Tuning reactivity and chemoselectivity in electron transfer initiated cyclization reactions: Applications to carbon-carbon bond formation

Article abstract of DOI:10.1021/ja029139v

In this communication, we demonstrate that the scope of our electron transfer initiated cyclization reaction can be significantly broadened by exploiting the relationship between the oxidation potentials of homobenzylic ethers and the mesolytic benzylic c

Full text of DOI:10.1021/ja029139v

Published on Web 02/06/2003
Tuning Reactivity and Chemoselectivity in Electron Transfer Initiated
Cyclization Reactions: Applications to Carbon-Carbon Bond Formation
John R. Seiders, II, Lijun Wang, and Paul E. Floreancig*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received October 29, 2002 ; E-mail: florean@pitt.edu
When properly substituted, organic radical cations undergo
mesolytic cleavage reactions to form radical fragments and cationic
fragments.1 Generating electrophiles through this process nicely
complements acid-mediated functional group activation due to the
orthogonal chemoselectivity of acid-base interactions relative to
electron transfer reactions, the most common method of preparing
radical cations.2 Studies that define the relationship between a
Figure 1. General representation of ETIC reactions.
functional group’s oxidation potential and the propensity of its
radical cation to fragment will significantly aid in the development
of new and selective transformations based on oxidative cleavage.
We recently reported a photoinduced electron transfer initiated
heterocycle synthesis (Figure 1)3 that proceeds through mesolytic
carbon-carbon σ-bond cleavages of homobenzylic ethers or amides
to form benzyl radicals and oxocarbenium or acyliminium ions,
reactivity.
Figure 2. Effect of altering the arene oxidation potential on radical cation
respectively, under essentially neutral reaction conditions. Initial
attempts to form carbocycles through this process by utilizing
electron-rich olefins as nucleophiles were unsuccessful, however,
due to the preferential oxidation of the olefin over the arene. In
this communication, we illustrate that a simple mathematical model
aids in designing substrates that retain the reactivity of the parent
series while undergoing arene oxidation with enhanced selectivity.
We use this relationship to broaden the applicability of the method
Figure 3. Reactivity recovery through selective bond-weakening.
oxidation with greater selectivity.8 To test this hypothesis, we
prepared several analogues of 1b, in which the relevant carbon-
carbon bonds were weakened by adding radical-stabilizing groups
at the benzylic position,9 and subjected them to our standard
cyclization conditions (Figure 3). While all substitutions at the
benzylic center enhanced reactivity relative to 1b, phenyl substitu-
tion provided an exceptional rate enhancement, with substrate 5
displaying reactivity that essentially matches that of 1a.10 The
benefits of lowering the oxidation potential of the substrate are
manifested through the successful employment of ceric ammonium
nitrate,11 a mild oxidant that is unreactive toward 1a, to initiate the
cyclization of 5 to 2 in 45% yield under nonphotochemical
conditions.
Lowering the oxidation potential of the arene also allows a much
broader range of nucleophiles to be employed in this process. The
capacity of several electron-rich olefins to serve as nucleophiles in
carbocyclization reactions is shown in Table 1.12 Cyclizations
proceed with allylsilanes, allenylsilanes, and enol acetates (entries
1-3). Using trisubstituted olefins as the nucleophile (entry 4) creates
new possibilities for initiating oxidative cascade cyclization reac-
tions.13 For most of the carbocyclization reactions, nonphotochemi-
cal Ce(IV)-mediated conditions14,15 proved to be superior to
photochemical conditions. These reactions are essentially instan-
taneous at moderate temperatures.
to include electron-rich olefins as nucleophiles. We also show that,
by lowering the oxidation potential of the arene, ceric ammonium
nitrate can initiate cyclizations under nonphotochemical conditions.
To establish a relationship between the oxidation potential of
alkylarenes and the reactivity of their radical cations, we compared
the reactions of homobenzylic ether 1a with those of its more readily
oxidized2 p-methoxy-substituted analogue 1b (Figure 2). While 1a
undergoes rapid cyclization to form 2 when irradiated (medium-
pressure mercury lamp, Pyrex filter) in the presence of N-
methylquinolinium hexafluorophosphate (NMQPF6) under aerobic
conditions,4 1b fails to react. These results can be explained by eq
1,5 in which BDE(RC) defines the mesolytic bond dissociation
energy of the radical cation, BDE(S) defines the homolytic bond
dissociation energy of the same bond in the neutral substrate, Epa-
(S) defines the oxidation potential of the substrate, and Epa(E)
