Picosecond radical kinetics. Fast ring openings of secondary and tertiary trans-2-phenylcyclopropylcarbinyl radicals

Full text of DOI:10.1021/jo981020a

J . Org. Chem. 1998, 63, 8609-8613
8609
P icosecon d Ra d ica l Kin etics. F a st Rin g
Op en in gs of Secon d a r y a n d Ter tia r y
tr a n s-2-P h en ylcyclop r op ylca r bin yl
Ra d ica ls
Seung-Yong Choi, Patrick H. Toy, and
Martin Newcomb*
Department of Chemistry, Wayne State University,
Detroit, Michigan, 48202
Received May 29, 1998
Precursors to reactive intermediates that rearrange
have been applied widely in mechanistic probe studies
wherein one seeks to implicate a reactive intermediate
by the detection of rearranged products. For such
purposes, the rearrangement must be faster than com-
peting reactions of the unrearranged intermediate, and
very fast rearrangements often are desired. If the
reactive intermediate in question is a radical and the rate
constant for the radical rearrangement is known, the
intermediate can be referred to as a “radical clock” which
can be used to “time” competing radical processes.1,2 Our
interest in radical kinetics and in probe studies of
biochemical processes that might involve radical inter-
mediates led us to develop an indirect kinetic method,
the PTOC-thiol or PTOC-selenol method, for measuring
the kinetics of radicals that have lifetimes in the pico-
second range at room temperature.3-6 We have used this
method for the calibration of several ring openings of
phenyl-substituted cyclopropylcarbinyl radicals, 1a -3a ,7
4a and 5a ,8 and 6a -9a 9 (Figure 1), which are among the
fastest calibrated radical reactions.
F igu r e 1. Calibrated phenyl-substituted cyclopropylcarbinyl
radical clocks.
Sch em e 1
tochrome P450 (P450) enzymes.14-16 Probes 3b,14 5b,17
and 6b18 have also been used to study P450-catalyzed
hydroxylation reactions.
The calibration of ultrafast 2-arylcyclopropylcarbinyl
radical clocks has permitted quantitative applications of
the corresponding hydrocarbon precursors in studies of
enzyme-catalyzed hydroxylation reactions in an attempt
to implicate radical intermediates and to time the
“oxygen rebound” step in these processes. Probe 1b has
been used to study hydroxylation by a non-heme mo-
nooxygenase in cells of Pseudomonas oleovorans,10 re-
constituted soluble methane monooxygenase (sMMO)
hydroxylase from Methylococcus capsulatus (Bath) and
Methylosinus trichosporium OB3b,11 chloroperoxidase
(CPO) from Caldariomyces fumago,12,13 and various cy-
Probes 1b-9b are precursors to primary radicals 1a -
9a , which afford primary alkenes upon rearrangement
(Scheme 1). A report by Zaks and Dodds12 in which 1b
was used in a study of the mechanism of CPO-catalyzed
hydroxylation reactions combined with the known in-
compatibility of primary alkenes with CPO19 prompted
us to design probes that yield substituted alkenes upon
rearrangement for use in CPO mechanistic studies. To
obtain dialkyl- and trialkyl-substituted alkene rear-
rangement products, alkyl-substituted cyclopropylcarbi-
nyl radical precursors were required. Hence, probes 10b
and 11b were prepared, and their hydroxylations by
CPO13 and P45020 and, for probe 10b, in Gif oxidations21
(1) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317-323.
(2) Newcomb, M. Tetrahedron 1993, 49, 1151-1176.
(3) Newcomb, M.; Park, S.-U. J . Am. Chem. Soc. 1986, 108, 4132-
4134.
(4) Newcomb, M.; Glenn, A. G. J . Am. Chem. Soc. 1989, 111, 275-
277.
(13) Toy, P. H.; Newcomb, M.; Hager, L. P. Chem. Res. Toxicol. 1998,
11, 816-823.
(14) Atkinson, J . K.; Ingold, K. U. Biochemistry 1993, 32, 9209-
9214.
