H2/Pd-C (5%)

Acetone

(Cat. hydrogenation)

OH

CH2 CH2 CH3

O

1.Ac2O/NaOH(aq)

2. Dil.HCl

CH2

OAc

CH2 CH3

O

Experimental:

Step I: Synthesis of 4-(4-hydroxyphenyl)but-3-ene-2-one

p-hydroxybenzaldehyde (3 g), acetone (5 ml) and crushed ice (20 g) were taken in conical flask and 20% sodium hydroxide solution ( ml) was added to the stirred mixture. Stirring was continued one overnight and the reaction mixture was acidified with dilute HCl until the mixture become just acidic. The crude product was extracted with 150 ml ethyl acetate and washed with brine solution. Solvent was evaporated under reduced pressure and the yellow colour crystals were obtained. The crude product was pure enough to use for the second step.

8

TLC pattern:

SM

Pdt

SF

Origin

Developing solvent EtOAc:Hexane = 1:1

Step II: Synthesis of 4-(4-hydroxyphenyl)butan-2-one

4-(4-hydroxyphenyl)but-3-ene-2-one ( g), small amount of Pd-C (5%) catalyst and acetone solvent (25 ml) were taken in a two necked round bottomed flask and stirred under hydrogen atmosphere for one day. The reaction mixture was filtered to remove Pd-C catalyst and the solvent was removed under reduced pressure using rotary evaporator. A white solid crude product obtained was used for the third step in the synthesis of cue-lure. Percentage of yield was %.

TLC pattern:

RM SMOrigin

SMPdt

SF

Developing solvent Hexane : EtOAc = 3:2

9

Step III: Synthesis of cue-lure

4-(4-hdroxyphenyl) butan-2-one (0.022 mol), 10% sodium hydroxide (12 ml), crushed ice 30 g and acetic anhydride (4 ml) were taken in a quick fit conical flask and the reaction mixture was shaken vigorously for ten minutes. The resulting solution was transferred to a separatory funnel and the product was extracted with 2 x 75 ml ethyl acetate solvent. The solvent was removed under reduced pressure using rotary evaporator. The product is reasonably pure enough for the field application. Percentage of yield was %.

TLC pattern:

SF

SM

Origin

Expected product

Developing solvent Hexane : EtOAc = 3 : 2

References:

1. Text book of Practical Organic Chemistry by Vogel’s

2. Journal of Agriculture and Food Chemistry 1976, 24(4), 782-783

3. Organic synthesis Collective volume 3, p.17, 1923

4. Organic synthesis Collective volume 1, p.77, 1941

10

5. Designed methodology for the synthesis of pheromones

General Introduction

In this part of the report the compounds of interest are analyzed retrosynthetically to design methodology for the asymmetric synthesis routes. The retrosynthetic routes and the proposed synthetic routes based on the retrosynthetic studies are reported. The procedures for the synthetic routes were found in relevant literatures and quoted. These were not tested experimentally.

a. Coconut red palm weevil pheromone, Ferrugineol

Structure of Ferrugineol

Me

OH

Fig: Structure of ferrugineol

Retrosynthetic studies of ferrugineol

Fig: Retrosynthetic scheme of ferrugineol

11

Proposed Synthesis of ferrugineol based on retrosynthetic studies

Fig: Proposed synthetic scheme of ferrugineol

Experimental for the proposed synthetic path

Preparation of butyl magnesium bromide:

12

(a) Preparation of Butyl magnesium bromide:

In a 3-l. three-necked, round-bottomed flask, fitted with a 500-cc. separatory funnel, a liquid-sealed mechanical stirrer, and a reflux condenser, are placed 36.5 g. (1.5 gram atoms) of magnesium turnings and 500 cc. of absolute ether. A solution of 206 g. (1.5 moles) of n -butyl bromide (Org. Syn. Coll. Vol. I, 1941 , 28, 37) in 250 cc. of absolute ether is placed in the separatory funnel. The stirrer is started, and 10–15 cc. of the bromide solution is allowed to flow into the flask from the funnel; the reaction generally begins within a few minutes (Note 1). As soon as refluxing is vigorous, the flask is surrounded by ice and water and the rate of addition of the bromide is adjusted so that moderate refluxing occurs. After all the solution has been added (thirty to forty minutes), the cooling bath is removed. Stirring is continued for fifteen minutes longer, after which only a small residue of unreacted magnesium remains.

(b) Reaction of butyl magnesium bromide to ethyl formate (Grignard reaction):

The flask is cooled in an ice bath and a solution of 55.5 g. (0.75 mole) of pure ethyl formate (Note 2) in 100 cc. of absolute ether is placed in the separatory funnel. The stirrer is started and the ethyl formate solution is added at such a rate that the ether refluxes gently. This addition requires about one-half hour. The cooling bath is then removed and stirring is continued for ten minutes.

