Absolute Rate Constants for α-Amide Radical Reactions

Article abstract of DOI:10.1021/jo9717907

The 1-(diethylcarbamoyl)-6,6-diphenyl-5-hexenyl radical (4a), the 1-(diethylcarbamoyl)-7,7-diphenyl-6-heptenyl radical (4b), and the 1-(diethylcarbamoyl)-1-methyl-6,6-diphenyl-5-hexenyl radical (4c) were produced from the corresponding PTOC esters (anhydrides of the carboxylic acid and N-hydroxypyridine-2-thione) by laser flash photolysis methods. The kinetics of cyclizations of radicals 4a and 4b were measured at various temperatures, and that of cyclization of 4c was measured at ambient temperature. Radicals 4a and 4b were employed as radical clocks in indirect kinetic studies to determine rate constants for reaction of secondary α-amide radicals with Bu₃-SnH. The calibrated tin hydride trapping reaction was then employed to determine rate constants for cyclization of the 1-(diethylcarbamoyl)-5-hexenyl radical (12). The rate constants for 5-exo cyclizations of secondary α-amide radicals are similar to those of their isostructural alkyl radical analogues. The rate constants for the 5-exo cyclization of tertiary α-amide radical 4c and the 6-exo cyclization of the secondary α-amide radical 4b are smaller than those of the analogous alkyl radicals and α-ester substituted radicals, apparently due to steric effects. The rate constants for tin hydride trapping of secondary α-amide radicals are similar to those for reactions with secondary α-ester radicals.

Full text of DOI:10.1021/jo9717907

786
J . Org. Chem. 1998, 63, 786-793
Absolu te Ra te Con sta n ts for r-Am id e Ra d ica l Rea ction s
Osama M. Musa, Seung-Yong Choi, J ohn H. Horner,* and Martin Newcomb*
Department of Chemistry, Wayne State University, Detroit, Michigan 48202
Received September 26, 1997
The 1-(diethylcarbamoyl)-6,6-diphenyl-5-hexenyl radical (4a ), the 1-(diethylcarbamoyl)-7,7-diphenyl-
6-heptenyl radical (4b), and the 1-(diethylcarbamoyl)-1-methyl-6,6-diphenyl-5-hexenyl radical (4c)
were produced from the corresponding PTOC esters (anhydrides of the carboxylic acid and
N-hydroxypyridine-2-thione) by laser flash photolysis methods. The kinetics of cyclizations of
radicals 4a and 4b were measured at various temperatures, and that of cyclization of 4c was
measured at ambient temperature. Radicals 4a and 4b were employed as radical clocks in indirect
kinetic studies to determine rate constants for reaction of secondary R-amide radicals with Bu3-
SnH. The calibrated tin hydride trapping reaction was then employed to determine rate constants
for cyclization of the 1-(diethylcarbamoyl)-5-hexenyl radical (12). The rate constants for 5-exo
cyclizations of secondary R-amide radicals are similar to those of their isostructural alkyl radical
analogues. The rate constants for the 5-exo cyclization of tertiary R-amide radical 4c and the 6-exo
cyclization of the secondary R-amide radical 4b are smaller than those of the analogous alkyl radicals
and R-ester substituted radicals, apparently due to steric effects. The rate constants for tin hydride
trapping of secondary R-amide radicals are similar to those for reactions with secondary R-ester
radicals.
R-Amide radicals, usually produced by radical addi-
radicals which are better studied. In this work, we report
the calibration of R-amide “radical clocks”4 that can be
used for measuring absolute rate constants and rate
constants for reaction of tin hydride with secondary
R-amide radicals. The tin hydride trapping kinetics are
similar to those of secondary R-ester radicals, but the
rates of some R-amide radical cyclizations are slightly to
modestly reduced in comparison to the those of isostruc-
tural R-ester radicals. The kinetic information should
provide synthetic chemists with increased predictive
power for applications of R-amide radicals in chain
processes.
tions to acrylamides, but also available from atom
abstraction reactions, are common intermediates in
synthetic and polymer chemistry. In syntheses, the use
of these radicals obviously provides a functional group
for further synthetic conversions, but R-amide radicals
also are playing a prominent role in the rapidly evolving
area of acyclic stereoselection via radicals, especially in
asymmetric induction reactions employing chiral auxil-
iaries.1 The utility of R-amide radicals for accomplishing
and understanding stereoselectivity derives in part from
predictable conformational preferences in both the radi-
cals and their acrylamide precursors and the fact that
conformational equilibrations of these radicals are rela-
tively slow processes in comparison to most useful
elementary radical reactions. Rotation about the bond
between the R-carbon and carbonyl carbon in a simple
R-amide radical occurs with a rate constant of about 2 ×
104 s-1 at ambient temperature,2 and rotation about the
carbonyl carbon to nitrogen bond in these radicals also
appears to be slow3 as one might expect on the basis of
the slow C-N bond rotations of amides.
Resu lts
The general approach used was similar to that em-
ployed in developing kinetic scales for substituted carbon
radicals and heteroatom-centered radicals. Rate con-
stants for unimolecular reactions of selected R-amide
radicals were measured directly by laser flash photolysis
(LFP) methods. These calibrated reactions serve as
radical clocks for indirect kinetic studies of second-order
rate constants. Rate constants for reactions of tin
hydride with two of these clocks were measured by
indirect methods, and the tin hydride trapping reaction
was used to calibrate a simple R-amide radical clock.
Dir ect Kin etic Stu d ies. For direct LFP studies, we
employed PTOC ester5 radical precursors (1) derived from
malonic acid monoamides. PTOC esters have a long
wavelength absorbance centered at about 360 nm and
Few absolute rate constants for reactions of R-amide
radicals are available although one might expect that
these species will react with rate constants similar to
those of the structurally and electronically similar R-ester
(4) Griller, D.; Ingold, K. U. Acc. Chem. Res 1980, 13, 317-323.
(5) The acronym PTOC results from pyridine-2-thioneoxycarbonyl.
PTOC esters were initially developed by Barton for synthetic applica-
tions; see: Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901-3924. For early applications of PTOC esters in LFP
studies, see: Bohne, C.; Boch, R.; Scaiano, J . C. J . Org. Chem. 1990,
55, 5414-5418. Ha, C.; Horner, J . H.; Newcomb, M.; Varick, T. R.;
Arnold, B. R.; Lusztyk, J . J . Org. Chem. 1993, 58, 1194-1198.
(1) Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reactions: Concepts, Guidelines, and Synthetic Applications; VCH:
Weinheim, 1995.
(2) Strub, W.; Roduner, E.; Fischer, H. J . Phys. Chem. 1987, 91,
4379-4383.
(3) Curran, D. P.; Tamine, J . J . Org. Chem. 1991, 56, 2746-2750.
S0022-3263(97)01790-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/22/1998

Absolute Rate Constants for R-Amide Radical Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 787
Sch em e 1
F igu r e 1. Time-resolved spectrum observed following laser
irradiation of PTOC ester 1a in THF. The traces are for 51,
71, 101, and 161 ns after irradiation with the signals obtained
31 ns after irradiation subtracted to give a base line. The 161
ns trace contains symbols that show the wavelengths at which
measurements were made. The peaks at 340 and 390 nm are
growing with time. The decaying peak at 490 nm is from
radical 2, the byproduct of the photolysis. The inset shows a
kinetic trace at 338 nm where the X axis is time in µs.
(a) LiOH; (b) (COCl)2, Et2NH; (c) LiOH; (d) (COCl)2, N-hydroxy-
pyridine-2-thione sodium salt.
ously.6 Compounds 7 were converted to the R-ethoxy-
carbonyl amides 8 via the acid chlorides. Hydrolysis of
the ester groups in 8 gave malonic acid monoamides 9
that were converted to the PTOC esters 1 by a conven-
tional reaction sequence. All of the synthetic intermedi-
ates were characterized by NMR spectroscopy, and the
R-ethoxycarbonyl amides 8 were also characterized by
high-resolution mass spectrometry.
