(Hive Bee)
03-29-03 23:11
No 422345
(Rated as: excellent)
Here's another Friedel-Crafts reference, for bees who don't mind working with potential explosives
. This has to be the easiest Friedel-Crafts acylation I've ever seen, so I thought it deserved it's own thread. The reaction is solvent free, gives quantative yield, and the catalyst is completely regenerable - it really can't get much better than this. Here we go:LiClO4–acyl anhydrides complexes as powerful acylating reagents of aromatic compounds in solvent free conditions
Giuseppe Bartoli, a, Marcella Boscoa, Enrico Marcantonib, Massimo Massaccesia, Samuele Rinaldia and Letizia Sambria
a) Dipartimento di Chimica Organica `A. Mangini', v. le Risorgimento 4, I-40136, Bologna, Italy
b) Dipartimento di Scienze Chimiche, Via S. Agostino 1, I-62032, Camerino (MC), Italy
Received 4 July 2002; accepted 8 July 2002.
Abstract
The Friedel–Crafts acylation of various activated benzenes is smoothly carried out with acyl anhydrides in the presence of 2 equiv. of LiClO4, as reaction promoter, under solventless conditions.
Article outline
The Friedel–Crafts acylation is among the most fundamental transformations in organic chemistry and it is widely applied in industrial production of useful intermediates. In its classical formulation, the reaction requires more than 1 equiv. of a Lewis acid as the promoter (AlCl3) which can not be recovered and reused, owing to its instability in aqueous media.1 To obviate this problem, several approaches based on the employment of catalytic amounts of metal triflates have been recently developed.2, (a), (b), (c) and (d) In many of them, the addition of LiClO4 as promoter accelerates the acylation process and increases the yields.3, (a), (b), (c), (d) and (e) However, the action of LiClO4 seems to be limited to enhance the efficiency of the metal triflate catalyst, in fact it has been reported that the reaction does not work in the presence of LiClO4 alone,(a) and 4 in spite of its well-known Lewis acid character. 5, (a), (b), (c) and (d)
We wish to report now that LiClO4 itself can act as a very efficient promoter if the reaction is carried out in solventless conditions.6, (a) and (b)
Ac2O (1.05 equiv.) is added to LiClO4 (2 equiv.) and warmed to 60°C under stirring until the salt is completely dissolved. When 1 equiv. of anisole is added to this solution, a smooth Friedel–Crafts acylation occurs within 1 h leading to 4-methoxyacetophenone 2 in quantitative yields.
The reason of this unexpected activation is ascribed to the formation of a complex with a strong electrophilic character between LiClO4 and Ac2O in neat Ac2O.
The reaction is highly regioselective, the product of o-acetylation 3 being obtained only in traces (<1%).7 The observed regioselectivity has been reasonably interpreted in terms of the high steric requirement of the LiClO4–Ac2O complex.
If the reaction is carried out with less than 2 equiv. of LiClO4, the process becomes slower; moreover, the conversion of anisole is not complete even for prolonged reaction times when the perchlorate proportion is below 1 equiv.
This is not surprising if we consider that both the reaction product 2 and AcOH can coordinate to LiClO4 so destabilizing the LiClO4–Ac2O complex. In order to verify this hypothesis, some experiments were carried out in the presence of AcOH. Data reported in Table 1 indicate that the addition of AcOH at the beginning of the reaction slows the process and then a larger amount of LiClO4 is necessary to restore the normal reactivity.
Entry LiClO4 (equiv.) Solvent (equiv.) Time Yield (%)
1 0.5 - 7h 75
2 1 - 5h 85
3 1.5 - 2.5h 99
4 2 - 50min 99
5 3 - 45min 99
6 2 AcOH (1) 3h 99
7 3 AcOH (1) 3h 99
8 2 AcOH (2) 7h 95
9 3 AcOH (2) 2h 99
10 2 MeNO2 (2) 2h 99
11 3 MeNO2 (2) 1.5h 99
12 2 MeNO2 (19) 8h 70
Table 1. Acetylation of anisole (1 equiv.) with acetic anhydride (1.05 equiv.) at 60°C in the presence of LiClO4 under various conditions
An analogous decrease in reactivity is noted when increasing amounts of MeNO2 are initially added to the reaction mixture, since MeNO2 can compete with Ac2O in complexing the LiClO4. These findings account for the previously reported opinion that LiClO4 alone is not able to promote the acylation reaction,(a) and 4 since these experiments were carried out in MeNO2 solvent. We found that if the reaction is carried out with MeNO2 as solvent (1 ml/mmol of anisole, Table 1, entry 12) after 8 h the conversion is only 70%.
The addition of more than 2 equiv. of LiClO4 in solvent free conditions does not produce an appreciable increase in the reaction rate, but the mixture becomes extremely viscous and difficult to stir. Therefore a 2:1 ratio between LiClO4 and anisole has been chosen as the most convenient condition (standard procedure).