(c) Generation of Secondary alcohols in the recation work up

With vigorous stirring (Note 3), 100 cc. of water is added through the separatory funnel at such a rate that rapid refluxing occurs. Following this, a cold solution of 85 g. (46 cc., 0.85 mole) of concentrated sulfuric acid in 400 cc. of water is added. After the addition of the acid, the two layers become practically clear. A large part of the ethereal layer is decanted into a 1-l. round-bottomed flask, and the remainder, together with the aqueous layer, is transferred to a separatory funnel. The solid remaining in the flask is washed with two 25-cc. portions of ether, which are added to the material in the separatory funnel. The ethereal layer is separated and combined with the decanted portion. The flask is fitted with an efficient fractionating column, and the ether is distilled from a steam bath until the temperature of the vapor reaches about 50°. To the residual impure carbinol (Note 4) is added 75 cc. of 15 per cent aqueous potassium hydroxide solution and the flask is fitted with a reflux condenser. The mixture is boiled vigorously under reflux for three hours, after which the purified carbinol is removed by steam distillation, the volume in the flask being kept at 250–300 cc. The distillate is collected in a separatory funnel so that the lower aqueous layer can be drawn off periodically. The distillation is complete when about 1.5 l. of water has been collected.

The upper layer of di- n -butylcarbinol is separated and allowed to stand over 10 g. of anhydrous potassium carbonate for one hour. The liquid is decanted into a 500-cc. Claisen flask, and the residual potassium carbonate is washed with three 10-cc. portions of dry ether, which are added to the material in the distilling flask. After removing a small fraction of low-boiling material,

13

there is obtained 90–92 g. (83–85 per cent of the theoretical amount) of pure di- n -butylcarbinol , b.p. 97–98°/ 20 mm. (Note 5).

14

(d) ASYMMETRIC SYNTHESES USING THE SAMP-/RAMP-HYDRAZONE METHOD: ( S )-(+)-4-METHYL-3- HEPTANONE

A. 3-Pentanone SAMP hydrazone [(S)-2 ]. A 50-mL, one-necked, pear-snapped, flask equipped with a 10-cm Liebig condenser, a gas inlet tube, and a magnetic stirring bar is charged with 3.9 g (3.0 mmol) of SAMP (Note 1) and 3.79 mL (36 mmol) of 3-pentanone (Note 2) and the mixture is warmed at 60°C under argon overnight (Note 3). The crude product is diluted with 200 mL of ether in a 250-mL separatory funnel and washed with 30 mL of water. The organic layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by short-path distillation yields 5.18 g (87%) of a colorless oil, bp 70–75°C at 0.5 mm, [α]D20 +297° (benzene, c = 1). The SAMP-hydrazone (S)-2 should be stored in a refrigerator under argon (Note 4).

B. (S)-(+)-4-Methyl-3-heptanone SAMP hydrazone [(ZSS)-3] . A flame-dried, one-necked 250-mL flask with side arm, rubber septum, and magnetic stirring bar is flushed with argon (Note 5). The flask is then cooled to 0°C and 110 mL of dry ether (Note 6) and 2.97 mL (21 mmol) of dry diisopropylamine (Note 7) are added, followed by dropwise addition of 21 mmol of butyllithium (13.1 mL of a 1.6 N solution in hexane (Note 8)). Stirring is continued for 10 min and a solution of 3.96 g (20 mmol) of SAMP-hydrazone (S)-2 in 10 mL of ether is added to the stirred mixture over a 5-min period at 0°C. An additional 2 mL of ether is used to transfer all of the hydrazone (S)-2 into the reaction flask. Stirring is continued for 4 hr at 0°C, while the lithiated hydrazone precipitates. The mixture is cooled to −110°C (pentane/liquid nitrogen bath) and kept for 15 min at this temperature. Then 2.15 mL (22 mmol) of propyl iodide (Note 9) is added dropwise, and the mixture is allowed to reach room temperature overnight. The contents of the flask are poured into a mixture of 300 mL of ether plus 50 mL of water in

15

a 500-mL separatory funnel, the layers are separated, and the aqueous layer is extracted twice with 25 mL of ether. The combined organic layers are washed with 10 mL of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 4.3 g (90%) of crude (ZSS)-3 (Note 10).