The stability of R-amide PTOC esters 1 is noteworthy
for those who employ the PTOC protocol in synthesis.
Some PTOC esters are quite labile, and we previously
found that PTOC ester precursors to R-ester and R-nitrile
radicals were difficult to handle and that some decom-
posed or hydrolyzed upon attempted chromatography.6
The R-amide PTOC derivatives 1 prepared in the this
work, although still quite reactive, appeared to be more
stable than their R-ester analogues and could be purified
by silica gel chromatography. The samples of 1 were
judged to be >95% pure by NMR spectroscopy.
are cleaved efficiently by 355 nm light from a Nd:YAG
laser. The initial photochemical cleavage reaction pro-
duces the (2-pyridine)thiyl radical (2) and acyloxyl radi-
cals 3 that rapidly decarboxylate to give the desired
radicals for kinetic studies. The R-amide radicals 4 were
produced in LFP studies, and the rate constants for
cyclization of these radicals to the diphenylalkyl radicals
5 were measured. The diphenylalkyl radical moieties in
5 absorb strongly in the 330-340 nm region and are
detected readily by UV-spectroscopy.
Kinetic studies of radical 4a were routine. Following
the laser pulse, a transient grew in smoothly with first-
order kinetics. The time-resolved spectrum shown in
Figure 1 has been “background-adjusted” by subtraction
of the signals measured 31 ns after the laser pulse from
those obtained at later times. This procedure corrects
for the initial photochemical bleaching caused by de-
struction of the precursor which has a long wavelength
λmax at about 360 nm, and the spectrum at 31 ns (not
shown in Figure 1) would be a null spectrum with an
absorbance of zero at all wavelengths. All signals ap-
pearing above zero are growing in with time, and the
negative signal centered at 490 nm, from the instanta-
neously formed (2-pyridine)thiyl radical (2), is decaying
with time.
The LFP apparatus and the design of the kinetic
studies were conventional. In brief, the unit employs a
Nd:YAG laser for production of 355 nm light with an 8
ns duration. Due to the strong absorbance of the PTOC
esters at 355 nm, dilute flowing solutions of samples are
employed. Temperature control is achieved by circulat-
ing a solution from a constant temperature bath through
a jacket around the sample reservoir that contains a gas
dispersion tube through which helium is passed. Tem-
peratures are measured with a thermocouple inserted in
the flow cell and held about 1 cm above the irradiation
zone.
The radical precursors for LFP studies were prepared
by the sequence in Scheme 1. Alkylation of diethyl
malonate and diethyl methylmalonate with 5-bromo-1,1-
diphenyl-1-pentene and of diethyl malonate with 6-bromo-
1,1-diphenyl-1-hexene gave malonate esters 6 which were
partially hydrolyzed with LiOH to give the malonate
monoesters 7; compounds 6 and 7 were reported previ-
The growing spectrum in Figure 1, with a strong
absorbance centered at λ ) 338 nm, is typical for
diphenylalkyl radicals,7 and we assign it to radical 5a .
The rate constants for formation of 5a were similar to
those for 5-exo cyclizations of other diphenylethene-
(6) Newcomb, M.; Horner, J . H.; Filipkowski, M. A.; Ha, C.; Park,
S. U. J . Am. Chem. Soc. 1995, 117, 3674-3684.
(7) Chatgilialoglu, C. In Handbook of Organic Photochemistry; J .
C. Scaiano, J . C., Ed.; CRC Press: Boca Raton, FL, 1989; Vol. 2; pp
3-11.

788 J . Org. Chem., Vol. 63, No. 3, 1998
Musa et al.
Ta ble 1. Obser ved Ra te Con sta n ts for Cycliza tion s of
Ra d ica ls 4
all reactions that deplete the precursor, and we have
shown previously that in our experimental design radi-
cals react with residual oxygen and other radicals with
pseudo-first-order rate constants of about 5 × 103 s-1 at
ambient temperatures.9 Thus, an observed rate constant
of 1 × 104 s-1 will not be an accurate measure of the rate
of cyclization. Accordingly, the measured rate constants
for the 6-exo cyclization of the secondary R-amide radical
4b are only limiting values, and the actual rate constants
for cyclization are smaller than the measured values. We
would have estimated errors of about 25% in the mea-
sured rate constants for cyclization of 4b, but competition
studies involving tin hydride trapping (see below) suggest
that the error is smaller and a reasonable Arrhenius
function could be calculated from the observed kinetic
data (eq 3). The measured rate constant for 5-exo
cyclization of the tertiary R-amide radical 4c at 30 °C
was small enough such that it should contain about a
50% error, and we did not attempt variable temperature
studies of this cyclization reaction.
kobs (s-1
)
radical
solvent
THF
temp (°C)a
set 1
set 2
4a
-0.2
9.4
1.00 E7
1.28 E7
1.60 E7
1.94 E7
2.39 E7
2.76 E7
0.948 E7
1.22 E7
1.47 E7
1.86 E7
2.37 E7
2.65 E7
0.78 E4
1.58 E4
2.02 E4
3.12 E4
1.4 E4
1.02 E7
1.29 E7
1.59 E7
1.93 E7
2.37 E7
2.79 E7
0.951 E7
1.21 E7
1.47 E7
1.83 E7
2.32 E7
2.63 E7
19.2
29.0
40.7
49.6
-0.8
9.1
19.1
28.2
40.3
49.0
1.7
CH3CN
4b
THF
THF
18.7
27.8
37.3
29.5
4c
a
(0.2 °C.
containing radicals that are isostructural with radical
4a .6,8 Further confirmation of the course of the reaction
was obtained from preparative scale studies with the
PTOC precursor to 4a that gave the expected products
(see below).
The rate constants for the 5-exo cyclization of radical
4a are in the range of 107 s-1 which is where the LFP
results are most accurate. The dynamic limit of the unit
is about 2.5 × 108 s-1, so the reactions were slow enough
that deconvolution of the kinetics from the instrument
response times was not necessary. On the other hand,
the cyclizations of 4a were fast enough such that radical-
radical and radical-oxygen reactions could not compete
with the cyclizations. The latter point is important
because the measured rate constants for formation of 5a
are actually the sum of the rate constants for all reactions
that consume 4a .
Rate constants for cyclization of 4a were determined
over a 50 °C temperature range in both THF and
acetonitrile (Table 1). The observed kinetics have stan-
dard errors of only a few percent of the measured value,
and the major errors in the measurements result from
temperature fluctuations of (0.2 °C which occur during
the course of a measurement that typically involves a
summation of 12-15 independent runs. From the rate
constants in Table 1, the Arrhenius functions in eqs 1
and 2 were calculated where errors are 2σ and θ ) 2.3RT
in kcal/mol. Cyclizations of 4a (both cis and trans
products are formed, see below) are insensitive to the
solvent, showing that little if any polarization occurs in
the transition states.
log(kC × s)THF ) (9.0 ( 0.5) - (6.4 ( 0.7)/θ (3)
In d ir ect Kin etic Stu d ies. Radicals 4a and 4b were
used to calibrate the trapping reaction with Bu3SnH by
a conventional indirect kinetic method.10 The PTOC
esters 1a and 1b reacted in the presence of tin hydride
to give a mixture of acyclic amide products 10 and cyclic
amide products 11. The 5-exo cyclization of 4a gave a
1:1 mixture of cis-11a and trans-11a . The 6-exo cycliza-
tion of 4b displayed reasonably high diastereoselectivity
giving cis-11b and trans-11b in a 1:6 ratio. Authentic
samples of acyclic amides 10 were prepared by decar-
boxylation of the corresponding acids 9. Both diastere-
omers of cyclopentanecarboxamide 11a were isolated
from a preparative scale reaction of PTOC ester 1a .
Authentic samples of both diastereomers of cyclohexan-
ecarboxamide 11b were prepared from a mixture of
diastereomers of the (known) corresponding acid.