(5) Newcomb, M.; Manek, M. B. J . Am. Chem. Soc. 1990, 112, 9662-
9663.
(6) Newcomb, M.; Varick, T. R.; Ha, C.; Manek, M. B.; Yue, X. J .
Am. Chem. Soc. 1992, 114, 8158-8163.
(7) Newcomb, M.; J ohnson, C. C.; Manek, M. B.; Varick, T. R. J .
Am. Chem. Soc. 1992, 114, 10915-10921.
(8) Le Tadic-Biadatti, M. H.; Newcomb, M. J . Chem. Soc., Perkin.
Trans. 2 1996, 1467-1473.
(15) Atkinson, J . K.; Hollenberg, P. F.; Ingold, K. U.; J ohnson, C.
C.; Le Tadic, M.-H.; Newcomb, M.; Putt, D. A. Biochemistry 1994, 33,
10630-10637.
(16) Toy, P. H.; Newcomb, M.; Vaz, A. D. N.; Coon, M. J . J . Am.
Chem. Soc. 1998, 120, 9718-9719.
(17) Newcomb, M.; Le Tadic-Biadatti, M. H.; Chestney, D. L.;
Roberts, E. S.; Hollenberg, P. F. J . Am. Chem. Soc. 1995, 117, 12085-
12091.
(9) Martin-Esker, A. A.; J ohnson, C. C.; Horner, J . H.; Newcomb,
M. J . Am. Chem. Soc. 1994, 116, 9174-9181.
(10) Fu, H.; Newcomb, M.; Wong, C.-H. J . Am. Chem. Soc. 1991,
113, 5878-5880.
(18) Newcomb, M.; Le Tadic, M. H.; Putt, D. A.; Hollenberg, P. F.
J . Am. Chem. Soc. 1995, 117, 3312-3313.
(19) Dexter, A. F.; Hager, L. P. J . Am. Chem. Soc. 1995, 117, 817-
818.
(20) Toy, P. H.; Newcomb, M.; Hollenberg, P. F. J . Am. Chem. Soc.
1998, 120, 7719-7729.
(21) Newcomb, M.; Simakov, P. A.; Park, S. U. Tetrahedron Lett.
1996, 37, 819-822.
(11) Liu, K. E.; J ohnson, C. C.; Newcomb, M.; Lippard, S. J . J . Am.
Chem. Soc. 1993, 115, 939-947.
(12) Zaks, A.; Dodds, D. R. J . Am. Chem. Soc. 1995, 117, 10419-
10424.
10.1021/jo981020a CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/29/1998

8610 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
Sch em e 2a
were studied. In this report we present the indirect
determinations of the kinetics of the rearrangement of
radicals 10a and 11a by the PTOC-selenol method
(Scheme 1). These secondary and tertiary cyclopropyl-
carbinyl radicals react nearly as rapidly as their primary
radical analogue 1a .
a
Key: (a) (i) LHMDS, THF, -78 °C, (ii) MeI, rt. (b) LiOH,
MeOH, H2O. (c) (i) Et2Zn, CH2I2, CH2Cl2, -30 °C, (ii) m-CPBA,
CH2Cl2, rt. (d) 2,2′-dipyridyl disulfide bis-N-oxide, R3P, CH2Cl2.
Resu lts a n d Discu ssion
In the PTOC-selenol method, the radical precursors are
PTOC22 esters, a family of carboxylic acid derivatives
invented by Barton for synthetic applications.23 PTOC
esters 10d and 11d react mainly in radical chain reac-
tions to give acyloxyl radicals (10e and 11e) that rapidly
decarboxylate to give the radical of interest (10a and
11a ). As shown in Scheme 1, the radical is either trapped
by PhSeH or rearranges. The rearranged radical also
reacts with the trapping reagent, and the byproduct from
the trapping agent (PhSe‚) reacts with another PTOC
ester molecule in a chain propagation step. Because
benzeneselenol can be used in high concentrations, it
provides the fastest calibrated radical trapping agent
available.5,6 The product mixture is analyzed by GC, and
the rate constant for rearrangement is calculated from
the product ratio, the rate constant for trapping, and the
concentration of the trapping agent.24
P r ecu r sor s a n d P r od u cts. Use of the PTOC-selenol
method for calibration of radicals 10a and 11a will give
the cyclic and acyclic products shown. The preparations
of cyclic products 10b and 11b were previously reported.13
Samples of the known acyclic alkene products 12 and 13
were prepared by Wittig reactions according to the
methods of Vedejs25 and Dare,26 respectively.
