The β-(acyloxy)alkyl radical rearrangement revisited

Article abstract of DOI:10.1139/v03-148

A β-(acyloxy)alkyl radical precursor, containing a carboxylate residue suitably placed for the trapping of any intermediate alkene radical cations, has been constructed. In nonpolar solutions the probe, in the form of either the free acid or its tetrabuty

Full text of DOI:10.1139/v03-148

75
The ␤-(acyloxy)alkyl radical rearrangement
revisited1
David Crich and Dae-Hwan Suk
Abstract: A β-(acyloxy)alkyl radical precursor, containing a carboxylate residue suitably placed for the trapping of any
intermediate alkene radical cations, has been constructed. In nonpolar solutions the probe, in the form of either the free
acid or its tetrabutylammonium salt, undergoes the typical rearrangement reaction with no evidence of trapping, leading
to the conclusion that the reaction is either concerted or that collapse of any intermediate contact ion pair is so rapid
as to preclude the possibility of trapping.
Key words: radical, rearrangement, contact ion pair.
Résumé : Un précurseur de transposition d’un radical β-(acyloxy)alkyle, equippé d’un résidu carboxylate convenable-
ment placé pour piéger des intermediares alcene cation radicalaire, a été construit. En milieu apolaire la sonde, sous
forme d’acide carboxylique ou sel de tetrabutylammonium quaternaire, subit la transposition typique et ne manifest au-
cune évidence de piègage, ce qui mène à la conclusion que la réaction est soit concertée, soit a lieu par l’intermédiaire
d’une paire d’ions intime qui se réunit trop rapidement pour admettere la possibilité de piègage.
Mots clés : transposition radicalaire, paire d’ions intime.
Crich and Suk 79
Introduction
parameters for the fragmentation, with log(A) values typi-
cally in the vicinity of 10–12 (2, 3, 11). When the same ex-
periments are conducted in nonpolar solvents only the
rearranged radical is observed, but the Arrhenius parameters
for these rearrangements closely resemble those for the frag-
mentations in more polar solvents (2, 3, 12, 13). The con-
gruence between the two sets of Arrhenius parameters leads
to the conclusion that both involve rate-determining frag-
mentation to a contact radical ionic pair, but that in nonpolar
solvents rapid collapse to the product radical precludes the
possibility of cage escape and spectroscopic detection of the
radical cation. Note that, owing to the nanosecond timescale
of the instrument used in the LFP experiments and the ex-
pected sub-nanosecond times anticipated for the escape of
ions from contact ion pairs (14), only those radical cations
that live long enough to escape the initial contact pair can be
observed spectroscopically. Numerous trapping studies (6–
10) have pointed to the ability of nucleophiles to intervene
in this mechanism by trapping the alkene radical cation, and
the stereochemical information retained in some of them (9)
indicates that, with appropriate nucleophiles, trapping can
take place at the level of the contact radical ion pair.
Initially thought to be concerted (1), the β-
(phosphatoxy)alkyl radical rearrangement has recently been
shown to involve a rate-determining radical ionic fragmenta-
tion to a contact radical ion pair with subsequent collapse to
the product radical (Scheme 1, X = P(OR)2) (2, 3). The jury
is still out, however, in the case of the closely related β-
(acyloxy)alkyl radical rearrangement (1), otherwise known
as the Surzur–Tanner rearrangement (4). In this paper we de-
scribe attempts at trapping any intermediate contact ion pair,
which attest, at the least, to the rapidity of its collapse to the
product radical.
The evidence for the fragmentation mechanism in the re-
arrangement of β-(phosphatoxy)alkyl radicals is spectro-
scopic and kinetic (2, 3, 5) and is well supported by a range
of trapping experiments (6–10). Thus, in more polar sol-
vents, β-phenyl-β-(phosphatoxy)ethyl radicals fragment to
give the styryl radical cation, which is readily detected in
time-resolved laser flash photolytic experiments, and the
phosphate anion. Kinetic experiments reveal the Arrhenius
Significant effort has also been focused on the mechanism
of the β-(acyloxy)alkyl radical rearrangement (15). A variety
of stereochemical and isotopic labeling studies point to a re-
action that is the formal equivalent of a 2,3-sigmatropic shift
(Scheme 2) (1, 15). However, kinetic studies conducted by
classical competition and (or) ESR spectroscopic methods
(1, 15) and by time-resolved laser flash photolysis methods
(13) have revealed Arrhenius parameters, especially typical
log(A) values of 11.0–14.0, which closely parallel those of
the β-(phosphatoxy)alkyl radical rearrangements, thereby
strongly suggesting an analogous rate-determining fragmen-
tation followed by an extremely rapid collapse to the product
Received 1 July 2003. Published on the NRC Research Press
Web site at http://canjchem.nrc.ca on 1 December 2003.
This paper is dedicated to Professor Ed Piers (UBC) in
recognition of his many valuable contributions to organic
chemistry.
D. Crich2 and D.-H. Suk. Department of Chemistry,
University of Illinois at Chicago, 845 West Taylor Street,
Chicago, IL 60607, U.S.A.
1This article is part of a Special Issue dedicated to Professor
Ed Piers.
2Corresponding author (email: dcrich@uic.edu).
Can. J. Chem. 82: 75–79 (2004)
doi: 10.1139/V03-148
© 2003 NRC Canada

