An accelerating-reporting group for studies of radical heterolysis reactions and its application in an acid-catalyzed fragmentation reaction of an α,β-dimethoxy radical

Article abstract of DOI:10.1021/jo0357972

The 2,2-diphenylcyclopropyl group was employed to accelerate reactions of α-methoxy radicals containing β-leaving groups, to trap the products of either migration or heterolysis of the leaving group, and to provide a useful chromophore for laser flash pho

Full text of DOI:10.1021/jo0357972

VOLUME 69, NUMBER 20
OCTOBER 1, 2004
© Copyright 2004 by the American Chemical Society
Articles
An Acceler a tin g-Rep or tin g Gr ou p for Stu d ies of Ra d ica l
Heter olysis Rea ction s a n d Its Ap p lica tion in a n Acid -Ca ta lyzed
F r a gm en ta tion Rea ction of a n r,â-Dim eth oxy Ra d ica l
Martin Newcomb* and Neil Miranda
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
men@uic.edu
Received December 8, 2003
The 2,2-diphenylcyclopropyl group was employed to accelerate reactions of R-methoxy radicals
containing â-leaving groups, to trap the products of either migration or heterolysis of the leaving
group, and to provide a useful chromophore for laser flash photolysis kinetic studies. The reporting
group biases reactions in favor of heterolytic fragmentation and most likely intercepts radical cations
in ion pairs. The 1-methoxy-1-methyl-2-(diethylphosphatoxy)-2-(2,2-diphenylcyclopropyl)ethyl radical
(3a ) reacted faster than the kinetic resolution of the instrument (k > 2 × 108 s-1) in all solvents
studied, and the 2-acetoxy analogue (3b) reacted much faster than related radicals that do not
contain the cyclopropyl group (e.g., k ) 1.1 × 106 s-1 in CH3CN at ambient temperature). The rate
constants and Arrhenius parameters for reactions of 3b indicated that the rate-limiting step in
the reaction was heterolytic cleavage. The 1,2-dimethoxy-1-methyl-2-(2,2-diphenylcyclopropyl)ethyl
radical (26) reacted in a general acid-catalyzed heterolysis reaction, and rate constants for
protonation of the â-methoxy group by a series of carboxylic acids were determined. The results
suggest that acid-catalyzed reactions of â-alkoxy radicals might be employed in synthetic
conversions.
Radicals with â-leaving groups are attracting increas-
ing interest for synthetic chemistry. In high-polarity
media they react by heterolytic cleavage of the leaving
group to give radical cations under non-oxidative condi-
tions,1-5 and in low- and medium-polarity media they
react in facile rearrangement and nucleophilic substitu-
tion reactions.6,7 The reaction pathways in high- and low-
polarity solvents could be quite similar with initial
heterolytic fragmentation to give a contact ion pair (CIP)
that recombines to an isomer or reacts with a nucleophile
in low-polarity media or diffuses apart via a solvent-
separated ion pair (SSIP) to give a free radical cation in
high-polarity media (Scheme 1). Alternatively, compu-
tational results suggest that radicals with â-leaving
groups can react without heterolysis in concerted rear-
rangements and eliminations and associative nucleophilic
substitution reactions.8
(1) Cozens, F. L.; O’Neill, M.; Bogdanova, R.; Schepp, N. J . Am.
Chem. Soc. 1997, 119, 10652-10659. Newcomb, M.; Horner, J . H.;
Whitted, P. O.; Crich, D.; Huang, X. H.; Yao, Q. W.; Zipse, H. J . Am.
Chem. Soc. 1999, 121, 10685-10694. Newcomb, M.; Miranda, N.;
Huang, X. H.; Crich, D. J . Am. Chem. Soc. 2000, 122, 6128-6129. Taxil,
E.; Bagnol, L.; Horner, J . H.; Newcomb, M. Org. Lett. 2003, 5, 827-
830.
The time domains of ion pair reactions place a difficult
constraint on mechanistic studies of radicals with â-leav-
ing groups. Contact ion pairs react by solvation to SSIPs
or collapse on the picosecond time scale, and solvent-
(2) Whitted, P. O.; Horner, J . H.; Newcomb, M.; Huang, X. H.; Crich,
D. Org. Lett. 1999, 1, 153-156.
(3) Bales, B. C.; Horner, J . H.; Huang, X. H.; Newcomb, M.; Crich,
D.; Greenberg, M. M. J . Am. Chem. Soc. 2001, 123, 3623-3629.