in approximately a 3:1 ratio. Because the chiral center
at the cyclopropylcarbinyl position is lost in formation
of radical 10a , this mixture was not separated but taken
on to a mixture of diastereomers of PTOC ester 10d . Acid
11c was prepared in two steps from known ester 15.28
Cyclopropanation of 15 with diethylzinc and diiodo-
methane afforded the cyclopropaneacetate29 which was
saponified to give 11c. Conversion of 10c and 11c to
their corresponding PTOC esters 10d and 11d was
accomplished by the mild 2,2′-dipyridyl disulfide bis-N-
oxide-tributylphosphine method.30
Kin et ics of Cyclop r op ylca r b in yl R a d ica l R in g
Op en in gs. PTOC ester precursors 10d and 11d were
allowed to react in THF in the presence of PhSeH in
indirect kinetic studies similar to those previously re-
ported.7 The reaction mixtures were analyzed by GC to
give the results listed in Table 1. Ring opening of the
secondary radical 10a gave both cis and trans isomers
of the alkene product in approximately constant ratios
at each temperature. At 25 °C, this ratio was 2.7 which
gives a difference in activation free energies for the two
nonsymmetric transition states of 0.6 kcal/mol, in good
agreement with computations that indicate that the
barriers for the two transitions states for ring opening
of the 1-cyclopropylethyl radical differ by 0.9 kcal/mol.31
The total yields of products were quite high for the
tertiary system 11 but generally in the range of 50-60%
for the secondary system 10. In control reactions with
alkenes in the presence of PhSeH, we have not observed
loss of alkene under the reaction conditions of the kinetic
studies, but there exist two interfering processes that can
lead to reduced yields of hydrocarbon products.7 (1)
Benzeneselenol can react with the PTOC ester precursor,
an activated acylating agent, in a polar reaction, and (2)
the first-formed acyloxyl radical can be trapped by PhSeH
in competition with the fast decarboxylation step. Be-
cause these processes give either a carboxylic acid or an
acid derivative, they do not affect the kinetic results other
than to reduce the precision by reducing the overall yield
of hydrocarbon products. On the basis of the high yields
of hydrocarbon products from the tertiary system 11 and
the reduced yields in the secondary system 10, it seems
reasonable to conclude that competitive trapping of the
The PTOC ester radical precursors 10d and 11d were
prepared from the corresponding carboxylic acids, 10c
and 11c, which were synthesized as outlined in Scheme
2. Acid 10c was prepared in two steps from the known
methyl ester 14.27 Ester 14 was prepared from the
corresponding acetic acid7 by treatment with diaz-
omethane. This ester was methylated by treating it
sequentially with lithium bis(trimethylsilyl)amide (LH-
MDS) and iodomethane. Saponification of the alkylated
product afforded acid 10c as a mixture of diastereomers
(22) The acronym PTOC derives from pyridine-2-thioneoxycarbonyl.
(23) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901-3924.
(24) For a discussion of indirect kinetic methods applied to radical
reactions, see ref 2.
(28) van der Veen, R. H.; Cerfontain, H. J . Org. Chem. 1985, 50,
342-346.
(25) Vedejs, E.; Meier, G. P.; Snoble, K. A. J . J . Am. Chem. Soc.
1981, 103, 2823-2831.
(29) Otte, A. R.; Wilde, A.; Hoffmann, H. M. R. Angew. Chem., Int.
Ed. Engl. 1994, 33, 1280-1282.
(26) Dare, D. L.; Entwistle, I. D.; J ohnstone, R. A. W. J . Chem. Soc.
