Isomerization of Safrole to Isosafrole (Solventless/Microwave System)

Abstract

After proposing some new safe-easy and simple methods to isomerize safrole to isosafrole in previous publication, now in this paper we would like to report how to improve this reaction onto a high level The microwave chemistry can offer the conditions for realizing this reaction in a short time than before, in the presence of catalysts: KOH. KOt-Bu. KF-Al₂O₃ with or without the phase transfer catalyst Aliquat 336. The reaction was carried out in both reactors, multimode and monomode oven, the latter appears to he better than the first one, with since the lower power it can give the same yield.

Isosafrole 2 (trans-2a and cis-2b) may be prepared from Safrole 1. This is the best way to afford the starting material of the synthesis of heliotropin. There are a lot of methods presented for realizing this isomerization. But almost they are very difficult to apply, because the require some hard conditions such as in high or low pressure or use some strange catalysts and, moreover reaction is run with solvents^1-4. In previous paper we proposed to replace these above mentioned conditions by the new method in dry media condition, with or without phase transfer catalysts. With these conditions, we got some good results, but the reaction time was still long⁵.

Table 1
Yield of isosafrole in conventional heating

Entry	Catalyst	Temp	Time	GC (%)		Yield
Entry	Catalyst	Temp	Time	1	2	Yield
1	KOH	120°C	120 min	29.23	70.44	67%
2		150°C	60 min	4.49	95.63	91%
3		150°C	120 min	1.96	97.73	94%
4		180°C	120 min	trace	99.27	96%
5		150°C^*	45 min	trace	99.37	97%
6	KOt-Bu	80°C	30 min	3.63	96.37	91%
7		80°C	60 min	trace	99.45	96%
8		80°C^*	10 min	trace	99.73	97%
9	KF-Al₂O₃	150°C	60 min	7.88	91.91	87%
10		180°C	60 min	4.29	95.47	92%
11		180°C^*	45 min	trace	99.69	96%

Notes:

* with Aliquat 336 5% mol

The molar ratios of safrole:reagent are:
KOH (1:3); KOt-Bu (1:1); KF-Al₂O₃ (1:12)

In the first time, we apply the microwave chemistry⁶ in the domain of the isomerization of the safrole with both oven multimode (Sharp R-3SV5) and monomode (Maxidigest MX 350). And through this context, optimal conditions are found to collect the highest yield in the shortest reaction time. In this study we will use the catalyst of KOH and introduce two new ones: KOt-Bu and KF-Al₂O₃⁷. At first, we all tried to realize one reaction in the presence of Aliquat 336, as usual and cheap phase transfer catalyst (PTC), to find the further role of PTC because this reaction began by the attack of an anionic nucleophile. The second reason to use PTC here is that the chemist wants to know the part of PTC in the solid state reaction. Table 1 is some of our results in the conventional heating (oil bath with magnetic stirrer).

We found that in the case of KOH high temperature (180°C) and the long reaction time (2 hours) are very necessary for this reaction. In the case of KOt-Bu, high temperature is not essential. We can use the water bath (80°C) and the reaction time now (only one hour) is shorter than the case of KOH.

Table 2
Yield of isosafrole under microwave irradiation

Entry	Catalyst	Power	Time	Temp	GC (%)		Yield
Entry	Catalyst	Power	Time	Temp	1	2	Yield
1	KOH	300 W^a	5 min	dec.	-	-	-
2		300 W^a*	5 min	132°C	2.66	97.34	94%
2		45 W^b	5 min	dec.	-	-	-
4		45 W^b*		161°C	trace	99.49	97%
5	KOt-Bu	600 W^a	5 min	111°C	19.72	80.09	77%
6		600 W^a	6 min	141°C	trace	99.90	96%
7		150 W^b	6 min	93°C	20.34	79.66	76%
8		150 W^b	8 min	117°C	trace	99.17	96%
9		90 W^b*	15 min	146°C	trace	99.52	97%
10		120 W^b*	5 min	106°C	1.44	97.04	95%
11		120 W^b*	6 min	142°C	trace	99.35	97%
12	KF-Al₂O₃	400 W^a	3 min	190°C	5.12	93.24	94%
13		75 W^b	5 min	134°C	15.02	84.79	81%
14		90 W^b	5 min	139°C	6.7I	93.53	89%
15		90 W^b	9 min	142°C	5.92	94.10	90%
16		120 W^b	5 min	151°C	5.03	94.77	91%
17		75 W^b*	5 min	140°C	trace	99.49	96%

Notes:

* with Aliquat 5% mol a multimode b monomode

The molar ratios of safrole:reagent are:
KOH (1:1.5 in entry 2 and 4); (1:3 in entry 1 and 3).
KOt-Bu (1:1); KF-Al₂O₃ (1:10);

The activity of KF-Al₂O₃ is similar to KOH, but KF-Al₂O₃ is not corrosive and easier to keep and to practice than KOH. In all three cases, it is very interesting that the presence of Aliquat 336 with 5% mol, calculated on the base, increase the yield to maximum (99%) in shorter time (45 min. in the case of KOH, 10 min. for KOt-Bu and 45 min. for KF-Al₂O₃). The conventional heating above is compared to the microwave irradiation, and results collected are in Table 2.

We noted that in three cases of catalyst, the monomode oven (Maxidigest MX 350) always gives good yield in shorter time or at lower power than the multimode oven (Sharp 2SV5), for instance in the entry 2 (300 W) and 4 (45 W), entry 6 (600 W) and 8 (150 W), entry 12 (400 W) and 14 (90 W).

With the presence of KOH, reaction mixture is decomposed under microwave irradiation, expect when Aliquat 336 is present, as in the entry 2 and 4. As expected, from the Table 1 and 2, we recognized that under the irradiation of microwave, the isomerization of safrole took place very quickly in a few minutes instead of some hours in conventional heating. The presence of phase transfer catalyst Aliquat 336 is very necessary. It promoted all reactions in both cases with or without the use of microwave. In the microwave it is still the best one, because the reaction could attain the maximum yield in shorter reaction time.

The ratio of two isomers cis-2b:trans-2b is 25 to 30% in the case of KOH; 5 to 8% in the case of KOt-Bu; and 12 to 17% in the case of KF-Al₂O₃.

Experimental

KOH has been ground before using, KF-Al₂O₃ has been prepared as described in the previous paper of Singh⁷. We mix safrole and reagents steady to the homogeneous mixture before putting it in the oil bath or in the microwave oven. The yield has been measured on the result given by GC-MS HP 6890.

Isomerization of Safrole to Isosafrole

in Solventless System Promoted by Microwave Irradiation

Abstract

Experimental

References