(4) Newcomb, M.; Miranda, N.; Sannigrahi, M.; Huang, X.; Crich,
D. J . Am. Chem. Soc. 2001, 123, 6445-6446.
(5) Horner, J . H.; Taxil, E.; Newcomb, M. J . Am. Chem. Soc. 2002,
124, 5402-5410.
(6) Beckwith, A. L. J .; Crich, D.; Duggan, P. J .; Yao, Q. W. Chem.
Rev. 1997, 97, 3273-3312.
(7) Crich, D. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.
P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 188-206.
(8) Zipse, H. Acc. Chem. Res. 1999, 32, 571-578.
10.1021/jo0357972 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/14/2004
J . Org. Chem. 2004, 69, 6515-6520
6515

Newcomb and Miranda
SCHEME 1
SCHEME 3 a
SCHEME 2
a
Reagents and conditions: (a) LDA, -80 °C; (b) 2,2-diphenyl-
cyclopropanecarboxaldehyde; (c) (EtO)2(O)PCl; (d) CAN; (e) 2,2′-
dithiopyridine-1,1′-dioxide, Bu3P; (f) Ac2O, pyridine; (g) BDMAN,
(Me3O)(BF4); (h) KOH, EtOH.
of the leaving group would give rearranged radicals 5.
The diphenylcyclopropyl group was expected to trap
either 4 or 5, ring opening to give products 6 and 7,
respectively, and the diphenylalkyl radical moieties in 6
and 7 permit UV detection of these products. The 2,2-
diphenylcyclopropylcarbinyl radical ring opens with a
rate constant of 5 × 1011 s-1 at ambient temperature,10
and ring opening of radical cation 4 was expected to be
even faster given that the 2-phenylcyclopropylcarbinyl
cation ring opens with no activation energy.11
The synthetic routes to the radical precursors are
shown in Scheme 3. Deprotonation of ester 8 with LDA
followed by addition of 2,2-diphenylcyclopropanecarbox-
aldehyde and quenching with diethyl chlorophosphate
gave compound 9, which was isolated as a single dia-
stereomer. The dimethoxybenzyl group was removed by
ceric ammonium nitrate (CAN) oxidation to give acid 10
that was converted to PTOC ester 1a by the method of
Barton and Samadi.12 For the preparation of 1b, a
mixture of diastereomers of the â-hydroxy ester was
obtained from reaction of the enolate of 8 with the
aldehyde. This mixture was converted to the acetate
derivatives 11, and one diastereomer of 11 was isolated
by chromatography and converted to acid 12 and then
to PTOC ester 1b. An analogous hydroxyalkylation gave
a mixture of diastereomers of â-hydroxy ethyl ester 13.
The mixture was methylated with Meerwein’s reagent
in the presence of 1,8-bis(dimethylamino)naphthalene
(BDMAN) to give R,â-dimethoxy ester 14 that was
isolated as one diastereomer. Saponification of 14 gave
acid 15 that was converted to PTOC ester 16 (discussed
below). Although PTOC esters are unstable at temper-
atures above ca. 50 °C and react when exposed to visible
separated ion pairs desolvate to CIPs or dissociate to free
ions in subnanosecond time frames. Thus, unless an
exceptionally fast radical reaction is studied, transients
can only accumulate to detectable levels when diffusive
escape occurs to give free ions. A radical heterolysis
reaction in low-polarity solvent followed by ion pair
collapse or nucleophilic capture of the radical cation will
be indistinguishable from a concerted or associative
reaction of the radical, and mechanistic conclusions
concerning these reactions typically have been inferred
from products or kinetic correlations.6 To overcome the
inherent time constraints in studies of radicals with
â-leaving groups, we have explored the use of intra-
molecular reactions to intercept a radical cation.5 We
report here studies using a cyclopropyl moiety that
promotes radical heterolysis reactions and “captures” the
radical cation product in an ion pair via an ultrafast ring-
opening reaction.
Resu lts a n d Discu ssion
The experimental design is shown in Scheme 2. PTOC9
esters 1 were used as radical precursors. In laser flash
photolysis (LFP) reactions, the PTOC esters were cleaved
at the weak N-O bond by photolysis with 355-nm light
to give acyloxyl radicals 2 that decarboxylated to provide
the R-methoxy radicals 3. Heterolysis of the leaving group
X in radicals 3 would give radical cation 4, and migration
(10) Newcomb, M.; J ohnson, C. C.; Manek, M. B.; Varick, T. R. J .
Am. Chem. Soc. 1992, 114, 10915-10921.
(9) The acronym PTOC is for pyridine-2-thioneoxycarbonyl. PTOC
esters were originally developed by Barton’s group and are also known
as Barton esters; see: Barton, D. H. R.; Crich, D.; Motherwell, W. B.