C 1968, 977-980.
(30) Barton, D. H. R.; Chen, C.; Wall, G. M. Tetrahedron 1991, 47,
6127-6138.
(27) Perkins, M. J .; Peynircioglu, N. B.; Smith, B. V. J . Chem. Soc.,
Perkin Trans. 2 1978, 1025-1033.
(31) Horner, J . H.; Tanaka, N.; Newcomb, M. J . Am. Chem. Soc.
1998, 120, 10379-10390.

Notes
Ta ble 1. Resu lts of P h SeH Tr a p p in g of Ra d ica ls 10a
J . Org. Chem., Vol. 63, No. 23, 1998 8611
suggest, however, that the rate constants for ring open-
ings of 16 used in those calculations and the resulting
rate constants for PhSeH reactions are too large, and the
suggestion was made that the “top end” of the alkyl
radical kinetic scale should be reduced.32 At ambient
temperatures, the reductions in rate constants would
amount to about 30-40% of the values.
a n d 11a
b
d
tempa (°C)
[PhSeH]m
R/Uc
kr/kH (M)
% yielde
radical 10a
25
1.79
1.34
1.07
1.79
0.89
0.71
0.89
1.34
0.89
0.71
1.07
0.89
0.62
40.7
47.1
56.7
39.8
58.4
60.0
56.2
27.0
38.6
70.9
38.0
42.7
61.3
72.9
63.1
61.6
71.3
51.8
42.4
50.0
36.2
34.3
50.1
40.6
37.9
37.8
87
59
61
56
50
49
66
47
42
66
58
61
64
0
-21
-42
radical 11a
25
1.84
1.58
1.31
1.78
1.60
1.33
1.15
1.33
1.15
0.97
1.49
1.22
1.05
31.2
32.0
39.8
27.8
31.9
36.4
39.5
37.1
42.3
51.0
24.0
29.5
33.6
57.5
50.6
52.2
49.5
51.0
48.4
45.4
50.0
48.8
49.6
35.7
36.0
35.2
96
95
100
87
92
94
92
101
94
104
99
102
98
In the recent study, we found that radicals 17-19
reacted with PhSeH with nearly the same rate con-
stants.32 Therefore, we assume that the aryl-substituted
cyclopropylcarbinyl radicals will react with PhSeH with
rate constants equal to those of the appropriate analogue
among radicals 17-19. Using the absolute Arrhenius
functions for PhSeH reactions determined in that work,32
the absolute Arrhenius functions for ring openings of
radicals 1a , 10a , and 11a are given in eqs 4-6 where
errors have been propagated at 2σ. These functions give
rate constants for ring opening at 20 °C of 1.6 × 1011 s-1
(1a ), 7 × 1010 s-1 (10a ), and 7 × 1010 s-1 (11a ). Note that
the values for the rate constants for ring opening of 1a
are smaller than those previously reported7 due to the
adjustment of the PhSeH trapping kinetics.
0
-22
-48
(1 °C. Average concentration of PhSeH. c Ratio of rear-
ranged to unrearranged hydrocarbon products. Ratio of rate
constant for ring opening to that for trapping. e Yield of hydro-
carbon products determined by GC.
a
b
d
acyloxyl radical in competition with decarboxylation was
the major interfering process and that decarboxylation
of acyloxyl radical 11e was faster than that of 10e.
From the ratios of unrearranged to rearranged prod-
ucts and the known concentrations of PhSeH, relative
rate constants were calculated from each reaction, and
these are listed in Table 1. Relative Arrhenius functions
for ring opening and trapping calculated from these
values are given in eqs 2 and 3 where kr is the rate
constant for ring opening, kH is the rate constant for
trapping, θ ) 2.3RT in kcal/mol, and errors are at 2σ.
