PROCESS FOR THE PREPARATION OF 2,6,6- TRIMETHYL-1, 3-CYCLOHEXADIENE-1-CARBOXALDEHYDE
Technical field
The present invention relates to an improved single pot process for the preparation of 2,6,6-trimethyl-I, 3-cyclohexadiene-l-carboxaldehyde (Safranal HI) from P-Cyclocitral (I) by a process involving the steps of bromination and dehydrobromination. Background and prior art references
Since 1935, the isolation and identification of Safranal through several synthetic routes have been published (Agew.Chem -1935-26-403), but each differs either in synthetic approach or in the process conditions.
Kuhn & Vlendt (Ber- 1936-69-1549) oxidized p-Cyclocitral (I) with Se02 in one step to Safranal with the yield of only 2%.
Bachli & Karres (Helv.Chim.Acta- 1955-38-1863) used as many as five-step syntheses with the starting material methyl ester of a- Cyclogeranic acid and reported a yield of about 5% based on the starting material.
Mousseron Canet (C.R (C) -1966-1725) synthesized Safranal from a-Cyclocitral by ally lie bromination with N-Bromo succinimide followed dehydrobromination and reported a yield of 45 % based on Cyclocitral.
Karrer & Ochsner (Helv.Chim.Acta-1947-30-2092), in their attempted synthesis, started from a- and P-Cyclocitral by allylic bromination with N-Bromosuccinimide followed by dehydrobromination, but they could not isolate Safranal, in turn the isomeric 2,2,6-Trimethyl-3, 5-cyclohexadiene-l-carboxaldehyde was the only compound identified. Konst & Linde (Tetra.Lett-1974-36-3175) reported the synthesis of Safranal by bromination of a and p-Cyclocitral at -60°C with bromine followed by dehydrobromination using Qiiinoline and reported a 50% yield of Safranal based on Cyclocitral.
Kametani & Suzuki (Chem.Pharm.Bull-1981-29 (I)-105) reported six step selenium-assisted cyclisation for the synthesis of Safranal and obtained a yield of about 6% based the starting material i.e. Gcranyl acetate.
A Japanese Patent JP 8177236-1981 reported synthesis of Safranal from Geranyl acetate in as many as eight steps and got a yield of 4.5 % of Safranal on the starting material.

EP 262426-1988 reported the synthesis of Safranal from Methyl a-Cyclogeranate. The
process involved expensive materials viz.. Butyl lithium, Vitride etc and further making.
of Methyl cyclogeranate involves three additional steps from Citral.
An Indian patent IN 164929-1989 reported the synthesis of Safranal from a mixture a
and (J -Cyclocitral by bromination with Bromine followed by dehydrobromination.
However, the process involved handling of hazardous Bromine.
Giacomo (Essenze Deriv.Agrum-1993-63 (4)-407) reported the synthesis of Safranal
from Verbenone. Verbenone is not commercially available; it is prepared in low a yield
by the autooxidation of Pinene.
Boulin (Tetrahedron- 1998-54(12)-2753) reported the synthesis of Safranal from y-
Pyronene, which is not commercially available.
Some of the cited prior art processes referred to above, deal with the preparation of
Safranal starting from Beta-Cyclocitral but the drawback is poor yield. Hence, an
alternate route to obviate all these problems was felt necessary.
Objects of the invention
The primary object of the present invention is to provide a single pot process for the
manufacture of Safranal (III) from {3-Cyclocitral (I) in high yield.
Another object of the present invention is to provide a simple and economical process for
the manufacture of Safranal (III).
Yet another object of the present invention is to provide Safranal (III) with enhanced
stability for toxic free applications in flavor and perfumery formulations.
Still another object of the present invention is to provide Safranal (Til) without isolating
the intermediate bromocompound (II).
It is also an object of the present invention to provide a process, wherein the p-
Cyclocitral used in the present process is free of a-Cyclocitral having a minimum 98%
purity by GLC, since a-Cyclocitral is found to affect the bromination of (3-Cyclocitral, if
present even at the levels of 3-4% along with P-Cyclocitral.
Summary of the invention
The present invention relates to an improved single pot process for the manufacture of
Safranal (III) in high yields from 2.2,6-Trimethyl-5-cyclohexene-l-Carboxaldehyde (p-
Cyclocitral (I)), by way of allylic bromination using N-bromosuccinimide, followed by
dchydrobromination, without isolating the intermediate bromo compound (II) using
lithium carbonate in an organic solvent.

