Oxidative synthesis of cyclic acyl aminals through carbon-carbon σ-bond activation

Article abstract of DOI:10.1021/ol026538m

(matrix presented) Acyliminium ions can be prepared through photoinitiated single-electron oxidation reactions of homobenzylic amides and carbamates. Cyclic acyl aminals are formed when these acyliminium ions are appended to nucleophiles such as hydroxyl,

Full text of DOI:10.1021/ol026538m

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3443-3446
Oxidative Synthesis of Cyclic Acyl
Aminals through Carbon−Carbon
σ-Bond Activation
Danielle 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. Cyclic
acyl aminals are formed when these acyliminium ions are appended to nucleophiles such as hydroxyl, ether, and sulfonamide groups. The
scope of these reactions is discussed along with mechanistic issues relating to the energetics, chemoselectivity, and stereoelectronic effects
of bond activation.
Acyliminium ions have proven to be useful and versatile
intermediates in organic synthesis,1 serving as both potent
electrophiles and initiators of sigmatropic rearrangement
reactions. Conventional routes to form acyliminium ions
employ either acid-mediated condensation reactions of
primary amides and carbamates into aldehydes or solvolysis
reactions of R-halo-, -alkoxy-, or -acetoxy-substituted amides.2
Pioneering studies by Shono, Moeller, Yoshida, Mariano,
and others3-6 have shown that oxidative conditions can be
employed to form acyliminium ions from N-acyl amino
acids,3 R-trialkylstannylalkyl amides,4 R-trimethylsilylalkyl
amides,5 and even nonfunctionalized tertiary amides.6 In
addition to offering greater flexibility in acyliminium ion
precursor selection, oxidative protocols have been shown to
be efficacious for reactions in which substrates are not stable
toward standard reaction conditions. We recently reported7
a new cyclization reaction that proceeds through oxidatively
generated oxonium ions. This carbon-carbon σ-bond activa-
tion process is initiated by photoinduced (medium-pressure
mercury lamp, Pyrex filtration) single-electron oxidation
reactions of homobenzylic ethers that contain pendent
hydroxy and alkoxy groups (Figure 1). The selectivity for
Figure 1. Generalized depiction of ETIC reactions.
(1) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(2) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 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. Acta 1989, 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. Tetrahedron 1984, 40, 811.
carbon-carbon bond activation in preference to carbon-
hydrogen bond activation in these reactions can be attributed
to the ability of the alkoxy group to stabilize the incipient
cationic character at the homobenzylic position of the
intermediate radical cation,8 presaging that other electron-
(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.
10.1021/ol026538m CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002