For comparison, the relative Arrhenius function for ring
opening and PhSeH trapping of the primary radical
analogue 1a is given in eq 1.7
(for 1a )7
(for 10a )
(for 11a )
log(kr/s-1) )
(13.80 ( 0.38) - (3.46 ( 0.46)/θ (4)
log(kr/s-1) )
(12.52 ( 0.48) - (2.28 ( 0.57)/θ (5)
log(kr/s-1) )
(12.21 ( 0.38) - (1.85 ( 0.50)/θ (6)
Due to the magnitude of the errors in the parameters
in eqs 4-6, one probably should not attempt to interpret
differences in the apparent enthalpies and entropies of
activation of the ring-opening reactions. In addition, we
caution that the rate constants calculated from eqs 4-6
are likely to be increasingly in error as one moves farther
from ambient temperatures. For temperatures more
than 25 °C above ambient, the calculated rate constants
will be extrapolated from the temperature range studied
here and in the calibrations of PhSeH.32 At temperatures
below ambient, the calculated rate constants are likely
to incorporate larger accumulated errors that result in
part from the fact that the PhSeH trapping reactions are
partially diffusion controlled.32
(for 1a )7
(for 10a )
(for 11a )
log((kr/kH)/M) )
(3.07 ( 0.35) - (1.24 ( 0.42)/θ (1)
log((kr/kH)/M) )
(2.63 ( 0.44) - (1.14 ( 0.52)/θ (2)
log((kr/kH)/M) )
(2.24 ( 0.18) - (0.69 ( 0.22)/θ (3)
The precisions in the relative Arrhenius parameters
in eqs 1-3 are reasonably good, but bimolecular rate
constants for reactions of PhSeH with the radicals are
necessary for calculating the absolute rate constants for
the ring-opening reactions. In the original calibration
of radical 1a and other aryl-substituted primary cyclo-
propylcarbinyl radicals, the rate constants for the PhSeH
trapping reactions employed were those determined by
competition against ring opening of the cyclopropylcarbi-
nyl radical (16).6 Recent studies in our laboratory
Nevertheless, we believe the rate constants for ring
openings of these radicals at ambient temperatures are
reasonably accurate in an absolute sense and quite
accurate in a relative sense. The accuracy is indicated
in a comparison of the rate constants for ring opening of
the three series of 1°, 2°, and 3° cyclopropylcarbinyl
radicals shown in Figure 2 where relative rate constants
(32) Newcomb, M.; Choi, S.-Y.; Horner, J . H. Submitted for publica-
tion.

8612 J . Org. Chem., Vol. 63, No. 23, 1998
Notes
eomers. The NMR spectra are superimpositions of those of the
two diastereomers in an approximately 3:1 ratio. Spectra for
the major diastereomer follow. 1H NMR (CDCl3): δ 0.80-0.88
(1H, dt, J 1 ) 8.4 Hz, J 2 ) 5.4 Hz), 0.93-1.09 (1H, m), 1.15-
1.30 (1H, m), 1.30-1.35 (3H, m), 1.95-2.06 (1H, m), 2.30-2.52
(1H, m), 7.08-7.29 (5H, m), 11.2-11.8 (1H, bs). 13C NMR
(CDCl3): δ 14.0, 16.1, 22.4, 25.6, 43.9, 125.6, 126.2, 128.2, 142.3,
181.6.
1-[[[(tr a n s-2-P h en ylcyclop r op yl)et h yl]ca r b on yl]oxy]-
2(1H)-p yr id in eth ion e (10d ). To a solution of acid 10c (160
mg, 0.842 mmol) and 2,2′-dipyridyl disulfide bis-N-oxide (1.1
equiv, 234 mg, 0.93 mmol) in dry CH2Cl2 (10 mL) in a flame-
dried flask wrapped with aluminum foil was added Ph3P (1.1
equiv, 244 mg, 0.93 mmol) at room temperature under nitrogen.