C. (S)-(+)-4-Methyl-3-heptanone [(S)-4] . A 100-mL Schlenk tube, fitted with a gas inlet and Teflon stopcocks, is charged with 4.3 g (18 mmol) of crude (ZSS)-3 dissolved in 50 mL of dichloromethane (Note 11), and cooled to −78°C (acetone/dry ice bath) under nitrogen. Dry ozone (Note 12) is passed through the yellow solution until a green-blue color appears (ca. 4 hr). The mixture is then allowed to come to room temperature while a stream of nitrogen is bubbled through the solution to give the yellow nitrosamine (S)-5 (Note 13) and the title ketone (S)-4. The solvent is removed by distillation at 760 mm (60°C bath temperature) and the residue is transferred into a microdistillation apparatus (10-mL flask, 5-cm Vigreux column, spider, collector device, (Note 14)). After a small forerun (3–4 pale-yellow drops), a colorless liquid distills to afford 1.6–1.7 g (56–58% overall) of ketone (S)-4; bp 63–67°C at 40 mm (110–115°C bath temperature), GLC analysis 98.2%, [α]D20 + 21.4° to + 21.7° (hexane, c = 2.2), [α]D20 + 17.88° (neat) (Note 15). To recycle the chiral auxiliary SAMP, see (Note 16).

16

References

1. Organic Syntheses, Coll. Vol. 2, p.179 (1943); Vol. 15, p.11 (1935).

2. Title: Reactions and syntheses in the organic chemistry laboratory

Authors: Lutz-Friedjan Tietze, Theophil Eicher, Ulf Diederichsen, Andreas Speicher

3. Oxidation of alcohols to aldehydes and ketones: a guide to current common practice ( Basic reactions in organic synthesis)by Gabriel Tojo, Marcos I. Fernández, Marcos Fernández

4. Text book of Practical Organic Chemistry by Vogel’s

b. Rice weevil pheromone, sitophelure

Structure of sitophelure

OH

Me

O

Fig: Structure of sitophelure

Retrosynthetic studies of sitophelure

OH

Me

O FGI OH

Me

O

Me

OOAcFGI

Me

OAllylationO

17

Proposed synthesis of sitophelure based on retrosynthetic studies

Experimental for the proposed synthetic path

A. SAMP hydrazone [(S)-2 preparation .

A 50-mL, one-necked, pear-snapped, flask equipped with a 10-cm Liebig condenser, a gas inlet tube, and a magnetic stirring bar is charged with 3.9 g (3.0 mmol) of SAMP (Note 1) and 3.79 mL (36 mmol) of 3-pentanone (Note 2) and the mixture is warmed at 60°C under argon overnight (Note 3). The crude product is diluted with 200 mL of ether in a 250-mL separatory funnel and washed with 30 mL of water. The organic layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by short-path distillation yields 5.18 g (87%) of a colorless oil, bp 70–75°C at 0.5 mm, [α]D20 +297° (benzene, c = 1). The SAMP-hydrazone (S)-2 should be stored in a refrigerator under argon (Note 4).

18

B. Allylation of SAMP hydrazone [(ZSS)-3] .

A flame-dried, one-necked 250-mL flask with side arm, rubber septum, and magnetic stirring bar is flushed with argon (Note 5). The flask is then cooled to 0°C and 110 mL of dry ether (Note 6) and 2.97 mL (21 mmol) of dry diisopropylamine (Note 7) are added, followed by dropwise addition of 21 mmol of butyllithium (13.1 mL of a 1.6 N solution in hexane (Note 8)). Stirring is continued for 10 min and a solution of 3.96 g (20 mmol) of SAMP-hydrazone (S)-2 in 10 mL of ether is added to the stirred mixture over a 5-min period at 0°C. An additional 2 mL of ether is used to transfer all of the hydrazone (S)-2 into the reaction flask. Stirring is continued for 4 hr at 0°C, while the lithiated hydrazone precipitates. The mixture is cooled to −110°C (pentane/liquid nitrogen bath) and kept for 15 min at this temperature. Then 2.15 mL (22 mmol) of propyl iodide (Note 9) is added dropwise, and the mixture is allowed to reach room temperature overnight. The contents of the flask are poured into a mixture of 300 mL of ether plus 50 mL of water in a 500-mL separatory funnel, the layers are separated, and the aqueous layer is extracted twice with 25 mL of ether. The combined organic layers are washed with 10 mL of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 4.3 g (90%) of crude (ZSS)-3 (Note 10).