Tetrahedron 1985, 41, 3901-3924.
(11) Wiberg, K. B.; Shobe, D.; Nelson, G. L. J . Am. Chem. Soc. 1993,
115, 10645-10652.
(12) Barton, D. H. R.; Samadi, M. Tetrahedron 1992, 48, 7083-7090.
6516 J . Org. Chem., Vol. 69, No. 20, 2004

Acid-Catalyzed Fragmentation of an R,â-Dimethoxy Radical
diffusively free enol ether radical cation with a rate
constant of k ) 3 × 106 s-1 in the highly polar medium
5% 2,2,2-trifluoroethanol (TFE) in CH3CN,4 and â-phos-
phate radical 19 heterolyzed with a rate constant of k )
4 × 107 s-1 in the medium-polarity solvent CH3CN.5
Radical 20 provides a more dramatic comparison. In 20
F IGURE 1. (A) Time-resolved spectrum for reaction of radical
3b in CH3CN. The time slices are at 0.6, 0.8, 1.2, and 1.8 µs
with the spectrum at 0.5 µs subtracted to give a baseline. (B)
Arrhenius function for reaction of radical 3b in CH3CN.
the diphenyl phosphate leaving group is inherently more
reactive than the diethyl phosphate leaving group in
radical 3a , and the radical cation formed by heterolysis
of 20 is stabilized by both the phenyl group and the
methoxy group. Nonetheless, radical 20 reacted slower
in medium-polarity THF (k ) 3.4 × 106 s-1)3 than did 3a
in low-polarity cyclohexane.
SCHEME 4
Limited examples of â-acetoxy radical reactions are
available for comparison to radical 3b, but the high
reactivity of 3b is apparent nonetheless. The â-phenyl-
â-acetoxy radicals 21 react by acetate migration (assumed
to occur by heterolysis followed by ion recombination)14
to give the benzylic radical products 22. The rate con-
light, compounds 1a , 1b, and 16 were adequately robust
for electrospray ionization conditions and were character-
ized by NMR spectroscopy and HRMS analyses.
The â-phosphate radical 3a was studied to characterize
the reactivity of the probe system. Laser flash photolysis
(LFP) studies of dilute solutions of 1a were conducted in
a kinetic spectrometer unit with nanosecond resolution.
Unexpectedly, radical 3a reacted faster than the resolu-
tion of the unit in several solvents, including nonpolar
cyclohexane. Thus, the UV spectrum of a diphenylalkyl
radical product was obtained “instantly” following the
laser pulse (k > 2 × 108 s1).
stants for these rearrangement reactions are k ≈ 5 × 103
s-1 for reaction of 21a in acetonitrile at ambient temper-
ature and k ) 4 × 104 s-1 for reaction of 21b in benzene
at 70 °C.14,15 The reaction of â-acetoxy radical 21a is more
than 3 orders of magnitude slower than the reaction of
the corresponding â-diphenyl phosphate radical in the
same solvent,14 and thus one would predict that the
â-acetoxy radical analogue to radical 20 will react in THF
with a rate constant on the order of 103 s-1. Radical 3b
does not contain a phenyl group for stabilization of the
product radical cation, but it reacted in THF with a rate
The â-acetoxy radical 3b also reacted rapidly, but rate
constants for the reactions of this radical could be
measured. Figure 1A shows a portion of the time-resolved
spectrum for reaction of 3b in acetonitrile. The growing
signal with λmax ≈ 335 nm is typical for a diphenylalkyl
radical,13 indicating the formation of either 6 or 7. In a
preparative reaction, PTOC ester 1b was allowed to react
in THF in the presence of 0.1 M Bu3SnH at room
temperature, and ketone 17 (Scheme 4) was obtained,
indicating that radical 3b reacted in a heterolysis reac-
tion that gave radical cation 6.
In THF at room temperature, radical 3b reacted with
a rate constant of k ) 2 × 105 s-1, and in acetonitrile at
ambient temperature the rate constant for reaction was
k ) 1.1 × 106 s-1. Rate constants were obtained at various
temperatures in CH3CN to give the results shown
graphically in Figure 1B. The Arrhenius function ob-
tained from these data is log k ) (11.8 ( 0.14) - (7.7 (
0.2)/2.3RT (in kcal/mol), where the errors are 2σ.
The reactions of radicals 3a and 3b are much faster
than reactions of analogous R-methoxy radicals lacking
the cyclopropyl group. Radical heterolysis reactions are
sensitive to solvent polarity, which makes the fast
reaction of 3a in the low-polarity solvent cyclohexane (k
> 2 × 108 s-1) quite unusual. For comparison, the
R-methoxy-â-phosphate radical 18 heterolyzed to give a
constant of k ) 2 × 105 s-1
.