The reaction mixture was stirred for 3 h and then treated with
10 mL of a 10% aqueous Na2CO3 solution. The organic layer
was separated, and the aqueous layer was extracted with 10
mL of CH2Cl2. The combined organic extracts were washed with
a saturated aqueous NaCl solution (10 mL), dried over MgSO4,
and concentrated under reduced pressure. Column chromatog-
raphy of the residue on silica gel (hexanes/EtOAc, 7/3, v/v) under
subdued light gave PTOC ester 10d (170 mg, 0.57 mmol, 67.7%)
as a mixture of diastereomers. The NMR spectra are superim-
positions of those of the two diastereomers in an approximately
3:1 ratio. Spectra for the major diastereomer follow. 1H NMR
(CDCl3): δ 0.95 (1H, m), 1.12 (1H, m), 1.36-1.48 (1H, m), 1.52
(3H, d, J ) 7.2 Hz), 2.10-2.12 (1H, m), 2.36-2.48 (1H, m), 6.55-
6.60 (1H, dt, J 1 ) 6.9 Hz, J 2 ) 1.8 Hz), 7.08-7.30 (6H, m), 7.42-
F igu r e 2. Relative rate constants at 20 °C for ring openings
of 1°, 2°, and 3° radicals for each series.
at 20 °C are given. The data for radicals 20 is from a
variety of indirect kinetic studies,2,4,33 and those for
radicals 21 were obtained by direct LFP measurements.31
Good internal consistency of the relative rate constants
for these series is found even though radicals 1a , 10a ,
and 11a ring open 3 orders of magnitude faster than
radicals 20 and 21. The consistent trends appear to be
in line with computational results that indicate that
electronic effects of methyl substitution in the secondary
alkyl radical 20 (R ) Me, R′ ) H) are minor in compari-
son to steric effects.34
Exp er im en ta l Section
7.45 (0.7H, dd, J 1 ) 7.2 Hz, J 2 ) 1.5 Hz), 7.66-7.69 (1H, J 1
)
6.9 Hz, J 2 ) 1.8 Hz). 13C NMR (CDCl3): δ 14.4, 16.3, 22.7, 25.5,
42.4, 112.5, 125.8, 125.9, 128.3, 133.4, 137.4, 137.5, 141.7, 171.1,
175.7.
Gen er a l Meth od s. Commercially available reagents were
used as received. All moisture sensitive reactions were carried
out in flame-dried glassware under a nitrogen atmosphere. THF
was distilled under a nitrogen atmosphere from sodium and
benzophenone ketyl. Methylene chloride was distilled under a
nitrogen atmosphere from phosphorus pentoxide.
2-Meth yl-2-(tr a n s-2-p h en ylcyclop r op yl)p r op ion ic Acid
(11c). To a solution of 1528 (2.55 g, 12.5 mmol) and diethylzinc
(75.0 mL, 1.0 M in hexanes, 75.0 mmol) in CH2Cl2 (200 mL) at
-20 °C under a nitrogen atmosphere was added CH2I2 (12.1 mL,
150.2 mmol) slowly via syringe. The mixture was allowed to
warm to room temperature gradually, and after a total of 16 h,
the suspension was poured into a saturated aqueous NH4Cl
solution (300 mL). The mixture was extracted with CH2Cl2 (3
× 200 mL). The combined organic layers were washed with
water (200 mL) and brine (200 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was dissolved in
CH2Cl2 (100 mL), and 3-chloroperoxybenzoic acid (2.16 g, 12.5
mmol) was added. The mixture was stirred for 8 h at room
temperature and then diluted with additional CH2Cl2 (200 mL).
The mixture was washed with saturated aqueous NaHCO3 (200
mL), water (200 mL), and brine (200 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
chromatographed on silica gel (10% ethyl acetate in hexanes)
to afford the cyclopropyl ester (1.41 g, 6.46 mmol, 52%) as a clear,
colorless oil. 1H NMR (CDCl3): δ 0.87 (1H, dt, J 1 ) 8.7 Hz, J 2
) 5.4 Hz), 0.94-1.01 (1H, m), 1.17 (3H, s), 1.18 (3H, s), 1.33-
1.39 (1H, m), 1.90 (1H, dt, J 1 ) 9.3 Hz, J 2 ) 5.4 Hz), 3.69 (3H,
s), 7.07-7.17 (3H, m), 7.22-7.29 (2H, m). 13C NMR (CDCl3): δ
11.3, 19.1, 23.2, 23.4, 31.0, 41.7, 51.8, 125.5, 126.2 (2C), 128.2
(2C), 142.9, 177.8. HRMS: calcd for C14H18O2, 218.1307; found,
218.1304.