Detailed description of (he invention
Accordingly, the present invention provides a single pot process for the preparation of Safranal [2,6,6-trimethyl-l, 3-cyclohexadiene-l-carboxaldehyde] represented by formula (HI)
said process comprising the steps of:
(a) treating 2,2,6-Trimethyl-6-cyclohexene-1 -carboxaldehyde [p-cyciocitral-I]
having a minimum purity of 98% in an organic solvent with a brominating
agent, in the presence of a catalytic amount of peroxide to undergo allylic
bromination, at a temperature in the range of 20o-80°C, for a time period of
about 4 to 6 hours, to obtain an intermediate bromo compound of formula (LI);

(b) dehydrobrominating the bromo compound of formula (II) of step (a) with an alkali carbonate, without isolating the intermediate bromo compound, at a temperature in the range of SOX -120°C for about 2-10 hours;
(c) working up the reaction mixture of step (b) by removing the organic solvent at an atmospheric pressure and at the temperature in the range of 110 (IC to I60°C, to obtain a liquid residue;
(d) performing fractional distillation of liquid residue of step (c) at a temperature of about 70°C under reduced pressure of 5mm Hg, to obtain Safranal (III); and
(e) stabilising the Safranal(III) with a stabilizer.

An embodiment of the present invention, wherein in step (a) the hrominating agent is
selected from the group consisting of N-bromosuccinimide or dibromohydantoin,
preferably N-bromosuccinimide.
Yet another embodiment of (he present invention, wherein the brominating agent used is
N-bromosuccinimide.
Further embodiment of the present invention, wherein in step (a) the molar ratio of N-
bromosuccinimide: p-cyclocitral is in the range of 1.2 to].8:1 for performing the most
effective bromination reaction.
Yet embodiment of the present invention, wherein in step (a) the peroxide used is
selected from the group consisting of benzoyl peroxide, di-tertiarybutyl peroxide or 2, T-
azobisisobutyronitrile (AIBN).
Still another embodiment of the present invention, wherein the peroxide used is benzoyl
peroxide.
Further embodiment of the present invention, wherein the concentration of peroxide
catalyst in the reaction mixture is about 2% w/w.
Yet another embodiment of the present invention, wherein in step (a) the organic solvent
used for bromination is selected from the group consisting of toluene, dimethyl
formamide, chloroform, methylene chloride or carbon tetrachloride and preferably
toluene and dimethyl formamide.
Stiil another embodiment of the present invention, wherein the organic solvent used is a
mixture of toluene and dimethyl formamide having a ratio of 1:1 to 1:4 w/w based on p-
cyclocitral.
Yet another embodiment of the present invention, wherein the organic solvent used is a
mixture of toluene and dimethyl formamide having a ratio of 1:1 to 1:2 w/w based on ()-
cyclocitral.
Further embodiment of the present invention, wherein in step (a) the preferred reaction
temperature forallylic bromination is in the range of 60°C to 80°C.
Still another embodiment of the present invention, wherein in step (b) the preferred
reaction temperature fordehvdrobromination is in the range of 95 "C to 110°C.
Yet another embodiment of the present invention, wherein dehydrobromination is
performed with an alkali carbonate selected from the group consisting of sodium
carbonate, potassium carbonate, calcium carbonate or lithium carbonate. .