The results of the indirect kinetic studies of Bu3SnH
reactions are given in Table 2. The rate constants for
tin hydride trapping were calculated from the observed
product ratios, the mean concentration of tin hydride, and
the rate constants for the cyclization reactions of radicals
4a and 4b.10 The ratios of rate constants (kC/kH) for
reaction of tin hydride with radical 4a give the relative
Arrhenius function in eq 4. Subtraction of eq 4 from eq
1 gives the Arrhenius function for H-atom trapping in
eq 5. The rate constants for R-amide radical trapping
by Bu3SnH are slightly larger than those for reaction of
tin hydride with a secondary alkyl radical11 and similar
log(kC × s)THF ) (9.84 ( 0.05) - (3.53 ( 0.07)/θ (1)
log(kC × s)ACN ) (9.90 ( 0.08) - (3.63 ( 0.11)/θ (2)
Radicals 4b and 4c also cyclized to give diphenylalkyl
radical products, but these reactions were appreciably
slower than the cyclization of radical 4a with observed
rate constants in the 104 s-1 range (Table 1). The
observed rate constants for formation of the cyclic
radicals are actually the sums of the rate constants for
(9) Musa, O. M.; Horner, J . H.; Shahin, H.; Newcomb, M. J . Am.
Chem. Soc. 1996, 118, 3862-3868.
(10) Newcomb, M. Tetrahedron 1993, 49, 1151-1176.
(11) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J . C. J . Am. Chem.
Soc. 1981, 103, 7739-7742.
(8) J ohnson, C. C.; Horner, J . H.; Tronche, C.; Newcomb, M. J . Am.
Chem. Soc. 1995, 117, 1684-1687.

Absolute Rate Constants for R-Amide Radical Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 789
Ta ble 2. Resu lts of Bu 3Sn H Tr a p p in g of Ra d ica ls 4a a n d
4b in THF
Ta ble 3. Resu lts of Bu 3Sn H Tr a p p in g of Ra d ica l 12
in THF
e
temp [Bu3SnH]
%
(kC/kH)d
(M)
kH
tempa (°C) [Bu3SnH]b (M) [15]/[14] % yieldc (kC/kH)d (M)
radical (°C)a
(M)b
[11]/[10] yieldc
(Ms)-1
25
22
0
0.298
0.138
0.109
0.188
0.117
0.201
0.419
0.179
0.296
0.452
0.220
0.389
0.390
0.155
0.263
0.321
0.197
0.178
0.096
0.047
0.048
0.033
0.023
0.026
0.0112
0.0165
87
69
75
80
86
93
96
91
87
107
78
94
92
0.046
0.036
0.035
0.037
0.0209
0.0193
0.0197
0.0087
0.0099
0.0106
0.0057
0.0044
0.0064
4a
32
20
20
1
1
-20
-20
20
0.64
0.29
0.65
0.38
0.32
0.29
0.36
0.070
0.126
8.9
20.3
8.4
10.9
12.2
10.5
8.8
73
71
62
68
66
59
81
98
109
5.7
5.9
5.4
4.1
4.0
3.0
3.2
3.6 E6
2.7 E6
2.9 E6
2.6 E6
2.6 E6
2.0 E6
1.9 E6
-21
-40
4b
0.080
0.050
0.0055 2.9 E6
0.0063 2.5 E6
20
(1 °C. Average concentration of Bu3SnH. c Combined yield
a
b
of 11 and 10 determined by GC employing an internal standard.
Ratio of rate constants for cyclization versus trapping. e Rate
d
a
b
constant for hydrogen atom transfer.
(1 °C. Mean concentration of Bu3SnH. c Combined yield of
15 and 14 determined by GC employing an internal standard.
Ratio of rate constants for cyclization versus trapping.
d
Sch em e 2
Ta ble 4. Ra te Con sta n ts for Ra d ica l Cycliza tion s
a t 20 °Ca
to those found for reaction of a secondary R-ester radical
with tin hydride.6
log((kC/kH)/M)THF ) (2.2 ( 0.3) - (2.0 ( 0.4)/θ (4)
log(kH × Ms)THF ) (7.6 ( 0.3) - (1.5 ( 0.4)/θ (5)
a
b
Approximate rate constants in units of s-1
.
Data from refs
6, 12, 15. c This work. Data from refs 6, 14. f Data from refs 8,
d
14, 16.
It is possible that the activation parameters in eq 5
are not useful for calculating the entropy and enthalpy
of activation of the H-atom transfer reaction. This
caution results from the fact that the value of the log A
is smaller than that found for tin hydride trapping of a
secondary alkyl radical (log A ) 8.7),11 but we note that
the log A term for reaction of a secondary R-ester radical
with tin hydride also is somewhat small (log A ) 8.1).6
In any event, eq 5 accurately predicts the trapping rate
constants for the temperature range studied (-20 to 32
°C) and should be useful for calculating values at tem-
peratures up to 80 °C.
The tin hydride trapping reaction was used to calibrate
the 5-exo cyclization of the simple secondary R-amide
radical 12 (Scheme 2) which is more representative of
the R-amide radicals that one would envision in synthetic
applications. PTOC ester 13 was prepared by a sequence
of reactions similar to those used to prepare PTOC esters
1. Reaction of 13 in the presence of tin hydride gave the
acyclic amide 14 and cyclopentanecarboxamides 15
(Scheme 2) which were identified by comparison to
authentic samples prepared independently. As observed
for the 5-exo cyclization of radical 4a , the diastereose-
lectivity in the cyclization reaction of 12 was low with
cis-15 to trans-15 ratios of about 1:2.
Arrhenius function for cyclization of 12 in eq 7. The rate
constant for cyclization of 12 at 20 °C is 9 × 104 s-1
.
log((kC/kH)/M) ) (1.73 ( 0.32) - (4.28 ( 0.38)/θ (6)
log(kC × s) ) (9.3 ( 0.4) - (5.8 ( 0.6)/θ
(7)
Discu ssion
The kinetic studies in this work add to the growing
number of rate constants that are useful for predicting
the outcome of synthetic reactions employing radicals.
Kinetic values are important because most radical-based
synthetic sequences involve chain reactions in which
competitions between a desired reaction and an undes-
ired one are inevitable. We have collected some rate
constants for radical cyclizations and tin hydride trapping
reactions that can be compared to the values obtained
here for R-amide radicals.
Rate constants for cyclization of four series of isostruc-
tural radicals at 20 °C are listed in Table 4.6,8,10,12-16
Despite intuitive notions one might have regarding the
(12) Beckwith, A. L. J .; Easton, C. J .; Lawrence, T.; Serelis, A. K.
Aust. J . Chem. 1983, 36, 545-556.
The results of a series of competition kinetic studies
with radical 12 are given in Table 3. The relative rate
constants for cyclization versus trapping of 12 give the
function in eq 6. Addition of eq 6 to eq 5 gives the
(13) Lusztyk, J .; Maillard, B.; Deycard, S.; Lindsay, D. A.; Ingold,
K. U. J . Org. Chem. 1987, 52, 3509-3514.
(14) Newcomb, M.; Filipkowski, M. A.; J ohnson, C. C. Tetrahedron
Lett. 1995, 36, 3643-3646.
(15) Belcher, T. A.; Horner, J . H.; Newcomb, M. Unpublished results.

790 J . Org. Chem., Vol. 63, No. 3, 1998
Musa et al.
effects of radical stability on the kinetics of cyclizations,
it is clear that electronic factors are much less important
than steric effects in these reactions. The only influence
of the radical stabilizing groups in the 5-exo cyclizations
of the simple secondary radicals 16 and the diphe-
nylethene-substituted radicals 17 is to lead to an in-
creased rate of cyclization for the ester- and methoxy-
substituted systems. The reactivity in these cyclizations
is similar to the intermolecular reactivity observed in
additions of radicals to simple alkenes where the R-ester
radical 2017 adds to simple alkenes faster than does the
methyl radical,18 and the 1-methyl-1-hydroxyethyl radical
(21) adds somewhat less rapidly.19
rapid than cyclization of the R-ester and R-nitrile ana-
logues (18, X ) CO2Et, CN). We assume that this effect
results from the bulk of the amide group (but see below).