donating substituents could serve in the same capacity. In
conjunction with our efforts to expand the scope of these
electron transfer initiated cyclization (ETIC) reactions, we
have demonstrated that homobenzylic amide and carbamate
groups are also effective promoters of carbon-carbon bond
activation, leading to a new oxidative route to acyliminium
ions. In this communication we report electron transfer
initiated cyclization reactions to form (N,O)- and (N,N)-
acylaminals, discuss the mechanism and stereochemical
outcomes of the reactions, and demonstrate the importance
of electronic interactions and orbital overlap in predicting
the reaction pathways for the intermediate radical cations.
We prepared substrate 1a in order to test the ability of
homobenzylic amide groups to serve as promoters of
carbon-carbon bond activation. Exposing 1a to stoichio-
metric oxidative cyclization conditions (hν, 2 equiv of N-
methylquinolinium hexafluorophosphate (NMQPF6), NaOAc,
toluene, 1,2-dichloroethane) provided (N,O)-acylaminal 2a
in 86% yield (Figure 2).9 Conducting the reaction under our
Table 1. Examples of Nitrogen Group Incorporation into ETIC
Cyclizationsa
a Reaction conditions: hν, NMQPF6 (2.5 mol %), O2, NaOAc, Na2S2O3,
DCE, PhMe. b Diastereomeric ratio. The major diastereomer is shown in
1
the product column. Stereochemical assignments were based on H NMR
coupling constants. c 1:1 mixture of diastereomers. d Ar ) p-NO2C6H4.
Figure 2. Amides as electron-donating groups in ETIC reactions.
cations undergoing associative, SN2-type reactions. To
discount the possibility that the observed product ratios could
be ascribed to reaction through the associative pathway
followed by equilibration, we resubjected both diastereo-
merically pure 4 and its syn diastereomer to the reaction
conditions. While a small (approximately 10%) amount of
epimerization was observed upon prolonged exposure, the
rate was not sufficient to account for the observed product
ratios. Cyclization of tertiary amides 5 and 7 were exception-
ally stereoselective. We attribute this result to the enhanced
allylic strain in conformer 12 relative to 13 (Figure 3).
In addition to hydroxyl groups, sulfonamides proved to
be effective nucleophiles in these reactions (entries 4 and
catalytic aerobic conditions10 (hν, 0.025 equiv of NMQPF6,
O2 aeration, NaOAc, Na2S2O3, toluene, 1,2-dichloroethane)
resulted in the isolation of 2a in 75% yield. We employed
the catalytic protocol for subsequent cyclization reactions
because of the comparable efficiency and the significant
facilitation of product purification that results from minimiz-
ing aromatic waste production. Tertiary amides are also
competent substrates in these reactions, with 1b undergoing
cyclization to provide 2b in 71% yield.
Our initial efforts at establishing the displacement mech-
anism and studying the functional group compatibility of
these reactions are represented in Table 1. Alkyl groups are
tolerated at the bis-homoallylic position for both secondary
and tertiary amides. Regardless of whether substrates were
single diastereomers or mixtures of diastereomers, the
stereochemical outcomes of these reactions were identical
(entries 2 and 3). These results are consistent with a
mechanism in which discrete acyliminium ions are formed
from mesolytic cleavages of benzylic carbon-carbon bonds
in the substrate radical cations, in preference to the radical
(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 3. Stereocontrol in tertiary amide cyclizations.
Org. Lett., Vol. 4, No. 20, 2002
3444

5). The p-nitrobenzenesulfonamide group was selected
because of its high oxidation potential and ease of cleavage.11
Acyl aminal groups related to those in 9 and 11 are present
in numerous aza-sugars that function as potent glycosidase
inhibitors.12
Table 2. Incorporation of Oxygen-Containing Functional
Groups at the Bis-Homobenzylic Positiona
Incorporating oxygen-containing functional groups at the
bis-homobenzylic position would provide a desirable increase
in the utility of this method for complex molecule synthesis.
Placing inductively electron-withdrawing groups in this
position, however, will exert a detrimental effect on the
reactivity of the intermediate radical cation. The relationship
between structure and benzylic carbon-carbon bond strength
in the radical cations of these substrates is expressed in eq
1.13 In this relationship, BDERC defines the mesolytic bond
dissociation energy of the benzylic carbon-carbon bond in
the 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 that
would result from a homolytic cleavage of the benzylic
carbon-carbon bond. Therefore, increasing the oxidation
potential of the amidoalkyl radical by adding an inductively
electron withdrawing group is expected to increase BDERC
and retard cyclization.
BDERC ) BDES - OPS + OPE
(1)
As shown in Table 2, alkoxy groups are tolerated for
secondary amides but not tertiary amides. Acyloxazolidines
are particularly effective substrates for these reactions, but
cyclic carbamates do not react under our conditions (entries
3-5). We attribute this difference to the greater electron-
withdrawing capacity of an acyloxy group relative to that
of an alkoxy group, as predicted by eq 1. The failure of
trifluoroacetamide 21 (entry 6) to react under these conditions
provides further validation of the predictive utility of eq 1.
While hydroxy groups and THP-ethers function equally well
as nucleophiles, the substrates are often easier to handle as
the THP-ether. The excellent diastereoselectivity observed
in the cyclization of oxazolidines 17 and 19 was expected
on the basis of the kinetic preference14 of annulation reactions
to provide cis ring junctions.
a Reaction conditions: hν, NMQPF6 (2.5 mol %), O2, NaOAc, Na2S2O3,
DCE, PhMe. b Diastereomeric ratio. The major diastereomer is shown in
1
the product column. Stereochemical assignments were based on H NMR
coupling constants.
methyl 4-hydroxybutyrate from the oxidation of 16 indicates
that homobenzylic carbon-carbon bond activation is a
prominent reaction pathway for this substrate. This result is
consistent with oxidation of the amide group in preference
to the arene, in accord with the oxidation potentials of tertiary
amides and carbamates being approximately 0.5 V lower than
both secondary amides and carbamates15 and monoalkyl-
arenes.16 Upon formation of the amide radical cation, both
the benzylic and the homobenzylic carbon-carbon bonds
are activated toward fragmentation (Figure 4). For 16 the
preferred pathway appears to be cleavage of the homo-
benzylic carbon-carbon bond. Although σ-bonds between
alkyl groups and benzyl groups are, in general, weaker than
The efficient cyclization of oxazolidine 17 in contrast to
the decomposition of methoxy-substituted tertiary carbamate
16 merits comment. The formation of the THP-ether of
(9) All new compounds were characterized by 1H 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. Acta 1992, 75, 913.
(15) Reed, R. C.; Wightman, R. M. In Encyclopedia of Electrochemistry
of the Elements; Bard, A. J., Ed.; Marcel Dekker: New York, 1984; Vol.
15, p 83.
(16) Oxidation potentials of aromatic compounds can be estimated by
applying 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 extensive
collection of vertical ionization potentials, see: Rosenstock, M.; Draxl, K.;
Steiner, B. W.; Herron, J. T. J. Phys. Chem. Ref. Data 1977, 6, Suppl. 1.
Org. Lett., Vol. 4, No. 20, 2002
3445

