4
Lewis acid as a complex (CH3CN·AlI3).27,28 Exchange of the
solvent ligand by the methyl o-anisate (4) carbonyl oxygen leads
to the formation of complex 25. This complex then undergoes
demethylation via a six-membered transition state to afford
aluminum phenolate 6. Cleavage of the ester group is also
anchimerically assisted to give a six-membered cyclic
intermediate (7). Acidification of 6 and 7 affords 5 and 8,
respectively. It should be noted that AlCl3 will be deactivated in
acetonitrile through similar coordination (CH3CN·AlCl3)27 which
makes the Lewis acid unreactive for cleaving normal aryl methyl
ethers.1
cleavage by AlI3 in acetonitrile to afford m- or p-anisic acid. This
non-hydrolytic ester cleavage transformation can be improved
using pyridine as a coordination ligand to the Lewis acidic center.
When in the presence of excess AlI3, both ester and ether C-O
bonds are cleaved to afford m- or p-hydroxybenzoic acid. These
conditions were applied to the chemo-selective cleavage of the t-
butyl ester of acemetacin, which gave acemetacin and
indomethacin when conducted at room temperature, and O-
desmethyl indometacin at 80 oC. The use of AlI3-pyridine in
acetonitrile (80 oC) afforded indometacin along with an
unexpected ketone. Investigation of the ketone formation side-
reaction is in progress and will be disclosed in due course.
Figure 5. Proposed mechanism for the selective cleavage of
methyl o-anisate by AlI3
Acknowledgments
This work was supported by Jingchu University of
Technology (QDB201602, QDB201606, YY201601 and
QDB201707), Science and Technology Department of Hubei
Province (2016CFB149), and Hubei Provincial Key Laboratory
of Drug Synthesis and Optimization (OPP2016YB02). Shi is
grateful to Jingmen Municipal Bureau of Science and Technology
(YDKY2016025) for instruction.
Supplementary Material
Supplementary data (experimental procedures, compound
characterization data, 1H and 13C NMR spectra of 5, 8, 11-13, 15,
16, 19, 21-24, HSQC and HMBC spectrum of 23) associated
with this article can be found, in the online version, at.
References and notes
1. Bhatt, V. M.; Setty, S. K. S. Indian J. Chem. 1987, 26B, 467-468.
2. Node, M.; Nishide, K.; Sai, M.; Fuji, K.; Fujita, E. J. Org. Chem.
1981, 46, 1991-1993.
3. Node, M.; Nishide, K.; Sai, M.; Fujita, E. Tetrahedron Lett. 1978,
19, 5211-5214.
4. Mahajan, A. R.; Dutta, D. K.; Boruah, R. C.; Sandhu, J. S.
Tetrahedron Lett. 1990, 31, 3943-3944.
5. Wei, B.; Zhang, Z.; Dai, Z.; Zhang, K. Monatsh. Chem. 2011, 142,
1029-1033.
6. Michel, W.; Maryse, Z. Chem. Lett. 1982, 11, 333-336.
7. Lian, X.; Fu, S.; Ma, T.; Li, S.; Zeng, W. Appl. Organomet. Chem.
2011, 25, 443-447.
8. Groutas, W. C.; Felker, D. Synthesis 1980, 1980, 861-868.
9. Ho, T. L.; Olah, G. A. Angew. Chem. Int. Ed. Engl. 1976, 15, 774-
775.
10. Wu, X.; Ying, P.; Liu, J.; Shen, H.; Chen, Y.; He, L. Synth.
Commun. 2009, 39, 3459-3470.
11. Martínez, A. G.; Barcinaa, J. O.; del Veccio, G. H.; Hanack, M.;
Subramanian, L. R. Tetrahedron Lett. 1991, 32, 5931-5934.
12. Berthet, M.; Davanier, F.; Dujardin, G.; Martinez, J.; Parrot, I.
Chem. Eur. J. 2015, 21, 11014-11016.
13. Salomon, C. J.; Mata, E. G.; Mascaretti, O. A. Tetrahedron 1993,
49, 3691-3734.
14. Vivekananda Bhatt, M.; Kulkarni, S. U. Synthesis 1983, 15, 249-
282.
15. Tian, J.; Yi, C.; He, Z.; Yao, M.; Sang, D. ChemistrySelect 2017, 2,
9211-9214.
16. Weissman, S. A.; Zewge, D. Tetrahedron 2005, 61, 7833-7863.
17. Ranu, B. C.; Bhar, S. Org. Prep. Proced. Int. 1996, 28, 371-409.
18. Tian, J.; Sang, D. ARKIVOC 2015, (vi, 446-493.
19. Bhatt, M. V.; Babu, J. R. Tetrahedron Lett. 1984, 25, 3497-3500.
20. Sang, D.; Wang, J.; Zheng, Y.; He, J.; Yuan, C.; An, Q.; Tian, J.
Synthesis 2017, 49, 2721-2726.
21. Tian, J.; Yi, C.; Fang, H.; Sang, D.; He, Z.; Wang, J.; Gan, Y.; An,
Q. Tetrahedron Lett. 2017, 58, 3522-3524.
22. Sang, D.; Yao, M.; Tian, J.; Chen, X.; Li, L.; Zhan, H.; You, L.
Synlett 2017, 28, 138-142.
Regarding the ester preference for the reaction of p-anisate 10
in acetonitrile and ethyl acetate, the p-methoxy group remained
intact due to the absence of a neighboring group participation
effect, and thus methyl anisate was cleaved to afford acid 12 and
eventually 13 when in the presence of excess AlI3. Similarly, the
ester group was cleaved preferentially in the competing cleavage
experiment of methyl benzoate 17 and anisole 18 when treated
with equimolar AlI3. When performed in cyclohexane (Table 2,
Entry 2), coordination of the ester/ether oxygen to the Lewis
acidic center became non-selective, and the non-selective
cleavage of the ester and ether C-O occurred, giving an
equimolar mixture of phenol 11 and acid 12. Further cleavage of
11 and 12 by AlI3 afforded acid 13. Since p-anisate 10 was non-
selectively cleaved by AlI3 in cyclohexane, the low polarity of
carbon disulfide is unlikely to be a factor for the chemoselectivity
in cleaving 10 (Table 2, Entry 1). Additionally, carbon disulfide
has little tendency to coordinate to the Lewis acidic center.11 Thus,
the ether cleavage preference of AlI3 in carbon disulfide remains
unclear.
3. Conclusion
In summary, the mode for AlI3 mediated ether and ester
cleavage of methyl o-anisate is different from those of m-anisate
and p-anisate. Cleavage of o-anisate is markedly affected by an
anchimeric assistance effect and tends to afford o-
hydroxybenzoate via ether cleavage. Further cleavage of the
benzoate at elevated temperatures affords salicylic acid involving
a second anchimeric assistance. Cleavage of m- or p-anisate, on
the other hand, is more susceptible to solvents, and gave variant
products in carbon disulfide, cyclohexane or acetonitrile under
different conditions. The ester C-O bond is preferentially
23. Wilson, J. W.; Worrall, I. J. J. Chem. Soc. A 1968, 316-317.
24. Samaan, S.; Horstmann, H. US Pat. 4,600,783, 1986.
25. Shen, T. Y.; Windholz, T. B.; Rosegay, A.; Witzel, B. E.; Wilson, A.
N.; Willett, J. D.; Holtz, W. J.; Ellis, R. L.; Matzuk, A. R.; Lucas,