Oxidative Synthesis of Cyclic AcylAminals through Carbon−Carbonσ-Bond ActivationDanielle L. Aubele and Paul E. Floreancig*

Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260

florean+@pitt.edu

Received July 16, 2002

ABSTRACT

Acyliminium ions can be prepared through photoinitiated single-electron oxidation reactions of homobenzylic amides and carbamates. Cyclicacyl aminals are formed when these acyliminium ions are appended to nucleophiles such as hydroxyl, ether, and sulfonamide groups. Thescope of these reactions is discussed along with mechanistic issues relating to the energetics, chemoselectivity, and stereoelectronic effectsof bond activation.

Acyliminium ions have proven to be useful and versatileintermediates in organic synthesis,1 serving as both potentelectrophiles and initiators of sigmatropic rearrangementreactions. Conventional routes to form acyliminium ionsemploy either acid-mediated condensation reactions ofprimary amides and carbamates into aldehydes or solvolysisreactions ofR-halo-, -alkoxy-, or -acetoxy-substituted amides.2

Pioneering studies by Shono, Moeller, Yoshida, Mariano,and others3-6 have shown that oxidative conditions can beemployed to form acyliminium ions fromN-acyl aminoacids,3 R-trialkylstannylalkyl amides,4 R-trimethylsilylalkylamides,5 and even nonfunctionalized tertiary amides.6 Inaddition to offering greater flexibility in acyliminium ionprecursor selection, oxidative protocols have been shown tobe efficacious for reactions in which substrates are not stabletoward standard reaction conditions. We recently reported7

a new cyclization reaction that proceeds through oxidativelygenerated oxonium ions. This carbon-carbonσ-bond activa-tion process is initiated by photoinduced (medium-pressuremercury lamp, Pyrex filtration) single-electron oxidationreactions of homobenzylic ethers that contain pendenthydroxy and alkoxy groups (Figure 1). The selectivity for

carbon-carbon bond activation in preference to carbon-hydrogen bond activation in these reactions can be attributedto the ability of the alkoxy group to stabilize the incipientcationic character at the homobenzylic position of theintermediate radical cation,8 presaging that other electron-

(1) Speckamp, W. N.; Moolenaar, M. J.Tetrahedron2000, 56, 3817.(2) Speckamp, W. N.; Hiemstra, H.Tetrahedron1985, 41, 4367.(3) (a) Boto, A.; Herna´ndez, R.; Sua´rez, E.Tetrahedron Lett.1999, 40,

5945. (b) Harding, K. E.; Liu, L. T.; Farrar, D. G.; Coleman, M. T.; Tansey,S. K. Synth. Commun.1991, 1409. (c) Seebach, D.; Charczuk, R.; Gerber,C.; Renaud, P.; Berner, H.; Schneider, H.HelV. Chim. Acta1989, 72, 401.

(4) (a) Yoshida, J.-i.; Ishichi, Y.; Isoe, S.J. Am. Chem. Soc.1992, 114,7594. (b) Narasaka, K.; Kohno, Y.Bull. Chem. Soc. Jpn. 1993, 66, 3456.

(5) (a) Yoshida, J.-i.; Isoe, S.Tetrahedron Lett.1987, 28, 6621. (b) Wu,X.-D.; Khim, S.-K.; Zhang, X.; Cederstrom, E. M.; Mariano, P. S.J. Org.Chem.1998, 63, 841. (c) Sun, H.; Moeller, K. D.Org. Lett.2002, 4, 1547.

(6) (a) Suga, S.; Okajima, M.; Yoshida, J.-i.Tetrahedron Lett.2001,42, 2173. (b) Moeller, K. D.; Rutledge, L. D.J. Org. Chem.1992, 57,6360. (c) Shono, T.Tetrahedron1984, 40, 811.

(7) (a) Kumar, V. S.; Floreancig, P. E.J. Am. Chem. Soc.2001, 123,3842. (b) Kumar, V. S.; Aubele, D. L.; Floreancig, P. E.Org. Lett.2002,4, 2489.

Figure 1. Generalized depiction of ETIC reactions.