Further embodiment of the present invention, wherein the alkali carbonate used is lithium
carbonate.
Still another embodiment of the present invention, wherein the ratio of alkali carbonate to
p-Cyclocitral used for dehydrobromination reaction is in the range of 0.5 to 1.5:1.
Yet another embodiment of the present invention, wherein in step (c) the organic solvent
is removed at a temperature in the range of 110-160 C under atmospheric pressure.
Further embodiment of the present invention, wherein in step (d) the fractional
distillation is performed at 5 mm Hg at a temperature of about 70 °C.
Yet another embodiment of the present invention, wherein in step (d) the product
Safranal obtained, is in the yield of about 75% and having a purity of 95% (GLC).
Still another embodiment of the present invention, wherein in step (b) the moisture level
in the dehydrobromination reaction mixture, is maintained below 2% by using only dry
solvents.
Yet another embodiment of the present invention, wherein in step (e) the stabilizer used
is Vitamin-E Acetate, 2,6-Di-tert-butyl-4-methylphenol (BHT),2(3)-tert-butyl-4-
hydroxyanisole (BHA) or Propylgallate.
Still another embodiment of the present invention, wherein the stabilizer used is Vitamin-
E Acetate
Yet another embodiment of the present invention, wherein the concentration of the
stabilizer used is in the range of 10-100 ppm of Safranal (III).
Further embodiment of the present invention, wherein in step (e) the enhanced stability
of Safranal having the retention of odor and flavor with minimum purity level up to 95%
by GLC is obtained by using the stabilizer.
Yet another embodiment of the present invention, wherein the process for the preparation
of Safranal [2,6,6-trimethyl-1. 3-cyclohex.adiene-l-carboxaldehyde] represented by
formula (III) substantially as herein described with reference to the examples.
Yet another embodiment of the present invention, wherein P-Cyciocitral used in our
process is free of a-Cyclocitral having minimum 98% purity by GLC, as a-Cyclocitral is
found to affect the bromination of p-Cyclocitral, if present even in the levels of 3-4%
with p-Cyclocitral.
The schematic steps of the reaction are represented in the form of the following diagram:


The following embodiments further explain the subject matter of the invention. In an embodiment of the present invention, moisture in the reaction mixture is found to affect the efficacy of the reaction drastically. It is also further observed that moisture levels up to 1% based on Cyclocitral as result of solvents and benzoyl peroxide have not affected the yields of Safranal. A systematic study of moisture levels of 2% and above, based on Cyclocitral indicate reduction in the yields of Safranal, more particularly when the moisture content is 5% and above based on Cyclocitral. Hence, in the process of present invention, the moisture levels are constantly monitored and kept low by adopting the usage of only dry solvents.
In yet another embodiment of the present invention, the traces of the intermediate bromide (II) that remain in the finished product, cause an unacceptable reddish brown color, hence removal of even traces of the intermediate bromide (II) is very essential for getting Safranal with an acceptable flavor. Along with this, the stability of Safranal (min 95% purity by GLC), with and without stabilizer has also been studied. It is found in the absence of stabilizer, Safranal (95%min) at 40 °C is found to attain a brown color with a disagreeable odor in 30 days. Safranal with stabi|izerl0-100 ppm based on Safranal is found to maintain its color and flavor qualities at 40°C, for 90 days.

The present invention is further illustrated in the form of Examples. However, these examples should not be construed to limit the scope the present invention.
Example 1
Preparation of 2,6,6-TrimethyM,3-cyclohexadiene-l-carboxaldeh.yde from P-Cyc!ocitral.
To a stirred solution containing P -Cyclocitral (lOOgms), Toluene (100 ml) and Benzoyl peroxide (2 gms); N-bromosuccinimide (NBS) (120gms) dissolved in dimethyl formamide (DMF) (240ml) is added slowly over a period of 45 minutes, by maintaining the temperature of the solution at 60° C for about 2 hours. The mass is cooled to 25°C and Lithium carbonate (50 gins) is added and the mixture is heated for further four hours and then cooled to 2Q°C. The reaction mixture is then neutralized with sodium carbonate solution (5%). The toluene layer containing the product is separated and dried over anhydrous sodium sulphate. Toluene is recovered at an atmospheric pressure and at a temperature of 110° C. The residual product is separated and purified by fractional distillation to give Safranal (III) 65 gms and having a purity of 95%(GLC).
BP=700C(5mm),n/=1.520,d2Q=0.9725,
FT1R:
3037,2954,2923,2866,2814,2754,1664.1559,1457,1403,1379,1301,1145,1117,721,652
UV(lvIax): 300.196
Example 2
Preparation of 2,6,6-Trimethyt-1.3-cyclohexadiene-l-carboxaldehyde from p-Cyclocttral.
To a stirred solution containing p -Cyclocitral (lOOgms). Toluene (100 ml) and Benzoyl peroxide (2 gms), NBS (I20gms) dissolved in DMF (240ml) is added slowly over a period of 45 minutes, by maintaining the temperature of the solution at 60°C for about 2 hours. The mass is cooled to 25 C and Lithium carbonate (100 gms) is added and the mixture is heated for further four hours and then cooled (o 20°C. The reaction mixture is then neutralized with sodium carbonate solution (5%). The toluene layer containing the product is separated and dried over anhydrous sodium sulphate. Toluene is recovered at