For example, 24 and 25 show two of the possible
conformations for cyclization of 4c. The indicated steric
interactions could be avoided for an R-ester radical and
would not exist for an R-nitrile radical. For the 6-exo
cyclizations of the secondary radicals 19, the R-amide
radical 4b again appears to suffer an order of magnitude
kinetic retardation due to a steric effect that is not
present in the R-ester radical, and we again assume this
results from the two substituents on the nitrogen of the
amide.
The close similarity of the rate constants for 5-exo
cyclizations in the series of radicals 16 and in the series
of radicals 17 also suggests that the transition states for
these reactions are at most only slightly polarized. That
fact was demonstrated directly in this work for cyclization
of radical 4a (17, X ) C(O)NEt2) in that the rate
constants in THF and acetonitrile were indistinguishable.
In a similar manner, the rate constants for cyclization
of the methoxy-substituted radicals 17 and 18 (X )
OCH3) were the same in THF and acetonitrile.8,16
Unlike the case with the secondary radicals, the
kinetics of 5-exo cyclizations of the tertiary radicals 18
display strong substituent effects. On the basis of the
absence of significant electronic effects in the cyclizations
of the secondary radicals 16 and 17, one assumes that
electronic effects are also minor in the case of the tertiary
radicals 18. Accordingly, the observed rate reductions
for radicals 18 containing electron-withdrawing groups
appear to reflect sterics. We have noted this phenomenon
for 5-exo cyclizations of tertiary radicals previously and
suggested that it results from an enforced planarity at
the radical center.6,14 Thus, the tertiary alkyl radical 18
(X ) CH3) can deform from planarity with little or no
energy penalty, but an energy penalty would result from
deformation of the planar radical center in the conjugated
tertiary radicals 18 (X ) C(O)NEt2, CO2Et, CN). In any
transition state for a 5-exo radical cyclization of a tertiary
radical, one group at the radical center will interact with
the vinyl group if the planar radical does not deform
(arrows in 22 and 23). The enforced planarity argument
explains how the relatively small electron-withdrawing
group in the tertiary R-nitrile radical 18 (X ) CN) can
lead to a reduction in the rate of cyclization comparable
to that observed for the ester group in 18 (X ) CO2Et).
It is noteworthy that the rate constants for cyclization
of radicals 4b and 4c are quite similar to the rate
constant Fischer reported for rotation about the C-C
bond between the carbonyl carbon and the radical center
in a simple R-amide radical.2 This raises the interesting
possibility that the measured kinetics for 4b and 4c
might actually be those for a slow conformational inter-
conversion (shown below for (Z)-4b and (E)-4b) that is
followed by a faster radical cyclization. We do not have
adequate kinetic data to exclude this possibility for 4c,
but the activation parameters obtained for 4b are not
consistent with this hypothesis. Specifically, the confor-
mational interconversion of 4b via rotation should have
only a slightly negative entropy of activation leading to
a log A term of 12-13.20 The observed log A ) 9 for 4b
is consistent with the well-organized transition state of
a 6-exo cyclization reaction; for example, log A ) 9 for
cyclization of radical 19 (X ) CH3) in which conforma-
tional equilibrations are not an issue.14
The slow interconversion of rotamers in the R-amide
radicals might be important in regard to the observed
low diastereoselectivity in the 5-exo cyclizations of radi-
cals 4a and 12. One does not know the rotamer popula-
tions of these radicals, and the rate constants for their
cyclizations are greater than or of the same order of
magnitude as those for rotamer interconversion. There-
fore, the observed low diastereoselection in the 5-exo
cyclization reactions does not necessarily require that the
diastereoselectivity is low for the cyclization of each
particular rotamer. Synthetic chemists should not dis-
miss the possibility that good diastereoselectivity in 5-exo
cyclizations of secondary R-amide radicals might be
possible if the radical rotamer population can be con-
An additional steric effect apparently is present in the
cyclization of the tertiary R-amide radical 4c (18, X )
C(O)NEt2) which is more than order of magnitude less
(16) Tronche, C. F., Ph.D. Thesis, Wayne State University, 1996.
(17) Wu, J . Q.; Beranek, I.; Fischer, H. Helv. Chim. Acta 1995, 78,
(19) Heberger, K.; Fischer, H. Int. J . Chem. Kinet. 1993, 25, 913-
194-214.
920.
(18) Zytowski, T.; Fischer, H. J . Am. Chem. Soc. 1996, 118, 437-
(20) Benson, S. W. Thermochemical Kinetics; 2nd ed.; Wiley: New
York, 1976.
439.

Absolute Rate Constants for R-Amide Radical Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 791
Ta ble 5. Ra te Con sta n ts for Rea ction of Bu 3Sn H w ith
organic phase was combined and dried over MgSO4, filtered,
and concentrated at reduced pressure to yield crude R-ethoxy-
carbonyl amides 8 which were purified by column chromatog-
raphy on silica gel.
RCH(•)X
X
Arrhenius functiona
k20 °C (M-1 s-1
)
b
CH3
log k ) 8.7 - 3.5/θ
log k ) 7.6 - 1.5/θ
log k ) 8.1 - 2.2/θ
log k ) 8.4 - 3.8/θ
1.2 E6
3.0 E6
3.2 E6
3.6 E5
Syn th esis of r-Ca r boxy Am id es 9. Meth od B. R-Ethox-
ycarbonyl amides 8 (1 equiv) and LiOH (1.1 equiv) in 95%
EtOH were heated at reflux for 5 h. The mixture was cooled
and concentrated. The residue was dissolved in water, and
the resulting solution was acidified with HCl. The mixture
was extracted three times with ether, and the combined
ethereal extracts were washed with saturated NaCl solution
and dried over MgSO4. Concentration under reduced pressure
gave crude 9 which was purified by column chromatography
on silica gel.
c
C(O)NEt2
CO2Etd
OMee
a
d
θ ) 2.3RT in kcal/mol. b Reference 11. c This work. Reference
6. e Reference 8.
trolled; such control might be achieved by Lewis acid
complexation by an appropriately functionalized radical
precursor.
P r ep a r a tion of P TOC Ester s 1. Meth od C. To a
solution of R-carboxy amide 9 (1 equiv) in dry benzene were
added oxalyl chloride (1.5 equiv) and two drops of DMF. The
mixture was stirred until gas evolution ceased, and excess
oxalyl chloride was removed by distillation under reduced
pressure. The residue was dissolved in dry benzene, and the
resulting solution was transferred via cannula into a light-
shielded vessel containing a suspension of N-hydroxypyridine-
2-thione sodium salt (1.1 equiv) and a catalytic amount of
DMAP in dry benzene. The mixture was stirred for 2 h. The
reaction mixture was washed with saturated NaHCO3 solution
and saturated aqueous NaCl solution. After drying over
MgSO4, the solution was concentrated to give the crude PTOC
esters 1 which were purified by column chromatography on
silica gel.
N,N-Diet h yl-2-(et h oxyca r b on yl)-7,7-d ip h en yl-6-h ep -
ten a m id e (8a ) was prepared by method A from 7a (0.50 g,
1.81 mmol). Column chromatography (hexanes-EtOAc, 3:1)
gave 0.50 g of 8a (1.23 mmol, 68%). 1H NMR: δ 7.37-7.15
(m, 10H), 6.07 (t, 1H, J ) 7.2 Hz), 4.15 (q, 2H, J ) 7.2 Hz),
3.45-3.20 (m, 5H), 2.16 (q, 2H, J ) 7.5 Hz), 1.96 (q, 2H, J )
6.9 Hz), 1.50-1.43 (m, 2H), 1.22 (t, 3H, J ) 7.2 Hz), 1.15-
1.09 (m, 6H). 13C NMR: δ 170.09, 167.79, 142.63, 142.09,
140.11, 129.86, 129.16, 128.30, 128.17, 128.04, 127.20, 126.91,
126.85, 61.06, 48.53, 42.53, 42.14, 40.59, 29.47, 28.87, 27.71,
14.49, 14.09, 12.80. MS: m/z (rel intens) 407 (100.0), 261
(23.4), 260 (23.5), 206 (41.6), 205 (18.4), 191 (14.1), 187 (40.8),
178 (12.5), 167 (13.0), 165 (15.8), 129 (13.3), 128 (25.3), 115
(26.7), 100 (28.9), 91 (35.4), 74.1 (27.0), 73 (15.5), 72 (58.9), 58
(21.0). HRMS: calcd for C26H33NO3, 407.2460; found, 407.2463.