defines the oxidation potential of the radical corresponding to the
fragment that ultimately becomes the electrophile (the alkoxyalkyl
radical in the present case).6 Thus, lowering the oxidation potential
of a cyclization substrate strengthens the benzylic carbon-carbon
bond and suppresses cyclization despite the increased facility of
radical cation formation.7
BDE(RC) ) BDE(S) - Epa(S) + Epa(E)
(1)
In addition to forecasting the inverse relationship between
oxidation potential and radical ion reactivity, eq 1 also suggests
that lowering BDE(S) should facilitate radical cation cleavage. Thus,
cyclization substrates can be rationally designed to retain the high
reactivity of the parent system while undergoing single electron
An improvement in the atom economy16 of the reaction can be
envisioned through incorporating the bond-activating group into
the product instead of the leaving group. This can be accomplished
by placing an olefin at the homobenzylic position and appending
the nucleophilic group onto the ether linkage (Figure 4). We tested
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10.1021/ja029139v CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Carbon Nucleophiles in ETIC Reactionsa
oxidized under mild conditions while still undergoing efficient
mesolytic cleavage reactions. This strategy allows electron-rich
olefins to be used in ETIC reactions that are initiated by Ce(IV)
under nonphotochemical conditions. An alternate substrate design
further validates the utility of eq 1 in substrate design and allows
for the inclusion of the bond-activating substituent in the product,
thereby improving the atom economy of the process. The ability
to utilize the interplay between oxidation potential and bond
dissociation energies is expected to be extremely valuable in the
design of new radical ion fragmentation processes for unique
synthesis and materials applications.
Acknowledgment. Funding for this work was provided by the
NSF, the University of Pittsburgh, and the Research Corporation
through a Research Innovation Award.
Supporting Information Available: Synthetic schemes for all
cyclization substrates. Experimental procedures and characterization
for all cyclization reactions (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
a Reaction conditions: 2.5 equiv of CAN in CH3CN was added to a
suspension of the substrate, NaHCO3, and 4 Å molecular sieves in DCE at
45 °C (entries 1-3). b Ar2CH ) p-MeOPhC(H)Ph. c See the Supporting
Information for substrate syntheses. d Isolated yields of purified products.
e Product was isolated as a 3:2 mixture of diastereomers. f Product was
isolated as a 1:1 mixture of diastereomers after a Bu4NF workup.
g Photochemical conditions were employed. Stereochemistry was assigned
(1) For reviews of radical cation cleavage patterns, see: (a) Schmittel, M.;
Burghart, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 2550. (b) Baciocchi,
E.; Bietti, M.; Lanzalunga, O. Acc. Chem. Res. 2000, 33, 243.
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(6) Oxidation potentials are normally reported in volts. One volt is equivalent
to 23 kcal/mol.
1
by analyzing H NMR coupling constants.
(7) This effect has been reported for oxidative solvolysis reactions. (a)
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Figure 4. Placement of the bond-weakening group in the product fragment.
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this strategy by subjecting 14 to our photochemical conditions. As
predicted, we observed the smooth production of acetal 15.
Ce(IV)-mediated cyclization resulted in acetal hydrolysis, presum-
ably due to the mild Lewis-acidity of Ce(III).11 Notably, this design
also accommodates carbon nucleophiles, with enol acetate 16
undergoing cyclization under Ce(IV)-mediated conditions to form
tetrahydropyrone 17 in 91% yield.
In summary, we have shown that the facility of carbon-carbon
bond cleavage reactions for alkylarene radical cations correlates
with expected trends for the oxidation potentials of the substrates,
with diminished reactivity being observed at lower oxidation
potentials. A simple relationship between the arene’s oxidation
potential and the bond dissociation energy of the benzylic carbon-
carbon bond has been exploited to design substrates that can be
(11) For a review of cerium in organic synthesis, see: Molander, G. A. Chem.
ReV. 1992, 92, 29.
1
(12) All new compounds were characterized by H NMR, 13C NMR, IR, and
HRMS. See the Supporting Information for details.
(13) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(14) For Ce(IV) initiated fragmentation reactions from R-stannylalkyl ethers
resulting in carbon-carbon bond formation, see: Chen, C.; Mariano, P.
S. J. Org. Chem. 2000, 65, 3252.
(15) For electrochemically initiated fragmentation reactions resulting in carbon-
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