an atmospheric pressure. I he residual product is separated and purified by fractional distillation to give Safranal (III) 70 gins and having a purity of 95%(GLC).
Example 3
Preparation of 2.6,6-Trimelhyl-l,3-cyclohexadiene-l-carboxaldehyde from p-Cyclocitral.
To a stirred solution containing p -Cyclocitral (lOOgms), Toluene (100 ml) and Benzoyl peroxide (2 gms), NBS (150gms) dissolved in DMF (240ml) is added slowly over a period of 45 minutes, by maintaining the temperature of the solution at 80° C for about 2 hours. The mass is cooled to 25°C and Lithium carbonate (100 gms) is added and the mixture is heated for further four hours and then cooled to 20 C. The reaction mixture is then neutralized with sodium carbonate solution (5%). The toluene layer containing the product is separated and dried over anhydrous sodium sulphate. Toluene is recovered at an atmospheric pressure. The final product is separated and purified by fractional distillation to give Safranal ([II) 75 gms and having a purity of 95%(GLC).
Example 4
Preparation of 2.6.6-Trimethyl-1.3-cyclohexadienc-l-carboxaldehyde from p-Cyclocitral.
To a stirred solution containing p -Cyclocitral (lOOgms), Toluene (100 ml) and Benzoyl peroxide (10 gms), NBS (120gms) dissolved in DMF (240ml) is added slowly over a period of 45 minutes, by maintaining the temperature of the solution at 60°C for about 2 hours. The mass is cooled to 25°C and Lithium carbonate (100 gms) is added and the mixture is heated for further four hours and then cooled to 20"C. The reaction mixture is then neutralized with sodium carbonate solution (5%). The toluene layer containing the product is separated and dried over anhydrous sodium sulphate. Toluene is recovered at an atmospheric pressure. The final product is separated and purified by fractional distillation to give Safranal (III) 75 gms and having a purity of 95%(GLC).
Example 5
100 gms Safranal (90%) and 50ppm Vitamin-E acetate is taken in a glass bottle with a small vent provided to it. The bottle is kept in an oven at 40UC. The change in color is noted down every two days by means of Lovibond color comparator 2000. ft is observed

that the original yellowish color of Safranal (III) is maintained for 90 days. The odor quality is also confirmed to be the same as of the sample taken for the stability test.
Example 6
100 gms Safranal (90%) and l00ppm BUT is taken in a glass bottle with a smali vent provided to it. The bottle is kept in an oven at 40° C. The change in colour is noted down every two days by means of Lovibond color comparator 2000. It is observed that the original yellowish color of Safrana! (Ill) is maintained for 30 days. The odor quality is also confirmed to be the same as of the sample taken for the stability test.
Advantages of the present invention
1. The Safranal (III) has applications in the fields of flavor and perfumery formulations.
2. The single pot process does not involve the isolation or separation of the intermediate compound bromide (II).
3. The present invention is economical and provides high yields of Safranal (III).
4. Safranal having the purity of above 95% and free from bromides is obtained.

We Claim:
1) A single pot process for the preparation of Safranal [2.6,6-trimethyl-1. 3-
cyclohexadiene-l-carbo\aldehydeJ represented by formula (III)

said process comprising the steps of:
(a) treating 2,2,6-Trimethyl-6-cyclohexcne-l-earboxa]dehyde [(3-cycloci!ral-IJ
having a minimum purity of 98% in an organic solvent with a brominating
agent, in the presence of a catalytic amount of peroxide to undergo allylic
bromination, at a temperature in the range of 20°-80°C, for a time period of
about 4 to 6 hours, to obtain an intermediate bromo compound of formula (II);