19

Asymmetric allylic acetoxylation

1. Procedure

Palladium acetate (1.12 g, 0.005 mol), benzoquinone (2.16 g, 0.02 mol), manganese dioxide (10.44 g, 0.12 mol), and anhydrous acetic acid (250 mL) (Note 1) are placed in a 1-L, round-bottomed flask equipped with a reflux condenser and a magnetic stirring bar. This heterogeneous mixture is equilibrated by efficient stirring for 30–60 min. Cycloheptene (9.61 g, 0.1 mol) (Note 2) is added, and the stirring is continued at 60°C for 28 hr (Note 3). After the solution is cooled to room temperature, 250 mL of pentane/ether (1 : 1) is added and the mixture is stirred for another 30 min. The two-phase mixture is filtered with suction through a Büchner funnel, which contains a layer of Celite (5–10 mm). The Celite layer is washed successively with 250 mL of pentane/ether (1 : 1), 250 mL of water, 100 mL of pentane/ether (1 : 1), and 250 mL of water. After the organic phases are separated, the aqueous phase is extracted 3 times with 250 mL of pentane/ether (1 : 1). The combined organic phases are washed successively with 250 mL of water, 250 mL and then 100 mL of aqueous sodium hydroxide (2 N) (Note 4), 250 mL of water, and finally dried over anhydrous magnesium sulfate. After evaporation or distillation of the solvent, the product is purified by distillation (Note 5) to give 2-cyclohepten-1-yl acetate (11.25 g, 73%), bp 61–62°C (5 mm), lit.3 bp 70°C (6 mm) (Note 6).

2. Notes

1. All the reagents used are analytical-grade, commercially available products, which are used without further purification. Darkened benzoquinone was purified by sublimation. Activated grade manganese dioxide was used; however, it was not shown that "activation" of manganese dioxide is necessary for the reaction.

2. Reaction conditions for other olefins are shown in Table I.

3. The time for optimized conversion has been determined by GLC for all olefins. It is crucial for all reactions to be stopped at optimum conversion, because slow decomposition of the allylic product occurs during the reaction. To obtain optimum yields one should follow the reaction by GLC. Optimized conversion is defined as allylic acetate/allylic acetate plus remaining olefin.

4. Caution should be observed during the alkaline washings because they are exothermic.

5. The crude reaction products can easily be purified by distillation or by flash chromatography, with hexane/ether (95 : 5) as eluant.

6. The product exhibits the following NMR spectra: 1H (200 MHz, CDCl3) δ: 1.30–2.30 (m, 8 H), 2.05 (s, 3 H), 5.40 (m, 1 H), 5.65 (m, 1 H), 5.82 (m, 1 H); 13C (50.3 MHz, CDCl3) δ: 21.20, 26.43, 26.48, 28.33, 32.70, 74.13, 131.38, 133.56, 170.24.

3. Discussion

20

Allylic acetates are usually prepared by esterification from allylic alcohols. However, the corresponding alcohols are often only accessible by the fairly expensive hydride reduction of carbonyl compounds. Consequently, direct allylic functionalization of easily available olefins has been intensively investigated.4

Most of these reactions involved peroxides5 or a variety of metal salts.6,7 However, serious drawbacks of these reactions, (e.g., toxicity of some metals, stoichiometric reaction conditions, or nongenerality) may be responsible for their infrequent use for the construction of allylic alcohols or acetates.

Allylic acetoxylation with palladium(II) salts is well known;8 however, no selective and catalytic conditions have been described for the transformation of an unsubstituted olefin. In the present system use is made of the ability of palladium acetate to give allylic functionalization (most probably via a palladium–π-allyl complex) and to be easily regenerated by a co-oxidant (the combination of benzoquinone–manganese dioxide). In contrast to copper(II) chloride (CuCl2) as a reoxidant,8 our catalyst combination is completely regioselective for alicyclic alkenes; with aliphatic substrates, evidently, both allylic positions become substituted. As yet, no allylic oxidation reagent is able to distinguish between the two allylic positions in linear olefins; this advantage is overcome when the allylic acetates are to be used as precursors for π-allyl complexes (e.g., in palladium-catalyzed substitution reactions).

Hydrolysis of acetate ester

Using standard procedure elsewhere in the literature

Ref: Protective group in organic synthesis by Green

Text book of Practical Organic Chemistry by Vogel’s

Catalytic hydrogenation

Hydrogenation could be carried out using standard protocol

Reference: Text book of practical organic chemistry by Vogel’s

21

22

References

1. Angew. Chem.Int.Ed.Engl, 2oo8, 47, (34), pp.648-651

2. Tetrahedron Asymmetry, Vol.22, Issue 12, 2011, pp.1347-1352

3. Organic Synthesis, Coll. Vol.8,p.403 (1993); vol.65, p.183 (1987)

4. Angew.Chem.Int.Ed.Engl., 1986, 25,1109

23

c. Tobacco beetle pheromone, serricornine

Structure of serricornine

O

Me Me

OAc

Retrosynthetic studies of serricornine

24

Proposed synthesis of serricornine based on retrosynthetic studies

OHC

+ Brenolate alkylation

OHC

OH

Reduction

LAH

BrFGI

Br OAc

Allylic acetoxylation

Fig: Synthesis of fragment I

OSAMP hydrazone formation

NN

OMe

Br

Me

OAc

Me Me

OAcO

Fig: Synthesis of serricornine

25

Experimental for the proposed synthetic path

Step I: Alpha- alkylation of aldehyde via SAMP hydrazone:

A. 3-Pentanone SAMP hydrazone [(S)-2]. A 50-mL, one-necked, pear-snapped, flask equipped with a 10-cm Liebig condenser, a gas inlet tube, and a magnetic stirring bar is charged with 3.9 g (3.0 mmol) of SAMP (Note 1) and 3.79 mL (36 mmol) of 3-pentanone (Note 2) and the mixture is warmed at 60°C under argon overnight (Note 3). The crude product is diluted with 200 mL of ether in a 250-mL separatory funnel and washed with 30 mL of water. The organic layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by short-path distillation yields 5.18 g (87%) of a colorless oil, bp 70–75°C at 0.5 mm, [α]D20 +297° (benzene, c = 1). The SAMP-hydrazone (S)-2 should be stored in a refrigerator under argon (Note 4).

B. (S)-(+)-4-Methyl-3-heptanone SAMP hydrazone [(ZSS)-3] . A flame-dried, one-necked 250-mL flask with side arm, rubber septum, and magnetic stirring bar is flushed with argon (Note 5). The flask is then cooled to 0°C and 110 mL of dry ether (Note 6) and 2.97 mL (21 mmol) of dry diisopropylamine (Note 7) are added, followed by dropwise addition of 21 mmol of butyllithium (13.1 mL of a 1.6 N solution in hexane (Note 8)). Stirring is continued for 10 min and a solution of 3.96 g (20 mmol) of SAMP-hydrazone (S)-2 in 10 mL of ether is added to the stirred mixture over a 5-min period at 0°C. An additional 2 mL of ether is used to transfer all of the hydrazone (S)-2 into the reaction flask. Stirring is continued for 4 hr at 0°C, while the lithiated hydrazone precipitates. The mixture is cooled to −110°C (pentane/liquid nitrogen bath) and kept for 15 min at this temperature. Then 2.15 mL (22 mmol) of propyl iodide (Note 9) is added dropwise, and the mixture is allowed to reach room temperature overnight. The contents of the flask are poured into a mixture of 300 mL of ether plus 50 mL of water in a 500-mL separatory funnel, the layers are separated, and the aqueous layer is extracted twice with 25 mL of ether. The combined organic layers are washed with 10 mL of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield 4.3 g (90%) of crude (ZSS)-3 (Note 10).

26

Step II: SAMP hydrazone cleavage

Step III: Reduction of aldehyde by Lithium Aluminium hydride,LiAlH4

27

Step IV & V: Transformation of alcohol to mesylate an then to bromide28

PhD thesis, Dr.Ove Nordin, Mid Sweden University

Step VI: Allylic acetoxylation

29

Step VI: SAMP hydrazone preparation and alkylation of the second fragment of the molecule

Indicated above

Step VII: SAMP hydrazone cleavage: Indicated above

Indicated above

References

1. Organic synthesis Collective volume 8, p.403, 1993

2. Organic Synthesis Collective Volume 65, p.183, 1987

3. Text Book of Practical Organic Chemistry Vogel’s

4. Angew. Chem. Int. Ed, 2008, 47, p.1-5

5. Title: Reactions and syntheses in the organic chemistry laboratory

Authors: Lutz-Friedjan Tietze, Theophil Eicher, Ulf Diederichsen, Andreas Speicher

30

d. 2-acetyl-1-pyrroline

Structure of 2-acetyl-1-pyrroline

Fig: 2-acetyl-1-pyrroline

Synthesis protocol of 2-acetyl-1-pyrroline

Fig: Synthesis of fragment I

31

Fig: Synthesis of 2-AP

Fig: Synthesis of fragment II

Experimental Protocol

N-(2-Propenyl)-4-methylbenzenesulfonamide TM II.

A 1-L, two-necked, round-bottomed flask equipped with a magnetic stirring bar, internal thermometer and powder funnel is charged with p-toluenesulfonyl chloride (97.2 g, 0.51 mol) (Note 1). The powder funnel is replaced with a rubber septum connected to a positive pressure of argon and an oil bubbler. The apparatus is flushed with argon and charged with tetrahydrofuran (THF) (400 mL, (Note 2)) and pyridine (42.9 mL, 0.53 mol). The flask is placed in an ice bath and, after the reaction mixture has cooled to ca. 10°C, allylamine (37.5 mL, 0.50 mol) (Note 3) is added portion-wise by syringe over ca. 40 min (exothermic) maintaining the internal temperature below 15°C. The ice bath is removed and the resulting solution is allowed to warm to room temperature. After 4 hr the rubber septum is removed and the mixture is treated with 75 mL of a 2M aqueous

32

solution of sodium hydroxide. After another 4 hr, the reaction mixture is transferred to a separatory funnel, the organic phase is separated, and the aqueous phase is extracted with two 100-mL portions of ethyl acetate (EtOAc). The combined organic phases are washed with brine (50 mL) and dried with magnesium sulfate (MgSO4) in the presence of activated carbon (4 g). The solution is filtered through a plug of silica gel (diameter: 5 cm; height: 3 cm) and the cake is washed with EtOAc (300 mL). The combined filtrate and washes are concentrated under reduced pressure. The crude product is recrystallized from 275 mL of 30% EtOAc/hexanes to afford 65 g (62%) of allyl tosylamide as a first crop. A second crop of 27 g (26%, 88% in total) is obtained from the mother liquor (Note 4).