ORGANICLETTERS

2002Vol. 4, No. 203443-3446

10.1021/ol026538m CCC: $22.00 © 2002 American Chemical SocietyPublished on Web 09/11/2002

donating substituents could serve in the same capacity. Inconjunction with our efforts to expand the scope of theseelectron transfer initiated cyclization (ETIC) reactions, wehave demonstrated that homobenzylic amide and carbamategroups are also effective promoters of carbon-carbon bondactivation, leading to a new oxidative route to acyliminiumions. In this communication we report electron transferinitiated cyclization reactions to form (N,O)- and (N,N)-acylaminals, discuss the mechanism and stereochemicaloutcomes of the reactions, and demonstrate the importanceof electronic interactions and orbital overlap in predictingthe reaction pathways for the intermediate radical cations.

We prepared substrate1a in order to test the ability ofhomobenzylic amide groups to serve as promoters ofcarbon-carbon bond activation. Exposing1a to stoichio-metric oxidative cyclization conditions (hν, 2 equiv ofN-methylquinolinium hexafluorophosphate (NMQPF6), NaOAc,toluene, 1,2-dichloroethane) provided (N,O)-acylaminal2ain 86% yield (Figure 2).9 Conducting the reaction under our

catalytic aerobic conditions10 (hν, 0.025 equiv of NMQPF6,O2 aeration, NaOAc, Na2S2O3, toluene, 1,2-dichloroethane)resulted in the isolation of2a in 75% yield. We employedthe catalytic protocol for subsequent cyclization reactionsbecause of the comparable efficiency and the significantfacilitation of product purification that results from minimiz-ing aromatic waste production. Tertiary amides are alsocompetent substrates in these reactions, with1b undergoingcyclization to provide2b in 71% yield.

Our initial efforts at establishing the displacement mech-anism and studying the functional group compatibility ofthese reactions are represented in Table 1. Alkyl groups aretolerated at the bis-homoallylic position for both secondaryand tertiary amides. Regardless of whether substrates weresingle diastereomers or mixtures of diastereomers, thestereochemical outcomes of these reactions were identical(entries 2 and 3). These results are consistent with amechanism in which discrete acyliminium ions are formedfrom mesolytic cleavages of benzylic carbon-carbon bondsin the substrate radical cations, in preference to the radical

cations undergoing associative, SN2-type reactions. Todiscount the possibility that the observed product ratios couldbe ascribed to reaction through the associative pathwayfollowed by equilibration, we resubjected both diastereo-merically pure4 and its syn diastereomer to the reactionconditions. While a small (approximately 10%) amount ofepimerization was observed upon prolonged exposure, therate was not sufficient to account for the observed productratios. Cyclization of tertiary amides5 and7 were exception-ally stereoselective. We attribute this result to the enhancedallylic strain in conformer12 relative to13 (Figure 3).

In addition to hydroxyl groups, sulfonamides proved tobe effective nucleophiles in these reactions (entries 4 and

(8) (a) Arnold, D. R.; Lamont, L. J.Can. J. Chem.1989, 67, 2119. (b)Freccero, M.; Pratt, A.; Albini, A.; Long, C.J. Am. Chem. Soc.1998, 120,284. For reviews of radical cation cleavage patterns, see: (c) Schmittel,M.; Burghart, A.Angew. Chem., Int. Ed. Engl.1997, 36, 2550. (d) Baciocchi,E.; Bietti, M.; Lanzalunga, O.Acc. Chem. Res. 2000, 33, 243.

Figure 2. Amides as electron-donating groups in ETIC reactions.

Table 1. Examples of Nitrogen Group Incorporation into ETICCyclizationsa

a Reaction conditions:hν, NMQPF6 (2.5 mol %), O2, NaOAc, Na2S2O3,DCE, PhMe.b Diastereomeric ratio. The major diastereomer is shown inthe product column. Stereochemical assignments were based on1H NMRcoupling constants.c 1:1 mixture of diastereomers.d Ar ) p-NO2C6H4.

Figure 3. Stereocontrol in tertiary amide cyclizations.