Formula (II)
(b) dehydrobrominating the bromo compound of formula (II) of step (a) with an alkali carbonate, without isolating the intermediate bromo compound, at a temperature in the range of 80°C -120°C for about 2-10 hours;
(c) working up the reaction mixture of step (b) by removing the organic solvent at an atmospheric pressure and at the temperature in the range of 110 °C to 160°C, to obtain a liquid residue;
(d) performing fractional distillation of liquid residue of step (c) at a temperature of about 70°C under reduced pressure of 5mm Hg, to obtain Safranal (HI); and
(e) stabilising the Safranal(III) with a stabilizer.
2) The process according to claim 1, wherein in step (a) the brominating agent is selected from the group consisting of N-bromosuccinimide or dibromohydantoin, preferably N-bromosuccinimide.

3) The process according io claim 2. wherein the brominating agent used is N-bromosuccinimide.
4) The process according to claim 3. wherein the molar ratio of N-broniosuccinimide: P-cyclocitral is in the range of 1.2 tol.8:l for performing the most effective bromination reaction.
5) The process according to claim 1. wherein in step (a) the peroxide used is selected from the group consisting of benzoyl peroxide, di-tertiarybutyl peroxide or 2,2'-azobisisobutyronitrilc (AIBN).
6) The process according to claim 5, wherein the peroxide used is benzoyl peroxide.
7) The process according to claim 5. wherein the concentration of peroxide catalyst in the reaction mixture is about 2% w/w.
8) The process according to claim I, wherein in step (a) the organic solvent used for bromination, is selected from the group consisting of toluene, dimethyl formamide, chloroform, methylene chloride or carbon tetrachloride and preferably toluene and dimethyl formamide.
9) The process according the claim 8. wherein the organic solvent used is a mixture of toluene and dimethyl formamide having a ratio of 1:1 to 1:4 w/w based on p-cyclocitral.
10)The process according the claim 9, wherein the organic solvent used is a mixture of
toluene and dimethyl formamide having a ratio of 1:1 to 1:2 w/w based on p-
cyclocitral. ll)The process according to claim 1. wherein in step (a) the preferred reaction
temperature forallylic bromination is in the range of 60 to 80°C. 12)The process according to claim I. wherein in step (b) the preferred reaction
temperature for dehydrobromination is in the range of 95 to HOC. l3)The process according to claim 1. wherein dehydrobromination is performed with an
alkali carbonate selected from the group consisting of sodium carbonate, potassium
carbonate, calcium carbonate or lithium carbonate. . 14)The process according to claim 13. wherein the alkali carbonate used is lithium
carbonate. 15)The process according to claim 1, wherein the ratio of alkali carbonate to p-
Cyclocitral used for dehydrobromination reaction is in the range of 0.5 to 1.5:1.

16) The process according to in claim 1. wherein in step (e) the organic solvent is removed at a temperature in the range of 110-160°C under atmospheric pressure.
3 7) The process according to claim 1, wherein in step (d) the fractional distillation is performed at 5 mm Hg at a temperature of about 70 °C.
18) The process according to claim 1, wherein in step (d) the product Safranal obtained, is
in the yield of about 75% and having a purity of 95% (GLC).
19) The process according to claim 1. wherein in step (b) the moisture level in the
dehydrobromination reaction mixture is maintained below 2% by using only dry
solvents.
20) The process according to claim 1, wherein in step (e) the stabilizer used is Vitamin-E Acetate, 2,6-Di-tert-butyl-4-methylphenol (BHT),2(3)-tert-butyt-4-hydroxyanisole (BHA)orPropylgallate.
21) The process according to claim 20, wherein the stabilizer used is Vilamin-E Acetate.
22) The process according to claim 20. wherein the concentration of the stabilizer used is
in the range of 10-100 ppm of Safranal (III).
23) The process according to claim 1. wherein in step (e) the enhanced stability of
Safranal having the retention of odor and flavor with minimum purity level up to
95% by GLC is obtained by using the stabilizer.
24) The process according lo claim 1. wherein the process for the preparation of Safranal
[2,6,6-trimethyl-l, 3-cyclohexadiene-l-carboxaIdehyde] represented by formula (III)
substantially as herein described with reference to the examples.