3-bromo-4-penten-2-one TM XAllylic bromination with NBS

Method I

3-bromo-4-penten-2-one dimethyl ketal (Keto group protected as dimethyl ketal) TM VIII

Protection of Ketone as cyclic ketal Method I

33

Synthesis of Target Molecule TM III

N-Tosylation

B. N-(2-Propenyl)-N-(2-propynyl)-4-methylbenzenesulfonamide (3). A 500-mL, single-necked, round-bottomed flask equipped with a Teflon-coated stirring bar (Note 1) is charged with allyl tosylamide (31.7 g, 150 mmol), anhydrous potassium carbonate (K2CO3) (24.8 g, 1.2 equiv, 180 mmol) (Note 5), 1-bromo-2-propyne (20.0 mL, 1.2 equiv, 180 mmol), and acetone (300 mL). The flask is equipped with a water-cooled condenser fitted with a rubber septum. The apparatus is flushed with argon introduced through the septum and a positive pressure of argon is maintained with an argon-filled balloon (Note 6). The reaction mixture is heated to reflux with stirring for 24 hr. After complete consumption of starting material, monitored by thin layer chromatography (TLC, (Note 7)), the reaction mixture is allowed to cool and is concentrated under reduced pressure on a rotary evaporator. The residue is diluted with EtOAc (250 mL) and water (125 mL) and the organic phase is separated. The aqueous phase is extracted with 200 mL of EtOAc and the combined organic phases are washed with brine (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure with a rotary evaporator. The residue is recrystallized from 2.5 mL of ether and 250 mL of 20% EtOAc/hexanes to afford ca. 30 g (80%) of 3 as nearly colorless crystals. A second crop totaling 5.9 g (16%, 96% in total) is also obtained (Note 8).

Target molecule TM IVDeprotection of ketal

Cyclization of Target molecule TM IV to TM V34

Cyclization diallyl amine via Ring Clossing Metathesis (Method of Choice)

Catalytic hydrogenation of Ntosyl-2-acetyl-3-pyrroline TM V to TM VI

35

1,2-elimination reaction of N-tosyl-acetylpyrroline TM VI to 2-acetyl-1-pyrroline TM VII

Procedure to be found

JOC 1997

JACS 1997

36

Appendix

37

SYNTHESIS OF METHYL EUGENOL FROM CINNAMON LEAF OIL:

A GREEN PROTOCOL

Thiruchittampalam Sothyrupan1 and Radhika Samarasekara2

1,2Synthesis Unit, Industrial Technology Institute, 363 Baudhaloka Mawatha, Colombo 07,

Sri Lanka

1 sothyrupan@gmail.com and 2radhika@iti.lk

Abstract

Fruit flies (Diptera: Tephritidae) are the major pest of many vegetables and fruits which includes mango, melon, pumpkin and tomato. Flies cause severe damage to the fruits and vegetables and thereby reducing the yield and market values of the products. As agriculture is one of the economically important fields in Sri Lanka there is a need to control the fruit flies in an efficient way to increase the productivity. Methyl eugenol is one of the semiochemical widely used in agriculture sector in the control of fruit flies. Existing method for the production of methyl eugenol by the methylation of eugenol using dimethyl sulfate as methylating reagent, involves chemicals presently categorized as hazardous according to OSHA standards and the product is not safe enough for consumer use. The objective of the present study is to report a green protocol utilizing natural ingredient as starting material and nontoxic methylating reagent for the synthesis of methyl eugenol.

Cinnamon leaf oil containing 80% eugenol by GC analysis was used as the starting material. Other minor constituents of the leaf oil contained myrceane, linalool, β-caryophyllene, cinnamaldehyde, eugenyl acetate and benzyl eugenol. Methylation of cinnamon leaf oil involves the methyl iodide as methylating agent. A mixture of cinnamon leaf oil (25 ml, 0.13 mol eugenol), anhydrous potassium carbonate (3 x 18 g, 3 x 0.13 mol), dry acetone (200 ml) and methyl iodide (3 x 12 ml, 3 x 0.2 mol) was boiled under reflux for 21 hours (3 x 7 hours) followed by the standard reaction work up end up in clean pale yellow oil, mainly contain methyl eugenol as the major constituent. The final solution was analyzed by GC (Shimadzu GC 2010, Column type RPX-Wax, Temperature program 60oC-225oC, 5oC /minutes) and was found to contain 72% methyl eugenol (0.1 mol). The synthesis of methyl eugenol from cinnamon leaf oil by methylation with the mixture of methyl iodide, potassium carbonate and acetone is reported first time according to the available literatures.