A solution of the above ester (0.32 g, 1.47 mmol) and LiOH‚
H2O (0.62 g, 14.7 mmol) in water (5 mL) and methanol (20 mL)
was stirred at room temperature for 6 h. The solvents were
removed in vacuo, and the resulting white solid was dissolved
in water (25 mL). This solution was made acidic (concentrated
HCl) and then extracted with CH2Cl2 (3 × 25 mL). The
combined organic layers were washed with brine (50 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to afford 11c
(0.25 g, 1.22 mmol, 83%) as a white solid. Mp: 60-61 °C. 1H
NMR (CDCl3): δ 0.94 (1H, dt, J 1 ) 9.0 Hz, J 2 ) 5.4 Hz), 1.04-
1.11 (1H, m), 1.23 (3H, s), 1.26 (3H, s), 1.44-1.50 (1H, m), 1.99
(1H, dt, J 1 ) 9.0 Hz, J 2 ) 5.1 Hz), 7.14-7.34 (5H, m), 11.95
(1H, bs). 13C NMR (CDCl3): δ 11.5, 19.2, 22.8, 23.3, 30.7, 41.6,
125.6, 126.2 (2C), 128.3 (2C), 142.8, 184.5. HRMS: calcd for
C13H16O2, 204.1150; found, 204.1155.
NMR spectra were acquired at 300 and 75 MHz for 1H and
13C, respectively. Gas chromatographic analyses were performed
using flame ionization detection with 15 m × 0.54 mm bonded
phase SE-54 and Carbowax columns. Gas chromatography/mass
spectral (GC/MS) analyses were performed using a Hewlett-
Packard model 5890 GC interfaced to a Hewlett-Packard model
5971 mass selective detector (30 m × 0.25 mm capillary bonded
phase Carbowax column, Alltech). High-resolution mass spec-
tral analyses were performed by the Central Instrumentation
Facility at Wayne State University (Detroit, MI). Melting points
are uncorrected. Radial chromatography was performed on
plates coated with TLC grade silica gel with gypsum binder and
fluorescent indicator.
2-(tr a n s-2-P h en ylcyclop r op yl)p r op ion ic Acid (10c).
A
solution of methyl (trans-2-phenylcyclopropyl)acetate27 (14) (1.30
g, 6.83 mmol) in THF (50 mL) under a nitrogen atmosphere was
cooled to -78 °C. To this was added a solution of LHMDS (1.0
M in THF, 7.0 mL, 7.00 mmol). After 15 min, iodomethane (1.3
mL, 20.2 mmol) was added. The mixture was allowed to warm
gradually to room temperature, and after 16 h, the reaction
mixture was poured into a saturated, aqueous NH4Cl solution
(100 mL) and extracted with ether (3 × 50 mL). The combined
organic phase was washed with water (75 mL) and brine (75
mL), dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was chromatographed on silica gel (10% ethyl
acetate in hexanes) to afford
a mixture of diastereomers,
inseparable by GC, of methyl 2-(trans-2-phenylcyclopropyl)-
propionate (0.58 g, 2.84 mmol, 42%) as a clear, colorless oil.
Reduction of the inseparable mixture of esters with LAH
afforded a mixture of diastereomeric alcohols in a 3:1 ratio as
determined by GC. GC/mass spectral analysis of the mixture
showed that both isomers had (M+) at m/z ) 176.
Hydrolysis of a mixture of diastereomers of the above ester
(180 mg, 0.882 mmol) with LiOH‚H2O (185 mg, 4.41 mmol) in
methanol (9 mL) and H2O (3 mL) at room temperature gave the
corresponding acid 10c (161 mg, 96%) as a mixture of diaster-
(33) Bowry, V. W.; Lusztyk, J .; Ingold, K. U. J . Am. Chem. Soc. 1991,
113, 5687-5698. Engel, P. S.; He, S. L.; Banks, J . T.; Ingold, K. U.;
Lusztyk, J . J . Org. Chem. 1997, 62, 1210-1214.