Two kinetic effects can contribute to the high reactivity
of radicals 3a and 3b. A cyclopropyl group results in a
3-kcal/mol stabilization of an adjacent radical center,16
which is much less than the 12-kcal/mol radical stabiliza-
tion afforded by a phenyl group.17 In the case of carboca-
tions, however, adjacent cyclopropyl and phenyl groups
result in approximately the same degree of thermo-
dynamic stabilization,18 and the cyclopropyl group ac-
celerates heterolysis reactions of closed shell molecules
(14) Choi, S. Y.; Crich, D.; Horner, J . H.; Huang, X. H.; Newcomb,
M.; Whitted, P. O. Tetrahedron 1999, 55, 3317-3326.
(15) Beckwith, A. L. J .; Duggan, P. J . J . Am. Chem. Soc. 1996, 118,
12838-12839.
(16) Halgren, T. A.; Roberts, J . D.; Horner, J . H.; Martinez, F. N.;
Tronche, C.; Newcomb, M. J . Am. Chem. Soc. 2000, 122, 2988-2994.
(17) Berkowitz, J .; Ellison, G. B.; Gutman, D. J . Phys. Chem. 1994,
98, 2744-2765.
(18) Kirmse, W.; Krzossa, B.; Steenken, S. J . Am. Chem. Soc. 1996,
118, 7473-7477.
(13) Chatgilialoglu, C. In Handbook of Organic Photochemistry;
Scaiano, J . C., Ed.; CRC Press: Boca Raton, FL, 1989; Vol. 2, pp 3-11.
J . Org. Chem, Vol. 69, No. 20, 2004 6517

Newcomb and Miranda
SCHEME 5
â-phosphate radical that gave a mixture of diffusively free
radical cation and rearrangement product in acetonitrile
reacted with an entropic term of log A ) 10.6.2 The
R-methoxy radical 19, which is closely related to radical
3a in that it has the same leaving group, reacted by rate-
limiting heterolysis, presumed to give the SSIP, with log
A ) 10.3.5 All of these reactions appear to have similar
organizational demands in the transition states for
heterolysis.
to a greater extent than does a phenyl group,19 in part
because the transition state for heterolysis of a cyclo-
propylcarbinyl system is readily achieved. It is reasonable
to expect that the cyclopropyl groups in radicals 3a and
3b accelerate the heterolysis reactions appreciably, even
though the products are radical cations instead of car-
bocations, and this effect could be greater than the
acceleration by the phenyl group in radical 20. In any
event, the large kinetic acceleration found in reactions
of radicals 3 is consistent with a heterolysis pathway. In
concerted migration reactions where the incipient prod-
ucts develop radical character, one would expect phenyl-
substituted systems to react faster than cyclopropyl-
substituted systems.
Cyclopropyl group acceleration of the heterolysis reac-
tion might account entirely for the high reactivity of
radicals 3a and 3b, but another property of these systems
can affect the observed kinetics. The diphenylcyclopropyl
reporter group in radical cation 4 will fragment rapidly
to give the ring-opened distonic radical cation product 6
that is observed. The rate constant for ring opening of
the 2,2-diphenylcyclopropylcarbinyl radical is 5 × 1011
s-1 at ambient temperature,10 and fragmentation of this
moiety in radical cation 4 should be even faster. It is
likely that the fragmentation reaction competes with ion
collapse of a contact ion pair (CIP) and diverts this
species to product 6 such that ion recombination does not
occur. Thus, the observed rate constants for reactions of
radicals 3 are expected to be the rate constants for the
initial heterolysis reactions giving the CIP. When dif-
fusively free radical cations are detected, as was the case
for radical 18, the kinetics reflect equilibrations between
the CIP and the radical and between the SSIP and the
CIP coupled with the rate constant for escape from the
SSIP. Radical 19 contains an internal reporter group that
was estimated to cyclize with a rate constant of k ≈ 2 ×
109 s-1, but this reaction is not likely to be fast enough
to intercept the CIP in competition with ion collapse to
the neutral radical; thus, the kinetics for radical 19 might
be those for equilibration between the CIP and the
neutral radical coupled with solvation of the CIP to the
SSIP.