Acknowledgement

38

The authors thank ITI Treasury Grant of GOSL for financial assistance.

SYNTHESIS OF METHYL EUGENOL FROM CINNAMON LEAF OIL:

A GREEN PROTOCOL

Thiruchittampalam Sothyrupan1 and Radhika Samarasekara2

1,2Synthesis Unit, Industrial Technology Institute, 363 Baudhaloka Mawatha, Colombo 07,

Sri Lanka

2radhika@iti.lk

Abstract

Fruit flies, Ceratis capitata (Diptera: Tephritidae) are the major pest of many vegetables and fruits and thereby reducing the yield and market values of the products. As agriculture is one of the economically key sector in Sri Lanka there is a need of pest control including fruit flies in an efficient way to increase the productivity. Methyl eugenol is one of the semiochemical widely used in agriculture sector in the control of fruit flies The objective of the present study is to report a green protocol utilizing natural ingredient as starting material and nontoxic methylating reagent for the synthesis of methyl eugenol. Methylation of cinnamon leaf oil to obtain methyl eugenol involves the methyl iodide as methylating agent, anhydrous potassium carbonate and dry acetone as solvent. The final synthesized product was analyzed by GC and was found to contain 72% methyl eugenol.

Key words: Methylation of cinnamon leaf oil; green protocol; Ceratis capitata; methyl eugenol

Introduction

Fruit flies, Ceratis capitata (Diptera, Tephritidae) cause large losses to fruits and vegetables throughout the world, and are recognized today as major insect pests of the fruits farm and horticultural industries (1). The enormous losses they cause in food production in all levels of are significant specifically international trade (2). Fruit flies have been the subject of experimentation and control for many years (3, 4, 5). Despite an intensive program of biological control, a long term method of control; the sterile insect release methods and the use of insecticide use in fruits and vegetable gardens, the high fly populations and abundance of fruits throughout the year combined to maintain the status of the fruit flies as the major pests of cultivated fruits (6).

39

Males of many fruit flies are strongly attracted to methyl eugenol, a compound found naturally in a variety of plant species (7). Methyl eugenol plays a major role in male mating behavior by serving as pheromonal precursor. The usefulness was realized when Howlett (8) recognized methyl eugenol as one of the main constituents of citronella oil which attracted fruit flies of various kinds. Laboratory studies showed that methyl eugenol could be used as a trapping agent for the male fruit fly attraction to control the pest. At present methyl eugenol is used in traps as one of the integrated pest management strategies.

In the present study methyl eugenol was synthesized from naturally available cinnamon (Cinnamonnum zeylanicum) leaf oil which contains the major constituents as eugenol. Cinnamon leaf oil containing 80% eugenol by GC analysis was used as the starting material. GC analysis showed other minor constituents of myrceane, linalool, β-caryophyllene, cinnamaldehyde, eugenyl acetate and benzyl eugenol. In an early attempt to synthesize the methyl eugenol from cinnamon leaf oil involved the methylation of cinnamon oil by treating with dimethyl sulphate in presence with sodium hydroxide as base. Although this method was successful the method involved the carcinogenic dimethyl sulphate as the methylating agents(9, 10). Further it was found difficulty to purify completely the methylated mixture of cinnamon leaf oil to remove from dimethyl sulphate as its high boiling points. Presence of trace amount of dimethyl suphate in the final mixture of the pheromone gives red colour to the methyl eugenol solution in addition to the hazardous nature of the methyl eugenol. We are now reporting a new method of synthesizing the methyl eugenol from cinnamon leaf oil using a less toxic compound.

Methods

Synthesis

A mixture of cinnamon leaf oil (25 ml, 0.13 mol), dry acetone (150 ml) (11), potassium carbonate (3 x 18 g) and iodomethane (12 ml, 3 x 0.2 mol) were refluxed under anhydrous condition for 21 hours (3 x 7 hours) (12). Fresh portions of iodomethane (12 ml) and potassium carbonate 18 g were added every seven hours gap in order to ensure the presence of iodomethane in the reaction mixture (Since the boiling point of iodomethane is 40oC, the iodomethane has the chance of escaping from the reaction flask). After 21 hours reflux the reaction mixture was cooled to room temperature and was subjected to reduced pressure distillation to remove most part of the acetone. Then the reaction mixture was transferred to separatory funnel and extracted with ethyl acetate (70 ml). The organic layer was washed with 10% sodium hydroxide (2 x 100 ml) followed by brine solution (60 ml). Organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by reduced pressure to get the pure methyl eugenol as pale yellow colour liquid. The GC analysis showed yield percent as 72 %.