N ,N -Die t h yl-2-(e t h oxyca r b on yl)-8,8-d ip h e n yl-7-oc-
ten a m id e (8b) was prepared by method A from 7b (2.23 g,
6.09 mmol). Column chromatography (hexanes-EtOAc, 3:1)
gave 1.67 g of 8b (1.23 mmol, 65%). 1H NMR: δ 7.38-7.14
(m, 10H), 6.05 (t, 1H, J ) 7.5 Hz), 4.15 (q, 2H, J ) 6.9 Hz),
3.49-3.22 (m, 5H), 2.12 (q, 2H, J ) 7.5 Hz), 1.90 (q, 2H, J )
7.5 Hz), 1.53-1.43 (m, 2H), 1.32-1.27 (m, 2H), 1.25-1.16 (m,
6H), 1.11 (t, 3H, J ) 7.2 Hz). 13C NMR: δ 170.15, 167.88,
142.75, 141.70, 140.19, 129.85, 129.70, 128.11, 128.01, 127.16,
126.82, 126.76, 61.06, 48.87, 42.12, 40.61, 29.86, 29.55, 29.25,
27.28, 14.50, 14.08, 12.77. MS: m/z (rel intens) 421 (100.0),
246 (14.4), 205 (10.6), 200 (10.5), 193 (14.1), 192 (10.3), 191
(14.4), 187 (37.0), 180 (14.5), 178 (15.8), 167 (17.6), 165 (13.7),
128 (26.6), 115 (36.7), 100 (34.4), 91 (31.5), 74 (38.7), 73 (14.2),
72 (61.2), 58 (25.7). HRMS: calcd for C27H35NO3, 421.2617;
found, 421.2626.
N,N-Dieth yl-2-(eth oxycar bon yl)-2-m eth yl-7,7-diph en yl-
6-h ep ten a m id e (8c) was prepared by method A from 7c (2.13
g, 5.82 mmol). Column chromatography (hexanes-EtOAc, 3:1)
gave 1.54 g of 8c (3.66 mmol, 63%). 1H NMR: δ 7.37-7.14
(m, 10H), 6.07 (t, 1H, J ) 7.2 Hz), 4.15 (q, 2H, J ) 6.9 Hz),
3.35 (q, 2H, J ) 6.6 Hz), 3.11 (q, 2H, J ) 6.6 Hz), 2.13 (q, 2H,
J ) 7.2 Hz), 1.94-1.75 (m, 2H), 1.48-1.30 (m, 2H), 1.39 (s,
3H), 1.23 (t, 3H, J ) 7.5 Hz), 1.11-1.04 (m, 6H). 13C NMR:
δ 174.63, 170.03, 142.59, 142.04, 140.10, 129.83, 129.17,
128.13, 128.03, 127.14, 126.85, 126.80, 61.05, 52.43, 41.02,
39.96, 36.23, 30.00, 24.49, 21.84, 14.09, 13.41, 12.29. MS: m/z
(rel intens) 421 (87.4), 348 (11.2), 276 (11.3), 275 (50.7), 274
(47.6), 228 (10.3), 207 (17.7), 206 (100.0), 205 (22.0), 201 (20.2),
193 (18.1), 192 (10.3), 191 (20.7), 183 (15.4), 178 (18.1), 167
Rate constants for reactions of tin hydride with sec-
ondary radicals are collected in Table 5.6,8,10,11 For the
hydrogen atom transfer reaction from Bu3SnH to a
radical, the C-H bond dissociation energies will reflect
the thermodynamics of the reactions, and the tin hydride
reaction with a secondary alkyl radical is more exother-
mic than reactions with the substituted radicals. The
fact that the rate constants for reaction of tin hydride
with the R-amide and R-ester radicals are slightly greater
than that for reaction with the alkyl radical apparently
reflects a favorable polarity match between the electron
deficient radicals and the electron rich tin hydride that
results in a polarization in the transition states for
reactions of the electron deficient radicals. For the
electron rich methoxy-substituted radical, the rate con-
stant for reaction of tin hydride is smaller than that for
reaction of the alkyl radical as one would expect.8
In summary, the rate constants for cyclizations of and
hydrogen atom transfer to R-amide radicals are subject
to the same minor electronic effects one observes in
related R-ester radicals. Steric effects, however, can lead
to reductions in the rate constants of R-amide radical
cyclization reactions greater than those observed with
other electron deficient radicals. The bulk of the amide
group and the relatively slow rates of conformational
interconversion about the C-C (carbonyl to radical
center)2 and C-N (carbonyl to nitrogen) bonds should be
considered in attempts to incorporate R-amide radical
cyclizations into synthetic schemes. That the rate con-
stant for 5-exo cyclization of the prototypical R-amide
radical 12 is faster than conformational equilibration
might be important for achieving high diastereoselec-
tivities in cyclization reactions.
Exp er im en ta l Section
Gen er a l. NMR spectra of CDCl3 solutions were obtained
at 300 or 500 MHz (1H) and 75 or 125 MHz (13C). Radial
chromatography was performed on a model 7924T Chroma-
totron (Harrison Research). Melting points were obtained on
a Thomas-Hoover capillary melting point apparatus. Diethyl
malonates 6 and the malonate monoesters 7 were prepared
by the methods previously reported.6 N-Hydroxypyridine-2-
thione sodium salt was prepared as described previously.21
Syn th esis of r-Eth oxyca r bon yl Am id es 8 (Meth od A).
Carboxylic acid chlorides were prepared by reaction of the
corresponding acids 7 (1 equiv) in benzene cooled at 5 °C under
nitrogen with a catalytic amount of DMF and oxalyl chloride
(1.5 equiv) added dropwise. The mixture was stirred until gas
evolution ceased, and the excess oxalyl chloride was removed
by distillation under reduced pressure. Diethylamine (2 equiv)
and triethylamine (1 equiv) were added dropwise to the crude
residue of acid chloride in diethyl ether at 0 °C. The solution
was stirred for 12 h. After filtration of the ammonium salts,
the filtrate was washed with water, 1 M NaOH, 1 M HCl,
saturated aqueous NaHCO3, and saturated aqueous NaCl. The

792 J . Org. Chem., Vol. 63, No. 3, 1998
Musa et al.
(11.3), 165 (15.3), 142.1 (11.9), 141 (10.0), 129 (16.0), 128 (17.5),
115 (35.6), 105 (13.2), 100 (41.2), 91 (46.9), 73 (21.5), 72 (43.7),
69 (12.7), 58 (17.4). HRMS: calcd for C27H35NO3, 421.2617;
found, 421.2625.
isolated by silica gel chromatography (hexanes-acetone, 8:2)
as a yellow oil (20.5 mg, 0.061 mmol, 77%). 1H NMR: δ 7.39-
7.14 (m, 10H), 6.08 (t, 1H, J ) 7.2 Hz), 3.35 (q, 2H, J ) 6.9
Hz), 3.24 (q, 2H, J ) 7.2 Hz), 2.25-2.10 (m, 4H), 1.71-1.61
(m, 2H), 1.54-1.46 (m, 2H), 1.15-1.07 (dt, 6H, J ) 9.6, 6.9
Hz). 13C NMR: δ 171.9, 142.7, 141.7, 140.2, 129.9, 129.7,
128.1, 128.0, 127.2, 126.8, 126.7, 41.9, 40.0, 32.8, 29.7, 29.5,
24.9, 14.4, 13.1. MS: m/z (rel intens) 335 (100.0), 262 (10),
206 (23), 168 (45), 128 (78), 115 (70), 100 (41), 91 (34), 72 (40),
58 (23). HRMS: calcd for C23H29NO, 335.2249; found, 335.2248.