76
Can. J. Chem. Vol. 82, 2004
Scheme 1. The fragmentation–recombination mechanism for the rearrangement of ester-substituted radicals.
Scheme 3. Possible reaction pathways for carboxy-substituted β-
(acyloxy)alkyl radicals.
Scheme 2. A concerted mechanism for the [2,3]-rearrangement
of β-(acyloxy)alkyl radicals.
radical (Scheme 1, X = CR). In contrast to the phosphates,
though, is the failure of several trapping studies to subvert
the rearrangement reaction and the lack of any direct obser-
vation of the intermediate alkene radical cation in such a
mechanism. These apparent inconsistencies may be recon-
ciled with the fragmentation mechanism if it is supposed
that the carboxylate anion is much more basic than the
diphenylphosphate anion, which leads to an even more rapid
collapse of the contact ion pair, with which neither trapping
nor cage escape can compete (16–18).3
The investigations reported in this paper were spurred by
the possibility that carboxylates homoallylic to alkene radi-
cal cations might undergo facile decarboxylation (Scheme 3,
path a) (19), analogous to the way in which glycine-based
aminium radical cations suffer rapid decarboxylation (20,
21). Alternatively, it was considered possible that the radical
cation might be trapped in a 5-endo-trig manner to yield γ-
lactone-based products (Scheme 3, path b). There also exists
the possibility that the alkene radical cation takes part in a 4-
exo-cyclization to afford an azetidinone-substituted methyl
radical (Scheme 3, path c), but, as these are known to frag-
ment with rate constants of 105–106 s–1 at 80 °C (19), any
equilibrium of this kind was expected to favor the open-
chain product. Any or all of these processes could possibly
divert the initial contact ion pair from collapse to the rear-
ranged radical (Scheme 3, path d) and so potentially provide
evidence for the intervention of alkene radical cations in the
β-(acyloxy)alkyl radical rearrangement.
A suitable radical precursor was synthesized, as outlined
in Scheme 4, with the main design feature being the use of
the 2-(2-bromophenyl)ethanesulfenyl group (22) as a stable
radical precursor β to the potentially enolizable carboxylate
function. Thus, oxidation of 2-benzyl dihydrocinnamalde-
hyde 1 with lead tetraacetate afforded the acetoxyaldehyde
2, which was immediately converted to the allyl ester 3 by
Wittig olefination. Conjugate addition of 2-(2-
bromophenyl)ethanethiol 4 (23) gave adduct 5 in poor but
sufficient yield. Finally, removal of the allyl ester to give the
product 6 was achieved with palladium(0) catalysis in the
presence of pyrrolidine as nucleophile, the choice of ester
and cleavage conditions being dictated by the desire to mini-
mize elimination of the sulfide group.
3 Against this background of experimental evidence it must be recognized that a series of computational investigations have supported the
concerted mechanisms for rearrangement, although the more recent versions admit the possibility of a dissociative mechanism (16–18).
© 2003 NRC Canada