3444 Org. Lett., Vol. 4, No. 20, 2002

5). The p-nitrobenzenesulfonamide group was selectedbecause of its high oxidation potential and ease of cleavage.11

Acyl aminal groups related to those in9 and11 are presentin numerous aza-sugars that function as potent glycosidaseinhibitors.12

Incorporating oxygen-containing functional groups at thebis-homobenzylic position would provide a desirable increasein the utility of this method for complex molecule synthesis.Placing inductively electron-withdrawing groups in thisposition, however, will exert a detrimental effect on thereactivity of the intermediate radical cation. The relationshipbetween structure and benzylic carbon-carbon bond strengthin the radical cations of these substrates is expressed in eq1.13 In this relationship, BDERC defines the mesolytic bonddissociation energy of the benzylic carbon-carbon bond inthe radical cation, BDES defines the homolytic bond dis-sociation energy of the same bond in the neutral substrate,OPS defines the oxidation potential of the substrate, and OPE

defines the oxidation potential of the amidoalkyl radical thatwould result from a homolytic cleavage of the benzyliccarbon-carbon bond. Therefore, increasing the oxidationpotential of the amidoalkyl radical by adding an inductivelyelectron withdrawing group is expected to increase BDERC

and retard cyclization.

As shown in Table 2, alkoxy groups are tolerated forsecondary amides but not tertiary amides. Acyloxazolidinesare particularly effective substrates for these reactions, butcyclic carbamates do not react under our conditions (entries3-5). We attribute this difference to the greater electron-withdrawing capacity of an acyloxy group relative to thatof an alkoxy group, as predicted by eq 1. The failure oftrifluoroacetamide21 (entry 6) to react under these conditionsprovides further validation of the predictive utility of eq 1.While hydroxy groups and THP-ethers function equally wellas nucleophiles, the substrates are often easier to handle asthe THP-ether. The excellent diastereoselectivity observedin the cyclization of oxazolidines17 and19 was expectedon the basis of the kinetic preference14 of annulation reactionsto providecis ring junctions.

The efficient cyclization of oxazolidine17 in contrast tothe decomposition of methoxy-substituted tertiary carbamate16 merits comment. The formation of the THP-ether of

methyl 4-hydroxybutyrate from the oxidation of16 indicatesthat homobenzylic carbon-carbon bond activation is aprominent reaction pathway for this substrate. This result isconsistent with oxidation of the amide group in preferenceto the arene, in accord with the oxidation potentials of tertiaryamides and carbamates being approximately 0.5 V lower thanboth secondary amides and carbamates15 and monoalkyl-arenes.16 Upon formation of the amide radical cation, boththe benzylic and the homobenzylic carbon-carbon bondsare activated toward fragmentation (Figure 4). For16 thepreferred pathway appears to be cleavage of the homo-benzylic carbon-carbon bond. Althoughσ-bonds betweenalkyl groups and benzyl groups are, in general, weaker than

(9) All new compounds were characterized by1H NMR, 13C NMR, IR,and HRMS. See Supporting Information for details.

(10) Kumar, V. S.; Aubele, D. L.; Floreancig, P. E.Org. Lett. 2001, 3,4123.

(11) Fukuyama, T.; Jow, C.-K.; Cheung, M.Tetrahedron Lett.1995, 36,6373.

(12) (a) Ganem, B.Acc. Chem. Res.1996, 29, 340. (b) Nishimura, Y.;Shitara, E.; Takeuchi, T.Tetrahedron Lett.1999, 40, 2351. (c) Umezawa,H.; Aoyagi, T.; Komiyama, H.; Morishima, H.; Hamada, M.; Takeuchi, T.J. Antibiot.1974, 27, 963.

(13) Popielarz, R.; Arnold, D. R.J. Am. Chem. Soc.1990, 112, 3068.(14) For example, see: Seebach, D.; Lamatsch, B.; Amstutz, R.; Beck,

A. K.; Dobler, M.; Egli, M.; Fitzi, R.; Gautschi, M.; Herradon, B.; Hidber,P. C.; Irwin, J. J.; Locher, R.; Maestro, M.; Maetzke, T.; Maurin˜o, A.;Pfammater, E.; Plattner, E.; Schickli, C.; Schweizer, W. B.; Seiler, P.;Stucky, G.HelV. Chim. Acta1992, 75, 913.

(15) Reed, R. C.; Wightman, R. M. InEncyclopedia of Electrochemistryof the Elements; Bard, A. J., Ed.; Marcel Dekker: New York, 1984; Vol.15, p 83.