In a demonstration of the sensitivity of the hypersensi-
tive probe approach, we applied it in a study of an R,â-
dimethoxy radical. A considerable amount of computa-
tional results has been reported for reactions of the
related R,â-dihydroxy radical (the ethylene glycol radical)
because this species is an intermediate in the rearrange-
ment catalyzed by diol dehydratase enzymes. The com-
putational works agree that a concerted migration of a
hydroxy group in the neutral 1,2-dihydroxyethyl radical
to give the 2,2-dihydroxyethyl radical is a high-energy
process.21-25 An acid-catalyzed migration reaction was
postulated years ago,21 but the acid-catalyzed process was
later computed to result in a dissociation reaction.22
Recent works by Golding and Radom have focused on the
possibility that concerted migration of the â-hydroxy
group can occur with “partial protonation” by an acid
(hydrogen bonding to an acid)23 and a more complex
reaction pathway with “partial protonation” of the mi-
grating hydroxy group and “partial deprotonation” of the
hydroxy group at the radical center.25 Experimentally,
acid-catalyzed reactions of the ethylene glycol radical,
presumed to involve formation of a radical cation by
dissociation of water, have been known for many years.26
Photolysis of PTOC ester 16 gave the R,â-dimethoxy
radical 26 (Scheme 6). In acetonitrile solution, no di-
phenylalkyl radical product was formed (k < 1000 s-1),
but in the presence of carboxylic acids, radical 26 reacted
to give a diphenylalkyl radical product with a UV
spectrum similar to that observed from reaction of radical
3b (Figure 2A). The observed rate constants for reactions
with several carboxylic acids were linearly dependent on
acid concentrations (Figure 2B), indicating rate-limiting
protonation reactions, that is, general acid catalysis.
Although specific acid catalysis of glycol radical reactions
is well-known,26 we are not aware of previous reports of
general acid catalysis. Second-order rate constants for
protonation (kprot) are listed in Table 1; these values were
determined from eq 1 , where kobs is the observed rate
kobs ) k0 + kprot[acid]
(1)
The Arrhenius function for reaction of radical 3b in
acetonitrile is consistent with the heterolysis reaction
pathway. The entropic term, log A ) 11.8, is similar to
that found in radical reactions that were demonstrated
or thought to occur by heterolysis of the leaving group.
The most important comparison is with radical 23, which
was found to heterolyze to an observable solvent-
separated ion pair (24) that collapsed to rearranged
product 25 (Scheme 5); the entropic term in the heteroly-
sis reaction of radical 23 was log A ) 11.0.20 A related
(20) Bagnol, L.; Horner, J . H.; Newcomb, M. Org. Lett. 2003, 5,
5055-5058.
(21) Golding, B. T.; Radom, L. Chem. Commun. 1973, 939-941.
Golding, B. T.; Radom, L. J . Am. Chem. Soc. 1976, 98, 6331-6338.
(22) George, P.; Glusker, J . P.; Bock, C. W. J . Am. Chem. Soc. 1995,
117, 10131-10132. George, P.; Glusker, J . P.; Bock, C. W. J . Am. Chem.
Soc. 1997, 119, 7065-7074.
(23) Smith, D. M.; Golding, B. T.; Radom, L. J . Am. Chem. Soc. 1999,
121, 5700-5704.
(24) Toraya, T.; Yoshizawa, K.; Eda, M.; Yamabe, T. J . Biochem.
1999, 126, 650-654. Toraya, T. Chem. Rec. 2002, 2, 352-366.
(25) Smith, D. M.; Golding, B. T.; Radom, L. J . Am. Chem. Soc. 2001,
123, 1664-1675.
(19) Shono, T.; Oku, A.; Oda, R. Tetrahedron 1968, 24, 421-425.
Brown, H. C.; Peters, E. N. J . Am. Chem. Soc. 1977, 99, 1712-1716.
Brown, H. C.; Ravindranathan, M.; Peters, E. N. J . Org. Chem. 1977,
42, 1073-1076.
(26) Buley, A. L.; Norman, R. O. C.; Pritchett, R. J . J . Chem. Soc.,
B 1966, 849-852. Walling, C.; J ohnson, R. A. J . Am. Chem. Soc. 1975,
97, 2405-2407.
6518 J . Org. Chem., Vol. 69, No. 20, 2004

Acid-Catalyzed Fragmentation of an R,â-Dimethoxy Radical
no evidence of formation of the dimethylacetal (from
methoxy group migration) in the NMR spectrum of the
crude reaction mixture. Although computational results
predict that protonation of the â-hydroxy group in the
ethylene glycol radical will reduce the barrier for a
concerted migration,23 the low-energy pathway for reac-
tion of radical 26 in the presence of acids apparently is
heterolytic fragmentation of the methoxy group.