N,N-Dieth yl-2-car boxy-7,7-diph en yl-6-h epten am ide (9a)
was prepared by method B from 8a (1.5 g, 3.69 mmol). Column
chromatography (hexanes-EtOAc, 1:1) gave 1.3 g of 9a (3.43
mmol, 93%). 1H NMR: δ 11.83 (bs, 1H), 7.39-7.13 (m, 10H),
6.02 (t, 1H, J ) 7.2 Hz), 3.62-3.50 (m, 1H), 3.47 (t, 1H, J )
6.9 Hz), 3.39-3.17 (m, 3H), 2.14 (q, 2H, J ) 7.2 Hz), 1.87 (q,
2H, J ) 7.5 Hz), 1.60-1.50 (m, 2H), 1.18 (t, 3H, J ) 6.9 Hz),
1.14 (t, 3H, J ) 7.2 Hz). 13C NMR: δ 172.13, 171.44, 142.53,
142.42, 139.94, 129.81, 128.38, 128.20, 128.08, 127.19, 126.10,
46.43, 42.45, 41.20, 32.20, 29.27, 27.05, 14.41, 12.74.
N,N-Dieth yl-2-ca r boxy-8,8-d ip h en yl-7-octen a m id e (9b)
was prepared by method B from 8b (2.0 g, 4.75 mmol).
Column chromatography (hexanes-EtOAc, 1:1) gave 1.78 g
of 9b (4.53 mmol, 95%). 1H NMR: δ 12.00 (bs, 1H), 7.39-
7.13 (m, 10H), 6.03 (t, 1H, J ) 7.5 Hz), 3.56-3.44 (m, 2H),
3.34-3.21 (m, 3H), 2.15 (q, 2H, J ) 7.2 Hz), 1.83 (q, 2H, J )
6.6 Hz), 1.47-1.38 (m, 4H), 1.21 (t, 3H, J ) 6.9 Hz), 1.13 (t,
3H, J ) 6.9 Hz). 13C NMR: δ 172.34, 171.23, 142.60, 142.03,
140.06, 129.82, 129.16, 128.16, 128.04, 127.16, 126.91, 126.85,
46.48, 42.43, 41.20, 32.67, 29.49, 29.34, 26.44, 14.43, 12.72.
N,N-Diet h yl-2-ca r b oxy-2-m et h yl-7,7-d ip h en yl-6-h ep -
ten a m id e (9c) was prepared by method B from 8c (0.89 g,
2.11 mmol). Column chromatography (hexanes-EtOAc, 1:1)
gave 0.74 g of 9c (1.88 mmol, 89%). 1H NMR: δ 11.20 (bs,
1H), 7.38-7.13 (m, 10H), 6.04 (t, 1H, J ) 7.5 Hz), 3.34 (bs,
2H), 3.21 (bs, 2H), 2.12 (q, 2H, J ) 7.2 Hz), 1.85 (t, 2H, J )
8.7 Hz), 1.44 (s, 3H), 1.40-1.30 (m, 2H), 1.09 (t, 6H, J ) 6.6
Hz). 13C NMR: δ 179.50, 170.11, 142.54, 142.13, 140.06,
129.88, 129.00, 128.14, 128.05, 127.16, 126.89, 126.86, 52.39,
41.55, 40.56, 36.12, 29.93, 24.56, 22.06, 13.08, 12.34.
1-[[(1-(N,N-Diet h ylca r b a m oyl)-6,6-d ip h en yl-5-h exen -
yl)ca r bon yl]oxy]-2(1H)-p yr id in eth ion e (1a ) was prepared
by method C from 9a (0.26 g, 0.69 mmol). Column chroma-
tography (hexanes-EtOAc, 1:1) gave 0.27 g of 1a (0.51 mmol,
73%). 1H NMR: δ 7.67 (dd, 1H, J ) 8.7, 1.5 Hz), 7.60 (dd,
1H, J ) 7.2, 1.5 Hz), 7.38-7.16 (m, 11H), 6.60 (dt, 1H, J )
6.9, 1.8 Hz), 6.07 (t, 1H, J ) 7.2 Hz), 4.01 (t, 1H, J ) 6.9 Hz),
3.56-3.27 (m, 4H), 2.24-2.12 (m, 2H), 2.02-1.96 (m, 2H),
1.66-1.57 (m, 2H), 1.25 (t, 3H J ) 6.9 Hz), 1.16 (t, 3H, J )
7.2 Hz). 13C NMR: δ 175.68, 166.79, 165.84, 142.51, 142.38,
140.03, 137.84, 137.11, 133.73, 129.86, 128.70, 128.32, 128.23,
128.07,127.22, 127.00, 126.91, 112.63, 46.95, 42.95, 40.89,
29.45, 28.74, 27.46, 14.71, 12.84.
N,N-Dieth yl-8,8-d ip h en yl-7-h ep ten a m id e (10b) was ob-
tained by thermal decarboxylation of acid 7b (32 mg, 0.081
mmol) at 170-175 °C for 30 min. The acyclic amide 10b was
isolated by silica gel chromatography (hexanes-acetone, 8:2)
as a yellow oil (22 mg, 0.063 mmol, 78%). 1H NMR: δ 7.40-
7.15 (m, 10H), 6.07 (t, 1H, J ) 7.5 Hz), 3.35 (q, 2H, J ) 6.9
Hz), 3.27 (q, 2H, J ) 7.2 Hz), 2.25 (t, 2H, J ) 7.2 Hz), 2.11 (m,
2H), 1.62 (m, 2H), 1.47 (m, 2H), 1.34 (m, 2H), 1.19-1.05 (dt,
6H, J ) 9.6 Hz, J ) 6.9 Hz). 13C NMR: δ 172.1, 142.8, 141.5,
140.3, 130.0, 129.9, 128.1, 128.0, 127.2, 126.8, 126.7, 41.9, 40.0,
33.0, 29.8, 29.7, 29.2, 25.4, 14.4, 13.1. MS: m/z (rel intens)
349 (95.0), 276 (3), 156 (24.0), 148 (38.0), 115 (100.0), 91 (28.0),
72 (32.0), 58 (28.0). HRMS: calcd for C24H31NO, 349.2406;
found, 349.2405.
cis- a n d tr a n s-N,N-Dieth yl-2-(d ip h en ylm eth yl)cyclo-
p en ta n eca r boxa m id e (11a ) were isolated from the reaction
of the corresponding PTOC ester 1a (60 mg, 0.123 mmol) and
5 equiv of Bu3SnH (0.178 g, 0.614 mmol) in 10 mL of dry THF.
The reaction mixture was sealed with a septum, flushed with
nitrogen, and photolyzed with visible light for 3 h at room
temperature. GC and GC-mass spectral analyses showed
that a 1:1 mixture of diastereomeric cyclization products was
formed in addition to the acyclic product. Both diastereomers
(cis-11a : 12 mg, 29%, mp 100-101 °C, trans-11a : 10 mg, 22%,
mp 98-99 °C) were isolated by radial chromatography on silica
gel (hexanes-acetone, 8:2).
cis-11a was characterized as follows: 1H NMR: δ 7.37-
7.03 (m, 10H), 4.24 (d, 1H, J ) 11.1 Hz), 3.35 (sextet, 1H, J )
7.5 Hz), 3.05 (sextet, 1H, J ) 7.0 Hz), 2.90 (m, 2H), 2.51 (m,
2H), 2.00-1.84 (m, 3H), 1.80-1.70 (m, 1H), 1.68-1.46 (m, 2H),
1.03 (t, 3H, J ) 7.2 Hz), 0.69 (t, 3H, J ) 6.9 Hz). 13C NMR:
δ 174.8, 145.4, 145.1, 128.4, 128.3, 128.1, 127.7, 126.1, 125.9,
53.0, 49.5, 41.6, 41.3, 40.4, 31.8, 31.2, 24.4, 14.3, 13.1. MS:
m/z (rel intens) 335 (100.0), 262 (9.5), 206 (19.3), 168 (43.4),
128 (73.3), 115 (59.9), 100 (36.2), 72 (36.6), 58 (17.3). HRMS:
calcd for C23H29NO, 335.2249; found, 335.2253.
