This document describes research into using silver(I) salts to catalyze the regioselective cyclization of epoxy alcohols and alkenols to form substituted tetrahydrofurans. The researchers found that silver(I) triflate (AgOTf) was the most effective catalyst, promoting clean intramolecular cyclization of 4-phenyl epoxy alcohols to form the 5-member ring product exclusively. 4-Alkyl epoxy alcohols were unreactive under the conditions tested. Cyclization of 4-phenyl alkenols was slower than epoxy alcohols and required more catalyst and heating. The results support the hypothesis that silver(

1. Silver(I)-Catalyzed Regioselective
Cyclization: Convenient Access to
Substituted Tetrahydrofurans
Introduction
•Lewis acid-catalyzed ring-opening reaction followed by
intramolecular cyclization is an attractive strategy for
constructing cyclic molecules.
•Silver (Ag)-catalyzed reactions have gained popularity due
to:
• Mild Lewis acidity of Ag-salts
• Environmentally benign nature of the catalyst
• Readily available and Cost effective.
•Due to the oxophilic nature of Ag(I) metal, we hypothesized
that epoxide ring can be opened using different Ag(I) salt
catalysts.
•We are interested in developing a general methodology for
constructing mono- or di-substituted oxygen-containing
heterocyclics via Ag(I)-catalyzed reactions.
• These ring structures are prevalent in biologically
important natural products.
• We have used various silver(I)-salts for
intramolecular cyclizations of epoxy-alcohols and
alkenols, and observed the regioselectivity favoring
the formation of a five-member ring over a four-
member ring.
Methods
•Substrate Preparation: Substrates prepared by reducing
trans-styrylacetic acid with LiAlH4 in the presence of mCPBA
•General Procedure for the Catalytic Reactions: General
methodology utilized Ag(I) salt catalysts to open an epoxide
three-member ring or carbon-carbon double bond to form a
five-member heterocycle via regioselectivity
•Crude products purified by silica filtration and removal of
solvent
•Reaction monitoring by thin-layer chromatography and final
product analysis by NMR and IR spectroscopy
•Methods are meant to test the hypothesis that various Ag(I)
salts could open the three-member ring of an epoxide and
create a five-member heterocycle based on the nucleophilic
nature of the catalyst
Summary of Our Results
•In general, 4-phenyl substituted epoxy-alcohols underwent clean
intramolecular cyclization reactions in the presence of Ag(I)-salts.
•We have found that Ag(I)OTf was the ideal choice for a catalyst.
•4-Alkyl substituted epoxy-alcohol was unreactive under current
conditions.
•The cyclization of 4-phenyl substituted alkenol was slower and
required more catalyst as well as heating.
•Results support our hypothesis that Ag(I) salts catalyze the
epoxide ring opening reaction to form five-membered heterocyclic
molecules.
Discussion
•There were two possible outcomes for the product of our Ag(I)-catalyzed cyclization reactions: a compound
with a five-membered ring, or a compound with a four-membered ring.
•In all successful reactions, the five-membered ring was formed preferentially over four-membered ring,
which was determined by proton NMR. We have hypothesized that the observed regioselectivity is dictated
by the electrophilicity of the specific epoxy carbon. In this case, the benzylic position is more succeptible to
nucleophilic attack because of its higher reactivity.
•It is also well known that the preferred orbital hybridization of the cyclized carbon is sp3
and in tetrahedral
geometry with a bond angle of 109.5°. It is speculated that In the case of the five-member ring formation,
the ideal bond angle is closely maintained, whereas in the case of a four-member ring, the angel is 90°
resulting in higher ring strain.
Acknowledgements
•Dr. Biswajit Saha
•North Central College Office of Academic Affairs
•North Central College Undergraduate Summer Research Fund
References
1)Kyungsoo Oh; William K. E. Tetrahedron, 2009, 65, 2966.
2)Weibel, J. M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149.
3)Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132.
4)(a) Yanagisawa, A.; Nakashima, H.; Ishiba, A.; Yamamoto, H. J.
Am. Chem. Soc. 1996, 118, 4723. See also: (b) Bianchini, C.;
Glendenning, L. Chemtracts: Inorg. Chem. 1997, 10, 339. (c)
Cozzi, P. G.; Tagliavini, E.; Umani-Ronchi, Gazz. Chim. Ital. 1997,
127, 247. (d)Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.;
Yamamoto, H. J. Am. Chem. Soc. 1997, 119, 9319.
5)Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2003, 125, 4018.
6)(a) Najera, C.; Retamosa, M. D.; Sansano, J. M. Angew. Chem.
Int. Ed. 2008, 47, 6055. (b) Najera, C.; Retamosa, M. D.; Martin-
Rodriguez, M.; Sansano, J. M.; de Cozar, A.; Cossio, F. P. Eur. J.
Org. Chem. 2009, 5622.
Conclusion
•We have developed an efficient methodology for cyclizing 4-
phenyl epoxy alcohols.
•Alterations may be needed for effective cyclization of aromatic
alkenols and aliphatic epoxy alcohols.
•Phenyl group stabilizes the incipient carbocation at C-4 of 3,4-
epoxy hex-3-en-1-ol allowing the preferred cyclization reaction.
•Methods of purification are minimal and environmentally benign.
•This method has potential use in chemical or pharmaceutical
industrial research.
Future Research
•Expand this current methodology for the cyclization of more
aromatic or aliphatic epoxy-alcohols.
•Study Ag(I)-catalyzed reactions resulting in six-membered
heterocycles containing oxygen.
•Synthesize five-member heterocycles with the addition of a para-
methyl or methoxy group on phenyl ring.
•Apply the current method to synthesize nitrogen-containing
heterocycles.
Juan Perez Jr., Rachel DiPietro. Faculty Advisor: Dr. Biswajit Saha, Department of Chemistry
Table1: Results of Ag(I)-catalyzed cyclization
reactions of epoxy-alcohol
Table 2: Results of Ag(I)-catalyzed cyclization
reactions of alkenol
Catalyst
(mol %)
Solvent Conversion
Ratio of
Product
(1:2)
Ag(I)OTf (10%) CH2Cl2 100% 100:0
Ag(I)OTf (5%) CH2Cl2 100% 100:0
Ag(I)OTf (5%) Ether 100% 100:0
Ag(I)OTf (5%) Toluene 50% 100:0
Ag(I)OTf (5%)/ (S)-
BINAP (5%)
CH2Cl2 100% 100:0
Ag(I)OTf (1%) CH2Cl2 92% 100:0
Ag(I)ClO4 (5%) CH2Cl2 100% 100:0
Ag(I)OCOCF3 (5%) CH2Cl2 25% 100:0
None CH2Cl2 0% 0
Ag2SO4 (5%) CH2Cl2 0% 0
Ag(I)BF4 (5%) CH2Cl2 33% 100:0
Catalyst
(mol%)
Solvent Conversion
Ratio of
Product
(3:4)
Ag(I)OTf
(10%)
CH2Cl2 0% 0
Ag(I)OTf
(10%)
Toluene 0% 0
Ag(I)BF4
(12%)
Toluene 0% 0
Ag(I)OTf
(10%)
Toluene,
under reflux
70% 100:0
Ag(I)OTf
(15%)
Toluene,
under reflux
70% 100:0
Possible Mechanism
Selected NMR