carbamate SOMO and between the lone pair of the oxygen
in the oxazolidine and the σ*-orbital of the homobenzylic
carbon-carbon bond cannot attain the proper alignment for
bond cleavage. The dramatic influence of stereoelectronic
effects on the kinetics of radical ion fragmentation processes
strongly demonstrates the need for orbital alignment con-
sideration in predicting reaction pathways.
The successful, though somewhat less efficient, cyclization
of trifluoromethyl-substituted oxazolidine 19 (Table 2, entry
4) provides additional support for the reaction proceeding
through amide oxidation. Incorporating the trifluoromethyl
group is expected to increase the oxidation potential of the
arene by approximately 0.3 V.16 This would be expected to
inhibit the reaction if the relevant pathway required the
formation of the arene radical cation.
We have demonstrated that secondary and tertiary amides
and carbamates function as effective homobenzylic substit-
uents in promoting carbon-carbon σ-bond activation of
alkylarene radical cations. This process constitutes a new
oxidative method for forming acyliminium ions and leads
to cyclization reactions to form both (N,O)- and (N,N)-
acylaminals. Stereocontrol can be accomplished in these
reactions when the tertiary amides and acyl oxazolidines are
employed as homobenzylic substituents. Tertiary amides
appear to be oxidized in preference to monosubstituted
arenes, providing alternate fragmentation pathways. The
radical cations of cyclic oxazolidines undergo preferential
cleavage of the exocyclic carbon-carbon bond over to the
endocyclic bond, demonstrating the importance of orbital
alignment considerations in predicting the outcomes of these
reactions.
Figure 4. Reaction pathways for amide radical cations.
bonds between alkyl groups and alkoxyalkyl groups,17 this
cleavage can be attributed to the stability of the oxonium
ion18 that forms from homobenzylic bond cleavage.
Arnold, however, has demonstrated19 that thermodynamic
analyses of bond dissociations are valid only when proper
orbital alignment can be achieved between the fragmenting
carbon-carbon σ-bond and the SOMO and between the
oxygen lone pair and the σ*-orbital of the breaking carbon-
carbon bond (Figure 5). Constraining the carbamate group
Figure 5. Ideal geometries for â-alkoxy carbamate radical cation
carbon-carbon bond fragmentation.
Acknowledgment. This work was supported by the
University of Pittsburgh and the Research Corporation
through a Research Innovation Award. We thank Professor
Dennis Curran for helpful discussions.
and the ether oxygen in an oxazolidine ring prohibits these
alignments. A model of 17 clearly shows that the dihedral
angles between the endocyclic carbon-carbon bond and the
Supporting Information Available: Synthetic schemes
for cyclization substrates and detailed experimental proce-
(17) McMillen, D. F.; Golden, D. M. Annu. ReV. Phys. Chem. 1982, 33,
1
dures, characterizations, and H and 13C NMR spectra for
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.
all cyclization products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL026538M
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