It is important to emphasize that the slow step in the
acid-catalyzed heterolysis of radical 26 is the protonation
reaction and not the fragmentation reaction. Thus, the
accelerating influence of the cyclopropyl group on the
heterolysis has no bearing on the potential utility of the
reaction sequence in synthesis. In R,â-dialkoxy radicals
that lack the cyclopropyl group, heterolysis of the â-alkoxy
group following protonation will be faster than heteroly-
sis of an acetate group and is likely to be faster than
heterolysis of a dialkyl phosphate group. Thus, in a case
where, for example, a â-phosphate ester radical has been
employed in a synthetic conversion,6,7 it should be pos-
sible to substitute a â-alkoxy radical and an acid such
as CF3CO2H.
F IGURE 2. (A) Time-resolved spectrum from reaction of
radical 26 in CH3CN containing ca. 0.03 M CF3CO2H. The time
slices are at 96, 146, 296, and 596 ns with the spectrum at 56
ns subtracted to give a baseline. (B) Observed rate constants
for reactions of radical 26 in the presence of representative
acids.
SCHEME 6
In summary, the diphenylcyclopropyl moiety promotes
rapid heterolysis reactions in radicals containing â-leav-
ing groups and intercepts the radical cations in ion pairs
to give UV-detectable distonic radical cations. This “ac-
celerating-reporting” element provides a new approach
for studying radicals that contain poor â-leaving groups
and would not be expected to give diffusively free radical
cations even in polar solvents. The kinetic characteriza-
tion of the heterolysis of the â-acetoxy radical 3b dem-
onstrates that the entropic demands in the transition
states for a variety of radical heterolysis reactions are
similar, and the acid-catalyzed heterolysis reaction of the
â-methoxy group in the R,â-dimethoxy radical 26 sug-
gests the possibility that â-alkoxy-substituted radicals
might be employed synthetically in acid-catalyzed nu-
cleophilic substitution and isomerization reactions.
TABLE 1. Secon d -Or d er Ra te Con sta n ts for
Acid -Ca ta lyzed Rea ction s of Ra d ica l 26a
b
acid
pKa
kprot (M-1 s-1
)
CF3CO2H
0.23
0.65
1.24
1.29
4.76
1.0 × 108
9.4 × 107
3.9 × 106
3.3 × 106
1.3 × 106
CCl3CO2H
CHF2CO2H
CHCl2CO2H
CH3CO2H
Exp er im en ta l Section
2,4-Dim eth oxyben zyl 3-(Dieth ylp h osp h a toxy)-3-(2,2-
diph en ylcyclopr opyl)-2-m eth oxy-2-m eth ylpr opion ate (9).
To a solution of diisopropylamine (0.72 mL, 5.12 mmol) in THF
at 0 °C under nitrogen was added 1.6 M BuLi in hexanes (2.95
mL, 4.72 mmol). After being stirred for 15 min at 0 °C, the
reaction mixture was cooled to -78 °C, and a solution of 2,4-
dimethoxybenzyl 2-methoxypropionate3 in THF (1.0 g, 3.93
mmol) was added dropwise. The mixture was allowed to stir
at -78 °C for 1 h. A solution of 2,2-diphenylcyclopropanecar-
boxaldehyde27 (0.874 g, 3.93 mmol) in THF was added drop-
wise, and the reaction mixture was stirred for another 2 h at
-78 °C. The reaction mixture was quenched by addition of
diethyl chlorophosphate (0.625 mL, 4.33 mmol), and the
mixture was allowed to warm to room temperature. The
mixture was diluted with ether, washed with saturated
aqueous NH4Cl solution and brine, and dried over MgSO4. The
solvent was removed, and the crude product mixture was
subjected to column chromatography on silica gel (EtOAc/
hexanes 1:5). One diastereomer of the desired diethylphos-
phatoxy ester (0.88 g, 37%) was isolated from the mixture for
further use. 1H NMR δ 7.42-7.15 (m, 11H), 6.49-6.46 (m, 2H),
5.26 (d, 1 H, J ) 12 Hz), 5.07 (d, 1 H, J ) 12 Hz), 4.06 (dd, 1
H, J ) 12.6, 10.2 Hz), 3.97-3.86 (m, 4 H), 3.82 (s, 3 H), 3.77
a
b
In acetonitrile solvent at (20 ( 2) °C. Aqueous pKa value.
constant, k0 is the background rate constant, kprot is the
second-order protonation rate constant, and [acid] is the
concentration of acid. The protonation rate constants for
reactions in CH3CN correlate crudely with aqueous pKa
values.