Crich and Suk
77
Scheme 4. Synthesis of the radical precursor 6.
Scheme 5. Rearrangement of 6 to 7.
Table 1. Rearrangement of acid 6 and its salts.
Recovered 6
Yield 7
Substrate
Solvent
(%)a
(%)a
9
45
49
0
6
Benzene
Benzene
Tetrahydrofuran
Benzene
40
35
20
63
6 Bu4N+ salt
6 Bu4N+ salt
6 K+ salt
aYields refer to isolated material.
tions employed to minimize the possibility of premature
radical trapping by the hydride.
Overall we are driven to the conclusion that in nonpolar
solvents the β-acyloxyalkyl rearrangement is either con-
certed or proceeds via a contact ion pair in which the rate of
recombination to give the rearranged radical significantly ex-
ceeds that of trapping by intramolecular carboxylates. Given
that the rate constant for intermolecular attack of acetate an-
ion on the resonance-stabilized, photochemically generated
4-methoxystyrene radical cation in acetonitrile solution is
4 × 1010 (mol L–1)–1 s–1 (24), it is perhaps not surprising that
collapse of the acetate onto the alkene radical cation, within
the confines of the putative contact ion pair, out-competes
other modes of trapping, even intramolecular.
Exposure of 6 to tributyltin hydride and benzene at reflux,
with initiation by AIBN, afforded the rearrangement product
7 in 40% isolated yield, thereby establishing the viability of
the rearrangement in question (Scheme 5, Table 1).
Similar results were obtained (Table 1) when 6 was first
converted to its tetrabutylammonium salt before exposure to
tributyltin hydride and AIBN in both benzene and THF at
1
reflux. Careful inspection of the H NMR spectra of the re-
action mixtures in each case did not provide any evidence
for the formation of products that may have been anticipated
as arising from pathways a, b, and c of Scheme 3. In each
case the only discernible products were 7, arising from the
rearrangement and the unreacted substrate 6. Finally, neu-
tralization of a methanolic solution of 6 with potassium hy-
droxide followed by azeotroping to dryness, then treatment
with tributyltin hydride and AIBN in benzene at reflux also
resulted only in the formation of the rearranged product 7
(Table 1). The relatively poor mass balances in some of
these reactions are attributed to decomposition on silica gel
chromatography, particularly the elimination of acetate from
7. Under most conditions significant amounts of unreacted
Experimental part
2-Acetoxy-2-benzyldihydrocinnamaldehyde (2)
To
a solution of 2-benzyldihydrocinnamaldehyde 1
(27.1 g, 0.12 mol) and Pb(OAc)4 (58.9 g, 0.13 mol) in ben-
zene (250 mL) was added BF3OEt2 (15.3 mL, 0.12 mol)
(25). After stirring overnight at room temperature, the reac-
tion mixture was washed with Na2CO3 solution and the
washings back extracted with Et2O (100 mL). The combined
organic layer was washed with brine and then dried over
MgSO4. Evaporation of the solvent under reduced pressure
followed by column chromatography on silica gel (eluent:
hexane → hexane–EtOAc, 20:1) gave the title product
(11.9 g, 35%), which was used immediately in the next step.
1H NMR (CDCl3) δ: 2.11 (s, 3H), 3.16 (d, 2H, J = 8.6 Hz),
3.23 (d, 2H, J = 8.6 Hz), 7.13–7.31 (m, 10H), 9.26 (s, 1H).
substrate
6 remained after prolonged treatment with
tributyltin hydride and AIBN. While other explanations are
possible, this is most likely symptomatic of the difficulty of
sustaining good chain propagation under the dilute condi-
© 2003 NRC Canada