trans-11a was characterized as follows: 1H NMR: δ 7.20-
7.05 (m, 10H), 3.66-3.51 (m, 2H), 3.25 (sextet, 1H, J ) 7.5
Hz), 3.08 (sextet, 1H, J ) 7.2 Hz), 2.75 (m, 2H), 2.55 (m, 1H),
1.95-1.50 (m, 5H), 1.35-1.24 (m, 1H), 0.96 (t, 3H, J ) 7.9
Hz), 0.65 (t, 3H, J ) 8.1 Hz), 1.95-1.72 (m, 3H), 1.72-1.60
(m, 2H). 13C NMR: δ 175.9, 145.0, 144.6, 128.5, 128.4, 128.3,
127.8, 126.2, 126.0, 59.1, 46.7, 46.0, 41.5, 40.6, 33.5, 33.3, 26.1,
14.1, 13.0. MS: m/z (rel intens) 335 (100.0), 262 (8.0), 206
(11.0), 168 (78.8), 167 (61.1), 115 (36.4), 72 (27.3), 41 (10.5).
HRMS: calcd for C23H29NO, 335.2249; found, 335.2255.
1-[[(1-(N,N-Dieth ylcar bam oyl)-7,7-diph en yl-6-h epten yl)-
ca r bon yl]oxy]-2(1H)-p yr id in eth ion e (1b) was prepared by
method C from 9b (0.27 g, 0.69 mmol). Column chromatog-
raphy (hexanes-EtOAc, 1:1) gave 0.26 g of 1b (0.48 mmol,
68%). 1H NMR: δ 7.67 (dd, 1H, J ) 9.0, 1.5 Hz), 7.61 (dd,
1H, J ) 7.5, 1.5 Hz), 7.37-7.14 (m, 11H), 6.60 (dt, 1H, J )
6.9, 1.8 Hz), 6.05 (t, 1H, J ) 7.5 Hz), 4.00 (t, 1H, J ) 7.2 Hz),
3.58-3.26 (m, 4H), 2.22-2.10 (m, 2H), 2.02-1.92 (m, 2H),
1.47-1.42 (m, 4H), 1.27 (t, 3H, J ) 6.0 Hz), 1.14 (t, 3H, J )
7.2 Hz). 13C NMR: δ 175.54, 166.83, 165.85, 142.66, 141.89,
140.1, 137.85, 136.95, 133.89, 129.83, 129.44, 128.32, 128.20,
128.07, 127.12, 126.92, 126.83, 112.76, 46.98, 42.96, 40.92,
29.68, 29.43, 29.06, 26.87, 14.75, 12.87.
1-[[(1-(N,N-Dieth ylca r ba m oyl)-1-m eth yl-6,6-d ip h en yl-
5-h exen yl)ca r bon yl]oxy]-2(1H)-p yr id in eth ion e (1c) was
prepared by method C from 9c (0.17 g, 0.43 mmol). Column
chromatography (hexanes-EtOAc, 1:1) gave 0.14 g of 1c (0.26
mmol, 60%). 1H NMR: δ 7.66 (dd, 1H, J ) 9.0, 1.8 Hz), 7.47
(d, 1H, J ) 6.6 Hz), 7.37-7.14 (m, 11H), 6.58 (t, 1H, J ) 7.2
Hz), 6.09 (t, 1H, J ) 7.2 Hz), 3.48-3.31 (m, 4H), 2.17 (q, 2H,
J ) 7.2 Hz), 2.08 (t, 2H, J ) 7.8 Hz), 1.74 (s, 3H), 1.39-1.51
(m, 2H), 1.13 (t, 6H, J ) 6.9 Hz). 13C NMR: δ 180.86, 168.33,
145.09, 142.48, 142.33, 140.05, 137.53, 133.34, 129.84, 128.78,
128.20, 128.06, 127.17, 126.92, 112.55, 53.43, 42.53, 40.76,
35.89, 29.81, 24.91, 22.33, 13.55, 12.32.
cis- a n d tr a n s-N,N-Dieth yl-2-(d ip h en ylm eth yl)cyclo-
h exa n ca r boxa m id e (11b) were prepared by method A from
2-(diphenylmethyl)cyclohexanecarboxylic acid22 (0.07 g, 0.24
mmol). Column chromatography (hexanes-EtOAc, 3:1) gave
0.04 g of trans-11b (0.115 mmol, 48%) and 0.02 g of cis-11b
(0.057 mmol, 24%).
cis-11b was characterized as follows: 1H NMR: δ 7.34-
7.07 (m, 10H), 4.04 (d, 1H, J ) 11.7 Hz), 3.36-3.24 (m, 1H),
3.23-3.12 (m, 1H), 2.73-2.64 (m, 2H), 2.47-2.29 (m, 2H),
2.25-2.13 (m, 1H), 1.78-1.45 (m, 5H), 1.30-1.15 (m, 2H), 1.09
(t, 3H, J ) 7.2 Hz), 0.50 (t, 3H, J ) 7.2 Hz). 13C NMR: δ
173.40, 144.76, 144.14, 128.58, 128.36, 128.33, 127.95, 126.08,
125.85, 55.68, 43.33, 41.48, 39.90, 36.31, 30.21, 26.34, 26.27,
N,N-Dieth yl-7,7-d ip h en yl-6-h ep ten a m id e (10a ) was ob-
tained by thermal decarboxylation of acid 7a (30 mg, 0.079
mmol) at 170-175 °C for 30 min. The acyclic amide 10a was
(21) Esker, J . L.; Newcomb, M. J . Org. Chem. 1993, 58, 4933-4940.
(22) Smith, L. I.; Agre, C. L.; Leekley, R. M.; Pritchard, W. W. J .
Am. Chem. Soc. 1939, 61, 7-11.

Absolute Rate Constants for R-Amide Radical Reactions
J . Org. Chem., Vol. 63, No. 3, 1998 793
21.33, 13.53, 12.99. MS: m/z (rel intens) 349 (100.0), 182
(31.1), 167 (30.4), 165 (15.4), 128 (23.1), 115 (27.9), 100 (23.4),
91 (10.0), 72 (16.2). HRMS: calcd for C24H31NO, 349.2406;
found, 349.2406.
(49.8), 58 (100.0), 55 (31.7), 44 (20.2), 41 (20.5), 28 (26.6).
HRMS: calcd for C11H21NO, 183.1623, found 183.1620.
N,N-Dieth yl 2-m eth ylcyclop en ta n eca r boxa m id es (15)
were prepared by method A from 2-methylcyclopentanecar-
boxylic acid23 (0.87 g, 6.80 mmol). Column chromatography
(hexanes-EtOAc, 3:1) gave 0.98 g of 15 (5.36 mmol, 79%). GC
analysis showed that a 3.6:1 mixture of diastereomers was
formed. 1H NMR: δ 3.66-2.81 (m, 4H), 2.38-2.02 (m, 2H),
1.92-1.77 (m, 2H), 1.75-1.31 (m, 8H), 1.15 (t, 3H, J ) 6.9
Hz), 1.06 (t, 3H, J ) 7.2 Hz), 0.93 (d, 2.3H, J ) 6.6 Hz), 0.80
(d, 0.7H, J ) 6.9 Hz). 13C NMR: δ 174.90, 173.18, 49.15, 44.73,
41.68, 41.39, 40.18, 39.77, 39.14, 36.17, 34.67, 34.47, 30.93,
28.50, 24.30, 24.12, 19.00, 16.59, 14.90, 14.47, 13.11, 12.96.