(34) Martinez, F. M.; Schlegel, H. B.; Newcomb, M. J . Org. Chem.
1998, 63, 1226-1232.
1-[[[1-Meth yl(tr a n s-2-ph en ylcyclopr opyl)eth yl]car bon yl]-
oxy]-2-(1H)-p yr id in eth ion e (11d ). To a solution of acid 11c
(220 mg, 1.08 mmol) and 2,2′-dipyridyl disulfide bis-N-oxide (1.1
equiv, 299 mg, 1.19 mmol) in dry CH2Cl2 (10 mL) in a flame-

Notes
J . Org. Chem., Vol. 63, No. 23, 1998 8613
dried flask wrapped with aluminum foil was added n-Bu3P (1.1
equiv, 294 µL, 1.19 mmol) at 0 °C under nitrogen. After 2 min,
the ice bath was removed. The reaction mixture was stirred
for 40 min before 10% aqueous Na2CO3 (10 mL) was added. The
organic layer was separated, and the aqueous layer was ex-
tracted with 10 mL of CH2Cl2. The combined organic extracts
were washed with a saturated NaCl solution (10 mL), dried over
MgSO4, and concentrated under reduced pressure. Column
chromatography of the residue on silica gel (hexanes/EtOAc, 7/3,
v/v) under subdued light gave PTOC ester 11d (220 mg, 0.70
mmol, 64.8%). 1H NMR (CDCl3): δ 1.01 (1H, dt, J 1 ) 8.7 Hz,
J 2 ) 5.7 Hz), 1.15 (1H, dt, J 1 ) 9.3 Hz, J 2 ) 6.0 Hz), 1.40 (3H,
s), 1.43 (3H, s), 1.55-1.62 (1H, m), 2.01-2.08 (1H, m), 6.53-
6.58 (1H, dt, J 1 ) 6.9 Hz, J 2 ) 1.8 Hz), 7.11-7.19 (4H, m), 7.24-
7.27 (2H, m), 7.33-7.36 (1H, dd, J 1 ) 6.9 Hz, J 2 ) 1.5 Hz), 7.63-
7.67 (1H, dd, J 1 ) 8.7 Hz, J 2 ) 1.8 Hz). 13C NMR (CDCl3): δ
11.5, 19.3, 22.7, 23.2, 30.5, 41.9, 112.5, 125.8, 126.0, 128.3, 133.2,
137.5, 142.0, 172.7, 175.9.
was determined by GC prior to use. The indirect method used
was similar to those previously reported.7 A flame-dried tube
shielded from light containing a small stir bar, a mixture of
radical precursor (0.04-0.05 M), PhSeH, and a hydrocarbon
standard (dodecane or octane) in freshly distilled THF was
sparged with nitrogen. The tubes were equilibrated in
a
temperature-regulated bath for several minutes. The shields
were removed, and the stirring mixture was irradiated with a
150-W tungsten filament lamp placed 0.4 m from the tube. After
40 min, the tubes were cooled at -78 °C and analyzed by GC.
All yields reported for indirect kinetic experiments were calcu-
lated from response factors determined with authentic samples.
Ack n ow led gm en t. This work was supported by
grants from the National Institutes of Health (GM-
48722) and the National Science Foundation (CHE-
9614968).
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 10c, 10d , 11c, and 11d (8 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
In d ir ect Kin etics. Benzeneselenol, prepared by the method
of Foster,35 was distilled under subdued light. Samples were
divided into 1-mL portions and sealed under vacuum in ampules
that were stored at ca. -70 °C. The amount of diphenyl
diselenide contaminant (typically <4%) in each sample of PhSeH
(35) Foster, D. G., Organic Syntheses; Wiley: New York, 1955;
Collect. Vol. III, p 772.
J O981020A