4
Tetrahedron
intermediate in the sequence (see Scheme 2). The higher yield
the excess Lewis acid. This coordination would diminish the
nucleophilicity of the ortho hydroxyl group and slow the oxa-
Michael addition to the enone double bond. Once ring closure of 12
to 13 occurs in the bismuth(III) catalyzed reaction, proton transfer to
generate 14, disengagement of the catalyst to give enol 15, and
tautomerization would lead to the final product.
obtained from the 3-methoxyphenyl ester 1g (versus the reaction of
5g with 6) is notable, however, and shows the potential effect of
water on acid-sensitive substrates. When starting from the acid,
water generated in the esterification process, and not immediately
removed by the boiling toluene, could potentially react with the
catalyst to form traces of triflic acid sufficient to cleave the methoxy
ether and lower the yield. Starting from the ester, however, water
would not be produced and the reaction might be expected to give a
higher yield of the desired product. Finally, to rule out water as a
problem in the sealed tube reactions of 2,5-dialkylphenols, ester 1e
was heated in a sealed tube with 20 mol% of bismuth(III) triflate in
toluene at 120 oC for 24 h. By this route, the yield of chromanone 4e
was essentially the same as that achieved from phenol and the acid,
which supports our supposition that steric factors were largely
responsible for the low yields from these substrates.
A plausible mechanism for the conversion of 5c and 6 to 4c is
shown in Scheme 2. Close monitoring of the process by thin layer
chromatography indicated that the first intermediate was the aryl
ester 1c. While this produces an equivalent of water, which could
decompose the catalyst, the boiling toluene solvent should remove
most of this product from the reaction by azeotropic distillation into
the reflux condenser, thus minimizing catalyst degradation. The ester
would then undergo a Fries rearrangement via 10 and 11 to give 1-
(2-hydroxy-4-methylphenyl)-3-methyl-2-buten-1-one (3c). While
In conclusion, we have described an efficient bismuth(III)
catalyzed tandem reaction to prepare 4-chromanones from electron-
rich phenols and 3,3-dimethylacrylic acid or trans-crotonic acid. The
procedure is convenient to perform, product purification is
straightforward, and the target heterocycles are isolated in fair to
excellent yields. A reasonable selection of substrates has been
surveyed to define the scope of the reaction. Limitations are
predictably associated with deactivating groups on the aromatic
nucleus and steric hindrance toward reattachment of the acyl group
to the aromatic ring during the Fries rearrangement. Additionally,
experiments have confirmed that the sequence of events during the
reaction involves (1) esterification of the acid by the phenol, (2)
Fries rearrangement of the 2-butenyl acylium fragment to the less
hindered ortho position and (3) oxa-Michael ring closure of the
phenolic OH to the side chain enone of the Fries product. We are
continuing our work to identify mild catalytic processes for the
synthesis of heterocyclic compounds of interest to natural product
and drug research.
Acknowledgments
Bi(OTf)3
Bi(OTf)3
+
R.T. wishes to thank the 2016 REU Program at Oklahoma State
University (NSF CHE-1559874) for a summer appointment. The
authors also wish to acknowledge the NSF (BIR-9512269), the
Oklahoma State Regents for Higher Education, the W. M. Keck
Foundation, and Conoco, Inc. for funding to establish the Oklahoma
Statewide Shared NMR Laboratory. The College of Arts and
Sciences at OSU is also acknowledged for funds to purchase a new
400 MHz NMR for this facility.
HO
OH
O
O
–H2O
(removed as
azeotrope)
O
5c
6
1c
O
O
–Bi(OTf)3
rearomatize
O
Bi(OTf)2
O
Bi(OTf)2
O
:
HO
..
TfO
TfO
10
11
OTf
Bi(OTf)2
3c
Supplemental information
OTf
Bi(OTf)2
Supplementary information associated with this article
(experimental procedures and spectral data) can be found, in the
O
O
Bi(OTf)3
oxa-Michael
~H
O
H
HO
..
12
:
References
13
1. Timar, T.; Levai, A.; Eszenyi, T.; Sebok, P. J. Heterocycl. Chem.
2000, 37, 1389-1417.
2. Emami, S.; Ghanbarimasir, Z. Eur. J. Med. Chem. 2015, 93, 539-
563.
3. Zhu, M.; Kim, M. H.; Lee, S.; Bae, S. J.; Kim, S. H.; Park, S. B. J.
Med. Chem. 2010, 53, 8760-8764.
OTf
Bi(OTf)2
H
O
OH
O
O
O
taut.
–Bi(OTf)3
O
4c
14
15
4. Friden-Saxin, M.; Seifert, T.; Landergren, M. R.; Suuronen, T.;
Lahtela-Kakkonen, M.; Jarho, E. M.; Luthman, K. J. Med. Chem.
2012, 55, 7104-7113.
5. Draper, R. W.; Hu, B.; Iyer, R. V.; Li, X.; Lu, Y.; Rahman, M.;
Vater, E. J. Tetrahedron 2000, 56, 1811-1817.
Scheme 2. A plausible mechanism for the Bi(OTf)3 catalyzed synthesis of 4-
chromanones.
6. Friden-Saxin, M.; Seifert, T.; Malo, M.; Andersson, K. d. S.;
Pemberton, N.; Dyrager, C.; Friberg, A.; Dahlen, K.; Wallen, E. A.
A.; Groetli, M.; Luthman, K. Eur. J. Med. Chem. 2016, 114, 59-64.
7. Bunce, R. A.; Cox, A. N. Org. Prep. Proced. Int. 2010, 42, 83-93.
8. Bunce, R. A.; Cain, N. R.; Cooper, J. G. Org. Prep. Proced. Int.
2012, 44, 131-145.
this compound proved to be a significant product in the reaction
promoted by excess aluminum chloride, a control experiment
demonstrated that bismuth(III) triflate rapidly and quantitatively
converted 3c, presumably via intermediates 12-15, to the ring-closed
product 4c. The failure of 3c to completely cyclize under the
aluminum chloride conditions likely resulted from strong
coordination of both the phenol and side chain ketone functions by
9. Bunce, R. A.; Cain, N. R.; Cooper, J. G. Org. Prep. Proced. Int.
2013, 45, 28-43.