Gas Chromatography Analysis

The purity and the percentage yield of the eugenol and methyl eugenol were determined by GC Shimadzu GC 2010 instrument equipped with FID. Capillary Column of the type RPX- Wax of column dimension 30 m length and 0.25 mm inner diameter was used in the GC analysis. Oven temperature program was set as 60oC as initial temperature and 225oC as the final temperature. Column was heated in the rate 5oC/min. Injection port of the column was set as 230oC. Detector temperature was set as 240oC. Argon was used as the carrier gas at a flow rate of 1 ml / min. The eugenol and methyl eugenol were identified by comparing GC retention times with their authentic sample and by peak enrichment.

40

Results and discussion

All reagents and solvents were purified according to the standard protocol described in literatures. All the reactions were carried out in an efficient fume cupboard in order to avoid health hazard. Starting material for the synthesis of methyl eugenol was obtained from natural cinnamon leaf oil which contains more than 80% eugenol according to GC analysis. Methyl eugenol was synthesized successfully via green protocol in a pure form and the colour of the methyl eugenol is pale yellow.

OH

MeO MeI, K2CO3

Acetone, reflux

MeO

MeO

Eugenol Methyl Eugenol

Scheme: Eugenol to methyl eugenol conversion

Since the methyl iodide was a low boiling component in the reaction mixture a fresh portion of methyl iodide was added after every seven hours reflux of the reaction media. This ensures most part of the starting material of eugenol consumed in the reaction. Further, excess molar equivalent of iodomethane was used in the reaction. The reaction was monitored by the TLC analysis. As the potassium carbonate transformed into potassium iodide and there will be reaction with moisture a fresh portion potassium iodide was used to replace every seven hours reflux. Potassium carbonate has two functions in the reaction. It act as a base in generating the electrophile, Me+ and in the mean time the side product HI formed in the reaction removed by the potassium carbonate, an in situ trapping agent. The unreacted eugenol was extracted into the aqueous layer during the sodium hydroxide wash at last in the extraction protocol. The unreacted hydroxyl group of eugenol forms phenoxide ion with sodium hydroxide which then extracted into the aqueous phase during the reaction work up. The percentage of yield was 72% according to GC analysis. The low percentage yield was attributed to the escape of iodomethane from the reaction vessel as the iodomethane has low boiling point of 40oC. Further, the amount of the methylation of phenolic hydroxyl group depends on the pH of the hydroxyl group. Since the eugenol has allyl and methoxy substituent in the benzene nucleous the pH of the hydroxyl group is reduced and therefore the generation of nucleophile is little suppressed by the substituents already present in the nucleous.

Conclusion

Methyl eugenol was synthesized by using green protocol with reasonable purity. The percentage yield was 72% according to GC.

Acknowledgement

Financial support from ITI TG grant was gratefully acknowledged.

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References

1. S.Permallow, Biological and Taxonomic studies on parasitoids associated with some Tephritidae (Diptera), PhD thesis, University of Wales, UK, 1989

2. A.J.Allwood and R.A.I.Drew (Edit.), Management of Fruit Flies in the Pacific, Proceedings of the the Australian Center for International Agricultural Research28-31 October, 1996

3. Anon, The natal fruit fly project, Annual report, Entomology Division, Ministry of Agriculture, Fisheries and Natural Resources, 1983

4. Anon, National fruit fly control Program: Experimentation, Annual report, Entomology division, Ministry of Agriculture, Fisheries and Natural resources, Mauritius

5. Landell Mills, Fruit fly control in Mauritius, 1991

6. K.Saeidi and Nur Azura Adam, Efficiency of methyl eugenol as attractant for Acanthiophilus helianthi Rossi, 1794 (dipteral: Tephritidae), International research journal of Agricultural Science and Soil Science 1(10), pp. 412-416, 2011

7. R.L.Mitcalf and E.R.Mitcalf, Plant kairomones in insect ecology and control, Chapman and Hall, p.168, 1992

8. F.M.Howlett, Chemical reaction of fruit flies, Bulletin of Entomology Research, 6, 297-305, 1915

9. Organic synthesis Collective Volume 6, p.859, 1988

10. Organic synthesis Collective Volume 53, p.90, 1973

11. Armago, Perins and Perins, Purification of Laboratory Chemicals, (6E),

12. Lutz F.Tietze, Theophil Eicher, Ulf Diederichsen And Andreas Speicher, Reactions and synthesis in the organic chemistry laboratory, Wiley-VCH 2007

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Gas Chromatogram of Cinnamon leaf oil

43

Gas chromatogram of Methyl Eugenol

44