The reaction pathway for radical 26 apparently in-
volves rate-limiting protonation of the â-methoxy group
followed by fast heterolysis of the distonic radical cation
27 by loss of methanol to give radical cation 4, which
gives observable product 6 (Scheme 6). The neutral
alcohol leaving group in 27 is expected to cleave faster
than the diethyl phosphate anionic leaving group in
radical 3a , which reacted too fast for kinetic measure-
ments in all solvents. Therefore, protonation would be
the “slow” reaction in the sequence, consistent with the
experimental observation of general acid catalysis.
The heterolysis pathway was supported by the results
of a preparative reaction of PTOC ester 16 in THF in
the presence of 0.05 M CF3CO2H and 0.1 M Bu3SnH.
Ketone 17 was isolated from this reaction, and there was
(27) Horner, J . H.; Tanaka, N.; Newcomb, M. J . Am. Chem. Soc.
1998, 120, 10379-10390.
J . Org. Chem, Vol. 69, No. 20, 2004 6519

Newcomb and Miranda
(s, 3 H), 3.35 (s, 3 H), 2.33 (ddd, 1 H, J ) 9.6, 6.3, 3.3 Hz),
1.59-1.54 (m, 4 H), 1.25-1.16 (m, 7 H). 13C NMR δ 171.9,
161.1, 158.7, 145.9, 140.0, 131.2, 129.4 (2 C), 127.9, 127.6,
125.9 (2 C), 115.9, 103.8, 98.2, 82.7, 82.0 (d, J ) 7.3 Hz), 63.2
(d, J ) 5.2 Hz), 63.0 (d, J ) 5.2 Hz), 62.1, 55.2, 55.1, 51.9,
34.8, 27.3, 17.3, 17.0, 15.8, 15.7. HRMS [M + Na]+ calcd for
(d, J ) 7.5 Hz), 63.7 (d, J ) 5.2 Hz), 63.6 (d, J ) 5.2 Hz), 53.3,
34.8, 27.4, 16.6, 15.8 (d, J ) 7.2 Hz), 15.7 (d, J ) 7.2 Hz), 14.9
(thione C not observed). HRMS [M + Na]+ calcd for C29H34
-
NO7NaPS 594.1691, found 594.1675.
La ser F la sh P h otolysis Stu d ies. The LFP experimental
method was the same as that previously described.14
A
C
33H41O9NaP 635.2386, found 635.2402.
Continuum Nd:YAG laser producing ca. 50 mJ of 355-nm light
in a 7-ns pulse was employed. Reactions of radical 3a were
studied in various solvents (acetonitrile, THF, cyclohexane),
and in all cases the UV-vis spectrum of 6 or 7 was completely
formed “instantly” (k > 2 × 108 s-1). Radical 3b was studied
in THF and in acetonitrile, and a portion of the time-resolved
spectrum from reaction of 3b is shown in Figure 1. Radical
26 showed no apparent reaction in acetonitrile, but reactions
were observed when carboxylic acids were present; a portion
of the time-resolved spectrum is shown in Figure 2. The results
of kinetic measurements of reactions of radical 26 are in Table
S1 of the Supporting Information.
P r ep a r a tive Rea ction of 1b. A solution of PTOC ester 1b
(0.112 g) was dissolved in THF (10 mL) containing 0.1 M Bu3-
SnH. The solution mixture was irradiated with a 150-W flood
lamp and stirred for 2 h. The solvent was evaporated, and the
crude mixture was purified by chromatography on silica gel
to give 6,6-diphenylhex-3-ene-2-one (17) (0.02 g, 35%). 1H NMR
δ 7.33-7.17 (m, 10 H), 6.67 (dt, 1 H, J ) 15.9, 6.9 Hz), 6.06
(d, 1 H, J ) 15.9 Hz), 4.10 (t, 1 H, J ) 7.8 Hz), 2.98 (dd, 2 H,
J ) 8.9, 6.9 Hz), 2.14 (s, 3 H). 13C NMR δ 145.7, 143.3, 132.5,
128.4, 127.5, 126.3, 50.2, 38.3, 26.6 (carbonyl C not observed).
HRMS [M•]+ calcd for C18H18O 250.1358, found 250.1370.