Results reported in Table 2 show that it is possible to introduce various acyl groups into the para-position of anisole under the standard conditions. Only in the case of the solid benzoic anhydride it has been necessary to carry out the reaction in the presence of 4 equiv. of MeNO2 at higher temperature. In all cases yields are almost quantitative.
Entry (RCO)2O Solvent (equiv.) Time (h) Yield (%)
1 (EtCO)2O - 1 99
2 (I-PrCO)2O - 1.5 99
3 (C5H11CO)2O - 1.5 92
4 (PhCO)2O - 6 78
5 (PhCO)2O MeNO2 4 97
Table 2. Acylation of anisole with various anhydrides under standard conditions unless otherwise mentioned [1-3 carried out at 60oC, 4 and 5 at 100oC]
The standard method was applied to the acetylation of various activated aromatic compounds. Data and reaction conditions are reported in Table 3. The results confirm the high regioselectivity of the reaction: the 4-substituted acylated products are exlusively obtained from ortho-substitued substrates (Table 3, entries 1, 4, and 8).
Substrate Conditions Product Yield(%)
2-methoxytoluene 1.5h, 60oC 3-Me-4-MeO-acetophenone 99
4-methoxytoluene 3h, 100oC 5-Me-2-MeO-acetophenone 99
3-methoxytoluene 2h, 60oC 2-Me-4-MeO-acetophenone 66
4-Me-2-MeO-acetophenone 28
2-bromoanisole 5h, 100oC 3-Br-4-MeO-acetophenone 99
3-bromoanisole 5h, 100oC 2-Br-4-MeO-acetophenone 56
4-Br-2-MeO-acetophenone 38
3-fluoroanisole 1h, 100oC 2-F-4-MeO-acetophenone 69
4-F-2-MeO-acetophenone 30
[Entry 7 omitted]
ortho-xylene 1.5h, 100oC 3,4-diMe-acetophenone 65
meta-xylene 1.5h, 100oC 2,4-diMe-acetophenone 75
Table 3. Acetylation of activated benzenes with standard procedure under various reaction conditions
Prolonged reaction times and higher temperatures are required when acetylation can occur only at the sterically hindered ortho-position
Higher temperatures are obviously required when the substrate is deactivated with respect to anisole (Table 3, entries 4, 5, 6, 8, and 9). Again steric interactions can account for the formation of two acetylated derivatives in the reactions of meta-substituted anisoles (Table 3, entries 3, 5, and 6). In all cases yields are almost quantitative, with the exception of xylenes, but it was reported (a) that these compounds suffer from decomposition phenomena when kept at high temperatures for long times.
The present method appears to be competitive and in some cases superior to recently reported catalytic procedures, in which LiClO4 is used as additive in quantities ranging from 1 to 10 equiv. to enhance the effectiveness of the catalyst; in fact, our reaction proceeds smoothly in solvent free conditions, an increasingly important feature for the development of green chemistry; moreover, LiClO4 is not expensive and it is stable to moisture. In addition, although it has to be employed in more than stoichiometric amounts, it can be quantitatively recovered and reused after activation. The recovery procedure and recycling are very simple: after the reaction is complete and cooled to room temperature, CH2Cl2 is added under stirring; LiClO4 precipitates and can be quantitatively separated by filtration or centrifugation. The precipitate can be reactivated by heating in vacuum at 140°C and reused. We repeated this procedure four times for the acetylation of anisole without any loss of activity. This simple work up also allows facile recovery of the reaction products.
Typical procedure: 2 equiv. of commercial anhydrous LiClO4 were dried in vacuo (0.1 Torr) at 140°C for 2 h. After cooling, the anhydride (1.05 equiv.) was added to LiClO4 and the mixture was heated at the desired temperature until LiClO4 was dissolved. Then the substrate (1 equiv.) was added dropwise and the reaction was monitored by GLC. After the reaction was complete, it was cooled and CH2Cl2 was added. The precipitated LiClO4 was recovered by centrifugation and reutilized. The organic layer was treated with aqueous NaHCO3 and dried over MgSO4. The reaction product was recovered by simple removal of the solvent and purified by column chromatography when necessary.
CAUTION: Lithium perchlorate and oxidizable materials could lead to devastating explosions and must be handled with care. While we have never experienced any problem even when reactivating it by heating, we urge users to protect themselves and to take appropriate safety measures.8
Acknowledgements
Work carried out in the framework of the National Project `Stereoselezione in Sintesi Organica. Metodologie e Applicazioni' supported by MURST, Rome, and by the University of Bologna, and in the framework of `Progetto di Finanziamento Pluriennale, Ateneo di Bologna 2001–2002'.