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Can. J. Chem. Vol. 82, 2004
13C NMR (CDCl3) δ: 21.5, 40.3, 86.4, 127.5, 128.8, 131.0,
3-Acetoxy-4-benzyl-5-phenylpentanoic acid (7)
134.8, 171.3, 201.6.
A solution of Bu SnH (59.6 L, 0.22 mmol) and AIBN
µ
(1.5 mg, 9.2 µmol) i3n benzene (3.1 mL) was added dropwise
over 3 h with the aid of a syringe pump to a solution of 6
(100 mg, 0.18 mmol) in benzene (3.1 mL) at reflux under
Ar. After heating to reflux for a further 1 h, the reaction
mixture was cooled to room temperature and concentrated
under reduced pressure. The residue was dissolved in MeCN
(1 mL) and extracted with hexanes (3 × 3 mL). The
acetonitrile layer was concentrated under reduced pressure
and purified by column chromatography on silica gel
Allyl 4-acetoxy-4-benzyl-5-phenyl-2E-pentenoate (3)
To a solution of 2 (12.9 g, 45.7 mmol) in benzene
(200 mL) was added (allyloxycarbonylmethylidene)tri-
phenylphosphorane (16.5 g, 45.7 mmol) (26). The mixture
was heated to reflux overnight, then cooled to room temper-
ature, diluted with EtOAc, and washed with water and brine,
then dried over MgSO4. Evaporation of the solvent under re-
duced pressure followed by column chromatography on sil-
ica gel (eluent: hexane) gave the target product 3 (9.1 g,
1
(eluent: hexane–EtOAc, 2:1) to afford 7 (24.1 mg, 40%) H
NMR (CDCl3) δ: 1.96 (s, 3H), 2.42–2.46 (m, 1H), 2.55–2.71
(m, 6H), 5.23–5.26 (m, 1H), 7.07–7.30 (m, 10H). 13C NMR
(CDCl3) δ: 21.3, 36.3, 36.6, 45.4, 71.8, 126.6, 126.7, 128.8,
128.9, 129.33, 129.39, 140.1, 140.3, 170.8, 175.6: ESI-HR-
MS calcd. for C20H22NaO4: 349.1416; found: 349.1428
([M + Na]+).
1
54%). H NMR (CDCl3) δ: 1.95 (s, 3H), 3.20 (d, 2H, J =
8.3 Hz), 3.63 (d, 2H, J = 8.3 Hz), 4.62–4.64 (m, 2H), 5.23–
5.31 (m, 2H), 5.64 (d, 1H, J = 9.5 Hz), 5.86–5.94 (m, 1H),
6.90 (d, 1H, J = 9.5 Hz), 7.10–7.27 (m, 10H). 13C NMR
(CDCl3) δ: 22.5, 43.4, 65.4, 84.8, 118.4, 120.9, 127.3, 128.5,
131.0, 132.5, 135.7, 150.1, 165.9, 170.7. Anal. calcd. for
C23H24O4: C 75.80, H 6.64; found: C 75.96, H 6.69.
Acknowledgement
We thank the National Science Foundation (NSF) (CHE
9986200) for support of this work.
Allyl 4-acetoxy-4-benzyl-3-[2-(2-
bromophenyl)ethylsulfanyl]-5-phenylpentanoate (5)
To an ice-cooled solution of 3 (4.5 g, 12.3 mmol) and 2-
(2-bromophenyl)ethylthiol 4 (23) (2.7 g, 12.3 mmol) in
DMSO (20 mL) was added NaH (50 mg, 1.2 mmol). The re-
action mixture was stirred overnight at room temperature be-
fore it was diluted with CH2Cl2, then washed with water and
brine, and dried over MgSO4. Evaporation of the solvent un-
der reduced pressure followed by column chromatography
on silica gel (eluent: hexane → hexane–EtOAc, 10:1) gave
the thioether 5 (1.7 g, 24% based on 0.52 g recovered start-
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in CH2Cl2 (50 mL) was added pyrrolidine (1.6 mL). After
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1
98%). H NMR (CDCl3) δ: 1.72–1.78 (m, 1H), 2.04 (s, 3H),
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© 2003 NRC Canada