3-(Dieth ylp h osp h a toxy)-3-(2,2-d ip h en ylcyclop r op yl)-
2-m eth oxy-2-m eth ylp r op ion ic Acid (10). To a solution of
9 (0.391 g, 0.66 mmol) in 10:1 acetonitrile/water (8 mL) was
added ceric ammonium nitrate (0.791 g, 1.4 mmol). The
reaction was stirred at room temperature for 1 h and quenched
by addition of water (10 mL). The resulting solution was
extracted in EtOAc (3 × 10 mL). The organic layers were
combined, washed with brine, and dried over MgSO4. The
solvent was evaporated to give an orange oil. The oil was taken
up in EtOAc (20 mL), and the mixture was stirred with 15%
NaHSO3 (20 mL) for 2 h. The layers were separated, and the
organic layer was washed with saturated NaHCO3 solution
(2 × 20 mL). The aqueous layer was separated, acidified with
HCl, and extracted into ether (2 × 40 mL). The ether layer
was washed with brine and dried over MgSO4. Evaporation of
1
the solvent yielded 0.15 g (50%) of acid 10. H NMR δ 7.32-
7.17 (m, 10 H), 4.12-4.02 (m, 2 H), 3.90-3.80 (m, 2 H), 3.69
(dd, 1 H, J ) 10.5, 5.7 Hz), 3.32 (s, 3 H), 2.13 (ddd, 1 H, J )
9.9, 6.0, 3.9 Hz), 1.65 (t, 1 H, J ) 6.0 Hz), 1.53 (s, 3 H), 1.42
(dd, 1 H, J ) 10.2, 4.5 Hz), 1.33 (t, 3 H, J ) 6.9 Hz), 1.12 (t,
3 H, J ) 6.9 Hz), (COOH not observed). 13C NMR δ 172.3,
145.0, 139.2, 129.6, 128.8, 128.1, 127.9, 126.3, 126.2, 84.3, 83.9
(d, J ) 8.3 Hz), 64.0 (d, J ) 5.2 Hz), 63.8 (d, J ) 5.2 Hz), 51.9,
34.9, 26.4 (d, J ) 10.3 Hz), 18.0, 17.3, 15.9 (d, J ) 7.2 Hz),
15.6 (d, J ) 7.2 Hz). HRMS [M + Na]+ calcd for C24H31O7NaP
485.1705, found 485.1713.
P r ep a r a tive Rea ction of 16. PTOC ester 16 (0.121 g) was
dissolved in THF (10 mL) containing 0.1 M Bu3SnH and 0.05
M TFA. The mixture was irradiated with a 150-W flood lamp
and was stirred for 2 h. The solvent was evaporated, and an
NMR spectrum of the crude mixture showed no signals
consistent with methoxy peaks in a dimethylacetal. The crude
mixture was purified by chromatography on silica gel to yield
6,6-diphenylhex-3-ene-2-one (17) (0.015 g, 22%).
(1H)-2-Th ioxo-1-p yr id yl 3-(Dieth ylp h osp h a toxy)-3-(2,2-
diph en ylcyclopr opyl)-2-m eth oxy-2-m eth ylpr opion ate (1a).
The method of Barton and Samadi was used.12 To a solution
of the acid 10 (0.137 g, 0.33 mmol) and 2,2′-dithiopyridine-
1,1′-dioxide (0.09 g, 0.36 mmol) in CH2Cl2 was added Bu3P
(0.04 mL, 0.16 mmol) at 0 °C under nitrogen. The reaction was
allowed to warm to room temperature and was stirred for 1.5
h. The reaction mixture was washed with saturated NaHCO3
solution and brine and dried over MgSO4. Flash chromatog-
raphy (silica gel, EtOAc:hexanes 1:3, v:v) in the dark afforded
Ack n ow led gm en t. This work was supported by a
grant from the National Science Foundation (CHE-
0235293). We thank Dr. V. Krongauz for producing the
cover art.
1
(0.1 g, 55%) PTOC ester 1a . H NMR δ 8.26 (d, 1 H, J ) 6.9
Hz), 7.67 (dd, 1 H, J ) 9.0 Hz, 1.5 Hz), 7.44 (d, 2 H, J ) 7.2
Hz), 7.32-7.14 (m, 9 H), 6.67-6.65 (m, 1 H), 4.16 (t, 1 H, J )
9.3 Hz), 4.03-3.75 (m, 4 H), 3.62 (s, 3 H), 2.11 (ddd, 1 H, J )
9.3, 6.3, 2.7 Hz), 1.99 (t, 1 H, J ) 6.0 Hz), 1.82 (s, 3 H), 1.37
(dd, 1 H, J ) 9.3, 5.4 Hz), 1.25 (t, 3 H, J ) 6.9 Hz), 1.16 (t, 3
H, J ) 7.2 Hz). 13C NMR δ 161.6, 145.6, 139.2, 138.8, 136.5,
133.2, 129.4, 129.3, 128.0, 127.7, 126.2 (2 C), 112.8, 84.0, 80.2
Su p p or tin g In for m a tion Ava ila ble: Kinetic results for
reactions of radical 26, synthetic details for preparation of
compounds 11, 12, 1b, 14, 15, and 16, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0357972
6520 J . Org. Chem., Vol. 69, No. 20, 2004