MS: m/z (rel intens) 183 (52.5), 168 (36.1), 142 (35.0), 140
(10.8), 128 (91.6), 111 (11.5), 100 (44.7), 83 (100.0), 74 (12.1),
67 (11.7), 58 (68.0, 55 (69.4). HRMS: calcd for C11H21NO,
183.1623, found 183.1619.
trans-11b was characterized as follows: 1H NMR: δ 7.31-
7.11 (m, 10H), 4.23 (d, 1H, J ) 6.0 Hz), 3.43-3.29 (m, 1H),
3.22-3.11 (m, 1H), 2.84 (q, 2H, J ) 7.5 Hz), 2.78-2.65 (m,
1H), 2.21 (t, 1H, J ) 10.2 Hz), 1.79-1.50 (m, 5H), 1.30-1.14
(m, 3H), 1.08 (t, 3H, J ) 6.9 Hz), 0.87 (t, 3H, J ) 7.2 Hz). 13C
NMR: 174.69, 143.53, 142.00, 130.42, 128.48, 128.13, 127.88,
126.32, 125.61, 53.40, 43.81, 43.73, 41.56, 40.09, 31.33, 27.49,
25.92, 25.75, 14.21, 12.99. MS: m/z (rel intens) 349 (100.0),
182 (52.3), 167 (30.1), 165 (15.8), 128 (20.2), 115 (25.6), 100
(39.1), 72 (19.2). HRMS: calcd for C24H31NO, 349.2406; found,
349.2403.
1-[[(1-(N,N-Dieth ylcar bam oyl)-5-h exen yl)car bon yl]oxy]-
2(1H)-p yr id in eth ion e (13). N,N-Diethyl-2-(ethoxycarbonyl)-
6-heptenecarboxamide was prepared by method A from ethyl
2-carboxy-6-heptenoate (0.89 g, 4.43 mmol). Column chroma-
tography (hexanes-EtOAc, 3:1) gave 0.80 g of the desired
amide (3.14 mmol, 71%). 1H NMR: δ 5.80-5.65 (m, 1H),
4.97-4.87 (m, 2H), 4.14-4.06 (m, 2H), 3.47-3.21 (m, 5H),
2.09-1.98 (m, 2H), 1.91-1.84 (m, 2H), 1.39-1.28 (m, 2H), 1.16
(dt, 6H, J ) 6.9, 3.3 Hz), 1.06 (dt, 3H, J ) 6.9, 3.3 Hz). 13C
NMR: δ 170.08, 167.84, 138.11, 128.22, 114.73, 61.02, 48.73,
42.03, 40.55, 33.50, 28.73, 26.78, 14.41, 13.99, 12.68. MS: m/z
(rel intens) 255 (12.1), 210 (14.9), 187 (31.2), 182 (16.5), 100
(47.1), 74 (10.4), 73 (19.5), 72 (100.0), 58 (59.3), 55 (17.4).
HRMS: calcd for C14H25NO3, 255.1834, found 255.1839. Some
of the NMR signals were obscured due to coalescence.
N,N-Diethyl-2-carboxy-6-heptenecarboxamide was prepared
by method B from the above amide (0.49 g, 1.92 mmol).
Column chromatography (hexanes-EtOAc, 1:1) gave 0.41 g
of the desired amide (1.81 mmol, 94%). 1H NMR: δ 8.90 (bs,
1H), 5.78-5.64 (m, 1H), 5.00-4.91 (m, 1H), 3.56-3.41 (m, 2H),
3.40-322 (m, 3H), 2.08-2.00 (m, 2H), 1.89-1.81 (m, 2H),
1.50-1.39 (m, 2H), 1.20 (t, 3H, J ) 6.9 Hz), 1.11 (t, 3H, J )
7.5 Hz). 13C NMR: δ 171.79, 171.60, 137.60, 115.25, 46.59,
42.42, 41.12, 33.09, 31.55, 25.93, 14.36, 12.66.
PTOC ester 13 was prepared by method C from the above
amide (0.46 g, 2.03 mmol). Column chromatography (hex-
anes-EtOAc, 1:1) gave 0.51 g of 13 (1.52 mmol, 75%). 1H
NMR: δ 7.64 (dd, 1H, J ) 8.7, 1.5 Hz), 7.60 (dd, 1H, J ) 6.9,
1.2 Hz), 7.18 (dt, 1H, J ) 7.2, 1.8 Hz), 6.59 (dt, 1H, J ) 6.9,
1.5 Hz), 5.84-5.71 (m, 1H), 5.05-4.94 (m, 2H), 4.02 (t, 1H, J
) 7.2 Hz), 3.61-3.30 (m, 4H), 2.18-2.08 (m, 3H), 2.00-1.91
(m, 1H), 1.60-1.48 (m, 2H), 1.27 (t, 3H, J ) 7.2 Hz), 1.14 (t,
3H, J ) 6.9 Hz). 13C NMR: δ 175.62, 166.85, 165.79, 137.81,
137.03, 133.78, 115.19, 112.66, 46.96, 42.89, 40.81, 33.31,
28.50, 26.36, 14.68, 12.77.
La ser fla sh p h otolysis k in etic stu d ies5,6,8 were per-
formed on an Applied Photophysics LK-50 kinetic spectrometer
employing a Spectron Nd:YAG laser. Solutions of the PTOC
esters in spectral grade THF or acetonitrile were prepared
such that the total absorbance at 355 nm was ca. 0.4. The
solutions were sparged with helium and thermally equilibrated
in a jacketed addition funnel; a solution of methanol-water
from a temperature-regulated bath was pumped through the
jacket. The solutions were allowed to flow through a flow cell
for the LFP studies. Temperatures were measured with a
thermocouple placed in the flowing stream approximately 1
cm above the irradiation zone. Time-resolved spectra were
determined for each radical 4. Kinetic measurements were
obtained in the region 330-335 nm. Each kinetic value
reported is an average of 12-15 independent runs.
In d ir ect Kin etic Stu d ies.10 In flame-dried tubes contain-
ing a small stir bar, mixtures of radical precursors 1a , 1b, or
13 (ca. 0.04 M), Bu3SnH, and a hydrocarbon standard (eicosane
for 1 or dodecane for 13) in freshly dried THF were sparged
with nitrogen. The tubes were placed in a constant temper-
ature bath while being shielded from light. After thermal
equilibration, the solutions were irradiated with a 150 W
tungsten-filament lamp at a distance of ca. 0.4 m for 40 min.
The reaction mixtures were analyzed by GC with thermal
conductivity detectors employing 15 m × 0.53 mm columns
(SE-30 for analysis of products from precursors 1 or Carbowax
for analysis of products from precursor 13). Yields reported
for indirect kinetic experiments were calculated from response
factors determined with authentic samples.
Ack n ow led gm en t. We are grateful to the National
Science Foundation for support (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 new compounds (36 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.
N,N-Dieth yl-6-h ep ten a m id e (14) was prepared by method
A from commercially available 6-heptenoic acid (0.50 g, 3.9
mmol). Column chromatography (hexanes-EtOAc, 3:1) gave
0.57 g of 14 (3.11 mmol, 80%). 1H NMR: δ 5.77-5.64 (m, 1H),
4.94-4.81 (m, 2H), 3.26 (q, 2H, J ) 6.9 Hz), 3.20 (q, 2H, J )
4.8 Hz), 2.20 (t, 2H, J ) 7.2 Hz), 2.01-2.01-1.97 (m, 2H),
1.61-1.51 (m, 2H), 1.39-1.31 (m, 2H), 1.07 (t, 3H, J ) 6.9
Hz), 1.00 (t, 3H, J ) 6.9 Hz). 13C NMR: δ 171.91, 138.53,
114.36, 41.83, 39.90, 33.50, 32.81, 28.63, 24.84, 14.28, 13.00.
MS: m/z (rel intens) 183 (30.9), 142 (20.4), 128 (47.3), 115
(87.1), 100 (68.3), 87 (12.8), 86 (14.2), 74 (11.0), 58 (59.3), 72
J O9717907
(23) Perterson, E. M.; Xu, K.; Holland, K. D.; McKeon, A. C.;
Rothman, S. M.; Ferrendelli, J . A.; Covey, D. F. J . Med. Chem. 1994,
37, 275-286.