References
1. Olah, G. A. Friedel–Crafts and Related Reactions; Interscience: New York, 1964; Vol. 3, Part 1.
2. (a). C. Le Roux and J. Dubac Synlett (2002), p. 181.
(b). A. Kawada, S. Mitamura and S. Kobayashi Synlett (1994), p. 545.
(c). S. Kobayashi and S. Iwamoto Tetrahedron Lett. 39 (1998), p. 4697.
(d). T. Mukaiyama and J. Izumi Chem. Lett. (1996), p. 739.
3. (a). C.J. Chapman, C.G. Frost, J.P. Hartley and A.J. Whittle Tetrahedron Lett. 42 (2001), p. 773.
(b). J. Matsuo, K. Odashima and S. Kobayashi Synlett (2000), p. 403.
(c). A. Kawada, S. Mitamura, J. Matsuo, T. Tsuchiya and S. Kobayashi Bull. Chem. Soc. Jpn. (2000), p. 2325.
(d). I. Hachiya, M. Moriwaki and S. Kobayashi Tetrahedron Lett. 36 (1995), p. 409.
(e). T. Mukaiyama, K. Suzuki, J.S. Han and S. Kobayashi Chem. Lett. (1992), p. 435.
4. A. Kawada, S. Mitamura and S. Kobayashi J. Chem. Soc., Chem. Commun. (1996), p. 183.
5. (a). A. Kumar and S.S. Pawar J. Org. Chem. 66 (2001), p. 7649.
(b). G. Springer, C. Elam, A. Edwards, C. Bowe, D. Boyles, J. Bartmess, M. Chandler, K. West, J. Williams, J. Green, R.M. Pagni and G.W. Kabalka J. Org. Chem. 64 (1999), p. 2202.
(c). R.M. Pagni, G.W. Kabalka, S. Bains, S. Plesco, J. Wilson and J. Bartmess J. Org. Chem. 58 (1993), p. 3130.
(d). M.A. Forma and W.P. Dailey J. Am. Chem Soc. 113 (1991), p. 2761.
6. (a). Y. Nakae, I. Kusaki and T. Sato Synlett (2001), p. 1584.
(b). B.P. Bandgar, V.T. Kamble, V.S. Sadavarte and L.S. Uppalla Synlett (2002), p. 735.
7. Detected by GLC analysis.
8. Schumacher, J. C.; Perchlorates––Their Properties, Manufacture and Uses, ACS Monograph Series, Reinhold: New York, 1960.
(Hive Bee)
03-31-03 20:26
No 422813
The post above is finished now; entry seven in table 3 was a napthalene derivative whose name wouldn't fit nicely into my table.
But what has happened to my beautiful karma? Yesterday it was excellent
. This is one of the nicest acylation procedures I've ever seen; hopefully somebee will try it on benzodioxole or 1,4-dimethoxybenzene soon. I'll ask him to report back if so
.
(Chief Bee)
03-31-03 20:30
No 422816
Excellent ratings disappear upon editing, as the board software cannot judge for itself if the post is still excellent after someone has edited it. I have replaced the rating now, the post sure is worthy.
(Hive Bee)
05-14-03 15:00
No 433132
The above procedure has been tried twice on benzodioxole with 1.05 and 2 equivalents of propionic anhydride, both times with 2 equivalents lithium perchlorate and with stirring for 2 hours at 60oC. Both times, nothing was recovered but benzodioxole
; at least it wasn't demethylated at that temperature as would have happened with any other Lewis acid. The procedure will be attempted again soon with anisole (possibly at a higher temperature) and if that doesn't work, a mixed trifluoroacetic acid-propionic acid anhydride may have to be employed. The mixed anhydride would lend itself to a couple of interesting possiblities
A 32 page document singing the praises of lithium perchlorate can be found at http://www.gfschemicals.com/technicallib
The first obvious one is on page 18, with the rearrangement of allyl vinyl ethers to aldehydes. If this could work on an aromatic system it would be very good news. Page 19 has the conversion of epoxides to carbonyls in good to excellent yield.
Page 21 has some rather interesting epoxide and ring opening reactions, which could be a very interesting pathway to the BOX series, and page 22 might be interesting if that alpha,beta-unsaturated carbonyl could be replaced by nitroethane.. There's more, and it's worth a look.
An important note on safety. Lithium perchlorate seems the safest to work with of all the perchlorate salts, but it still isn't something to mess around with. There is a useful link for anyone who ever finds themselves confronted by perchloric acid or any of its salts, and wants to know how to safely make good use of them: http://www.gfschemicals.com/technicallib
It may be interesting to consider lithium iodide, or even bromide as suitable alternatives to lithium perchlorate. All are lithium salts of strong acids with approximately equivalent pKa values of around -10, and both lithium iodide and perchlorate are soluble in organic solvents; lithium bromide is soluble in alcohol but I'm not sure about ether.