(16) Oxidation potentials of aromatic compounds can be estimated byapplying Kochi’s empirical relationship to the vertical ionization potential:Howell, J. O.; Goncalves, J. M.; Amatore, C.; Klasinc, L.; Wightman, R.M.; Kochi, J. K. J. Am. Chem. Soc.1984, 106, 3698. For an extensivecollection of vertical ionization potentials, see: Rosenstock, M.; Draxl, K.;Steiner, B. W.; Herron, J. T.J. Phys. Chem. Ref. Data1977, 6, Suppl. 1.

BDERC ) BDES - OPS + OPE (1)

Table 2. Incorporation of Oxygen-Containing FunctionalGroups at the Bis-Homobenzylic Positiona

a Reaction conditions:hν, NMQPF6 (2.5 mol %), O2, NaOAc, Na2S2O3,DCE, PhMe.b Diastereomeric ratio. The major diastereomer is shown inthe product column. Stereochemical assignments were based on1H NMRcoupling constants.

Org. Lett., Vol. 4, No. 20, 2002 3445

bonds between alkyl groups and alkoxyalkyl groups,17 thiscleavage can be attributed to the stability of the oxoniumion18 that forms from homobenzylic bond cleavage.

Arnold, however, has demonstrated19 that thermodynamicanalyses of bond dissociations are valid only when properorbital alignment can be achieved between the fragmentingcarbon-carbon σ-bond and the SOMO and between theoxygen lone pair and theσ*-orbital of the breaking carbon-carbon bond (Figure 5). Constraining the carbamate group

and the ether oxygen in an oxazolidine ring prohibits thesealignments. A model of17 clearly shows that the dihedralangles between the endocyclic carbon-carbon bond and the

carbamate SOMO and between the lone pair of the oxygenin the oxazolidine and theσ*-orbital of the homobenzyliccarbon-carbon bond cannot attain the proper alignment forbond cleavage. The dramatic influence of stereoelectroniceffects on the kinetics of radical ion fragmentation processesstrongly demonstrates the need for orbital alignment con-sideration in predicting reaction pathways.

The successful, though somewhat less efficient, cyclizationof trifluoromethyl-substituted oxazolidine19 (Table 2, entry4) provides additional support for the reaction proceedingthrough amide oxidation. Incorporating the trifluoromethylgroup is expected to increase the oxidation potential of thearene by approximately 0.3 V.16 This would be expected toinhibit the reaction if the relevant pathway required theformation of the arene radical cation.

We have demonstrated that secondary and tertiary amidesand carbamates function as effective homobenzylic substit-uents in promoting carbon-carbon σ-bond activation ofalkylarene radical cations. This process constitutes a newoxidative method for forming acyliminium ions and leadsto cyclization reactions to form both (N,O)- and (N,N)-acylaminals. Stereocontrol can be accomplished in thesereactions when the tertiary amides and acyl oxazolidines areemployed as homobenzylic substituents. Tertiary amidesappear to be oxidized in preference to monosubstitutedarenes, providing alternate fragmentation pathways. Theradical cations of cyclic oxazolidines undergo preferentialcleavage of the exocyclic carbon-carbon bond over to theendocyclic bond, demonstrating the importance of orbitalalignment considerations in predicting the outcomes of thesereactions.

Acknowledgment. This work was supported by theUniversity of Pittsburgh and the Research Corporationthrough a Research Innovation Award. We thank ProfessorDennis Curran for helpful discussions.

Supporting Information Available: Synthetic schemesfor cyclization substrates and detailed experimental proce-dures, characterizations, and1H and 13C NMR spectra forall cyclization products. This material is available free ofcharge via the Internet at http://pubs.acs.org.

OL026538M

(17) McMillen, D. F.; Golden, D. M.Annu. ReV. Phys. Chem.1982, 33,493.

(18) Wayner, D. D. M.; McPhee, D. J.; Griller, D.J. Am. Chem. Soc.1988, 110, 132.

(19) (a) Perrott, A. L.; de Lijser, H. J. P.; Arnold, D. R.Can. J. Chem.1997, 75, 384. (b) Perrott, A. L.; Arnold, D. R.Can. J. Chem.1992, 70,272.

Figure 4. Reaction pathways for amide radical cations.

Figure 5. Ideal geometries forâ-alkoxy carbamate radical cationcarbon-carbon bond fragmentation.

3446 Org. Lett., Vol. 4, No. 20, 2002